Cardiology I

Cardiology I
Orly Vardeny, Pharm.D., BCACP
University of Wisconsin
Madison, Wisconsin
Cardiology I
Cardiology I
Orly Vardeny, Pharm.D., BCACP
University of Wisconsin
Madison, Wisconsin
ACCP Updates in Therapeutics® 2016: Ambulatory Care Pharmacy Preparatory Review and Recertification Course
2-3
Cardiology I
Learning Objectives Self-Assessment Questions

Answers and explanations to these questions can be
1. Formulate appropriate oral anticoagulant treat- found at the end of the chapter.
ment strategies for patients who develop venous
thromboembolism (VTE) (deep venous thrombosis 1. A 55-year-old, 78-kg man with a history of hyperten-
or pulmonary embolism) consistent with available sion (HTN) for 5 years and an acute pulmonary embo-
consensus panel guidelines, recent U.S. Food and lism (PE) is ready for hospital discharge. He was treat-
Drug Administration (FDA) approvals, and ran- ed with an intravenous heparin infusion for 2 days,
domized clinical trials. and his current activated partial thromboplastin time
2. Describe key differences in onset of action, dosing, ad- (aPTT) is 77 seconds. His only medication is losartan
ministration, absorption, effects on common coagula- 50 mg orally twice daily. His serum creatinine con-
tion tests, and drug interactions between dabigatran, centration (SCr) is 0.88 mg/dL. He will initiate therapy
rivaroxaban, apixaban, and warfarin in the manage- with an oral anticoagulant now, with the heparin infu-
ment of nonvalvular atrial fibrillation (AF) and treat- sion discontinued at the time of the first dose. Accord-
ment and prevention of VTE. ing to the U.S. Food and Drug Administration (FDA)
3. Develop a comprehensive education and monitor- approvals or favorable results in clinical trials, which
ing plan for patients receiving oral anticoagulants for option best reflects the correct treatment regimen with
treatment and prevention of VTE, stroke prevention in an intended duration of at least 6 months?
nonvalvular AF, and stroke prevention associated with A. Warfarin 10 mg orally daily to an international
mechanical heart valves. normalized ratio (INR) of 2–3.
4. Develop patient-specific, guideline-driven treatment, B. Rivaroxaban 20 mg orally daily with a meal.
monitoring, and follow-up plans for patients with C. Apixaban 10 mg orally twice daily for 7 days;
heart failure (HF). then decrease to 5 mg orally twice daily.
5. Develop patient-specific, guideline-driven treatment, D. Dabigatran 150 mg orally twice daily for 7
monitoring, and follow-up plans for rate and pharma- days; then decrease to 75 mg orally twice daily.
cologic rhythm control in a patient with AF.
6. Identify patient-specific appropriate antiarrhythmic 2. A patient with permanent atrial fibrillation (AF)
drugs for rhythm control in AF and ventricular tachy- taking rivaroxaban presents with acute heart failure
cardia (VT). (HF), hypotension, and a new pericardial effusion
7. Describe the role of catheter ablation in rhythm control suggestive of malignancy. An urgent diagnostic
management of AF and VT. and therapeutic pericardiocentesis is planned. The
8. Develop a patient-specific monitoring plan for guide- interventional cardiologist would like to avoid do-
line-based medical therapies for heart failure. ing the procedure until the rivaroxaban dose has
9. Describe current practice standards for agent selection worn off. Which is the best laboratory test to assess
and duration of antithrombotic therapy for stroke pre- whether rivaroxaban is present?
vention after transcatheter aortic valve replacement for
A. International normalized ratio (INR).
aortic stenosis.
B. Activated partial thromboplastin time.
10. Identify treatment goals, common adverse effects,
C. Activated clotting time.
clinically important drug interactions, monitoring, and
D. Anti−factor Xa (anti-Xa) concentration.
REMS (Risk Evaluation and Mitigation Strategies)
requirements for oral pharmacotherapy of pulmonary
3. Which is the preferred antithrombotic management
arterial hypertension.
strategy at hospital discharge for a patient with mi-
tral stenosis in normal sinus rhythm (NSR) after
placement of a bioprosthetic heart valve?
A. Aspirin 325 mg orally daily.
B. Dabigatran 150 mg orally twice daily.
C. Warfarin at a goal INR of 2.0–3.0.
D. Warfarin at a goal INR of 2.5–3.5.
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Cardiology I
4. A 78-year-old man with heart failure with reduced 40 mg orally twice daily. A decision is made to per-
ejection fraction (HFrEF) and creatinine clearance form cardioversion after initiation of an antiarrhyth-
(CrCl) of 45 mL/minute is initiating therapy with mic drug. The patient is scheduled for DCC in 3
eplerenone 25 mg orally every other day. Which days. Which antiarrhythmic drug is the best choice,
option best reflects the frequency of serum potas- representing that recommended in the 2014 ACCF/
sium and SCr monitoring recommended in the 2013 AHA/Heart Rhythm Society (HRS) AF guidelines
American College of Cardiology Foundation/Ameri- for maintenance of NSR, for this patient?
can Heart Association (ACCF/AHA) HF guidelines? A. Digoxin.
A. In 3 days, in 1 week, and then monthly for B. Sotalol.
the first 6 months. C. Amiodarone.
B. Weekly for the first 6 months. D. Flecainide.
C. In 2 weeks and then monthly for the first
6 months. 7. According to the 2012 HRS consensus guidelines for
D. In 1 week and then monthly for the first the catheter ablation of AF, which option best exem-
6 months plifies a patient who is not a candidate for ablation?
A. A patient with paroxysmal AF who has signs
5. A 68-year-old woman with HTN was recently hospi- of HF and is not maintained in NSR with
talized for heart failure with preserved ejection frac- dofetilide.
tion (HFpEF) and newly diagnosed nonvalvular AF B. A patient with persistent AF and palpitations
(NVAF). She is seen today in the cardiology clinic 2 with a history of amiodarone intolerance
weeks after hospital discharge. She is being treated because of hyperthyroidism who is
with metoprolol 12.5 mg orally twice daily, enalapril maintained in NSR with dofetilide.
5 mg orally daily, furosemide 20 mg orally twice C. An asymptomatic patient with permanent AF
daily, and dabigatran 150 mg orally twice daily. She taking no antiarrhythmic medications.
is scheduled to undergo direct current cardioversion D. A patient with paroxysmal AF with
(DCC) in 1 week. Her blood pressure (BP) is 125/80 hospitalizations secondary to rapid ventricular
mm Hg, heart rate (HR) is 140 beats/minute, and response who is not maintained in NSR with
CrCl is 68 mL/minute. Her 12-lead electrocardio- dronedarone and sotalol.
gram (ECG) shows AF and a ventricular response of
139 beats/minute. Which is the best option regarding
8. A 56-year-old patient with HFrEF and a history
a guideline-recommended course of action currently?
of ventricular tachycardia (VT) is seen in the ar-
A. No change in medications. rhythmia clinic. The patient has a biventricular im-
B. Initiate warfarin therapy and discontinue plantable defibrillator that shows no firing for VT
dabigatran now. within the past 6 months. He has New York Heart
C. Increase enalapril to 10 mg orally daily. Association (NYHA) class II HF symptoms, which
D. Increase metoprolol to 25 mg orally twice daily. have been stable for 6 months. His current medica-
tions include spironolactone, carvedilol, lisinopril,
6. A 50-year-old man with nonischemic cardiomyopa- furosemide, and simvastatin. Amiodarone was ini-
thy and HFrEF is admitted to the hospital for AF tiated 6 months ago. In addition to a 12-lead ECG
associated with acute HF exacerbation. He has a and chest radiography, which set of tests would be
biventricular pacemaker (cardiac resynchronization best to monitor for amiodarone toxicity?
therapy [CRT]) with an implantable defibrillator. His A. Slit lamp examination and lipid panel.
BP is 100/80 mm Hg, his HR is 115 beats/minute, B. SCr and sodium assays.
and his laboratory test results are normal. His PR C. Thyroid-stimulating hormone and liver
interval is 0.2 second, and his QTc is 480 millisec- function tests (LFTs).
onds. His current medications include carvedilol 25 D. Pulmonary function tests and creatine
mg orally twice daily, lisinopril 20 mg orally daily, phosphokinase assay.
spironolactone 25 mg orally daily, and furosemide
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Cardiology I
9. A 68-year-old patient with HTN, AF, and HFpEF

is initiating amiodarone therapy. When you review
the patient’s medication history, which is the best
example of a concomitant medication that would
require a dose adjustment currently?
A. Warfarin.
B. Rivaroxaban.
C. Atorvastatin.
D. Metoprolol.
10. An 80-year-old woman has HTN, severe aortic ste-

nosis, HFpEF, and new-onset angina. She is cur-
rently being treated with metoprolol tartrate 75
mg orally twice daily and furosemide 20 mg orally
daily. Her BP is 130/80 mm Hg, and HR is 50 beats/
minute. Which is the best recommendation for
treating her angina currently?
A. Increase the metoprolol tartrate dose to
100 mg orally twice daily.
B. Add diltiazem sustained release 120 mg
orally daily.
C. Add isosorbide mononitrate 60 mg
orally daily.
D. Add amlodipine 10 mg orally daily.
11. According to current practice standards, which is

the optimal antithrombotic regimen for stroke pre-
vention after transcatheter aortic valve replacement
(TAVR) for a patient in NSR?
A. Warfarin orally at a goal INR of 2–3 for 6
months.
B. Warfarin orally at a goal INR of 2–3 plus
aspirin 81 mg orally daily for 3 months.
C. Prasugrel 10 mg orally daily for 6 months.
D. Clopidogrel 75 mg orally daily plus aspirin 81
mg orally daily for 3 months.
12. In a patient being treated for pulmonary arterial

hypertension (PAH), which option best represents
the agent requiring LFT monitoring for early rec-
ognition of hepatotoxicity, even if the patient has no
signs/symptoms of liver toxicity?
A. Macitentan.
B. Sildenafil.
C. Bosentan.
D. Riociguat.
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Cardiology I
THROMBOEMBOLISM
I. ANTITHROMBOTIC THERAPY FOR VENOUS THROMBOEMBOLISM
A. Epidemiology
1. Up to 2,000,000 symptomatic and asymptomatic cases of venous thromboembolism (VTE) occur in
the United States each year, and more than 100,000 patients die of pulmonary embolism (PE).
2. Incidence of VTE doubles in each decade of life after age 50 years.
3. African American individuals are at a higher risk of VTE than are white individuals, whereas
Hispanic people appear to be at a slightly lower risk.
B. Etiology (Domain 1, Task 1)

1. In many cases, VTE is the result of converging combinations of inherited and acquired thrombotic
risk factors.
2. Many individuals with hereditary hypercoagulable conditions experience a first VTE only
after being placed in situations of high risk of thrombosis such as orthopedic surgery, trauma,
immobilization, use of estrogen-containing oral contraceptives, or pregnancy.
C. Risk Factors for VTE (Domain 1, Task 2)

1. Diagnostic workup should include a search for risk factors in the patient’s medical history.
2. Cancer and prior VTE are the most significant risk factors for VTE occurrence.
3. The effects of VTE risk factors are additive. The higher the number of risk factors, the higher the
likelihood of thrombosis occurring.
Table 1. Risk Factors for VTE in Hospitalized Medical Patients

Risk Factor Pointsa
Active cancer 3
Previous VTE involving deep veins 3
Reduced mobility 3
Thrombophilia 3
Trauma or surgery within 30 days 2
Age ≥ 70 years 1
Heart and/or respiratory failure 1
Acute myocardial infarction or ischemic stroke 1
Acute infection or rheumatologic disorder 1
Obesity (BMI ≥ 30 kg/m ) 2
1
Hormonal treatment 1
a
Padua Prediction Score, high risk = 4 points or greater.
BMI = body mass index; VTE = venous thromboembolism.
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Cardiology I
Table 2. VTE Risk Stratification for Surgical Populations

GI, Urologic,
Plastic and
Vascular, Breast,
Reconstructive
and Thyroid
Surgery
Procedures
Other Populations in Risk Estimated Baseline
AT-9 Risk
Caprini Scorea Caprini Scorea Category VTE Risk Without
Category
Prophylaxis, %
Most outpatient or same-day
Very low 0 0–2 <0.5
surgery
Spinal surgery for nonmalignant
Low 1–2 3–4 1.5
disease
Gynecologic surgery
Noncancer cardiac surgery
Moderate 3–4 5–6 Most thoracic surgery 3.0
Spinal surgery for malignant
disease
Bariatric surgery
Gynecologic cancer surgery
Pneumonectomy
Craniotomy
High ≥5 7–8 6.0
Traumatic brain injury
Spinal cord injury
Other major trauma
Elective joint arthroplasty
a
Caprini score: 5 points each for stroke (<30 days), elective arthroplasty, hip, pelvis, or leg fracture, or spinal cord injury (<30 days); 3 points
each for age ≥ 75 years, history of VTE, family history of VTE, thrombophilia; 2 points each for age 61–74 years, arthroscopic procedure, major
open surgery (>45 minutes), laparoscopic procedure (>45 minutes), malignancy, confined to bed >72 hours, plaster cast, central venous access;
1 point each for age 41–60 years, minor surgery, BMI > 25 kg/m 2, swollen legs, varicose veins, pregnant or postpartum, history of unexplained
or recurrent abortion, hormone therapy, sepsis (<30 days), lung disease including pneumonia (<30 days), abnormal pulmonary function, acute
myocardial infarction, congestive heart failure, history of inflammatory bowel disease, medical patient at bed rest.
AT-9 = American College of Chest Physicians (ACCP) 9th eEdition of the Chest Guidelines on Antithrombotic Therapy and Prevention of
Thrombosis (AT9; BMI = body mass index; GI = gastrointestinal; VTE = venous thromboembolism.
D. Deep Venous Thrombosis (DVT) (Domain 1, Tasks 1–, 2, 3)

1. Clinical presentation
a. Most thrombi begin in the lower extremities.
b. DVTs embolize in up to 50% of cases.
c. Superficial vein thrombi do not embolize unless they extend into a deep vein.
d. Isolated calf DVTs are less likely to embolize than proximal DVTs.
e. Patients often present with nonspecific symptoms; therefore, objective testing is needed to
confirm the diagnosis.
f. Many patients never develop symptoms from the acute event.
g. Even in the absence of symptoms, patients may develop long-term consequences
(e.g., postthrombotic syndrome, recurrent VTE).
h. Most upper extremity DVTs are related to central lines.
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Cardiology I
2. Signs and symptoms of DVT

a. Unilateral leg swelling
b. Pain in the affected leg
c. Calf tenderness in affected leg
d. Increased leg warmth
e. Erythema of affected leg
f. A “palpable cord” may be felt in the affected leg.
3. Diagnosis
a. D-dimer test
i. D-dimer is a by-product of fibrin degradation.
ii. Almost always elevated during acute VTE. (Note: Other conditions can also cause elevation
such as recent surgery, trauma, pregnancy, cancer, and age older than 65 years.)
iii. A negative D-dimer test result is effective to rule out VTE in the setting of a low pretest
clinical probability.
iv. A positive result requires further diagnostic verification.
v. Sensitivity can be reduced if the duration of symptoms exceeds 2–3 days or if the patient
received an anticoagulant.
b. Duplex ultrasonography
i. The most commonly used test to diagnose DVT
ii. Preferred to venography
iii. Can measure the rate and direction of blood flow and visualize clot formation in proximal
veins of the legs
iv. Cannot reliably detect small blood clots in distal veins
v. Noninvasive test – Does not carry the adverse effects of venography (hypotension, cardiac
arrhythmias, vessel wall irritation, and nephrotoxicity caused by the contrast medium)
vi. A positive duplex ultrasound finding in combination with a moderate to high pretest clinical
probability score or a positive D-dimer test result can be used to confirm the diagnosis.
vii. Negative test result does not exclude DVT, particularly in calf veins.
viii. The ability to diagnose a new DVT can be difficult in patients with a history of DVT.
c. Venography
i. The “gold standard” for the diagnosis of DVT
ii. An invasive test that involves the injection of radiopaque contrast dye into a foot vein
iii. Expensive; can cause anaphylaxis and nephrotoxicity
d. Clinical assessment
i. Clinical assessment significantly improves the diagnostic accuracy of noninvasive tests.
ii. Simple assessment checklists can be used to determine whether a patient has a high, moderate,
or low probability of VTE.
e. Putting it all together
i. Calculate pretest probability of DVT (see below).
ii. If patient has low pretest probability, is younger than 65 years, and has a negative D-dimer test
result, DVT is ruled out.
iii. Everyone else requires duplex ultrasonography or other imaging study to confirm diagnosis.
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Cardiology I
Table 3. Wells Clinical Model for Evaluating the Pretest Probability of DVTa,b
Clinical Characteristic Score
Active cancer (cancer treatment within previous 6 months or currently receivingon palliative treatment) 1
Paralysis, paresis, or recent plaster immobilization of the lower extremities 1
Recently bedridden for ≥3 days or major surgery within the previous 12 weeks requiring
1
general or regional anesthesia
Localized tenderness along the distribution of the deep venous system 1
Entire leg swollen 1
Calf swelling at least 3 cm larger than that on the asymptomatic side (measured 10 cm below
1
tibial tuberosity)
Pitting edema confined to the symptomatic leg 1
Collateral superficial veins (non-varicose) 1
Previously documented DVT 1
Alternative diagnosis at least as likely as DVT −2
a
Clinical probability of DVT: Low < 0; moderate 1–2; high > 3. In patients with symptoms in both legs, the more symptomatic leg is used.
b
Calculator available at www.mdcalc.com/wells-criteria-for-dvt/.
DVT = deep venous thrombosis.
E. Pulmonary Embolism (Domain 1, Tasks 1–, 2, 3)

1. Signs and symptoms
a. Much like patients with DVT, patients with PE often present with atypical symptoms.
b. Signs/symptoms are nonspecific, making diagnosis of PE challenging.
c. Sudden death may occur before effective treatment can be initiated if symptoms are not recognized.
Table 4. Signs and Symptoms of PE

Common Signs/Symptoms
Dyspnea
Pleuritic chest pain with clear radiograph
Tachypnea
Less Common Frequent Signs/Symptoms
Cough Systolic murmur
Hemoptysis (tricuspid regurgitation)
Fever ECG findings: Right bundle branch block,
Syncope S1Q3T3, and T-wave inversions in leads V1–V4
Diaphoresis Wheezing
Nonpleuritic chest pain Hypotension
Apprehension Tachycardia
Rales Cyanosis
Increased pulmonic component (P2) Pleural rub
of the second heart sound Elevated neck veins
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Cardiology I
Table 4. Signs and Symptoms of PE (continued)
Signs and Symptoms of Massive PE

Hemodynamic instability 50% or more absent perfusion of the lung
Cardiac arrest on angiography or ventilation/perfusion scanning
Cyanosis Right ventricular strain on ECG
Hypotension Elevated pulmonary arterial pressure
Hypoxia Elevated B-type natriuretic peptide
Oliguria Elevated troponin
ECG = electrocardiogram/electrocardiography; PE = pulmonary embolism.
2. Diagnosis
a. Laboratory tests
i. Serum concentrations of D-dimer are almost always elevated, but a negative D-dimer test
result combined with a low pretest probability score in patients younger than 65 years can
rule out PE.
ii. The patient may have an elevated erythrocyte sedimentation rate and white blood cell count.
b. Computerized tomography
i. Most commonly used test to diagnose PE
ii. Preferred option for PE diagnosis unless contraindications exist – Contrast dye is typically
used, which can make the test unsuitable for patients with poor renal function.
iii. Positive scan results have good specificity and generally confirm the diagnosis.
iv. Negative scan results may require further diagnostic studies if PE seems likely
because of clinical pretest probability scoring and/or D-dimer results.
v. Both the sensitivity and specificity of the scan are improved with central clots
compared with those that are more peripheral.
vi. False positives are more common for segmental/subsegmental embolism, and
follow-up testing may be needed.
c. Ventilation/perfusion (V/Q) scanning
i. Measures the distribution of blood f low and airf low in the lungs
ii. When there is a large mismatch between blood f low and airf low in one area of the
lung, the probability is high that the patient has a PE.
iii. Scans with positive findings have good sensitivity and help confirm the diagnosis.
iv. Specificity can be impaired by chronic obstructive pulmonary disease, asthma, and congestive HF.
v. A scan with negative findings also has good specificity and generally rules out the
diagnosis.
vi. An intermediate or low radiologic probability scan lacks sensitivity and requires
further diagnostic studies if PE seems likely.
vii. V/Q scanning is often preferred in patients with renal insufficiency or with allergies to contrast dye.
d. Pulmonary angiography
i. The gold standard for the diagnosis of PE
ii. An invasive test that involves the injection of radiopaque contrast dye into the pulmonary artery
iii. Expensive and associated with a significant risk of morbidity
e. Clinical assessment: Like in DVT, clinical assessment in PE significantly improves the diagnostic
accuracy of noninvasive tests, and it should be routinely performed.
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Cardiology I
Table 5. Wells Criteria Clinical Model for Evaluating the Pretest Probability of PE a.b
Cancer +1
Hemoptysis +1
Previous PE or DVT +1.5
Heart rate > 100 beats/minute +1.5
Recent surgery or immobilization +1.5
Clinical signs of DVT +3
Alternative diagnosis less likely than PE +3
a
Clinical probability of PE: Low 0–1; moderate 2–6; high ≥ 7.
b
Calculator available at www.mdcalc.com/wells-criteria-for-pulmonary-embolism-pe/.
DVT = deep venous thrombosis; PE = pulmonary embolism.
F. Treatment of VTE (Domain 1, Tasks 2, 5–, 6, 7; Domain 3, Tasks 1–, 2, 3; Domain 2, Task 5; Domain 5,
Task 1)
1. General treatment principles for patients with VTE (DVT and/or PE)
a. The diagnosis of VTE should be confirmed by objective testing.
b. Options for treatment are as follows:
i. Rapid-acting injectable anticoagulant (unfractionated heparin [UFH], low-molecular-
weight heparin [LMWH], or fondaparinux) transitioned to warfarin (minimum 5 days
of combined therapy)
ii. Rapid-acting injectable anticoagulant transitioned to dabigatran
iii. Sole treatment with rivaroxaban or dabigatran
c. If the patient’s therapy is changed to warfarin, the rapid-acting anticoagulant (UFH, LMWH,
or fondaparinux) should be overlapped with warfarin for at least 5 days and until the INR is
greater than 2 and stable enough to allow the vitamin K antagonist sufficient time to reach its full
anticoagulant effect. (Note: This is a Joint Commission VTE core measure.)
d. UFH is preferred for patients with severe renal insufficiency.
e. When intravenous UFH infusion is used, achieving a therapeutic aPTT in the first 24 hours has
been linked to decreased VTE recurrence rates.
f. Treatment at home is recommended for patients with uncomplicated DVTs and low-risk PEs.
Adequate home circumstances are required for home DVT and PE treatment, which includes well-
maintained living conditions, strong support from family or friends, telephone access, and ability to
return to the hospital quickly if deterioration occurs. Patient must feel well enough to be treated at
home (e.g., does not have severe leg symptoms or comorbidity).
Table 6. Simplified PESI Score to Predict 30-Day Mortality After Symptomatic PEa
Cancer history +1
Age > 80 years +1
Systolic blood pressure < 100 mm Hg +1
Heart rate ≥ 110 beats/minute +1
O2 saturation < 90% +1
a
Clinical probability of PE: Low 0, 1% 30-day mortality, 1.5% recurrent VTE or nonfatal bleeding; high ≥ 1, 8.9% 30-day mortality.
PE = pulmonary embolism; PESI = Pulmonary Embolism Severity Index; VTE = venous thromboembolism.
From: Jiménez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute
symptomatic pulmonary embolism. Arch Intern Med 2010;170:1383-9.
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Cardiology I
g. Warfarin can be initiated on the first day of therapy concurrently with the parenteral
anticoagulation.
h. Anticoagulants should be combined with the use of an elastic compression stocking with an ankle
pressure of 30–40 mm Hg to help prevent postthrombotic syndrome, if possible; stocking use
should continue for at least 2 years.
i. Upper extremity DVTs are generally treated similarly to lower extremity DVTs, but this is based
on limited data.
j. Encourage early ambulation as tolerated by the patient during the initial treatment phase.
k. Target-specific oral anticoagulants (TSOACs)
i. In the RE-COVER trial (double-blind), warfarin was compared with dabigatran 150 mg
twice daily (LMWH treatment was administered for at least 5 days [median of 9 days] to
both arms followed by dabigatran or warfarin with matching placebos and sham INRs in the
dabigatran group) in patients with acute DVT (69%), PE (21.2%), or both (9.5%). Dabigatran
was as effective as warfarin at preventing recurrent VTE or VTE-related death, with similar
major bleeding at 6 months.
ii. In the EINSTEIN trials (open-label), warfarin with enoxaparin cross-coverage at initiation
was compared with rivaroxaban alone (15 mg twice daily for 21 days, followed by 20 mg
once daily) for 3, 6, or 12 months in patients with acute DVT. Rivaroxaban was noninferior to
enoxaparin/warfarin for prevention of recurrent symptomatic VTE as well as major bleeding.
In EINSTEIN-PE, the same rivaroxaban protocol resulted in similar rates of recurrent
symptomatic VTE and fewer instances of major bleeding than warfarin in patients with acute
PE (1.1% vs. 2.2%).
iii. In the AMPLIFY trial (double-blind), warfarin with enoxaparin cross-coverage at initiation
was compared with apixaban alone (10 mg twice daily for 1 week then 5 mg twice daily)
for 6 months in patients with either DVT (65%), PE (25.2%) or both (9.4%). Apixaban was
noninferior to enoxaparin/warfarin for recurrent symptomatic VTE or VTE-related death,
and major bleeding was significantly reduced (0.6% vs. 1.8%).
iv. In the Hokusai-VTE trial (double-blind), warfarin was compared with edoxaban (both
were initiated with LMWH or UFH cross-coverage for at least 5 days and for a median of
7 days in the study) in patients with acute DVT (60%) or PE (40%). The edoxaban dose was
60 mg, which was reduced to 30 mg (17% of the study population) for patients who had a
CrCl of 30–50 mL/minute or weighed 60 kg or less or who were taking the concomitant
P-glycoprotein (P-gp) inhibitor verapamil or quinidine at baseline. Other P-gp inhibitors,
including erythromycin, azithromycin, clarithromycin, ketoconazole, and itraconazole, were
prohibited at randomization but, during the study, were permitted with the dose adjusted
down to 30 mg. If the P-gp inhibitor was discontinued, the edoxaban dose was increased
to 60 mg again if no other reason for the lower dose existed. Edoxaban was noninferior to
warfarin for preventing recurrent symptomatic VTE, with similar bleeding at a planned
treatment of 3–12 months (40% of patients were treated for 12 months).
v. Rivaroxaban and dabigatran are FDA approved for VTE treatment and prophylaxis after
knee or hip replacement surgery, and edoxaban is under review by the FDA for the treatment
of acute VTE but is not currently FDA approved.
vi. All trials excluded patients with CrCl below 30 mL/minute (estimated with actual body weight).
vii. Note that in all trials of TSOACs, the number of patients with cancer and moderate renal
insufficiency was small; therefore, results may not be generalizable to these patients.
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Cardiology I
2. Considerations for the use of injectable anticoagulants in the treatment of VTE
Table 7. Injectable Options for the Treatment of Acute VTE

Unfractionated Heparin
IV administrationa: Initial bolus and the initial rate of the continuous infusion can be either weight adjusted
(80 units/kg IV bolus, followed by 18 units/kg/hour infusion) or a fixed dose
(bolus 5000 units, followed by 1000 units/hour)
Adjust subsequent doses to attain a goal aPTT based on the institution-specific therapeutic range
or
Subcutaneous administration: 17,500 units (250 units/kg) given every 12 hours
(an initial 5000-unit IV bolus dose is recommended to attain rapid anticoagulation)
Adjust subsequent doses to attain a goal aPTT based on the institution-specific therapeutic range
or
Subcutaneous administration: 333 units/kg, followed by 250 units/kg given every 12 hours
(fixed-dose unmonitored dosing regimen)—Not practical for patients weighing more than 80 kg
because of injection volume issues
Low-Molecular-Weight Heparins
Dalteparin: 200 units/kg subcutaneously once daily or 100 units/kg subcutaneously twice dailyb
Enoxaparin: 1.5 mg/kg subcutaneously once daily or 1 mg/kg subcutaneously twice daily;
if CrCl is less than 30 mL/minute: 1 mg/kg subcutaneously once daily
Tinzaparin: 175 units/kg subcutaneously once daily
Factor Xa Inhibitor
Fondaparinux:
For body weight less than 50 kg (110 lb), use 5 mg subcutaneously once daily
For body weight 50–100 kg (110–220 lb), use 7.5 mg subcutaneously once daily
For body weight greater than 100 kg (220 lb), use 10 mg subcutaneously once daily
Contraindicated for CrCl less than 30 mL/minute
a
IV administration preferred because of improved dosing precision.
b
Not FDA approved for treatment of VTE in patients without cancer.
aPTT = activated partial thromboplastin time; CrCl = creatinine clearance; FDA = U.S. Food and Drug Administration; IV = intravenous; VTE
= venous thromboembolism.
3. Considerations for the use of warfarin in the treatment of VTE

a. Initial doses of 5−10 mg are preferred for otherwise healthy patients.
b. Lower doses may be needed in some populations that are sensitive to warfarin (e.g.,
malnourished, drug interactions, elderly).
c. Higher initial treatment doses (e.g., 10 mg) have been associated with obtaining a more rapid
therapeutic INR in outpatients being treated for DVT.
d. Ensure that all transitional care issues are addressed if initial therapy is given in the inpatient
setting (follow-up INR scheduled, provider is aware of discharge and transition plans, therapy
duration is communicated).
e. Patients must receive complete warfarin and VTE education (Joint Commission mandates and
part of the VTE core measures).
f. Desired goal INR range is 2–3; higher INR targets have been linked to more bleeding events
without greater VTE risk reduction, and lower INR targets (1.5–2) are not as effective, with no
clear benefit on bleeding outcomes.
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Cardiology I
4. Considerations for the use of newer target-specific oral anticoagulants for VTE
a. Study designs of trials differed with respect to initiation, dosing frequency,
and dose-intensity modulation.
b. Insufficient data to recommend use in patients with cancer
c. Few patients with a CrCl less than 60 mL/minute have been studied.
Table 8. Newer Target-Specific Oral Anticoagulants for Treatment of VTE (DVT and/or PE)
Direct Thrombin Inhibitor
Dabigatrana,b
150 mg orally twice daily initiated after initial treatment with LMWH
Factor Xa Inhibitors
Rivaroxabanb
15 mg twice daily (with a meal) for 21 days, followed by 20 mg orally daily (with a meal)
Apixabana,b
10 mg twice daily for 7 days followed by 5 mg twice daily
Edoxabana,b,c
60 mg orally daily (for patients with estimated CrCl > 50 mL/minute and body weight > 60 kg [and not taking
concomitant verapamil, quinidine, erythromycin, azithromycin, clarithromycin, ketoconazole, or itraconazole]),
initiated after initial treatment with either UFH or LMWH
30 mg orally daily for patients (1) with CrCl 30–50 mL/minute, (2) with body weight of 60 kg or less, or
(3) taking concomitant verapamil, quinidine, erythromycin, azithromycin, clarithromycin, ketoconazole, or
itraconazole, initiated after initial treatment with either UFH or LMWH
a
Not FDA approved for treatment of VTE as of March 1, 2014.
b
Patients with estimated CrCl < 30 mL/minute not studied.
c
Contraindicated for estimated CrCl < 30 mL/minute.
CrCl = creatinine clearance; DVT = deep venous thrombosis; FDA = U.S. Food and Drug Administration; LMWH = low-molecular-weight
heparin; PE = pulmonary embolism; UFH = unfractionated heparin; VTE = venous thromboembolism.
d. Patient counseling points (see Table 36)

5. Therapy duration
a. Patients should receive 3 months of anticoagulation therapy after provoked VTE.
b. For patients with unprovoked VTE or life-threatening PE, the long-term risks of anticoagulant use
(bleeding) must be weighed against the risk of repeated thrombosis after completing a minimum of
3 months of anticoagulation therapy.
c. The role of thrombophilia assessment to help guide the length of therapy decision is controversial.
Factors associated with increased risk of VTE recurrence include hereditary thrombophilia (1.5 x x),
antiphospholipid antibodies (2 x x), and residual thrombosis (1.6 x x). Normal D-dimer test result 1
month after warfarin withdrawal is protective (0.4 x x).
d. Distal DVT (below the knee) may be managed without anticoagulation but instead by monitoring
serial ultrasound findings. If the patient is very symptomatic or if the clot extends, anticoagulation
should be initiated as recommended for proximal VTE.
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Cardiology I
Table 9. Duration of Anticoagulation Therapy in Patients with VTE (DVT and/or PE)
Patient Characteristic Therapy Duration Comments
First episode of VTE secondary to 3 months Recommendation applies to both
a transient (reversible) risk factor proximal DVT and PE
First episode of VTE and cancer At least 3 months and Low-molecular-weight heparin is
consider extended duration recommended over warfarin;
until cancer resolves warfarin is recommended over
novel oral anticoagulants
First episode of unprovoked VTE At least 3 months Continue oral anticoagulant therapy
if patient is at low risk of bleeding
and adherent to therapy
The risk-benefit of indefinite
therapy should be reassessed at
periodic intervals
First episode of VTE with At least 3 months Continue oral anticoagulant therapy
inherited or acquired if patient is at low risk of bleeding
thrombophiliaa and adherent to therapy
Several abnormalities or homozygous
traits have at least additive risk
The risk-benefit of indefinite
therapy should be reassessed at
periodic intervals
Second unprovoked VTE Indefinite Applies to patients at low or
moderate risk of bleeding
a
Factor V Leiden; prothrombin G20210A; antiphospholipid antibody syndrome; excess factor VIII; deficiency in protein C, protein S, or
antithrombin.
DVT = deep venous thrombosis; PE = pulmonary embolism; VTE = venous thromboembolism.
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Cardiology I
Patient Cases
Questions 1–5 pertain to the following case.
R.R., a 62-year-old, overweight (weight 92 kg, height 60 inches) man, presents to the emergency department with
swelling of his entire right lower extremity, erythema, and soreness of his right calf. He had knee replacement
surgery 2 weeks ago. He reports no shortness of breath, cough, or chest pain. His medical history includes DVT
(after plaster casting for a leg fracture) at age 24 years, diabetes mellitus, HTN, chronic kidney disease, and
dyslipidemia. His estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk is 8%. His medications
are metformin 500 mg orally twice daily, losartan 50 mg orally twice daily, rosuvastatin 10 mg orally daily, and
aspirin 81 mg orally daily. Initial laboratory values include hematocrit 36.5% (normal 42%–52%), prothrombin
time (PT) 10.8 seconds (normal 9.9–11.2 seconds), INR 1.0, aPTT 23.6 seconds (normal 24–36 seconds), platelet
count 255,000/mm3 (normal 150,000–300,000/mm3), and CrCl 48 mL/minute.
1. Which risk level most accurately reflects the clinical probability of this patient’s having a DVT?
A. Low.
B. Moderate.
C. High.
D. Very high.
2. Which is the best diagnostic test to objectively confirm the DVT diagnosis in this patient?
A. D-dimer test.
B. Duplex ultrasound scan.
C. Venography.
D. Computed tomography (CT) scan.
3. Which time interval best represents how long this patient should be treated with anticoagulation therapy?
A. At least 3 months.
B. 6 months.
C. 12 months.
D. Indefinitely.
4. The decision is made to initiate anticoagulation therapy in the emergency department and to discharge the
patient home and treat him for DVT in the outpatient setting. Which is the best recommendation for an an-
ticoagulant initiation regimen for this patient?
A. Fondaparinux 5 mg subcutaneously daily and warfarin 10 mg/day orally adjusted to an INR of 2–3.
B. Rivaroxaban 15 mg orally daily.
C. Rivaroxaban 15 mg orally twice daily for 21 days and then 20 mg orally daily thereafter.
D. Enoxaparin 100 mg subcutaneously daily and warfarin 5 mg/day orally adjusted to an INR of 2–3.
5. Which is the best course of action currently with respect to the patient’s aspirin therapy taken for primary
prevention of ASCVD?
A. Continue aspirin 81 mg orally daily.
B. Continue aspirin 81 mg orally daily, and revise hthe patient’sis warfarin INR target to 2.0–2.5.
C. Increase the aspirin dose to 325 mg orally daily.
D. Discontinue aspirin while the patient is receiving anticoagulation.
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Cardiology I
II. ANTITHROMBOTIC THERAPY IN ATRIAL FIBRILLATION

A. Stroke Prevention in Atrial Fibrillation (AF) (Domain 1, Tasks 1–, 2, 3, 4, 5, 6, 7; Domain 3, Tasks 2, 3;
Domain 2, Tasks 2, 3; Domain 5, Tasks 1, 2)
1. AF is a major risk factor for cardiogenic embolic stroke and systemic arterial thromboembolism.
2. Around 90% of AF thromboembolic complications are stroke related, and the remaining 10% are
systemic embolism.
3. Thromboembolic risks associated with AF
a. Stasis or turbulence of blood flow within the left atrial appendage leads to thrombus formation.
b. Dysfunction of vascular endothelium predisposes to local or systemic hypercoagulability.
c. Conversion to normal sinus rhythm (NSR)—Spontaneous or intentional—May dislodge any
existing left atrial thrombi.
4. Morbidity and mortality associated with AF
a. 15% of all strokes occur in people with AF.
b. The annual stroke risk in untreated patients with AF varies from 1% to greater than 10%
(average is 4.5%), depending on concurrent individual risk factors.
c. Stroke risk in AF increases with age.
i. 1.5% in the 50- to 59-year-old age group
ii. 23.5% in the 80- to 89-year-old age group
5. Classification of AF
a. Acute AF: Onset within previous 48 hours
b. Paroxysmal AF: Terminates spontaneously within 7 days (may recur)
c. Recurrent AF: More than one episode
d. Persistent AF: Duration of more than 7 days without spontaneous termination
e. Permanent AF: Persistence of AF despite electrical or pharmacologic cardioversion attempts
f. Valvular AF: Eur Heart J 2013;34:1471-4: Associated with rheumatic valvular disease, mitral
stenosis, prosthetic heart valves (bioprosthetic and mechanical), or hypertrophic cardiomyopathy;
2012 European Society of Cardiology (ESC) AF guidelines: Associated with rheumatic disease
and prosthetic valves
6. Tools for nonvalvular atrial fibrillation (NVAF) stroke risk stratification

a. Various risk stratification schemes have been developed with the following goals:
i. Identifying patients with AF having such a low stroke risk that anticoagulation-associated
bleeding risk may outweigh stroke prevention benefit
ii. Encouraging anticoagulation therapy use in patients at high risk of AF stroke when its benefit
has been clearly shown
b. CHADS2 (congestive heart failure, hypertension, age at least 75 years, diabetes, previous stroke
or transient ischemic attack) score – Well validated and easy to use; most popular AF stroke risk
stratification tool
CHADS2 Stroke Risk Factor Points

Congestive HF =1
Hypertension =1
Age ≥ 75 years =1
Diabetes =1
Previous stroke/TIA/systemic embolus =2
CHADS2 = congestive heart failure, hypertension, age at least 75 years, diabetes, previous stroke or transient ischemic attack; HF = heart failure;
TIA = transient ischemic attack.
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Cardiology I
Table 10. CHADS2 Score and Recommended Antithrombotic Therapya−c

CHADS2 Adjusted Stroke Rate,
Recommended Therapy (2011 ASA/AHA Guidelines)
Score %/Yyear (95% CI)
0 1.9 (1.2–3.0) No antithrombotic therapy or aspirin for patients who choose active therapy
Warfarin (INR 2–3), apixaban, or dabigatran; for those with conditions not
1 2.8 (2.0–3.8) suitable for oral anticoagulation, aspirin or low-dose apixaban (2.5 mg bid)
is suggested over no antithrombotic therapy
2 4.0 (3.1–5.1)
3 5.9 (4.6–7.3) Warfarin (INR 2–3), apixaban, dabigatran, or rivaroxaban; for patients
4 8.5 (6.3–11.1) with conditions not suitable for oral anticoagulation, aspirin + clopidogrel
5 12.5 (8.2–17.5) is suggested over aspirin alone
6 18.2 (10.5–27.4)
a
Interpreted to mean the “one major risk factor” equals a CHADS2 point score of 1.
b
Higher CHADS2 score = higher AF stroke risk. Score of 0 = low risk; score of 1 = intermediate risk; score of ≥ 2 = high risk.
c
CHADS2 score calculator available at www.mdcalc.com/chads2-score-for-atrial-fibrillation-stroke-risk/.
AHA = American Heart Association; ASA = American Stroke Association; bid = twice daily; CHADS2 = congestive heart failure, hypertension,
age at least 75 years, diabetes, previous stroke or transient ischemic attack; CI = confidence interval; INR = international normalized ratio.
c. CHA2DS2-VASc (congestive heart failure, hypertension, age at least 75 years, diabetes, previous
stroke or transient ischemic attack, presence of vascular disease, and age 65–74 years) score –
Well validated; better than CHADS2 score at identifying truly low-risk patients; primarily used
for patients with a CHADS2 score of 0 or 1 to assess the impact of the presence of minor risk
factors on stroke risk; has been validated for patients post AF ablation
CHA2DS2-VASc Stroke Risk Factor a Points

Congestive HF =1
Hypertension =1
Age ≥ 75 years =2
Diabetes =1
Previous stroke/TIA/systemic embolus =2
Vascular disease (previous MI, angina, PCI, PAD, =1
CABG, or aortic plaque)
Age 65–74 years =1
Sex category (female) =1
a
CHA2DS2-VASc score calculator is available at www.mdcalc.com/cha2ds2-vasc-score-for-atrial-fibrillation-stroke-risk/.
CABG = coronary artery bypass grafting; CHA2DS2-VASc = congestive heart failure, hypertension, age at least 75 years, diabetes, previous stroke
or transient ischemic attack, presence of vascular disease, and age 65–74 years; HF = heart failure; MI = myocardial infarction; PAD = peripheral
arterial disease; PCI = percutaneous coronary intervention; TIA = transient ischemic attack.
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Cardiology I
Table 11. CHA2DS2-VASc Score and Recommended Antithrombotic Therapya

CHA2DS2- Adjusted Stroke Rate, Recommended Therapy
VASc Score %/Yyear (95% CI) (2012 ESC Guidelines)
0 0 (0–0) No antithrombotic therapy
1 0.6 (0–3.4) Oral anticoagulant therapy (VKA INR 2–3, apixaban, dabigatran, or
2 1.6 (0.3–4.7) rivaroxaban)
3 3.9 (1.7–7.6)
Consider the patient’s preferences, values, and bleeding risk
4 1.9 (0.5–4.9)
5 3.2 (0.7–9.0) Aspirin + clopidogrel or aspirin alone may be considered in patients
who refuse anticoagulation or cannot tolerate anticoagulants for any
reason unrelated to bleeding
6 3.6 (0.4–12.3)
7 8.0 (1.0–26.0)
8 11.1 (0.3–48.3)
9 100 (2.5–100)
a
In patients with a CHADS2 score of 0: 1-year stroke rates in patients with a CHA2DS2-VASc score of 0 = 0.84%; 1 = 1.75%; 2 = 2.69%; and 3 = 3.2%.
CHA 2DS2-VASc = congestive heart failure, hypertension, age at least 75 years, diabetes, previous stroke or transient ischemic attack, presence
of vascular disease, and age 65–74 years; CI = confidence interval; ESC = European Society of Cardiology; INR = international normalized
ratio; VKA = vitamin K antagonist.
d. Risk stratification considerations

i. No tool can incorporate all potential AF stroke risk factors. Risk stratification tools can
therefore best be used only as “rough guides” to help inform clinicians.
ii. Patient perspectives and preferences should also factor into clinical decision-making.
7. Treatment considerations
a. Rate versus rhythm control
i. In clinical trials, ischemic events occurred with similar frequency with either a rhythm or rate
control strategy, especially when anticoagulation therapy was discontinued or was subtherapeutic.
ii. Whether a rate or rhythm control strategy is used, patients with AF and thromboembolic risk
factors should probably receive chronic therapeutic anticoagulation.
b. Adjusted-dose warfarin versus aspirin therapy
i. Aspirin alone provides, at best, a modest reduction in the risk of nonfatal stroke in AF and is
inferior to adjusted-dose (INR 2–3) warfarin and combined therapy with clopidogrel.
ii. A pooled analysis of trials comparing aspirin with placebo yielded a relative risk reduction
estimate of 21% with a 95% confidence interval (CI) of 0%–38% compared with a relative
risk reduction of 68% (95% CI, 50%–79%) with warfarin.
iii. Compared with aspirin alone, the combination of clopidogrel and aspirin significantly
reduces the rate of major vascular events (mainly stroke), but it increases the risk of serious
bleeding, including intracranial hemorrhage. The American College of Chest Physicians
(ACCP) 9th eEdition of the Chest Guidelines on Antithrombotic Therapy and Prevention
of Thrombosis (AT-9) guidelines) state a preference for combined aspirin and clopidogrel
therapy over aspirin alone.
iv. A randomized comparison of warfarin versus clopidogrel plus aspirin was terminated early
after showing the superiority of warfarin.
v. Adding aspirin to warfarin therapy increases the risk of major bleeding and does not provide
further protection against ischemic stroke in patients with AF (possible exception is patients
with AF and prosthetic heart valve replacement).
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Cardiology I
c. Adjusted-dose warfarin versus newer anticoagulants

i. Adjusted-dose warfarin has been compared with dabigatran (RE-LY trial), rivaroxaban
(ROCKET AF), apixaban (ARISTOTLE), and edoxaban (ENGAGE-AF) for stroke
prevention in AF.
Table 12. Major Outcomes of New Anticoagulants vs. Adjusted-Dose Warfarina

RE-LY ROCKET-AF ARISTOTLE ENGAGE-AF
Outcome
(Dabigatran (Rivaroxaban (Apixaban (Edoxaban
(RR ± 95% CI)
150 mg bid) 20 mg/dayb) 5 mg bidc) 60 mg/dayd)
CHADS2 score 2.1 3.5 2.1 2.8
Warfarin TTR 64% 55% 62.2% 68.4%
Stroke/SEE 0.65 (0.52–0.81) 0.88 (0.75–1.03) 0.79 (0.66–0.95) 0.79 (0.63–0.99)
Ischemic stroke 0.76 (0.59–0.97) 0.94 (0.75–1.17) 0.92 (0.74–1.13) 1.00 (0.83–1.19)
Hemorrhagic stroke 0.26 (0.14–0.49) 0.59 (0.37–0.93) 0.51 (0.35–0.75) 0.54 (0.38–0.77)
Major bleeding 0.93 (0.81–1.07) 1.04 (0.90–1.20) 0.69 (0.60–0.80) 0.80 (0.71–0.91)
Intracranial
0.40 (0.27–0.60) 0.67 (0.47–0.93) 0.42 (0.30–0.58) 0.47 (9.34–0.63)
hemorrhage
CV mortality 0.85 (0.72–0.99) 0.89 (0.73–1.10) 0.89 (0.76–1.04) 0.92 (0.83–1.01)
All-cause mortality 0.88 (0.77–1.00) 0.85 (0.70-1.02) 0.89 (0.80–0.998) 0.86 (0.77–0.97)
Patients with CrCl < 30 mL/minute were excluded from RE-LY, ROCKET-AF, and ENGAGE-AF trials; patients with CrCl < 25 mL/minute
a
were excluded from ARISTOTLE trial. Patients with mechanical heart valves were excluded from all trials. Patients with bioprosthetic valves
were excluded from RE-LY, ROCKET-AF, and ARISTOTLE trials.
b
Dose adjusted to 15 mg/day for CrCl 30–49 mL/minute.
c
Dose adjusted to 2.5 mg bid for two or more of the following: Age ≥ 80 years, SCr ≥ 1.5 mg/dL, body weight < 60 kg.
d
Dose adjusted to 30 mg/day if CrCl 30–50 mL/minute, body weight ≤ 60 kg, or concomitant use of verapamil, quinidine, dronedarone;
concomitant use of azithromycin, clarithromycin, ketoconazole, itraconazole, cyclosporine, and ritonavir was prohibited.
bid = twice daily; CHADS2 = congestive heart failure, hypertension, age at least 75 years, diabetes, previous stroke or transient ischemic
attack; CI = confidence interval; CrCl = creatinine clearance; CV = cardiovascular; RR = relative risk; SCr = serum creatinine concentration;
SEE = systemic embolic event; TTR = therapeutic international normalized ratio range.
ii. The 2011 American Heart Association/American Stroke Association (AHA/ASA) guidelines
recommend warfarin over newer target-specific oral anticoagulants for patients with a CrCl less
than 15 mL/minute.
iii. No antidote is currently available for reversing the anticoagulant effect of any of the new
anticoagulants—Management of life-threatening bleeding is unclear. Prothrombin complex
concentrates (PCCs) can normalize elevated prothrombin time levels in patients treated
with direct-acting factor Xa inhibitors, but their utility in bleeding patients remains to be
determined.
iv. Acquisition costs for the newer target-specific oral anticoagulants are about 100 times
that for warfarin.
v. Cost-effectiveness of newer target-specific oral anticoagulants compared with warfarin has
been shown.
vi. Although routine laboratory monitoring is not required with the newer anticoagulants, careful
monitoring and coordination of therapy for invasive procedures are still required.
vii. When deciding which oral anticoagulant to use for patients with AF, consider individual
clinical features, including the ability to adhere to the requirements of therapy, the availability
of the anticoagulation management program, patient preferences, and cost.
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Cardiology I
8. Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE)

a. Can detect the presence of features associated with thromboembolism (TE), and anticoagulation
therapy in patients with these features reduces stroke risk (e.g., impaired left ventricular [LV]
systolic function, left atrial thrombus, dense spontaneous echo contrast [or “smoke”], or reduced
velocity of blood flow in the left atrial appendage). However, the absence of these echocardiographic
abnormalities has not been established as identifying a low-risk group of patients with AF who
could safely forgo warfarin therapy.
b. Valuable for detecting rheumatic mitral valve disease (there is universal agreement that these
patients should receive warfarin therapy)
i. Detection of a left atrial thrombus is a contraindication for cardioversion of AF.
ii. TEE surpasses TTE in the evaluation of cardiogenic risk factors in patients with AF.
9. Optimal intensity of anticoagulation for AF
a. Optimal anticoagulation intensity involves a careful balance between maximizing protection
against TE while minimizing bleeding risk (intracranial hemorrhage particularly rivals ischemic
stroke with respect to clinical importance).
b. The risk of ischemic stroke is low at INR levels of 2.0 or higher.
c. The risk of intracranial hemorrhage increases at INR levels of 3.5–4.0 and above, particularly in
the elderly.
d. An INR of less than 2.0 at admission for a new stroke substantially increases the likelihood of
death and severe disability from an AF-related stroke.
e. An INR target of 2.5 (range 2–3) should be used for most patients.
i. The suggestion of the American College of Cardiology (ACC)/AHA/ESC 2006 guidelines that
a lower target INR (1.6–2.5) may be considered in patients unable to tolerate standard-intensity
warfarin therapy is not evidence based.
ii. Narrower target ranges have been suggested in certain instances (e.g., INR 2.0–2.5 has been
recommended in patients requiring warfarin, aspirin, and clopidogrel after percutaneous
coronary intervention). However, such narrow ranges are not supported by good evidence, and
they make achieving therapeutic INRs more difficult, usually resulting in the need for more
frequent INR testing.
f. For patients with AF and stable coronary artery disease (i.e., no acute coronary syndrome in the
past year), warfarin (INR 2–3) alone without antiplatelet therapy is preferred.
10. Considerations during cardioversion
a. Systemic embolism is the most serious complication of cardioversion, whether NSR is reestablished
by electrical, pharmacologic, or spontaneous means.
b. There is no evidence that cardioversion, followed by prolonged maintenance of NSR, effectively
reduces TE in AF.
i. At least 4 weeks of therapeutic anticoagulation is recommended after successful cardioversion.
ii. Patients with risk factors for TE should continue anticoagulation beyond 4 weeks unless there
is convincing evidence that NSR is maintained.
c. Hemodynamically unstable patients requiring emergency cardioversion should receive
therapeutic anticoagulation with either intravenous UFH or LMWH or a newer target-specific
oral anticoagulant initiated as soon as possible, followed by at least 4 weeks of therapeutic
anticoagulation (limited/no evidence).
d. During the RE-LY trial, 1983 cardioversions were performed in 1270 patients: 647, 672, and
664 in the dabigatran 110-mg twice-daily, dabigatran 150-mg twice-daily, and warfarin groups,
respectively. The frequencies of stroke and major bleeding within 30 days of cardioversion in
patients taking the two doses of dabigatran were low and comparable with those in patients taking
warfarin with or without TEE guidance.
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Cardiology I
e. During the ROCKET-AF trial, 320 patients had a total of 460 cardioversions or AF ablations,
161 patients treated with warfarin and 160 treated with rivaroxaban. Three strokes occurred in
each group.
11. Considerations during ablation procedures
a. Patients with persistent AF who are in AF at the time of ablation should have TEE to screen for a
thrombus, even if warfarin anticoagulation was used before the procedure. Usually, intraprocedural
echocardiography is used to identify clot formation.
b. The most common anticoagulation strategy is to continue therapeutic anticoagulation with warfarin
and to add UFH during the procedure to inhibit activated clotting factors because warfarin just
prevents the formation of active clotting factors. Most centers have abandoned LMWH bridging
because it has been associated with excess bleeding risk.
c. UFH is continued for 12–24 hours post procedure, with a brief interruption for arterial sheath
pull. After the sheath pull, anticoagulation is resumed for 12–24 hours for periprocedural stroke
and PE prevention.
d. Warfarin, if selected for postablation anticoagulation, is reinitiated the evening of the procedure.
e. If a newer oral anticoagulant is selected or dabigatran continued, the oral dose is typically restarted
the morning after the procedure, once hemodynamic stability is assured and intrapericardial
bleeding ruled out.
f. Oral anticoagulation recommended in all patients for at least 2 months after an AF ablation
procedure (consider prolonged therapy of at least 6 months for CHADS2 score of 2 or more)
III. ANTITHROMBOTIC AGENTS: PHARMACOLOGIC AND CLINICAL CONSIDERATIONS
A. Unfractionated Heparin (Domain 1, Tasks 2, 3, 4, 7)

1. Pharmacology and pharmacokinetics
a. Rapid-acting, parenterally administered anticoagulant
b. Heterogeneous mixture of sulfated mucopolysaccharides of variable lengths and
pharmacologic properties
c. The anticoagulant profile and clearance vary depending on chain length.
d. UFH prevents the growth and propagation of a formed thrombus and allows the patient’s own
thrombolytic system to degrade the clot.
e. Derived from bovine lung or porcine intestinal mucosa; no differences in antithrombotic activity
have been shown between the two sources
f. The subcutaneous bioavailability of UFH is dose-dependent and ranges from 30% at low doses to
as much as 70% at high doses.
g. The onset of anticoagulant effect is usually evident 1–2 hours after subcutaneous injection and
peaks at 3 hours.
h. When UFH is administered intravenously, continuous infusion is preferable.
i. Intramuscular administration is discouraged because of erratic absorption and risk of large
hematoma formation.
j. UFH has a dose-dependent half-life of about 30–90 minutes, but it may be prolonged to as much as
150 minutes when given in high doses to some patients.
2. Dosing and administration
a. For prevention of VTE, UFH is given by subcutaneous injection. Typical dose for prophylaxis is
5000 units every 8–12 hours.
b. When immediate and full anticoagulation are required, an intravenous bolus dose followed
by continuous infusion is preferred (see Table 7: Initial dose of 80 units/kg followed by 18 units/kg/hour).
c. Subcutaneous UFH (see Table 7: Initial dose of 333 units/kg, followed by 250 units/kg every 12
hours) also provides adequate therapeutic anticoagulation for the treatment of acute VTE.
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Cardiology I
3. Monitoring
a. Administration of UFH by intravenous infusion requires close monitoring because of the
unpredictable anticoagulant patient response. The utility of monitoring subcutaneously
administered UFH is questionable, including at treatment doses.
b. Tests available to monitor UFH therapy in ambulatory patients
i. Activated partial thromboplastin time
(a) The most widely used test to determine the degree of therapeutic anticoagulation
(b) An institution-specific aPTT therapeutic range should be established that correlates with a
plasma heparin concentration of 0.3–0.7 unit/mL by an amidolytic anti-Xa assay.
(c) Should be measured before therapy initiation to determine the patient’s baseline
(d) When monitoring an aPTT during subcutaneous injections, the response to therapy
should be measured at the mid-dosing interval two or three doses after therapy initiation
or a dose change.
ii. Anti-Xa activity (also measured at the mid-dosing interval similarly to aPTT during
subcutaneous administration)
c. Heparin resistance should be suspected in patients who require more than 35,000 units of UFH
during a 24-hour period. In such cases, adjust the UFH dose according to anti-Xa concentrations.
4. Adverse effects
a. Bleeding
i. The presence of concomitant bleeding risks such as thrombocytopenia, the use of other
antithrombotic therapy, and a preexisting source of bleeding increase the risk of UFH-
induced hemorrhage.
ii. The risk of bleeding increases with age.
iii. Recent surgery, hemostatic defects, heavy alcohol consumption, renal failure, peptic ulcers,
and neoplasms also increase the risk of major bleeding while receiving UFH.
b. Bruising from minor trauma and at the sites of subcutaneous injections and venous access is
also common.
c. Local irritation, mild pain, erythema, histamine-like reactions, and hematoma can occur during
UFH administration.
d. Heparin-induced thrombocytopenia (HIT)
i. A rare but serious drug-induced problem requiring immediate intervention
ii. A baseline platelet count should be obtained before UFH therapy is initiated.
iii. If the patient has received UFH within the previous 100 days, or if previous UFH exposure is
uncertain, a repeated platelet count should be performed within 24 hours.
iv. Monitoring platelet counts every 2–3 days from days 4 to 14 of UFH treatment or until
discontinuation is recommended for patients for whom the estimated risk exceeds 1%.
v. The incidence of HIT is greater than 1% in postoperative patients receiving prophylactic or
therapeutic UFH doses. The incidence of HIT in medical patients receiving UFH ranges from
less than 0.1% to 1%.
vi. A fall in platelet count of greater than 50% from baseline but not less than 20 x 109/L is most
suggestive of HIT.
e. Long-term use of UFH has been reported to cause alopecia, priapism, and suppressed aldosterone
synthesis with subsequent hyperkalemia.
f. Use of UFH in doses of 20,000 units/day or greater for more than 3–6 months has been associated
with significant bone loss and may lead to osteoporosis.
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Cardiology I
B. Low-Molecular-Weight Heparin (Domain 1, Tasks 2, 3, 4, 7)

a. Like UFH, the LMWHs prevent the growth and propagation of formed thrombi.
b. Both UFH and LMWH inhibit both thrombin and factor Xa. UFH inhibits both equally and
LMWHs preferentially inhibit factor Xa.
c. Three LMWH products are commercially available in the United States: Ddalteparin, enoxaparin
(available as a generic), and tinzaparin.
d. Compared with UFH, the LMWHs have a more predictable anticoagulation response.
e. The bioavailability of the LMWHs is about 90% when administered subcutaneously.
f. The peak anticoagulation effect is seen in 3–5 hours.
g. The renal route is the predominant mode of elimination for the LMWHs.
h. Their biologic half-life may be prolonged in patients with renal impairment.
a. The LMWHs are given in fixed or weight-based doses according to the product and indication.
See Table 7: For VTE treatment indications or as bridging in AF, enoxaparin is administered
as 1 mg/kg subcutaneously twice daily or 1.5 mg/kg subcutaneously once daily. A reduced
dose of 1 mg/kg once daily is recommended for patients with an estimated CrCl of less than
30 mL/minute, but published experience with this dose is lacking because patients with a
CrCl of less than 30 mL/minute were excluded from clinical trials. Dalteparin is administered as
200 units/kg subcutaneously once daily.
b. Doses should be based on actual body weight, and studies of obese patients indicate that full
weight–based doses do not lead to elevated LMWH concentrations as compared with patients
of normal weight.
c. The LMWHs are generally given by subcutaneous injection in the abdominal area or the upper
outer part of the thigh while the patient is in a supine position.
d. The clinician or patient pinches a layer of skin between the thumb and forefinger and then
introduces the entire length of the needle into a skinfold at a 90-degree angle. Injection sites should
be alternated between right and left sides. After subcutaneous administration, the drug is absorbed
slowly, resulting in sustained antithrombotic activity for several hours.
3. Therapeutic monitoring
a. Because the LMWHs achieve a predictable anticoagulant response when given subcutaneously,
routine laboratory monitoring is unnecessary to guide the dosing of these agents.
b. Before initiating LMWH, a baseline complete blood cell count (CBC) with a platelet count and
SCr measurement should be obtained.
c. Although very limited data support the use of laboratory monitoring to guide LMWH therapy,
measuring anti-Xa activity has been suggested in patients who have significant renal impairment
(e.g., CrCl less than 30 mL/minute), weigh less than 50 kg, are morbidly obese, or are pregnant
(because of changing pharmacokinetic variables such as volume of distribution and renal function).
i. Anti-Xa monitoring should be used rarely because results above or below the “therapeutic
range” cause difficult clinical dilemmas.
ii. UFH is preferred for patients with a CrCl less than 30 mL/minute.
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Cardiology I
4. Adverse effects
a. Bleeding is the most common adverse effect of the LMWHs.
i. Major bleeding: Incidence is less than 3% and varies among the LMWH preparations,
their indication for use, the patient population, and the dose administered.
ii. Minor bleeding, particularly at the injection site, occurs often with LMWH use.
iii. Epidural and spinal hematomas resulting in long-term or permanent paralysis have been
reported with the use of LMWH during spinal and epidural anesthesia or spinal puncture.
The risk of these events is higher with the use of indwelling epidural catheters and concomitant
use of drugs that affect hemostasis.
b. Heparin-induced thrombocytopenia
i. The incidence of HIT is lower than that observed with the use of UFH in the postoperative
setting. The risk of HIT in patients treated for VTE is too low to discern a difference between
UFH and LMWH. Risk of HIT should not be a major determinant in selecting a parenteral
anticoagulant for VTE treatment.
ii. LMWHs have almost 100% cross-reactivity with heparin antibodies in vitro; they should be
avoided in patients with an established diagnosis or history of HIT.
c. Osteoporosis: Appears to be lower with the LMWHs than with UFH, but both agents have the
potential to produce osteopenia
C. Indirect Factor Xa Inhibitor (synthetic pentasaccharide) (Domain 1, Tasks 2, 3, 4, 7)

1. Fondaparinux is the only commercially available synthetic pentasaccharide.
2. Composed of a 5 sugar moiety; the first in a class of anticoagulants that selectively inhibits factor
Xa activity
a. Similar to UFH and the LMWHs, fondaparinux prevents thrombus generation and clot formation
by indirectly inhibiting factor Xa activity through its interaction with antithrombin.
b. After subcutaneous administration, bioavailability is 100%.
c. Peak plasma concentrations are achieved in about 2 hours after a single dose and in 3 hours with
repeated once-daily dosing.
d. Fondaparinux is primarily eliminated unchanged in the urine.
e. Contraindicated in patients with severe renal function impairment (CrCl less than 30 mL/minute);
use caution in moderate renal insufficiency (CrCl 30–50 mL/minute)
f. The terminal elimination half-life is 17–21 hours and is independent of the patient’s age and sex.
g. The anticoagulant effect of fondaparinux persists for 2–4 days after the drug is discontinued in
patients with normal renal function.
4. Dose and administration
a. In the setting of VTE prevention, the dose of fondaparinux is 2.5 mg injected subcutaneously once
daily starting 6–8 hours after surgery if hemostasis has been established. It is important to avoid
initiating fondaparinux too soon because a significant relationship exists between the timing of the
first dose and the risk of major bleeding complications.
b. Patients who weigh less than 50 kg should not be given fondaparinux for VTE prophylaxis.
c. For the treatment of DVT or PE, the dose of fondaparinux is 7.5 mg given subcutaneously once
daily. Patients who weigh more than 100 kg should be given 10 mg once daily, and those who weigh
less than 50 kg should receive 5 mg/day.
d. Similar to the LMWHs, fondaparinux is administered to the fatty tissue of the abdominal wall. Patients
should be instructed to pinch a fold of skin at the injection site and hold it throughout the injection. The
needle should be inserted at a 90-degree angle. Injection sites should be alternated from side to side.
2-26
Cardiology I
a. A CBC and SCr should be measured at baseline.
b. Kidney function should be monitored closely in patients at risk of developing renal failure.
c. Fondaparinux should be discontinued if the CrCl drops below 30 mL/minute.
d. Signs and symptoms of bleeding should be monitored daily, particularly in patients with a baseline
CrCl between 30 and 50 mL/minute. If neuraxial anesthesia has been used, patients should be
closely monitored for signs and symptoms of neurologic impairment.
e. Fondaparinux does not alter coagulation tests such as the aPTT and PT. The role of anti-Xa
monitoring during fondaparinux is not well defined. Patients receiving fondaparinux therapy do not
require routine coagulation testing.
6. Adverse effects
a. Bleeding is the primary adverse effect associated with fondaparinux therapy.
b. The rate of major bleeding in the VTE prophylaxis trials was around 2%–3%.
c. Similar to UFH and the LMWHs, fondaparinux should be used with extreme caution in patients
with neuraxial anesthesia or after a spinal puncture because of the risk of spinal or epidural
hematoma formation.
d. Unlike UFH and the LMWHs, fondaparinux has not been associated with HIT and does not
produce cross-sensitivity in vitro. Fondaparinux has been used in the treatment of HIT.
Table 13. Comparison of UFH, LMWHs, and Fondaparinux

Property UFH LMWH Fondaparinux
Molecular weight range a
3000–30,000 1000–10,000 1728
Average molecular weight a
12,000–15,000 4000–5000 1728
Anti−factor Xa/anti−factor 1:1 2:1–4:1 >100:1
IIa activity
aPTT monitoring required Yes No No
Inactivation by platelet Yes No No
factor 4
Capable of inactivating No Yes Yes
platelet-bound factor Xa
Inhibition of platelet ++++ ++ No
function
Increases vascular Yes No No
permeability
Protein binding ++++ + No
Endothelial cell binding +++ + No
Dose-dependent clearance Yes No No
Primary route of 1. Saturable binding Renal Renal
elimination processes and
depolymerization
2. Renal
Elimination half-life 30–150 minutes 2–6 hours 17 hours
a
Measured in daltons.
aPTT = activated partial thromboplastin time; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin.
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Cardiology I
D. Warfarin (Domain 1, Tasks 2, 3, 4, 5, 6, 7)

1. Currently, the most commonly used anticoagulant when long-term or extended anticoagulation is
indicated
2. Warfarin is FDA approved for the prevention and treatment of VTE, as well as for the prevention
of thromboembolic complications associated with AF, heart valve replacement, and myocardial
infarction (MI).
3. Because of its narrow therapeutic index, predisposition to drug and food interactions, and propensity
to cause hemorrhage, warfarin requires continuous patient monitoring and education to achieve
optimal outcomes.
a. Warfarin exerts its anticoagulation effect by inhibiting vitamin K epoxide reductase, the enzyme
responsible for the cyclic interconversion of vitamin K in the liver.
b. Reduced vitamin K is a cofactor required for the carboxylation of the vitamin K–dependent
coagulation proteins; factors II (prothrombin), VII, IX, and X; and the endogenous anticoagulant
proteins C and S.
c. Warfarin has no direct effect on previously circulating clotting factors or previously formed thrombi.
d. The time required for warfarin to achieve its pharmacologic effect depends on the elimination
half-lives of the coagulation proteins.
e. Given that prothrombin has a 2- to 3-day half-life, the full antithrombotic effect is not achieved
for 7–15 days after warfarin initiation.
f. By suppressing the production of active clotting factors, warfarin prevents the initial formation
and propagation of a thrombus.
Table 14. Elimination Half-lives of Vitamin K–Dependent Clotting Factors

Clotting Factor Half-life, hours
II 42–72
VII 4–6
IX 21–30
X 27–48
Protein C 9
Protein S 60
g. Warfarin is a racemic mixture of R- and S-enantiomers that differ with respect to elimination
half-life, metabolism, pathways of oxidative metabolism, and potency.
Table 15. Comparison of R- and S-Warfarin

R-Warfarin S-Warfarin
Elimination half-life 45 hr (20–70 hr) 29 hr (18–52 hr)
Metabolism 40% reduction 10% reduction
60% oxidation 90% oxidation
Oxidative metabolism 1A2 > 3A4 > 2C19 2C9 > 3A4
Potency 1.0 (reference) 2.7–3.8 times R-warfarin
hr = hours.
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Cardiology I
h. Warfarin is 99% bound to plasma proteins (mostly albumin).

i. Undergoes stereoselective metabolism by cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2C8, 2C18,
and 3A4 isoenzymes in the liver, with CYP2C9 being the main enzyme to modulate in vivo
anticoagulant activity
j. Pharmacokinetic variables of warfarin, particularly hepatic metabolism, vary substantially
between individuals, leading to large interpatient differences in dose requirements.
k. Genetic variations in the gene that codes for the CYP2C9 isoenzyme, vitamin K epoxide
reductase complex 1 (VKORC1), correlate with warfarin dose requirements.
l. Warfarin dosing algorithms that incorporate pharmacogenetic information are being evaluated,
but they have yet to show improved clinical outcomes (e.g., reduced bleeding).
m. Clinical utility and cost-effectiveness of using pharmacogenetic information to guide warfarin
initiation remain unproven.
a. The dose of warfarin is patient-specific depending on the desired intensity of anticoagulation and
the patient’s individual response.
b. Because of tremendous interpatient and intrapatient variability in dose response, the warfarin
dose must be based on continual clinical and laboratory monitoring.
c. Although the average weekly warfarin dose is between 25 and 55 mg, some patient-related
variables are associated with lower-than-usual dose requirements.
d. For most patients, initiating therapy with 5–10 mg/day and adjusting the dose according to the
INR response will produce therapeutic INRs in 5–7 days.
6. Initiation dosing of warfarin therapy. Outpatients: Warfarin initiation using the average
daily dosing method
a. This nomogram is useful in outpatients for whom INR cannot be checked on a daily basis.
b. The response to therapy should be measured every 1–3 days until stabilized.
c. Factors that increase sensitivity to warfarin
i. Age older than 75 years
ii. Clinical congestive HF
iii. Clinical hyperthyroidism
iv. Decreased oral intake
v. Diarrhea
vi. Drug-drug interactions
vii. Elevated baseline INR
viii. End-stage renal disease
ix. Fever
x. Hepatic disease
xi. Hypoalbuminemia
xii. Known CYP2C9 variant
xiii. Malignancy
xiv. Malnutrition
xv. Postoperative status
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Cardiology I
Table 16. Warfarin Initiation in Outpatients

Nonsensitive Patients Sensitive Patientsa
Initial dose 5 mg/day 2.5 mg/day
First INR 3 days 3 days
<1.5 7.5–10 mg/day 5–7.5 mg/day
1.5–1.9 5 mg/day 2.5 mg/day
2.0–3.0 2.5 mg/day 1.25 mg/day
3.1–4.0 1.25 mg/day 0.5 mg/day
>4.0 Hold Hold
Next INR 2–3 days 2–3 days
Subsequent dosing Continue dose escalation and frequent monitoring
and monitoring until lower limit of therapeutic range is reached
a
See earlier section for factors that influence sensitivity to warfarin.
INR = international normalized ratio.
7. Maintenance dosing of warfarin therapy

a. When adjusting the warfarin dose, the clinician should allow sufficient time for changes in
the INR to occur.
b. In general, maintenance dose changes should not be made more often than every 3 days.
c. Doses should be adjusted by calculating the weekly dose and reducing or increasing the
weekly dose by 5%–20%.
d. Use of dosing algorithms (computerized or paper-based) is strongly encouraged.
See www.warfarindosing.org.
e. The effect of dose changes may not become evident for 7 days or greater if alternate-day
dosing is used.
Table 17. Consideration for Adjustments of Warfarin Maintenance Dose for Goal INR of 2–3
(after at least 7 days of continuous dosing)a
INR Suggested Change in Total “Weekly” Dosage
<1.5 Give extra daily dose once and increase weekly dose by 10%–20%
1.5–1.9 Increase weekly dose by 5%–15% (may give extra daily dose x 1)b
2.0–3.0 Maintain same dose
3.1–4.0 Hold zero to one daily dose and decrease weekly dose by 5%–20%b
4.1–5.0 Hold up to two daily doses and decrease weekly dose by 10%–20%b
≥5 Hold dose, consider administration of vitamin K
a
Assumes no active bleeding.
b
If transient cause is identified or if previously stable and INR ≤ 0.5 unit is out of range, may not need to increase/decrease weekly dose.
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Cardiology I
a. Warfarin requires frequent laboratory monitoring to ensure optimal therapeutic outcomes and
to minimize bleeding complications.
b. The PT is used to monitor the anticoagulation effects of warfarin.
c. The PT measures the biologic activity of factor II, VII, and X activity and correlates well with
warfarin’s anticoagulation effect.
d. The INR corrects for differences in thromboplastin reagents.
e. Although the INR system has several potential problems, it is currently the best means available
to interpret the PT and is the preferred method for monitoring oral anticoagulation therapy.
f. The recommended target INR and associated goal range are based on the therapeutic indication.
g. For most indications, the target INR is 2.5 with an acceptable range of 2.0–3.0.
h. The target INR is higher for some patients with mechanical prosthetic heart valves
(target INR 3.0, range 2.5–3.5).
i. A baseline PT and CBC should be obtained before initiating warfarin therapy.
j. In patients with an acute thromboembolic event, an INR should be measured minimally
every 3 days during the first week of therapy (daily INRs are optimal to minimize need for
cross-coverage with injectable anticoagulants during outpatient DVT treatment).
k. Once the patient’s dose response is established, an INR should be determined every
7–14 days until it stabilizes and, optimally, every 4–6 weeks thereafter.
l. Recent evidence indicates INR recall intervals as long as 12 weeks may be used in patients
with very stable conditions.
m. When the warfarin dose is adjusted for significantly out-of-range INRs (e.g., greater than
4.0 or less than 1.5), an INR should be rechecked within 7 days. For INRs less severely out
of range, a 14-day recall interval is acceptable.
n. For patients with previously stable INR control, avoid changing the warfarin dose for mildly
out-of-range INR (e.g., 1.5–3.5); instead, increase INR monitoring frequency.
9. Patient assessment and management: With each INR, the patient should also be assessed for other
factors that can influence the anticoagulant effect of warfarin.
a. Verification of the warfarin dose administered or taken
b. Changes in current medications (prescription, over-the-counter, herbal)
c. Acute illnesses (nausea, vomiting, diarrhea)
d. Changes in diet (especially foods rich in vitamin K or decreased oral intake)
e. Binge alcohol use
f. Assess patient for signs and symptoms of TE.
g. Assess patient for signs and symptoms of bleeding.
10. Adverse effects
a. Bleeding
i. As with the other anticoagulants, bleeding is the most common adverse effect.
ii. The gastrointestinal (GI) tract and the nose are the most frequent sites of bleeding.
Intracranial hemorrhage is the most serious and feared complication related to warfarin
therapy, often resulting in permanent disability or death.
iii. The annual incidence of major bleeding ranges from 1% in highly selected patient
populations who are carefully managed to greater than 10% in patients who are medically
managed in less structured environments.
iv. Few studies have prospectively evaluated the incidence of minor bleeding, but it is likely to
be greater than 15% annually, even in the most expertly treated patients.
v. Several risk factors for bleeding while taking anticoagulation therapy have been identified.
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Cardiology I
Table 18. Risk Factors for Major Bleeding While Taking Anticoagulation Therapy
Anticoagulation intensity (e.g., INR > 4.0)
Therapy initiation (first few weeks)
Unstable anticoagulation response (INR control)
Age > 65 years
Concurrent antiplatelet drug use
Concurrent nonsteroidal anti-inflammatory drug use
History of gastrointestinal bleeding
Recent surgery or trauma
High risk of fall/trauma
Heavy alcohol use
Renal failure
Cerebrovascular disease
Malignancy
Reprinted from: Talbert RL, DiPiro JT, Matzke GR, et al., eds. Pharmacotherapy: A Pathophysiological Approach, 8th ed. New York: McGraw-
Hill, 2011. With permission from The McGraw-Hill Companies.
vi. Intensity of anticoagulation therapy appears to be the most powerful risk factor for bleeding.
vii. Patients whose target INR is greater than 3.0 have twice the incidence of major bleeding than
those having a target of 2.5.
viii. Unstable INR control also appears to be associated with an increased risk of bleeding.
ix. The risk of hemorrhage is greatest during the first few weeks of therapy.
x. However, bleeding can occur at any time, and the cumulative incidence steadily increases
over time.
xi. Scoring systems have been developed to assess the risk of major bleeding in patients taking
warfarin. To date, no bleeding prediction rule has shown sufficient predictive accuracy or
had sufficient validation to be recommended for routine use in practice.
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Cardiology I
Table 19. Scoring Systems to Assess the Risk of Major Bleeding in Patients Taking Warfarin (validated only in patients
with AF—Note also that CHADS2 scores correlate with bleeding risk [i.e., higher scores = higher bleeding risk])
Scoring System Criteria Point Scores Risk of Major Bleeding
Outpatient Bleeding Age > 65 years 1 Score MB/pt-yr
Risk Index History of GI bleed 1 Low (0) 3%
History of stroke 1 Intermediate (1–2) 8%
One or more of diabetes, hematocrit < 30%, 1 High (3–4) 30%
SCr > 1.5 mg/dL, or recent MI
HEMORR2HAGES Hepatic or renal disease 1 Score MB/pt-yr
scoring system Ethanol abuse 1 Low (0–1) 1.9%–2.5%
Malignancy 1 Intermediate (2–3)
Older (age > 75 years) 1 5.3%–8.4%
Reduced platelet count or function 1 High (≥4) 10.4%–12.3%
Rebleeding risk 2
Hypertension (uncontrolled) 1
Anemia 1
Genetic factors (CYP2C9 polymorphism) 1
Excessive fall risk 1
Stroke 1
HAS-BLEDa Uncontrolled hypertension (SBP > 160 mm Hg) 1 Score MB/pt-yr

Renal disease (SCr > 2.6 mg/dL, dialysis, Low (0) 0.9%
transplant) 1 Intermediate (1–2) 3.7%
Hepatic disease (cirrhosis, bilirubin > 2 x ULN, High (≥3) 6.7%
AST/ALT > 3 x ULN) 1
Stroke
Prior major bleeding or predisposition 1
Labile INR (<60% time in range) 1
Elderly (age > 75 years) 1
Drugs/alcohol concomitantly 1
(1 each)
ATRIA Anemia 3 Score MB/pt-yr
Severe renal disease 3 Low (0–3) 0.76%
Age ≥ 75 years 2 Intermediate (4) 2.62%
Any prior hemorrhage diagnosis 1 High (5–10) 5.76%
Diagnosed hypertension 1
a
HAS-BLED calculator available at www.mdcalc.com/has-bled-score-for-major-bleeding-risk/.
AF = atrial fibrillation; AST/ALT = aspartate aminotransferase/alanine aminotransferase; CHADS2 = congestive heart failure, hypertension, age at least
75 years, diabetes, previous stroke or transient ischemic attack; CYP = cytochrome P450; GI = gastrointestinal; INR = international normalized
ratio; MB = major bleeding; MI = myocardial infarction; pt-yr = patient-year; SBP = systolic blood pressure; SCr = serum creatinine; ULN = upper
limit of normal.
xii. Serious bleeding, such as intracranial hemorrhage, necessitates holding warfarin and
administering of 10 mg of vitamin K by slow intravenous infusion for 1 hour and PCC
administration. Only the four-factor PCC (Kcentra) is FDA approved for warfarin reversal.
The dose of Kcentra is based on the patient’s INR, body weight, and factor IX concentration
of the vial.
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Cardiology I
b. The “purple toe syndrome”

i. Manifested as a purplish discoloration of the toes
ii. An extremely rare event reported in a small percentage of patients
iii. The etiology of this unusual phenomenon is unknown, but it is thought to be the result of
cholesterol microembolization into the arterial circulation of the toes.
c. Warfarin-induced skin necrosis
i. An uncommon but very serious dermatologic reaction
ii. Manifested by a painful maculopapular rash and ecchymosis or purpura that subsequently
progresses to necrotic gangrene
iii. Usually appears in areas of the body rich in subcutaneous fat, such as the breasts, thighs,
buttocks, and abdomen
iv. Incidence is less than 0.1%.
v. Usually occurs in middle-aged women being treated for acute VTE
vi. Although symptoms generally appear during the first week of therapy, symptoms have been
reported in a few patients who had taken warfarin for months and even years.
vii. Patients with protein C or S deficiency appear to be at greater risk. Patients who receive large
“loading” doses of warfarin may also be at greater risk.
viii. Overlapping warfarin and injectable anticoagulants is especially important in any patient
thought to have a hypercoagulable state or with a strong family history of VTE. Warfarin-
induced skin necrosis can occur despite concomitant parenteral anticoagulation.
ix. If skin necrosis is suspected, warfarin therapy should be immediately discontinued, fresh
frozen plasma and vitamin K administered, and full-dose UFH or LMWH therapy initiated.
x. Warfarin therapy should be reinitiated with extreme caution in patients having a history
of skin necrosis, using small doses and gradual titration until a therapeutic INR has been
achieved, if at all.
11. Drug and dietary interactions
a. The pharmacokinetic and pharmacodynamic properties of warfarin, together with its narrow
therapeutic index, predispose this agent to numerous clinically important drug and food interactions.
b. Drug interactions
i. Pharmacokinetic drug interactions with warfarin are primarily a result of alterations in hepatic
metabolism or binding to plasma proteins.
ii. Drugs that inhibit or induce the CYP2C9, CYP1A2, and CYP3A4 isoenzymes have the greatest
potential to significantly alter the response to warfarin therapy.
iii. Protein-binding displacement interactions can also occur. However, in the absence of hepatic
disease or a diminished capacity to metabolize warfarin (e.g., concurrent CYP enzyme
inhibition), changes in protein binding should result in only transient changes in the INR.
iv. Drugs that alter hemostasis, platelet function, or the clearance of clotting factors (e.g., thyroid
hormone replacement) can alter the response to warfarin therapy or increase the risk of
bleeding by pharmacodynamic mechanisms.
v. In most cases, increasing the frequency of INR monitoring and adjusting the warfarin dose
as needed are preferable to preemptive empiric warfarin dose adjustment.
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Cardiology I
Table 20. Clinically Important Warfarin Drug Interactions

Medications That Medications That
Proposed Mechanism Proposed Mechanism
Increase INR Decrease INR
CYP3A4, CYP1A2, Carbamazepine Induces CYP3A4
Amiodarone
and CYP2C9 inhibitor
CYP3A4 and CYP1A2 Methimazole Unknown
Cimetidine
inhibitor
Ciprofloxacin CYP1A2 inhibitor Nelfinavir Unknown
Clarithromycin CYP3A4 inhibitor Nevirapine CYP3A4 inducer
Cyclosporine CYP3A4 substrate Phenobarbital Induces CYP3A4
Efavirenz CYP2C9 inhibitor Phenytoin Induces CYP3A4
Rifampin Induces CYP3A4 and
Erythromycin CYP3A4 inhibitor
CYP2C9
Ritonavir, Ritonavir/ CYP3A4 and
Fenofibric acid CYP2C9 inhibitor
Lopinavir CYP2C9 inducer
CYP3A4 and
Fluconazole
CYP2C9 inhibitor
Fluorouracil CYP2C9 inhibitor
Fluvastatin CYP2C9 inhibitor
Fluvoxamine CYP1A2 inhibitor
Itraconazole CYP3A4 inhibitor
Ketoconazole CYP3A4 inhibitor
Levofloxacin CYP1A2 inhibitor
Lovastatin CYP3A4 substrate
Metronidazole CYP3A4 inhibitor
Miconazole CYP3A4 inhibitor
Nelfinavir CYP3A4 inhibitor
Phenytoin CYP2C9 substrate
Prednisone CYP3A4 inhibitor
Rosuvastatin Unknown
Saquinavir CYP3A4 substrate
and inhibitor
Simvastatin CYP3A4 substrate
Sulfamethoxazole CYP3A4 substrate
Tamoxifen CYP2C9 substrate
Voriconazole CYP3A4 and
CYP2C9 inhibitor
CYP = cytochrome P450; INR = international normalized ratio.
Reprinted from: Levine GN. Cardiology Secrets, 4th ed. Philadelphia: Saunders, 2013. With permission from Elsevier.
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Cardiology I
c. Dietary interactions
i. Vitamin K
(a) Vitamin K can reverse warfarin’s pharmacologic activity, and many foods contain
sufficient vitamin K to reduce the anticoagulation effect of warfarin if a patient consumes
them in unusually large portions or repetitively within a short period.
(b) Patients should be given a list of vitamin K–rich foods and instructed to maintain a
relatively consistent intake. Patients with consistently higher intake of dietary vitamin
K have less variable INR response and warfarin dosing requirements; therefore, it is
important to stress consistency and moderation rather than abstinence.
(c) Abrupt changes in vitamin K intake should be considered when unexplained changes in
the INR occur.
(d) Alternative sources of vitamin K, such as multivitamins and nutritional supplements
(e.g., Sustacal and Ensure), should also be considered.
(e) Patients who require parenteral nutrition should not receive a weekly bolus dose of
vitamin K if they are receiving warfarin therapy.
Table 21. Vitamin K Content of Select Foodsa

Very High (>200 mcg) High (100–200 mcg) Medium (50–100 mcg) Low (<50 mcg)
Brussel sprouts Basil Apple, green Apple, red
Chickpea Broccoli Asparagus Avocado
Collard greens Chive Cabbage Beans
Coriander Coleslaw Cauliflower Breads, grains
Endive Cucumber (with peel) Mayonnaise Carrot
Kale Canola oil Nuts, pistachio Cereal
Lettuce, red leaf Green onion/scallion Squash, summer Celery
Parsley Lettuce, butterhead Coffee
Spinach Mustard greens Corn
Swiss chard Soybean oil Cucumber (without peel)
Tea, green Dairy products
Tea, black Eggs
Turnip greens Fruit (varies)
Watercress Lettuce, iceberg
Meats, fish, poultry
Pasta
Peanuts
Peas
Potato
Rice
Tomato
a
Approximate amount of vitamin K per 100-g (3.5 oz.) serving.
Reprinted from: Talbert RL, DiPiro JT, Matzke GR, et al., eds. Pharmacotherapy: A Pathophysiological Approach, 8th ed. New York: McGraw-
Hill, 2011. With permission from The McGraw-Hill Companies.
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Cardiology I
ii. Other dietary and herbal supplements

(a) All patients receiving warfarin therapy should be questioned regarding the use of herbal
drugs and dietary supplements.
(b) Clinicians should advise patients receiving warfarin therapy to seek information about
potential interactions with warfarin whenever they start to take a new drug product,
whether it is prescribed or purchased over the counter.
(c) If there is a known drug interaction or doubt about its potential to alter the response to
warfarin, more frequent INR testing after the new agent is initiated is prudent.
Table 22. Warfarin Drug Interactions with Dietary Supplements

Mechanism Effect Supplement
Inhibition of warfarin metabolism Increased INR Chinese wolfberry
Cranberry juice
Grapefruit juice
Contain coumarin derivatives Increased INR Dan shen
Dong quai
Fenugreek
Unknown Increased INR Curbicin
Devil’s claw
Glucosamine-chondroitin
Melatonin
Papaya extract
Guilinggao
Inhibition of platelet aggregation Increased bleeding Garlic
Ginger
Ginkgo
Contain vitamin K/derivatives Decreased INR Coenzyme Q10Green tea
Some multivitamins
Induction of CYP3A4 Decreased INR St. John’s wort
Unknown Decreased INR Ginseng

Melatonin
Table 23. Warfarin Drug-Disease State Interactions

Clinical Condition Effect on Warfarin Therapy
Advanced age Increased sensitivity to warfarin because of reduced vitamin K stores and/or lower
plasma concentrations of vitamin K–dependent clotting factors
Pregnancy Teratogenic; avoid exposure during pregnancy
Lactation Not excreted in breast milk; can be used postpartum by nursing mothers
Alcoholism Acute ingestion: Inhibits warfarin metabolism, with acute elevation in INR
Chronic ingestion: Induces warfarin metabolism, with higher dose requirements
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Cardiology I
Table 23. Warfarin Drug-Disease State Interactions (continued)
Clinical Condition Effect on Warfarin Therapy

Liver disease May induce coagulopathy by decreased production of clotting factors, with baseline
elevation in INR
May reduce clearance of warfarin
Renal disease Reduced activity of CYP2C9, with lower warfarin dose requirements
Heart failure Reduced warfarin metabolism because of hepatic congestion
Cardiac valve replacement Enhanced sensitivity to warfarin postoperatively because of hypoalbuminemia,
lower oral intake, decreased physical activity, and reduced clotting factor
concentrations after cardiopulmonary bypass
Nutritional status Changes in dietary vitamin K intake (intentional or because of disease, surgery,
etc.) alter response to warfarin, especially in patients with lower-than-average
baseline dietary vitamin K intake
Use of tube feedings Decreased sensitivity to warfarin, possibly caused by changes in absorption or
vitamin K content of nutritional supplements
Thyroid disease Hypothyroidism: Decreased catabolism of clotting factors requiring increased
dosing requirements
Hyperthyroidism: Increased catabolism of clotting factors causing increased
sensitivity to warfarin
Smoking and tobacco use Smoking: May induce CYP1A2, increasing warfarin dosing requirements
Chewing tobacco: May contain vitamin K, increasing warfarin dosing requirements
Fever Increased catabolism of clotting factors, causing acute increase in INR
Diarrhea Reduction in secretion of vitamin K by gut flora, causing acute increase in INR
Acute infection/ Increased sensitivity to warfarin
inflammation
Malignancy Increased sensitivity to warfarin by many factors; increased bleeding risk
E. Newer Target-Specific Oral Anticoagulants: Dabigatran (Domain 1, Tasks 2, 3, 4, 5, 6, 7; Domain 3, Tasks 2, 3)
Table 24. Dabigatran Characteristics

Characteristic Dabigatran
Protein binding 35%
Volume of distribution 50–70 L
Time to maximal serum concentrations 1 (fasted) to 2 (fed) hours
Elimination half-life CrCl ≥ 80 mL/minute = 13 hours
CrCl 50–80 mL/minute = 15 hours
Activation Prodrug dabigatran etexilate converted to active drug dabigatran by
esterase hydrolysis
Metabolism Conjugation
Renal excretion of unchanged drug 80% (of the absorbed dose, <7% of dabigatran etexilate absorbed)
Dialyzable Yes
CrCl = creatinine clearance.
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Cardiology I
Table 25. Dabigatran – Considerations for Use

Dosage availability 75- and 150-mg oral capsules
Do not chew, break, or open capsules; this can substantially increase the
bioavailability (once open, the bottle expires in 4 months)
Dosage form Capsules contain many drug pellets with a tartaric acid core (coated with
dabigatran etexilate) that creates an acidic microenvironment to improve
dissolution and absorption independently of gastric pH
Dosing Nonvalvular atrial fibrillation
CrCl > 30 mL/minute: 150 mg orally twice daily
CrCl 15–30 mL/minute: 75 mg orally twice daily
CrCl < 15 mL/minute or receiving dialysis: Not recommended

Hemodialysis Removes a substantial amount of dabigatran (62% at 2 hours, 68% at 4 hours); may
be considered if overdose
Instructions if Take on the same day as soon as possible; skip the missed dose if it cannot be taken at
missed dose least 6 hours before the next scheduled dose; dosing should not be doubled to make up
for a missed dose
Hepatic impairment No adjustment required
Elderly No significant pharmacokinetic differences in healthy elderly individuals,
but the elderly may be at higher bleeding risk from dabigatran
Reversal Activated charcoal may decrease absorption if used within 1–2 hours of ingestion
Hemodialysis (see above)
One case report of FEIBA and two with rFVIIa
(vitamin K, FFP, PCCs, protamine, and aminocaproic acid are not expected to have any effect)
Converting dabigatran Adjust the starting time of warfarin based on CrCl
to warfarin
CrCl > 50 mL/minute: InitiateStart warfarin 3 days before discontinuing dabigatran
CrCl 31–50 mL/minute: InitiateStart warfarin 2 days before discontinuing dabigatran
CrCl 15–30 mL/minute: InitiateStart warfarin 1 day before discontinuing dabigatran
CrCl < 15 mL/minute: Not recommended
Note: Dabigatran can elevate the INR; the INR will better reflect warfarin’s effect
after dabigatran has been discontinued for at least 2 days
Converting warfarin Discontinue warfarin and initiatestart dabigatran when the INR is below 2
to dabigatran
Converting to or from a When a parenteral anticoagulant is in use, initiatestart dabigatran 0–2 hours before the
parenteral anticoagulant next subcutaneous dose of parenteral drug was to have been administered or when a
continuously administered IV parenteral drug is discontinued
For patients currently taking dabigatran, wait 12 hours (CrCl ≥ 30 mL/minute) or

24 hours (CrCl < 30 mL/minute) after the last dabigatran dose before initiating the
parenteral (subcutaneous or IV) anticoagulant
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Cardiology I
Table 25. Dabigatran – Considerations for Use (continued)
Surgery or Discontinue dabigatran 2 days (CrCl ≥ 50 mL/minute) or 2 days

invasive procedures (CrCl 30-49 mL/minute) or 4 days (<30 mL/minute) before invasive or surgical
procedures, if possible, to reduce the risk of bleeding
Note: Depending on the risk of bleeding, urgency of the procedure, and thrombosis
risk, holding for a shorter period may be considered
Longer holding periods to establish complete hemostasis may be considered for

major surgery, spinal puncture, or placement of a spinal or epidural catheter or port
If a delay in surgery is not possible, the increased risk of bleeding should be

weighed against the urgency of intervention
Contraindications Active bleeding
History of serious hypersensitivity reaction to dabigatran
CrCl < 15 mL/minute
Mechanical heart valve
Avoid dabigatran in patients taking P-gp inhibitors with CrCl 15–30 mL/minute
Warnings and Risk of bleeding: Dabigatran can cause serious and sometimes fatal bleeding;
precautions promptly evaluate signs and symptoms of blood loss
Temporary discontinuation: Avoid lapses in therapy to minimize stroke risk
Discontinuation puts the patient at increased thrombosis risk

Adverse reactions GI adverse effects are the most common: Dyspepsia, nausea, vomiting, constipation
CrCl = creatinine clearance; FEIBA = factor eight inhibitor bypass activity; FFP = fresh frozen plasma; GI = gastrointestinal; INR = international
normalized ratio; IV = intravenous(ly); PCC = prothrombin complex concentrate; P-gp = P-glycoprotein; rFVIIa = recombinant factor VIIa.
Table 26. Dabigatran Drug Interactions

↑ Dabigatran serum concentration
• Amiodarone
• Dronedarone (reduce dose to 75 mg bid if CrCl 30–50 mL/minute)
• Quinidine
• Ketoconazole (reduce dose to 75 mg bid if CrCl 30–50 mL/minute)
• Verapamil
Avoid dabigatran if patient taking P-gp inhibitor and CrCl 15–30 mL/minute
↓ Dabigatran serum concentration
• Rifampin (significant interaction to avoid)
↑ Anticoagulation effect
• Other anticoagulants
• Antiplatelet agents
• Salicylates
• SSRIs
• SNRIs
bid = twice daily; CrCl = creatinine clearance; P-gp = P-glycoprotein; SNRI = serotonin-norepinephrine reuptake inhibitor;
SSRI = selective serotonin reuptake inhibitor.
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Cardiology I
F. Direct Xa Inhibitors; Oral Xa Inhibitors: Rivaroxaban, Apixaban, Edoxaban

(Domain 1, Tasks 2–, 3, 4, 5, 6, 7; Domain 3, Tasks 2, 3)
1. Rivaroxaban
Table 27. Rivaroxaban Characteristics

Characteristic Rivaroxaban
Protein binding 92%–95%
Volume of distribution 50 L
Time to maximal serum concentrations 2–4 hours
Elimination half-life 5–9 hours
Metabolism Oxidative metabolism by CYP3A4/5
Renal excretion of unchanged drug 66% of the total dose/33% of the absorbed dose
Dialyzable Unlikely (because of high plasma protein binding)
CYP = cytochrome P450.
Table 28. Rivaroxaban – Considerations for Use

Dosage availability 10-, 15-, and 20-mg oral film-coated tablets
CrCl > 50 mL/minute: 20 mg orally once daily with evening meal
CrCl 15–50 mL/minute: 15 mg once daily with evening meal
CrCl < 15 mL/minute or receiving dialysis: Avoid use
VTE treatment
CrCl ≥ 30 mL/minute: 15 mg once daily orally twice daily with a meal for 21 days;
then 20 mg orally once daily with a meal thereafter
CrCl < 30 mL/minute: Avoid use
VTE prophylaxis
CrCl ≥ 30 mL/minute: 10 mg once daily orally once daily with evening meal
CrCl < 30 mL/minute: Avoid use
Hemodialysis Because of high plasma protein binding, not expected to be dialyzable
Instructions if If a dose is not taken at the scheduled time, administer the dose as soon as possible
missed dose on the same day
Hepatic impairment Avoid use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C)
hepatic impairment or with any hepatic disease associated with coagulopathy
Elderly No significant pharmacokinetic differences in healthy elderly individuals,
but elderly may be at higher bleeding risk from rivaroxaban
Reversal Use of activated charcoal to reduce absorption in case of overdose may be considered
No specific antidote is available
Benefits of rFVIIa is unknown, limited evidence indicates four-factor PCCs

(Kcentra) may reverse anticoagulant effect
(vitamin K, FFP, protamine, and aminocaproic acid are not expected to have any effect)
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Cardiology I
Table 28. Rivaroxaban – Considerations for Use (continued)

Converting rivaroxaban No clinical trial data are available to guide converting patients’ therapy from
to warfarin rivaroxaban to warfarin
Rivaroxaban affects INR, so INR measurements made during coadministration with

warfarin may not be useful for determining the appropriate dose of warfarin
One (unproven) approach is to discontinue rivaroxaban and begin both a parenteral

anticoagulant and warfarin when the next dose of rivaroxaban would have been taken
(an increased rate of stroke was observed during the transition from rivaroxaban to
warfarin in clinical trials of patients with atrial fibrillation)
Another (unproven) approach is based on CrCl:
CrCl > 50 mL/minute: InitiateStart warfarin 4 days before discontinuing rivaroxaban
CrCl 31–50 mL/minute: InitiateStart warfarin 3 days before discontinuing rivaroxaban
CrCl 15–30 mL/minute: InitiateStart warfarin 2 days before discontinuing rivaroxaban

Converting warfarin Discontinue warfarin and initiate rivaroxaban as soon as the INR is below 3.0 to avoid
to rivaroxaban periods of inadequate anticoagulation
Converting to or from Initiate rivaroxaban 0–2 hours before the next scheduled evening administration of the
anticoagulants other drug (e.g., LMWH or non-warfarin oral anticoagulant) and omit administration of the
than warfarin other anticoagulant
For UFH being administered by continuous infusion, discontinue the infusion and
initiate rivaroxaban at the same time
For patients currently taking rivaroxaban and transitioning to an anticoagulant with

rapid onset, discontinue rivaroxaban and give the first dose of the other anticoagulant
(oral or parenteral) when the next rivaroxaban dose would have been taken
Surgery or invasive Discontinue at least 24 hours before the procedure; in deciding whether a procedure
procedures should be delayed until 24 hours after the last dose of rivaroxaban, weigh the increased
risk of bleeding against the urgency of intervention; reinitiate after the surgical or other
procedures as soon as adequate hemostasis has been established; if oral medication
cannot be taken after surgical intervention, consider administering a parenteral
anticoagulant
History of serious hypersensitivity reaction to rivaroxaban

Warnings and Risk of bleeding: Rivaroxaban can cause serious and sometimes fatal bleeding;
precautions promptly evaluate signs and symptoms of blood loss

Adverse reactions Low incidence of adverse reactions other than bleeding
CrCl = creatinine clearance; FFP = fresh frozen plasma; INR = international normalized ratio; LMWH = low-molecular-weight heparin; PCC =
prothrombin complex concentrate; rFVIIa = recombinant factor VIIa; UFH = unfractionated heparin; VTE = venous thromboembolism.
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Cardiology I
Table 29. Rivaroxaban Drug Interactions

↑ Rivaroxaban serum concentration
• Combined P-gp and strong CYP3A4 inhibitors (avoid use)
• Ketoconazole
• Itraconazole
• Lopinavir/ritonavir
• Ritonavir
• Indinavir/ritonavir
• Conivaptan
↓ Rivaroxaban serum concentration
• Combined P-gp and strong CYP3A4 inducers (avoid use)
• Carbamazepine
• Phenytoin
• Rifampin
• St. John’s wort
Weigh risk vs. benefit in patients with CrCl 15–50 mL/minute taking concomitant
P-gp and weak or moderate CYP3A4 inhibitors
• NSAIDs
• SSRIs
• SNRIs
CrCl = creatinine clearance; CYP = cytochrome P450; NSAID = nonsteroidal anti-inflammatory drug; P-gp = P-glycoprotein; SNRI = serotonin-
norepinephrine receptor inhibitor; SSRI = selective serotonin receptor inhibitor.
2. Apixaban
Table 30. Apixaban Characteristics

Characteristic Apixaban
Protein binding 87%
Time to maximal serum concentrations 3–4 hours
Elimination half-life 12 hours
Metabolism Oxidative metabolism primarily by CYP3A4
Renal excretion of unchanged drug 27% of total dose
Dialyzable Yes
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Cardiology I
Table 31. Apixaban – Considerations for Use

Dosage availability 2.5- and 5-mg film-coated oral tablets
5 mg orally bid for CrCl ≥ 15 mL/minute
Reduce dose to 2.5 mg orally bid if two of the following are present: Age > 80 years,
body weight ≤ 60 kg, SCr ≥ 1.5 mg/dL
Patients receiving hemodialysis (excluded from trials): Prescribing information

recommends a dose of 5 mg bid unless one of the following is present: Age > 80 years,
body weight ≤ 60 kg; then reduce dose to 2.5 mg orally bid
VTE and PE treatment

10 mg orally bid for days 1−7, then 5 mg orally bid
VTE prophylaxis
2.5 mg orally bid
Hemodialysis Dialysis clearance 18 mL/minute (compared with renal clearance in healthy normal
volunteers of 11 mL/minute), representing a 14% decrease in exposure compared with
an off-dialysis period; 7% of dose removed by hemodialysis
Instructions if If a dose is not taken at the scheduled time, administer the dose as soon as possible on
missed dose the same day, and twice-daily administration should be resumed
Hepatic impairment No dosage adjustment in mild hepatic impairment; avoid use in patients with severe
hepatic impairment
Benefits of rFVIIa are unknown; limited evidence indicates four-factor PCCs (not
available in the United States) may reverse anticoagulant effect
Converting apixaban Apixaban affects INR, so INR measurements made during coadministration with
to warfarin warfarin may not be useful for determining the appropriate dose of warfarin
One (unproven) approach is to discontinue apixaban and begin both a parenteral

anticoagulant and warfarin when the next dose of apixaban would have been taken (an
increased rate of stroke was observed during the transition from apixaban to warfarin
in clinical trials of patients with atrial fibrillation)
Converting warfarin Discontinue warfarin and initiate apixaban as soon as the INR is below 2.0 to avoid
to apixaban periods of inadequate anticoagulation
Converting to or from Initiate apixaban at the same time as the next scheduled dose and omit administration
anticoagulants other of the other anticoagulant
than warfarin
For UFH being administered by continuous infusion, discontinue the infusion and
initiate apixaban at the same time
For patients currently taking apixaban and transitioning to an anticoagulant with rapid
onset, discontinue apixaban and give the first dose of the other anticoagulant (oral or
parenteral) when the next rivaroxaban dose would have been taken
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Cardiology I
Table 31. Apixaban – Considerations for Use (continued)

Surgery or invasive Discontinue at least 24 hours before a procedure with a low bleeding risk and at least
procedures 48 hours before a procedure with a moderate or high bleeding risk; reinitiate after the
surgical or other procedures as soon as adequate hemostasis has been established; if
oral medication cannot be taken after surgical intervention, consider administering a
parenteral anticoagulant
History of serious hypersensitivity reaction to apixaban

Warnings and Risk of bleeding: Apixaban can cause serious and sometimes fatal bleeding; promptly
precautions evaluate signs and symptoms of blood loss

bid = twice daily; CrCl = creatinine clearance; FFP = fresh frozen plasma; INR = international normalized ratio; PCC = prothrombin complex
concentrate; PE = pulmonary embolism; rFVIIa = recombinant factor VIIa; SCr = serum creatinine concentration; UFH = unfractionated heparin;
VTE = venous thromboembolism.
Table 32. Apixaban Drug Interactions

↑ Rivaroxaban serum concentration
• Combined P-gp and strong CYP3A4 inhibitors (reduce 5-mg dose bid to 2.5 mg bid, and if 2.5 mg bid, avoid use)
• Ketoconazole
• Itraconazole
• Lopinavir/ritonavir
• Ritonavir
• Indinavir/ritonavir
• Clarithromycin
↓ Rivaroxaban serum concentration
• Carbamazepine
• Phenytoin
• Rifampin
• NSAIDs
• SSRIs
• SNRIs
bid = twice daily; CYP = cytochrome P450; NSAID = nonsteroidal anti-inflammatory drug; P-gp = P-glycoprotein; SNRI = serotonin-
norepinephrine receptor inhibitor; SSRI = selective serotonin receptor inhibitor.
2-45
Cardiology I
3. Edoxaban
Table 33. Edoxaban Characteristics

Characteristic Edoxaban
Protein binding 55%
Time to maximal serum concentrations 2 hours
Elimination half-life 12 hours
Metabolism Oxidative metabolism primarily by
CYP3A4, conjugation
Renal excretion of unchanged drug 50% of total dose
Dialyzable No
Table 34. Edoxaban – Considerations for Use

Dosage availability 30- and 60-mg film-coated oral tablets
60 mg orally daily for CrCl ≥ 50 mL/minute
Reduce dose to 30 mg orally daily if CrCl between 15 and -50 mL/minute
Patients receiving hemodialysis (excluded from trials): Not recommended
VTE and PE treatment

60 mg taken orally once daily after following 5 to 10 days of initial therapy with a
Hemodialysis A 4- hour hemodialysis session reduced total edoxaban exposure by less than 7%
Instructions if If a dose is not taken at the scheduled time, administer the dose as soon as possible on
missed dose the same day, and once-daily administration should be resumed the next day
Hepatic impairment No dosage adjustment in mild hepatic impairment; avoid use in patients with moderate
to severe hepatic impairment
Benefits of rFVIIa are unknown; limited evidence indicates four-factor PCCs (not
available in the United States) may reverse anticoagulant effect
Converting edoxaban Decrease edoxaban to 30 mg daily and initiatestart warfarin;
to warfarin continue edoxaban until INR ≥ 2.0
OR,
discontinue edoxaban and initiatestart warfarin
(recommend parenteral anticoagulation until INR > 2)
Converting warfarin InitiateStart edoxaban when INR is ≤ 2.5
to edoxaban
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Cardiology I
Table 34. Edoxaban – Considerations for Use (continued)

Converting to or from Initiate edoxaban at the same time as the next scheduled dose and omit administration
anticoagulants other of the other anticoagulant
than warfarin
For UFH being administered by continuous infusion, discontinue the infusion
and initiate edoxaban 4 hours later
For patients currently taking edoxaban and transitioning to an anticoagulant with

rapid onset, discontinue edoxaban and give the first dose of the other anticoagulant
(oral or parenteral) when the next edoxaban dose would have been taken
Surgery or invasive Discontinue at least 24 hours before invasive or surgical procedures; reinitiate after
procedures the surgical or other procedures as soon as adequate hemostasis has been established;
if oral medication cannot be taken after surgical intervention, consider administering a
History of serious hypersensitivity reaction to edoxaban
Warnings and Risk of bleeding: Eedoxaban can cause serious and sometimes fatal bleeding; promptly
precautions evaluate signs and symptoms of blood loss

bid = twice daily; CrCl = creatinine clearance; FFP = fresh frozen plasma; INR = international normalized ratio; PCC = prothrombin complex
concentrate; PE = pulmonary embolism; rFVIIa = recombinant factor VIIa; SCr = serum creatinine concentration; UFH = unfractionated heparin;
VTE = venous thromboembolism.
Table 35. Edoxaban Drug Interactions

↓ Edoxaban serum concentration
• Carbamazepine
• Phenytoin
• Rifampin
Verapamil: Ffor VTE, reduce dose to 30 mg daily
• NSAIDs
• SSRIs
•SNRIs
bid = twice daily; CYP = cytochrome P450; NSAID = nonsteroidal anti-inflammatory drug; P-gp = P-glycoprotein; SNRI = serotonin-norepinephrine
receptor inhibitor; SSRI = selective serotonin receptor inhibitor; VTE = venous thromboembolism..
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Cardiology I
Patient Cases
Questions 6–8 pertain to the following case.
S.K. is a 78-year-old, 58-kg woman with a history of uncontrolled HTN, diabetes mellitus, GI bleeding, chronic
kidney disease, and chronic NVAF. Her current medications include metformin, carvedilol, digoxin, aspirin, and
lansoprazole; her SCr is 0.94 mg/dL; and her calculated CrCl is 45 mL/minute.
6. Which is the best choice for S.K.’s CHADS2 score and classification for stroke risk?
A. 0 (Low).
B. 1 (Moderate).
C. 2 (High).
D. 3 (High).
7. Which is the best choice for S.K.’s HAS-BLED score and classification of bleeding risk?
A. 1 (Intermediate).
B. 2 (Intermediate).
C. 3 (High).
D. 4 (High).
8. A decision is made to administer anticoagulants to S.K. Which represents the most appropriate choice?
A. Apixaban 5 mg orally twice daily.
B. Rivaroxaban 20 mg orally daily.
C. Dabigatran 75 mg orally twice daily.
D. Aspirin 81 mg plus clopidogrel 75 mg orally daily.
IV. THERAPY PRECAUTIONS AND MANAGEMENT OF ADVERSE EVENTS (Domain 1, Tasks 2, 3, 4)
Table 36. General Contraindications to Anticoagulation Therapy

Active major bleeding
Hemophilia or other hemorrhagic tendencies
Severe liver disease with elevated baseline PT
Severe thrombocytopenia (platelet count < 20,000/mm3)
Malignant hypertension
Inability to meticulously supervise and monitor treatment
PT = prothrombin time.
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Cardiology I
Table 37. Reversal Considerations for LMWH or Fondaparinux

LMWHs Fondaparinux
Protamine can be used as a “partial” reversal agent for the effects of LMWH No specific antidote exists
Protamine neutralizes around 60% of the anti−factor Xa activity
If LMWH was given in the previous 8 hours, then 1 mg of protamine should

be administered for every 100 IU (or 1 mg) of the LMWH
If the LMWH dose is given in the previous 8–12 hours, a 0.5-mg dose of
protamine should be given for every 100 anti−factor Xa units
Use of protamine sulfate is not recommended if the LMWH was administered

more than 12 hours earlier
LMWH = low-molecular-weight heparin.
Table 38. Guidelines for Reversal of an Elevated INR in a Patient Taking Warfarin
INR Recommendation
<5 Lower or hold dose
5–10 Hold one or two doses
≥10 Hold warfarin and give vitamin K (2.5 mg orally); use additional vitamin K, if necessary
Serious bleeding Hold warfarin and give vitamin K (10-mg slow IV infusion) supplemented with
with high INR fresh frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa;
may repeat vitamin K every 12 hours, if necessary
Life-threatening bleeding Hold warfarin and give prothrombin complex concentrates or recombinant factor
VIIa supplemented with vitamin K (10-mg slow IV infusion); repeat as necessary
INR = international normalized ratio; IV = intravenous.
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Cardiology I
V. PATIENT EDUCATION CONSIDERATIONS
A. Oral Anticoagulants (Domain 2, Task 5)
Table 39. Key Elements of Patient Education Regarding Warfarin, Apixaban, Dabigatran, Rivaroxaban, and Edoxaban
Identification of generic and brand names
Purpose of therapy
Expected therapy duration
Dosing and administration
Visual recognition of drug and tablet or capsule dosage strength
Importance of taking exactly as prescribed
What to do if a dose is missed
Importance of prothrombin time/INR monitoring (warfarin only)
Importance of kidney function monitoring (apixaban, dabigatran, and rivaroxaban only)
Recognition of signs and symptoms of bleeding
Recognition of signs and symptoms of TE
What to do if bleeding or TE occurs
Potential for interactions with prescription and over-the-counter medications and natural/herbal products
Dietary considerations (warfarin only) and use of alcohol
MustNeed to take with food (rivaroxaban only)
Expiration of tablets (dabigatran only)
Importance of not crushing or breaking capsule (dabigatran only)
Avoidance of pregnancy
Significance of informing other health care providers that anticoagulant has been prescribed
When, where, and with whom follow-up will be provided
Ensure that the patient can pay for the drug before a final decision on treatment is made
INR = international normalized ratio; TE = thromboembolism.
B. LMWH/Fondaparinux for Home Use (Domain 2, Tasks 3, 5)
Table 40. Use of LMWH/Fondaparinux at Home

Ensure that the patient/caregiver is fully educated on administering the injection and is willing to adhere
Ensure that the follow-up appointments have been made for anticoagulation monitoring
Ensure that the outpatient provider clearly understands the treatment plan and the importance of making
sure the patient follows up
Ensure that the patient can pay for the drug before a final decision on treatment is made
Ensure that the pharmacy where the patient will obtain the drug has it in stock
Ensure that the patient has telephone numbers to call if he or she has any questions/concerns about
therapy when at home and that the care providers have the patient’s contact information, if needed
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Cardiology I
C. Periprocedural Anticoagulation Bridging (Domain 1, Tasks 2, 3, 4, 7)
Table 41. Risk Stratification for Determining the Need for Bridge Therapy
Indication for VKA Therapy
Risk Stratum
Mechanical Heart Valve Atrial Fibrillation Venous Thromboembolism
Any mitral valve prosthesis CHADS2 score of 5 or 6 Recent (within 3 months)
Older (caged-ball or tilting disk) Recent (within 3 months) stroke VTE
aortic valve prosthesis or transient ischemic attack Severe thrombophilia (e.g.,
High Recent (within 6 months) stroke Rheumatic valvular deficiency of protein C,
or transient ischemic attack heart disease protein S, or antithrombin;
antiphospholipid antibodies;
many abnormalities)
Bileaflet aortic valve prosthesis CHADS2 score of 3 or 4 VTE within the past
and one of the following: 3–12 months
Atrial fibrillation, previous (Consider VTE prophylaxis
stroke or transient ischemic rather than full-intensity
attack, hypertension, diabetes, bridge therapy)
congestive heart failure, Nonsevere thrombophilic
age > 75 years conditions (e.g.,
Moderate heterozygous factor
V Leiden mutation,
heterozygous factor II
mutation)
Recurrent VTE
Active cancer (treated
within 6 months or
palliative)
Bileaflet aortic valve prosthesis CHADS2 score of 0–2 Single VTE occurred greater
Low without atrial fibrillation and (no previous stroke or than 12 months ago and no
no other risk factors for stroke transient ischemic attack) other risk factors
CHADS2 = congestive heart failure, hypertension, age at least 75 years, diabetes, previous stroke or transient ischemic attack; VKA = vitamin
K antagonist; VTE = venous thromboembolism.
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Cardiology I
Table 42. Warfarin to Parenteral Anticoagulant Bridge Therapy Guidelines for Invasive Procedures
Thromboembolic
Renal Function Bridge Therapy
Riska
Low All patients Last dose of warfarin on day −6 pre procedure
Hold warfarin day from day −5 through day −1
Consider vitamin K 2.5 mg PO on day −2 or day −1 if INR ≥ 1.5
Resume warfarin 12–48 hours post procedure at usual maintenance
dose (decision based on postoperative assessment of bleeding risk)
High CrCl > 30 mLl/minute Last dose of warfarin on day −6 pre procedure
Hold warfarin day −5 through day −1
Start LMWH on day −3 (or when INR < lower limit of range)
Consider vitamin K 2.5 mg PO on day 2 or day 1 if INR ≥ 1.5
Last dose of LMWH 24 hours pre procedure
(On day −1, give one-half dose of LMWH if patient is receiving
once-daily LMWH)
Resume warfarin 12–24 hours post procedure at usual
maintenance dose (decision predicated on postprocedure
assessment of bleeding risk)
Resume LMWH 24 hours post procedure (or 48–72 hours for
major surgery or high bleeding risk procedure) and continue
until INR > lower limit of therapeutic range
CrCl ≤ 30 mLl/minute Last dose of warfarin on day –6 pre procedure
Hold warfarin day –5 through day –1
Consider vitamin K 2.5 mg PO or 1 mg IV x on day –2 or day –1 pre
procedure if INR ≥ 1.5
Admit on day –1 pre procedure and begin IV UFH (70 units/kg bolus,
15 units/kg/hour infusion and adjust per inpatient protocol)
Discontinue IV UFH 6 hours pre procedure
Resume warfarin 12–24 hours post procedure at the usual maintenance
dose (decision based on postoperative assessment of bleeding risk)
Resume IV UFH 24 hours post procedure (or 48–72 hours for major
surgery or high-bleeding-risk procedure) and continue until INR >
lower limit of therapeutic range
The decision to bridge patients with a moderate risk of thromboembolism should be based on surgery and patient-related factors.
a
CrCl = creatinine clearance; INR = international normalized ratio; IV = intravenous; LMWH = low-molecular-weight heparin; PO = orally;
UFH = unfractionated heparin.
VI. CONSIDERATIONS FOR PATIENT SAFETY AND DELIVERY OF QUALITY PATIENT CARE
A. Systematic Management (Domain 4, Task 1)

1. Anticoagulation therapy management services can improve the care of patients who take warfarin therapy.
2. Provides structured and comprehensive patient education and evaluation
3. Improves the safety and effectiveness of warfarin therapy compared with “usual” medical care
4. Lowers the overall cost of care by reducing the frequency of major bleeding and recurrent
thromboembolic events
5. However, the benefit of anticoagulation management services is not supported by
high-quality evidence.
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Cardiology I
B. Home Management of Warfarin Oral Anticoagulation: Portable Fingerstick INR Devices Are Available for
Monitoring Warfarin Therapy. (Domain 1, Task 5)
1. Self-monitoring at home: Requires that the patient report his or her test results to a health care
professional. The clinician continues to make warfarin dosing decisions.
2. Self-management at home: Highly motivated patients can be trained to manage dosing themselves,
independently altering the warfarin therapy dose according to their INR results.
3. Patients who engage in INR self-monitoring and warfarin self-management report high levels of
satisfaction with care, with modest improvement in percentage time in therapeutic INR range,
compared with those who are medically managed by “usual care.”
4. Home INR testing and self-management require careful patient selection and considerable education.
5. Most benefit is seen in the reduction of thromboembolic complication risk in patients with mechanical
valves who self-manage INRs. Minimal benefit has been shown with self-testing in patients with AF
(e.g., the THINRS [The Home INR Study] trial did not show any benefit of self-testing).
6. Patients with very stable conditions probably do not need the frequent testing usually used with self-
testing and self-management.
C. National Quality Initiatives (Domain 5, Tasks 1, 2)

1. The recent national focus on quality health care has been emphasized by the call to accountability
through the Joint Commission’s Agenda for Change; the Institute of Medicine’s report on medical
errors; the endorsed safe practices of the National Quality Forum (NQF); the Leapfrog Group’s
recommendations; and the demand for value by health care consumers.
Table 43. Organizations Monitoring Quality of Venous Thromboembolism Care

The Joint Commission - www.jointcommission.org
A not-for-profit health care accreditation organization that issues performance-based standards and
assesses organizational compliance with improved patient safety and quality of care
Leapfrog Group - www.leapfroggroup.org
An initiative of health care−purchasing organizations seeking improvements in safety, quality,
and affordability of health care, with funding from the Business Roundtable, Robert Wood Johnson Foundation,
and member organizations
National Quality Forum - www.qualityforum.org
A not-for-profit organization that develops and implements national strategies for health care
quality measurement and reporting
2. The NQF has developed national consensus standards for VTE prevention and treatment that will
apply to a variety of health care settings.
a. The outcomes of this effort will provide a framework for measuring the effective
screening, prevention, and treatment of VTE.
b. The NQF’s recommendations include developing organizational policies that address staff education,
treatment protocols, and compliance measurements to improve VTE prevention in the hospital.
c. The ultimate goal of the NQF consensus standards is to facilitate the early promulgation
of VTE policies, risk assessment, prophylaxis, diagnosis, and treatment services as well
as patient education and organizational accountability.
d. To that end, the Joint Commission has developed performance measures to enforce the
NQF’s recommendations.
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Cardiology I
Table 44. The Joint Commission’s Proposed Performance Measures for the Prevention and Treatment
of Venous Thrombosis
Number Description of Proposed Performance Measure
1 Documentation of Venous Thromboembolism Risk Assessment/Prophylaxis Within 24 Hours of
Hospital Admission
2 Documentation of Venous Thromboembolism Risk Assessment/Prophylaxis Within 24 Hours of
Transfer to ICU
3 Venous Thromboembolism Patients with Overlap of Parenteral and Warfarin Anticoagulation
Therapy
4 Venous Thromboembolism Patients Receiving Unfractionated Heparin by Nomogram/Protocol
with Platelet Count Monitoring
5 Venous Thromboembolism Discharge Instructions
6 Incidence of Potentially Preventable Hospital-Acquired Venous Thromboembolism
ICU = intensive care unit.
Table 45. The Joint Commission National Patient Safety Goals on Anticoagulation Therapy Elements of Performance
Use only oral unit-dose products, prefilled syringes, or premixed infusion bags when these types of products
are available – Note: For pediatric patients, prefilled syringe products should be used only if specifically
designed for children
Use approved protocols for the initiation and maintenance of anticoagulant therapy
Before initiating warfarin therapy for a patient, assess the patient’s baseline coagulation status; for all patients
receiving warfarin therapy, use a current INR to adjust this therapy; the baseline status and current INR are
documented in the medical record
Use authoritative resources to manage potential food and drug interactions for patients receiving warfarin
When heparin is administered both intravenously and continuously, use programmable pumps to provide
consistent and accurate dosing
A written policy addresses baseline and ongoing laboratory tests that are required for anticoagulants
Provide education regarding anticoagulant therapy to prescribers, staff, patients, and families; patient/family
education includes the following:
- The importance of follow-up monitoring
- Adherence
- Drug-food interactions
- The potential for adverse drug reactions and interactions
Evaluate anticoagulation safety practices, take action to improve practices, and measure the effectiveness of
those actions in a period determined by the organization
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Table 46. Useful Resources Involving Anticoagulation Therapy

Reference Web Site Comment
American College http://journal. The oldest and most established evidence-based guideline
of Chest Physicians publications.chestnet. involving antithrombotic therapy
guidelines org/ss/guidelines.aspx
Anticoagulation Forum www.acforum.org/ Multidisciplinary professional organization for those who
manage anticoagulation therapy; helpful clinical resources
are posted on the site as well as professional guidelines that
describe best practice for outpatient (2008) and inpatient
(2013) anticoagulation services
ClotCare www.clotcare.com/ Regularly updated site mainly focused on keeping
clotcare/index.aspx professionals abreast of cutting-edge information
involving antithrombotic therapy; site also contains helpful
information for patients
HEART FAILURE
VII. DIAGNOSIS
A. Symptoms Suggestive of HF (Domain 1, Task 2)

1. Dyspnea at rest or on exertion
2. Reduced exercise capacity, unexplained fatigue, or weakness
3. Orthopnea
4. Paroxysmal nocturnal dyspnea or nocturnal cough
5. Early satiety, nausea and vomiting, abdominal discomfort, or constipation
6. Wheezing or cough
7. Confusion, delirium, or depression
B. Physical Examination Findings (Domain 1, Task 2)

1. Elevated jugular venous pressure or hepatojugular reflux
2. S3 gallop
3. Rales
4. Displaced apical pulse, or PMI (“point of maximum impulse”)
5. Ascites
6. Edema
7. Cardiac enlargement
8. Cardiac murmurs suggesting valvular dysfunction
9. Narrow pulse pressure
10. Cool extremities
C. Other Pertinent Diagnostic and Laboratory Findings (Domain 1, Tasks 2, 3)

1. Assessment of B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) concentration is
recommended by guidelines, especially when the diagnosis is uncertain.
2. BNP greater than 100 pg/mL: May be used to monitor the success of goal-directed medical therapy (GDMT)
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Cardiology I
3. NT-proBNP cut points of more than 450 pg/mL for patients younger than 50 years, more than 900
pg/mL for patients 50–74 years of age, and more than 1800 pg/mL for patients 75 years and older are
predictive of HF. May be used to monitor the success of GDMT
4. Left ventricular ejection fraction (LVEF) less than 40% as determined by echocardiography, radionuclide
angiography (MUGA [multiple gated acquisition] blood scan, considered the gold standard for LVEF
measurement), or coronary angiography. Even though a MUGA scan provides the most accurate
assessment of ejection fraction (EF), it is seldom used because of its higher cost and invasiveness.
5. Models that can be used in ambulatory patients to predict mortality
a. Seattle Heart Failure Model (http://SeattleHeartFailureModel.org)
b. Heart Failure Survival Score (http://handheld.softpedia.com/dyn-search.php)
D. Definitions (Domain 1, Task 2)

1. HFrEF is HF with reduced LVEF (historically called systolic HF): A clinical syndrome characterized
by signs and symptoms of HF and reduced LVEF defined as 40% or less. Usually associated with LV
chamber dilation
2. HFpEF is HF with preserved LVEF (historically called diastolic HF): A clinical syndrome characterized
by signs and symptoms of HF with preserved LVEF defined as 50% or greater. Usually associated with a
nondilated LV chamber
3. NYHA classes I–IV and ACC/AHA stages A–D (Table 474)
Table 47. Clinical Classifications of Heart Failure Severity

NYHA Functional Classification ACC/AHA Stages of Heart Failure
Stage A At high risk of heart failure; no identified
structural or functional abnormality;
no signs or symptoms
Class I No limitation of physical activity; Stage B Developed structural heart disease that
ordinary physical activity does not cause is strongly associated with the
undue fatigue, palpitation, or dyspnea development of heart failure but
without signs or symptoms
Class II Slight limitation of physical activity; Stage C Symptomatic heart failure associated
comfortable at rest, but ordinary physical with underlying structural heart disease
activity results in fatigue, palpitation,
or dyspnea
Class III Marked limitation of physical activity;
comfortable at rest, but less than
ordinary activity results in fatigue,
palpitation, or dyspnea
Class IV Unable to carry on any physical activity Stage D Advanced structural heart disease and
without discomfort; symptoms present marked symptoms of heart failure at rest
at rest; if any physical activity is despite maximal medical therapy
undertaken, discomfort is increased
ACC/AHA = American College of Cardiology/American Heart Association; NYHA = New York Heart Association.
Reprinted with permission from: McMurray JJV. Systolic heart failure. N Engl J Med 2010;362:228-38.
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VIII. STANDARD PHARMACOLOGIC MANAGEMENT STRATEGIES FOR HEART FAILURE WITH

REDUCED LEFT VENTRICULAR EJECTION FRACTION
A. Angiotensin-Converting Enzyme (ACE) Inhibitors (Domain 1, Tasks 2, 3, 5, 6, 7; Domain 3, Tasks 2, 3)

1. ACE inhibitors are recommended in all patients with symptomatic HFrEF, unless contraindicated.
Randomized controlled trials with ACE inhibitors in HF have shown the following:
a. Improved survival
b. Reduced rate of HF hospitalizations, even among patients with asymptomatic HFrEF
2. In general, ACE inhibitor therapy is widely tolerated; however, ACE inhibitors should be avoided in
patients with the following:
a. History of angioedema
b. Bilateral renal artery stenosis
c. Severe aortic stenosis
d. Labile BP and hypotension, which increases risk of cardiogenic shock
e. Pregnancy
3. In general, ACE inhibitors should be used cautiously and with close monitoring in patients with a serum
potassium concentration greater than 5.5 mmol/L because of the potential for hyperkalemia.
4. Early worsening renal function (decrease in estimated glomerular filtration rate of 20% or greater) after ACE
inhibitor initiation is not predictive of smaller mortality benefit (compared with placebo in the Studies of Left
Ventricular Dysfunction [SOLVD] trial). Therefore, in practice, increases in SCr of 30%–50% are tolerated.
5. In patients admitted with acute HF and significant worsening of renal dysfunction, ACE inhibitors,
angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs) may be
temporarily discontinued until renal function improves. Every effort should be made to reinitiate an
ACE inhibitor or ARB and an MRA before hospital discharge.
6. Table 485 lists specific ACE inhibitors and recommended doses. In general, the benefits of ACE inhibitors
are considered to be a class effect, and doses should be titrated to doses proven effective in randomized
trials. In the ATLAS (Assessment of Treatment with Lisinopril and Survival) trial, patients randomly
assigned to receive high-dose lisinopril (32.5–35 mg/day) had a significantly lower risk of all-cause death or
all-cause hospitalization, as well as a lower risk of HF-specific hospitalization, than did patients randomly
assigned to receive low-dose lisinopril (2.5–5 mg/day); all-cause mortality alone was not significantly
different between the high- and low-dose groups.
Table 48. ACE Inhibitors and Doses

Mean Dose Achieved in
Generic Name Trade Name Initial Daily Dose Target Dose
Clinical Trials
Captopril Capoten 6.25 mg tid 50 mg tid 122.7 mg/day
Enalapril Vasotec 2.5 mg bid 10 mg bid 16.6 mg/day
Fosinopril Monopril 5–10 mg daily 80 mg daily N/A
4.5 mg/day (low-dose ATLAS)
a
Lisinopril Zestril, Prinivil 2.5–5 mg daily 20 mg daily
33.2 mg/day (high-dose ATLAS)
Quinapril Accupril 5 mg bid 80 mg daily N/A
Ramipril Altace 1.25–2.5 mg daily 10 mg daily N/A
Trandolapril Mavik 1 mg daily 4 mg daily N/A
a
No difference in mortality between high- and low-dose groups, but a 12% lower risk of death or hospitalization in high- versuss. low-dose group.
ACE = angiotensin-converting enzyme; ATLAS = Assessment of Treatment with Lisinopril and Survival; bid = twice daily; N/A = not applicable;
tid = three times daily.
Reprinted with permission from: Lindenfeld J, Albert NM, Boehmer JP, et al. HFSA 2010 comprehensive heart failure practice guideline. J
Card Fail 2010;16:e1-194.
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7. Monitoring
a. SCr assessed within 1–2 weeks after initiation and periodically thereafter
b. Serum potassium concentration assessed within 1–2 weeks after initiation and periodically thereafter
8. Major adverse effects
a. Angioedema
b. Hyperkalemia
c. Hypotension (potentiated by diuretics)
d. Worsening renal function (e.g., rapid increase of SCr by 30%–50% over baseline)
e. Persistent nonproductive cough
B. Angiotensin Receptor Blockers (Domain 1, Tasks 2, 3, 5, 6, 7; Domain 3, Tasks 2, 3)

1. ARBs for ACE inhibitor–intolerant patients
a. An ARB is a useful alternative to an ACE inhibitor because of intolerance.
i. Data from the ELITE II (Losartan Heart Failure Survival Study) trial showed no differences in
all-cause mortality for patients randomly assigned to the ARB losartan arm versus captopril.
ii. In the Candesartan in Heart Failure Assessment of Reduction in Morbidity and Mortality
(CHARM) Alternative study, candesartan was associated with a 23% reduction (hazard ratio 0.77;
95% CI, 0.67–0.89, p=0.0004) compared with placebo for the primary end point of cardiovascular
(CV) death or HF hospitalization among patients who were intolerant of ACE inhibitors.
b. In general, ARBs are routinely recommended for patients intolerant of ACE inhibitors because
of cough. However, ACE inhibitors are still considered the first-line vasodilator therapy in heart
failure because of stronger mortality data.
c. Patients intolerant of ACE inhibitors because of worsening renal function, hyperkalemia, or
hypotension are likely to experience similar effects with ARBs; thus, ARBs should also be used
cautiously and with close monitoring in those situations.
Table 49. Angiotensin Receptor Blockers and Recommended Doses

Mean Dose Achieved
in Clinical Trials
Candesartan Atacand 4–8 mg daily 32 mg daily 24 mg/day
Losartan Cozaar 12.5–25 mg daily 150 mg daily 129 mg/day
Valsartan Diovan 40 mg bid 160 mg bid 254 mg/day
bid = twice daily.
Reprinted with permission from: Lindenfeld J, Albert NM, Boehmer JP, et al. HFSA 2010 comprehensive heart failure practice guideline.
J Card Fail 2010;16:e1-194.
2. Addition of an ARB to ACE inhibitor therapy

a. Adding an ARB may be recommended for patients with HF who remain symptomatic despite
optimal treatment with ACE inhibitors and β-blockers (unless contraindications are present) and
for whom an MRA is not indicated or not tolerated.
b. Several studies have evaluated the addition of an ARB to background ACE inhibitor therapy
i. The Valsartan Heart Failure Trial (Val-HeFT) showed a 13% reduction (relative risk [RR]
0.87; 97.5% CI, 0.77–0.97; p=0.009) in the combined end point of mortality and morbidity for
patients randomly assigned to receive valsartan versus placebo. Mortality was similar between
groups. Around 93% of the patients studied received background ACE inhibitor therapy.
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ii. In the CHARM-Added trial, the addition of candesartan for patients with HF receiving
background ACE inhibitor therapy provided a 15% reduction (hazard ratio 0.85; 95% CI, 0.75–
0.96; p=0.011) in the primary end point of CV death or HF hospitalization, compared with placebo.
iii. Of note, combination therapy is associated with a higher risk of hyperkalemia and increase
in SCr; thus, patients should be carefully selected and closely monitored while receiving
combined ARB and ACE inhibitor therapy. In general, combination of ACE inhibitor and
ARB has fallen out of favor clinically.
3. ARBs for patients with evidence of LV systolic dysfunction post MI with or without HF symptoms
a. Valsartan showed noninferiority to captopril for the end points of mortality alone and fatal
and nonfatal CV events in the Valsartan in Acute Myocardial Infarction (VALIANT) trial;
thus, either ARB or ACE inhibitors are appropriate in this setting.
b. Combining valsartan with captopril was not associated with improvements in clinical outcomes;
however, adverse event rates were higher in this group. Thus, there is no advantage to using
combination therapy for these patients.
c. Use of ARBs in post-MI patients with reduced EF or HF symptoms who are intolerant of
ACE inhibitors is recommended by the ACC/AHA acute coronary syndrome guidelines
(class I recommendation).
C. Angiotensin Rreceptor Nneprilysin Iinhibitor (Domain 1, Tasks 2, 3, 5, 6, 7; Domain 3, Tasks 2, 3)

1. Natriuretic peptides, or NPs (atrial natriuretic peptide [ANP], B-type natriuretic peptide [BNP], and
c-type natriuretic peptides [CNPs]), are responsible for natriuresis, and help maintain sodium and
fluid balance. NPs are released in the setting of excess plasma volume and elevated left ventricular
filling pressures. Other benefits include cGMP-mediated vasodilation, and reduction in renin-
angiotensin-aldosterone (RAAS) activation.
a. NPs are cleared through the natriuretic receptor, and through peptide-mediated breakdown byvia
neprilysin. Because neprilysin also breaks down angiotensin II, an inhibitor of this enzyme must
needs to be combined with RAAS blockade.
b. A new drug, sacubitril/valsartan (formerly known as LCZ696), is an angiotensin receptor
neprilysin inhibitor, which is a fixed- dose combination of the ARB valsartan and the neprilysin
inhibitor sacubitril.
2. In the Prospective Comparison of ARNI wWith ACEI to Determine Impact on Global Mortality and
Morbidity in Heart Failure (PARADIGM-HF) trial, patients with NYHA functional classFC II–-IV
and reduced LVEF of less than <40% (, later changed to ≤35% or less) were randomly assignedized to
receive enalapril 10 mg twice daily or sacubitril/valsartan 200 mg twice daily. Compared to enalapril,
sacubitril/valsartan reduced the primary composite end point of cardiovascular death or HF heart
failure hospitalization by 20% (hazard ratio [HR]: 0.80; 95% confidence interval [CI],: 0.73– to 0.87;
p < 0.0000004), and reduced all-cause mortality by 16% (hazard ratioHR: 0,86XX; 95% CI,: 0.76– to
0.93; p < 0.0002).
3. In July 2015, sacubitril/valsartan was FDA approved to reduce the risk of cardiovascular death and
hospitalization for HF in patients with chronic HF heart failure (NYHA class II–IV) and reduced EF
ejection fraction, to be used in place of an ACE inhibitor or ARB. Updated HF heart failure treatment
guidelines will incorporate this new drug and provide recommendations on its place in therapy in the
setting of chronic HFheart failure.
4. Adverse effects of sacuibtril/valsartan include hyperkalemia, hypotension, and renal dysfunction.
5. Three doses of sacubitril/valsartan are available: 24/26 mg, 49/51 mg, and 97/103 mg. The starting
dose is 49/50 mg twice daily, titrated to a goal dose of 97/103 mg twice daily.
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Cardiology I
D. β-Adrenergic Blockers (Domain 1, Tasks 2, 3, 5, 6, 7; Domain 3, Tasks 2, 3)

1. β-Blockers, in conjunction with ACE inhibitors, are the cornerstone of HF pharmacotherapy.
2. Use of specific β-blockers (e.g., bisoprolol, carvedilol, or metoprolol succinate) is recommended
for all patients with HFrEF or without current symptoms and without contraindications because of
compelling evidence from randomized controlled trials.
3. Use of immediate-release metoprolol (metoprolol tartrate) is not recommended for patients with HF
because of the lack of compelling evidence in these patients.
4. These recommendations are based on four landmark studies (three that were placebo controlled and
one that compared carvedilol with metoprolol tartrate) evaluating β-blockers in HF: The Cardiac
Insufficiency Bisoprolol Study (CIBIS II), the Carvedilol Prospective Randomized Cumulative
Survival trial (COPERNICUS), the Metoprolol Randomized Intervention Trial in Congestive Heart
Failure (MERIT-HF), and the Carvedilol Or Metoprolol European Trial (COMET).
5. Data from the aforementioned trials consistently show a 34%–35% reduction in the primary end point
of all-cause mortality. All patients in these studies received background ACE inhibitor therapy.
6. β-Blockers inhibit the deleterious effects of the sympathetic nervous system (i.e., norepinephrine) on HF
progression, prevent/reverse cardiac remodeling, and reduce the risk of sudden cardiac death (SCD).
7. β-Blockers are generally well tolerated, but they should be newly initiated only in patients who are
currently clinically stable and euvolemic. Initiation at the lowest possible dose with uptitration at
2-week intervals (and potentially longer for older adults) is recommended to reduce the risk of short-
term worsening of HF symptoms.
8. Every effort should be made to up-titrate β-blocker doses to the concentration achieved in clinical
trials to promote reverse remodeling and improve LVEF. Studies consistently show that benefits of
therapy increase with higher doses.
9. During hospitalization for acute HF, every effort should be made to continue the β-blocker, and
a temporary dose reduction or discontinuation should be considered only for patients who have
recently initiated β-blocker therapy and who have marked volume overload or low cardiac output with
hemodynamic instability. The β-blocker should be reinitiated before hospital discharge.
10. In practice, metoprolol succinate is often used in patients who need HR control, such as those with
concomitant AF or post MI, whereas carvedilol is selected for patients needing additional vasodilating
effects, such as those with HTN.
Table 50. β-Blockers and Recommended Doses

Mean Dose Achieved in
Clinical Trials
Bisoprolol Zebeta 1.25 mg daily 10 mg daily 8.6 mg/day
Carvedilol Coreg 3.125 mg bid 25 mg bid a
37 mg/day
Carvedilol Coreg CR 10 mg daily 80 mg daily N/A
Metoprolol succinate Toprol XL 12.5–25 mg daily 200 mg daily 159 mg/day
a
A dose of 50 mg twice daily has been used in patients weighing more than 85 kg if lower doses have been tolerated.
bid = twice daily; CR = controlled release; N/A = not applicable; XL = extended release.
Reprinted with permission from: Lindenfeld J, Albert NM, Boe hmer JP, et al. HFSA 2010 comprehensive heart failure practice guideline. J
Card Fail 2010;16:e1-194.
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E. Mineralocorticoid Receptor Antagonists (Domain 1, Tasks 2, 3, 5, 6, 7; Domain 3, Tasks 2, 3)

1. Treatment with an MRA is recommended for patients with symptomatic HFrEF (NYHA class II− IV)
and LVEF of 35% or less. In NYHA class II, patients should also have a history of prior cardiovascular
hospitalization or elevated natriuretic peptide values.
2. Treatment with an MRA is recommended for patients post MI with an LVEF of 40% or less and either
HF symptoms or diabetes mellitus according to the results of the Eplerenone Post–Acute Myocardial
Infarction Heart Failure Efficacy and Survival Study (EPHESUS).
3. The 2013 ACCF (American College of Cardiology Foundation)/AHA guideline wording removed the
stipulation that patients must be treated with an optimized ACE inhibitor/ARB and β-blocker before
MRA initiation.
4. In the Randomized Aldactone Evaluation Study (RALES), spironolactone reduced the risk of all-cause
mortality by 30%, compared with standard therapy (RR 0.69; 95% CI, 0.58–0.82; p<0.001).
5. The Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms (EMPHASIS-HF)
study showed a reduced risk of death and hospitalization (hazard ratio 0.63; 95% CI, 0.54–0.74;
p<0.001) among patients with systolic HF and mild symptoms (NYHA class II). Patients underwent
randomization if they were 55 years or older, had NYHA class II symptoms, had EF of 30% or less,
and were receiving treatment with an ACE inhibitor or an ARB and a β-blocker (at maximally tolerated
doses). Eplerenone was initiated at 25 mg orally daily for the first 4 weeks and then titrated to 50 mg
orally daily thereafter, depending on the patient’s renal function.
6. In EPHESUS, eplerenone reduced all-cause mortality by 15% (RR 0.85; 95% CI, 0.75–0.96; p=0.008) and
CV death or CV hospitalization by 13% (RR 0.87; 95% CI, 0.72–0.94; p=0.005), compared with placebo.
7. Treatment with an MRA is not indicated in the following instances:
a. Patients with CrCl less than 30 mL/minute
b. SCr greater than 2.5 mg/dL in male individuals or greater than 2.0 mg/dL in female individuals
c. Serum potassium concentration greater than 5.0 mEq/L
d. Patients already receiving combination therapy with an ACE inhibitor plus an ARB (a combination
of an ACE inhibitor and an ARB already not preferred because of hyperkalemia risk)
Table 51. Other Evidence-Based Therapies and Recommended Doses

Mean Dose Achieved
in Clinical Trials
Aldosterone receptor antagonists
Spironolactone Aldactone 12.5–25 mg/day 25 mg/day 26 mg/day
Eplerenone Inspra 25 mg/day 50 mg/day 42.6 mg/day
Other vasodilators
Fixed-dose BiDil 37.5 mg 75 mg hydralazine/ 143 mg hydralazine/76 mg
hydralazine/ hydralazine/20 mg 40 mg isosorbide isosorbide dinitrate/day
isosorbide dinitrate isosorbide dinitrate tid dinitrate tid
Hydralazine Apresoline 37.5 mg tid 100 mg tid N/A
Isosorbide dinitrate Isordil 20 mg tid 40 mg tid N/A
Loop diuretics
Furosemide Lasix 20–40 mg/day or bid
Bumetanide Bumex 0.5–1.0 mg/day or bid
Torsemide Demadex 10–20 mg/day
bid = twice daily; N/A = not applicable; tid = three times daily.
Adapted from: Lindenfeld J, Albert NM, Boehmer JP, et al. HFSA 2010 comprehensive heart failure practice guideline. J Card Fail 2010;16:e1-
194.
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Cardiology I
8. Hyperkalemia is a significant complication of MRA therapy. In the RALES trial, the incidence
of hyperkalemia was only 2%, but it was 12% in EMPHASIS-HF. However, outside the rigorous
follow-up of a clinical trial, much higher rates of hyperkalemia have been reported (11 hyperkalemia-
associated hospitalizations per 100 patients treated).
9. The incidence of gynecomastia with spironolactone in the RALES trial was 10% and does not occur
with eplerenone.
10. Careful patient selection and close laboratory monitoring help minimize hyperkalemia-related
complications in these patients.
Table 52. Guidelines for Minimizing the Risk of Hyperkalemia in Patients Treated with MRAs
1. Serum potassium concentrations should be monitored at 3 days, 1 week, and monthly for at least
3 months after initiation of an MRA
2. Discontinue or reduce dose if serum potassium concentration ˃ 5.5 mEq/L
3. Initiate an MRA at a dose appropriate for the patient’s renal function, and increase it at
appropriate intervals
4. The risk of hyperkalemia is increased with the concomitant use of MRAs with higher doses of
ACEIs (captopril ≥ 75 mg/daily; enalapril or lisinopril ≥ 10 mg/daily)
5. Potassium supplements should be discontinued or reduced
6. Diarrhea or other causes of dehydration should be addressed emergently
ACEI = angiotensin-converting enzyme inhibitor; MRA = mineralocorticoid receptor antagonist.
Table 53. Dosing and Titration of MRAs

Estimated CrCl 30–49 mL/minute ≥50 mL/minute
MRA Eplerenone Spironolactone Eplerenone Spironolactone
Initial dose 25 mg every 12.5 mg daily or 25 mg daily 12.5–25.0 mg daily
(only if K+ ≤ 5.0 mEq/L) other day every other day
Maintenance dose 25 mg once daily 12.5–25.0 mg daily 50 mg daily 25 mg daily or bid
(after 4 wk for serum K+
≤ 5.0 mEq/L)a
After dose initiation, if potassium concentration increases to ≤6.0 mEq/L or worsening renal function, hold until potassium concentration < 5.0
a
mEq/L. Consider reinitiating reduced dose after confirming the resolution of hyperkalemia/renal insufficiency for at least 72 hours.
bid = twice daily; CrCl = creatinine clearance; K+ = potassium; MRA = mineralocorticoid receptor antagonist; wk = weeks.
Adapted from: Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American
College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147-239.
11. Both eplerenone and spironolactone are MRAs, but eplerenone is a selective MRA that has a lower
incidence of endocrine-related adverse effects (i.e., gynecomastia) because of its reduced affinity for
glucocorticoid, androgen, and progesterone receptors.
F. Hydralazine and Isosorbide Dinitrate (Domain 1, Tasks 2, 3, 5, 6, 7; Domain 3, Tasks 2, 3)

1. The combination of hydralazine and nitrate is recommended for African American patients with NYHA
class III and IV HFrEF added to ACE inhibitor and β-blocker (and MRA) therapy unless contraindicated.
2. The combination of hydralazine and nitrate is recommended for symptomatic patients with HFrEF who
are intolerant of ACE inhibitors or ARBs because of renal insufficiency, hyperkalemia, or, in some cases,
angioedema, regardless of race.
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3. The African American Heart Failure Trial (A-HeFT) showed a 43% reduction in all-cause mortality
(hazard ratio 0.57; p=0.01) for patients randomly assigned to receive hydralazine plus isosorbide
dinitrate compared with placebo.
4. The 2013 ACCF/AHA HF guidelines removed the specification that the product be a “fixed-dose”
combination. It is jJust stated that hydralazine and nitrates may be given in two pills three times daily.
G. Diuretics (Domain 1, Tasks 2, 3, 5, 6, 7; Domain 3, Tasks 2, 3)

1. In general, loop diuretics are preferred for patients with HF and symptoms related to hypervolemia
owing to their potency.
2. The lowest dose needed to achieve euvolemia should be prescribed.
a. Some patients with HF can be educated to “self-manage” diuretic dosing, using a dosing
approach dictated by the patient’s weight.
b. This approach requires careful patient education and access to a health care provider, should
problems or questions arise.
3. Not all patients with HF will require loop diuretic therapy, particularly in the early stages of HFrEF
when symptoms may be adequately managed with other evidence-based therapies; loop diuretics
provide only symptomatic relief, and they do not demonstrably affect mortality. Some retrospective
analyses have linked diuretics, particularly high doses, with harm.
4. Patients with HFpEF may be especially sensitive to the BP-lowering effects of diuretics.
5. Special attention should be paid to pharmacodynamic drug interactions. Diuretics may increase
the hypotensive response to ACE inhibitors. If hypotension or increases in SCr occur, it may be
reasonable to decrease the diuretic first (depending on whether the patient shows signs or symptoms
of congestion). This action may allow the ACE inhibitor to be maintained and/or the dose titrated.
6. Diuretic resistance is a clinical scenario whereby some patients have an inadequate response
to conventionally dosed loop diuretic regimens. In such cases, the following options should be
considered. (1) Emphasize sodium and fluid restriction. (2) Increase the loop diuretic dose. (3) If the
patient is taking furosemide, change to bumetanide or torsemide for improved oral absorption. (4)
Switch from oral dosing to parenteral dosing. (5) Consider adding a second diuretic agent (e.g., distal
tubular diuretics metolazone or chlorthalidone) given 30 minutes before loop diuretic administration
to augment diuretic effects. Use of ultrafiltration (discussed in further detail in the Ultrafiltration
section) may be an alternative strategy.
7. Routine laboratory studies (e.g., blood urea nitrogen, SCr, potassium) should be performed to monitor
patients for the development of renal impairment or electrolyte abnormalities. In addition, orthostasis
(sitting, standing BP, and HR) should be checked routinely to assess for volume depletion.
H. Digoxin (Domain 1, Tasks 2, 3, 5, 6, 7; Domain 3, Tasks 2, 3)

1. Digoxin continues to be used in patients with symptomatic HF after standard therapy. The optimal
therapeutic range is 0.5–0.9 ng/mL according to a post hoc analysis of the Digitalis Investigative
Group (DIG) trial (although the 2013 ACCF/AHA guidelines state 0.4–0.9 ng/mL).
2. In the DIG trial, digoxin was associated with a lower risk of HF hospitalization, compared with
placebo. Of note, the DIG trial was conducted before β-blockers were adopted as evidence-based
therapy; thus, the impact of adding digoxin to regimens including an ACE inhibitor and a β-blocker is
unknown. Digoxin had no mortality benefit in this trial.
a. Digoxin may be particularly useful in the subset of patients with AF and HFrEF.
b. There are no apparent differences in the effectiveness of digoxin in men and women, and there is
no evidence that women are at increased risk of mortality from digoxin.
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c. Signs and symptoms of digoxin toxicity include the following:

i. Arrhythmias, including ventricular ectopy, atrioventricular (AV) conduction block of
any degree (although rarely Mobitz type II), paroxysmal atrial tachycardia with block,
accelerated junctional rhythm, and bidirectional VT (rare)
ii. GI disturbances (usually observed first)
iii. Central nervous system disturbances
iv. Visual changes
d. Significant drug interactions with digoxin include the following (not all-inclusive):
i. Amiodarone
ii. Dronedarone
iii. Verapamil
iv. Erythromycin
v. Clarithromycin
vi. Telaprevir
vii. Quinidine
viii. Saquinavir
I. Ivabradine (Domain 1, Tasks 2, 3, 5, 6, 7; Domain 3, Tasks 2, 3)

1. Mechanism of action: Bblockade of hyperpolarization-activated cyclic nucleotide–-gated channel,
resulting in reduction of the spontaneous pacemaker activity of the cardiac sinus node by selectively
inhibiting the If current (If)
2. In the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) study, ivabradine
was found to reduce the primary composite end point of cardiovascular death or hospitalization for
HF heart failure by 18%, compared to placebo, in patients with symptomatic HFrEF. The results were
mainly driven by a reduction in heart failure hospitalizations for HF.
3. Ivabradine was approved in April 2015 to reduce the risk of hospitalization for worsening HF in
patients with stable, symptomatic chronic HF with an whose and LVEF of ≤ is 35% or less and whose
heart rate of ≥ is 70 beats/minute or above.
a. Patients should be receiving either on maximally tolerated doses of β-blockers or have a
contraindication to βbeta-blocker use.
b. Avoid use in patients with atrial fibrillation, in those who have third-3rd degree heart block, BP
below< 90/50mmHg, acute 90/50 mm Hg, acute HFheart failure, severe hepatic impairment,
pacemaker dependencyt, resting heart rate below< 60 beats/minute, or in combination with strong
cytochrome CYP3A4 inhibitors (diltiazem, verapamil, and grapefruit juice), or CYP3A4 inducers
(St. John’s wort, rifampicin, barbiturates, and phenytoin).
4. Adverse eEffects:
a. Bradycardia
b. Hypertension
c. Atrial fFibrillation
d. Phosphenes: Ttransiently enhanced brightness in a limited area of the visual field, halos, image
decomposition (stroboscopic or kaleidoscopic effects), colored bright lights, or several multiple
images (retinal persistency).
5. Dose: 5 mg twice daily, increase to 7.5 mg twice daily after 2 weeks.
a. In patients with conduction defects or in whom bradycardia could lead to hemodynamic
compromise, initiate dosing at 2.5 mg twice daily.
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Patient Cases
Questions 9 and 10 pertain to the following case.
R.R., a 68-year-old African American woman with HF, presents to your clinic. Comorbidities include HTN
and type 2 diabetes mellitus. During the past year, she has had two hospitalizations for decompensated HF
and significant volume overload with each hospitalization. Her current symptoms are shortness of breath with
minimal exertion and 2+ peripheral edema bilaterally. Other pertinent findings include BP 120/72 mm Hg,
HR 58 beats/minute, SCr 1.60 mg/dL (estimated CrCl 36 mL/minute), BUN 25 mg/dL, potassium 5.1 mEq/L,
sodium 140 mEq/L, hemoglobin A1C 7.1%, digoxin 0.5 ng/mL, and LVEF 28%. Current medications include
enalapril 10 mg twice daily, metoprolol XL (extended release) 150 mg once daily, metformin 500 mg twice daily,
digoxin 0.125 mg daily, and furosemide 40 mg twice daily.
9. Which of the following best describes R.R.’s current HF type, stage, and classification?
A. HFpEF, stage B, NYHA class II.
B. HFpEF, stage C, NYHA class III.
C. HFrEF, stage B, NYHA class II.
D. HFrEF, stage C, NYHA class III.
10. Which is the best recommendation for R.R.?

A. Increase the digoxin dose to 0.25 mg daily.
B. Add spironolactone 25 mg orally daily.
C. Add hydralazine 50 mg orally three times daily and isosorbide dinitrate 20 mg orally three times
daily.
D. Add eplerenone 50 mg orally daily.
11. P.N. is a 60-year-old, 78-kg, white man with ischemic cardiomyopathy and LVEF 25%. He was recently
hospitalized with acute MI and acute HF. He underwent percutaneous coronary intervention with bare metal
stent placement to his right coronary artery. He is currently treated with enalapril 10 mg orally twice daily,
carvedilol 25 mg twice daily, furosemide 40 mg/day, aspirin 81 mg/day, clopidogrel 75 mg/day, and atorv-
astatin 80 mg/day. He has stable NYHA class II HF symptoms. Other pertinent clinical findings include BP
114/70 mm Hg, HR 67 beats/minute, 1+ edema bilaterally, SCr 1.0 mg/dL, and potassium 4.0 mEq/L. Other
laboratory values are within normal limits. Which is the best recommendation for this patient currently?
A. Add valsartan 80 mg orally daily.
B. Add spironolactone 25 orally daily.
C. Add hydralazine 50 mg orally three times daily and isosorbide dinitrate 20 mg orally three times daily.
D. Increase enalapril dose to 20 mg orally twice daily.
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Cardiology I
IX. STANDARD PHARMACOLOGIC MANAGEMENT STRATEGIES FOR HEART FAILURE WITH

PRESERVED EJECTION FRACTION
A. Pathophysiology (Domain 1, Task 1)

1. Characterized by LV hypertrophy, concentric remodeling, increased extracellular matrix, abnormal
relaxation and filling, and decreased diastolic distensibility
2. Activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system is common.
B. Diagnostic Criteria (Domain 1, Tasks 2, 3)

1. Clinical signs and symptoms of HF
2. Evidence of preserved or normal LVEF
3. Evidence of LV diastolic dysfunction on echocardiography or LV angiography
4. Excludes other noncardiac causes of HF
C. Treatment (Domain 1, Tasks 2, 3, 5, 6, 7; Domain 3, Tasks 2, 3)

1. No therapy was shown to decrease morbidity and mortality in this population in an adequately
powered randomized controlled clinical trial.
2. In patients with HTN, BP should be monitored and optimally controlled.
3. Patients with HTN should be counseled to follow a low-sodium diet.
4. Diuretics are recommended for patients with volume overload.
5. ACE inhibitors or ARBs may be used for patients with HFpEF; however, there is no evidence that
these agents reduce morbidity or mortality.
a. The ARB irbesartan was studied in the Irbesartan in Heart Failure with Preserved Ejection
Fraction (I-PRESERVE) study, but irbesartan failed to show a clinical effect in this population.
In the irbesartan group, 36% died or experienced a CV hospitalization, compared with 37% in
the placebo group (hazard ratio 0.95; 95% CI, 0.86–1.05; p=0.35). No between-group differences
were detected in any of the secondary end points.
b. In the CHARM-Preserved study, there was no difference in the composite end point of CV death
or HF hospitalization for patients randomly assigned to receive candesartan versus placebo.
Fewer patients randomly assigned to receive candesartan were hospitalized for HF (p=0.017).
6. β-Blocker therapy is recommended in guidelines for patients with HFpEF, particularly if they are post
MI, or have AF requiring rate control.
7. TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone AnTagonist):
Spironolactone (15, 30, and 45 mg daily) versus placebo in patients with symptomatic HF, LVEF of
45% or greater, and either prior hospitalization for HF or elevated BNP or NT-proBNP concentration.
Excluded patients with a CrCl less than 30 mL/minute, serum potassium concentration greater than
5 mEq/L, AF and HR greater than 90 beats/minute, recent acute coronary syndrome, or uncontrolled
HTN. There was no significant difference in the 3-year primary composite outcome of CV
mortality, aborted cardiac arrest, or hospitalization for HF. High rate of study drug discontinuation
(spironolactone 34.3% and placebo 31.4%). Spironolactone (mean dose at 8 months of 25 mg/day)
reduced the secondary end point of hospitalization for HF by 15% (12.0% vs. 14.2%, p=0.042;
2.8/100 patient-years vs. 4.6/100 patient-years). Rates of hyperkalemia, defined as serum potassium
concentration of 5.5 mEq/L or greater, were higher with spironolactone than placebo (18.7% vs. 9.1%,
p<0.001). Post -hoc analyses revealed substantial regional differences in response to spironolactone,
such that participants from the Americas (USA, Canada, South America) had higher event rates
and observed benefits with spironolactone versus placebo, compared to patients in Russia and the
Republic of Georgia. Therefore, clinicians may find it reasonable to use spironolactone in the setting
of HFpEF as long as appropriate monitoring is in place for hyperkalemia.
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Patient Cases
J.J. is a 62-year-old, 88-kg white man with a history of HTN and intolerance of ACE inhibitors secondary to
cough. He was recently discharged from an HF-related hospitalization and presents to the clinic for follow-up
1 week after hospital discharge. Before hospitalization, his medication regimen included valsartan 80 mg twice
daily, metoprolol XL 100 mg/day, and furosemide 40 mg twice daily. The patient’s condition is now stable, with
no symptoms at rest and some shortness of breath when walking around his home. Other pertinent diagnostic
and laboratory findings include BUN 30 mg/dL, SCr 1.4 mg/dL, potassium 4 mEq/L, LVEF 65%, BP 154/70 mm
Hg, and HR 77 beats/minute.
12. Which of the following best describes J.J.’s HF type and classification?
A. HFpEF, NYHA class III.
B. HFpEF, NYHA class IV.
C. HFrEF, NYHA class III.
D. HFrEF, NYHA class IV.
13. Given J.J.’s persistent symptoms, which is the best recommendation for him?
A. Increase the furosemide dose to 80 mg orally twice daily.
B. Increase metoprolol succinate to 150 mg orally daily.
C. Add eplerenone 25 mg orally daily.
D. Add hydralazine 50 mg orally three times daily plus isosorbide dinitrate 20 mg orally three times daily.
X. STANDARD DEVICE MANAGEMENT STRATEGIES
A. Implantable Cardioverter Defibrillator (ICD) (Domain 3, Tasks 2, 3)

1. SCD accounts for about half of all HF-related deaths, particularly in patients with less
severe symptoms.
2. ICD therapy is indicated for primary prevention of SCD and to reduce mortality for patients with
LVEF of 35% or less, receiving GDMT, and with NYHA class II or III symptoms who have either
nonischemic dilated cardiomyopathy or ischemic heart disease and who are at least 40 days post MI.
3. In the SCD-HeFT trial, an ICD reduced all-cause mortality by 23% (hazard ratio 0.77; 97.5% CI,
0.62–0.96; p=0.007).
4. In the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II), an ICD reduced the
risk of all-cause mortality by 31% (hazard ratio 0.69; 95% CI, 0.51–0.93; p=0.016) compared with
conventional therapy among patients with a prior MI and LVEF 30% or less.
5. Antiarrhythmic therapies may be used as adjunctive therapies for the management of arrhythmia-prone
patients under special circumstances. Amiodarone, dofetilide, and sotalol reduce the frequency of ICD shock
therapy, thus increasing ICD generator battery life and reducing patient morbidity (namely posttraumatic
stress disorder). Amiodarone is the preferred agent for patients with significant renal impairment.
B. Cardiac Resynchronization Therapy (CRT) (Domain 3, Tasks 2, 3)

1. It is estimated that cardiac dyssynchrony affects 15%–30% of patients with HF, resulting in decreased
systolic function and increased systolic volumes.
2. By applying biventricular stimulation, CRT aims to restore appropriate activation of the
intraventricular septum and LV free wall.
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3. CRT therapy is indicated for patients with LVEF of 35% or less and NYHA class II, III, or ambulatory
class IV symptoms who are receiving GDMT and who fulfill the following criteria:
a. Have sinus rhythm or left bundle branch block (LBBB) with a QRS of 150 milliseconds or greater
on 12-lead ECG or
b. Have non-LBBB pattern with a QRS of 150 milliseconds or greater on 12-lead ECG or
c. Have LBBB with a QRS of 120–149 milliseconds on 12-lead ECG
d. Are undergoing new or replacement device implantation with anticipated ventricular pacing
(greater than 40%)
4. Initial studies observed improvements in NYHA functional class, quality of life, 6-minute walk
distance, exercise test duration, and EF for patients randomly assigned to CRT.
5. In the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION)
trial, CRT was associated with a 19% reduction (hazard ratio 0.81; 95% CI, 0.69–0.96; p=0.014) in
the primary end point of all-cause death or all-cause hospitalization among patients with NYHA
class III–IV HF, LVEF of 35% or less, and QRS of 120 milliseconds or more. The effect of CRT on
all-cause mortality alone did not reach statistical significance (hazard ratio 0.76; 95% CI, 0.58–1.01;
p=0.059). Patients randomly assigned to CRT plus an ICD showed a 20% reduction (hazard ratio 0.8;
95% CI, 0.68–0.95; p=0.01) in all-cause death or hospitalization and a 36% reduction (hazard ratio
0.64; 95% CI, 0.48–0.86; p=0.003) in all-cause mortality.
6. The Cardiac Resynchronization Heart Failure (CARE-HF) study evaluated CRT alone (without an
ICD) in 813 patients with NYHA class III–IV symptoms, LVEF of 35% or less, LV end-diastolic
dimension of at least 30 mm, and QRS duration of 120 milliseconds or more. CRT reduced the
primary end point of all-cause mortality or CV hospitalization by 37% (hazard ratio 0.63; 95% CI,
0.51–0.77; p<0.001). CRT was also associated with a 36% reduction in all-cause mortality (hazard
ratio 0.64; 95% CI, 0.48–0.85; p<0.002).
7. Echocardiographic measurements also improved for the CRT group compared with placebo, including
higher EF, lower end-systolic volume index, smaller area of mitral regurgitation, and shorter
interventricular mechanical delay, suggesting CRT exerted favorable effects on remodeling.
8. The 2012 device guideline update from ACCF/AHA/HRS increased the QRS requirement from
120 milliseconds, which was used in the trials described above, to 150 milliseconds according to
additional data from subgroup analyses and meta-analyses from the (five) trials reporting that patients
who benefited were those with a QRS of 150 milliseconds or greater and that a QRS of less than 150
milliseconds was a predictor of failure to respond to CRT.
C. LV Assist Device (LVAD) (Domain 3, Tasks 2, 3)

1. The application of LVADs is largely limited to use as a bridge to transplantation and to treating
patients with acute, severe myocarditis; however, some centers use LVADS as destination therapy.
Such use is typically reserved for selected patients with refractory end-stage HF and estimated 1-year
mortality greater than 50% with medical therapy.
2. 2011 data from the International Society for Heart & Lung Transplantation (ISHLT) mechanical
circulatory support device database show that 75% of patients survive for at least 1 year when devices
are implanted as a bridge to transplantation.
3. LVAD devices may also be used as permanent or destination therapy in selected patients with
refractory HF and an estimated 1-year mortality exceeding 50%.
4. Guidelines: The 2013 ISHLT data describe candidate selection.
a. Evaluate a candidate’s suitability for transplantation because current outcomes with transplants
are superior to those with LV assist devices.
b. An LVAD candidate has ventricular function that has been deemed unlikely to recover without
support or who cannot be weaned from inotropes.
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c. An LVAD candidate should have the capacity for meaningful recovery of end-organ function and
quality of life.
d. An LVAD candidate should have no irreversible end-organ damage.
5. The 2013 ISHLT guidelines recommend antithrombotic therapy for mechanical circulatory support
devices consisting of the following: Warfarin at a goal INR of 2–3 and aspirin 81–325 mg/day for
the HeartMate II device and the HeartWare HVAD; warfarin at a goal INR of 2.5–3.5 and aspirin
81–325 mg/day for the pulsatile mechanical circulatory support devices (e.g., the Thoratec PVAD
[paracorporeal ventricular assist device]/IVAD [implantable ventricular assist device]), and warfarin
at a goal INR of 2.5–2.5 and aspirin 81–325 mg/day and dipyridamole 75 mg three times daily for the
CardioWest temporary total artificial heart.
6. Recent data indicate that the HeartMate II device (Thoratec Corp.) thrombosis rates started to
increase in March 2011 and that they have continued to do so.
D. Ultrafiltration (Domain 3, Tasks 2, 3)

1. Ultrafiltration carries a class IIb recommendation for patients with volume overload and congestion
symptoms (level of evidence B) and for patients unresponsive to GDMT.
2. The Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalised for Acute Decompensated
Heart Failure (UNLOAD) study (n=200) showed a greater degree of weight loss at 48 hours among
patients randomly assigned to ultrafiltration compared with those treated with standard-care
intravenous diuretics. At 90 days, patients receiving ultrafiltration had fewer HF hospitalizations,
rehospitalization days, and unscheduled visits than did patients receiving intravenous diuretics alone.
No adverse safety signals were detected.
3. Typically, ultrafiltration is used in hospitalized patients whose condition is unresponsive to
high-dose diuretics.
E. Disease Management and the Role of the Pharmacist (Domain 1, Tasks 5, 6; Domain 2, Tasks 2, 3, 4;
Domain 4, Tasks 1, 4, 6, 7)
1. Pharmacists play a key role in HF management (Pharmacotherapy 2013;33:529-48; J Card Fail
2013;19:354-69).
2. Pharmacist involvement in care has been associated with a decreased HF readmission, all-cause
readmission, and emergency department visits.
3. Ensure use of GDMT.
4. Ensure use of target doses of evidence-based therapy.
5. Avoid/minimize drug-drug and drug-disease interactions.
6. Prevention of adverse reactions and medication errors
7. Medication reconciliation: Assist with patient follow-up, identify signs of worsening HF so
that appropriate therapeutic interventions can be implemented, and prevent the need for
hospitalization/rehospitalization.
8. Resources for health care providers to assist in preventing hospital readmissions for HF: Hospital
to Home (H2H) sponsored by the ACC and Institute for Healthcare Improvement (www.h2hquality.
org/): Patient appointment within 7 days of hospital discharge (See You in 7)
9. Provide patient education/adherence reinforcement (Pharmacotherapy 2013;33:558-80).
10. Dietary counseling
a. Fluid restriction
b. Sodium restriction (1500 mg/day or less)
c. Potassium-containing foods/salt substitutes for patients receiving MRAs
11. Disease education
12. End-of-life discussions when appropriate
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13. Ensure medication access: Assist patients in identifying patient assistance programs.
a. Several Web sites: www.rxassist.org, www.pparx.org, www.patientassistance.com
b Many local communities have programs/resources.
c. Suggest contacting individual companies as well – Some have programs that are not advertised –
Policies/procedures/requirements change often.
F. Quality of Care
1. Several studies have shown that a treatment gap exists between HF guideline–-recommended therapies
and the actual treatments received by patients with HF in both the inpatient and outpatient settings.
a. OPTIMIZE (inpatient)
b. IMPROVE (outpatient)
c. AHA Get With The Guidelines-Heart Failure
2. Performance improvement interventions are quite successful at improving the use of evidence-based
therapies both in the inpatient and outpatient settings: Improvements in use of β-blockers, MRAs,
CRT, ICDs, and delivery of HF education
3. Interventions include the following:
a. Clinical decision support tools (e.g., algorithms, pathways)
b. Structured improvement strategies
c. Chart audits with feedback
G. Resources for Patients with HF (Domain 5, Task 2)

1. American Heart Association: www.heart.org/HEARTORG/Conditions/HeartFailure/Heart-Failure_
UCM_002019_SubHomePage.jsp
2. Get With The Guidelines-Heart Failure (sponsored by AHA): www.heart.org/
HEARTORG/HealthcareResearch/GetWithTheGuidelinesHFStrokeResus/
GetWithTheGuidelinesHeartFailureHomePage/Get-With-The-Guidelines-Heart-Failure-Clinical-
Tools-Library_UCM_305817_Article.jsp
3. Heart Failure Society of America: www.hfsa.org/heart_failure_education_modules.asp
4. National Heart Lung and Blood Institute: www.nhlbi.nih.gov/health/dci/Diseases/Hf/HF_WhatIs.html
ARRHYTHMIAS
XI. ATRIAL FIBRILLATION AND ATRIAL FLUTTER
A. Atrial Fibrillation (Domain 1, Tasks 1, 2, 5, 6, 7; Domain 3, Tasks 2, 3)

1. Classification
a. Paroxysmal AF: Spontaneously self-terminates in fewer than 7 days; recurrent if two
or more episodes
b. Persistent AF
i. Continues for greater than 7 days
ii. Does not self-terminate, requires chemical or electrical cardioversion
c. Permanent AF: Does not convert with chemical or electrical cardioversion
d. Lone AF
i. Established or paroxysmal AF
ii. Patient is younger than 60 years and without heart disease.
e. Postoperative AF
i. AF that occurs 3–5 days after surgery
ii. Usually self-terminating
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Cardiology I
2. Epidemiology
a. The most common arrhythmia found in clinical practice
b. Accounts for about one-third of hospitalizations from arrhythmias
c. Affects 1.5%–2% of the general population
d. Average age is 75–85 years.
e. Sixty percent of those 75 years and older are women.
f. The 3-year incidence in patients with HF is 10%.
g. Mortality rate is double that of patients in NSR and is linked to the severity of the underlying
heart disease.
h. Presentation: 400–600 atrial beats/minute with varying ventricular response (irregularly
irregular rhythm)
i. Symptoms
i. Dizziness
ii. Shortness of breath or exacerbation of HF
iii. Fatigue
iv. Palpitations
v. Syncope
3. Pathophysiologic mechanisms
a. Enhanced automaticity in several rapidly depolarizing foci or reentry involving several circuits
b. Foci usually originate in the pulmonary veins.
c. Foci can also occur in the right atrium.
d. Foci infrequently occur in the superior vena cava or coronary sinus.
e. Longer episodes (greater than 24 hours) are more difficult to terminate because AF causes
mechanical and electrical remodeling of the atrial tissue.
f. Causes
i. Organic heart disease that activates the renin-angiotensin-aldosterone system through atrial stretch
(a) Ischemia/infarction
(b) Hypertensive heart disease
(c) Valvular disorders
(d) Dilated or hypertrophic cardiomyopathy
(e) In addition, there are disease states that cause right atrial stretch.
(1) Pulmonary embolism
(2) Pulmonary hypertension
ii. Associated with a high degree of adrenergic tone
(a) Surgery/anesthesia induction
(b) Thyrotoxicosis
(c) Alcohol withdrawal
(d) Sepsis
(e) Excessive physical exertion
iii. Perpetuated by high cholinergic tone
(a) After meals
(b) During sleep
iv. Idiopathic
4. Complications
a. Thromboembolic risk
i. Thrombi located in the left atrium; usually found in the left atrial appendage because of
blood stasis, endothelial dysfunction, and systemic hypercoagulability
ii. There is a 5-fold increase in risk of stroke in patients with NVAF compared with patients
without AF.
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iii. Risk increases with advanced age.

(a) 1.5% annual risk among 50- to 59-year-old individuals
(b) 23.5% annual risk among 80- to 89-year-old individuals
(c) Lone AF is at a lower risk of stroke.
b. Heart failure (3-fold incidence)
i. Tachycardia-induced cardiomyopathy
ii. Impaired diastolic filling
iii. Loss of atrial kick
c. Rapid ventricular response
i. AF conducted over an accessory pathway, potentially leading to lethal ventricular fibrillation
ii. Can exacerbate ischemia, HF, or tachycardia-induced cardiomyopathy
5. Treatment: Rate versus rhythm control strategy
a. Rate control
i. Indications
(a) No symptoms to minimal symptoms
(b) Treatment of choice for persistent or permanent AF
ii. Goal is an HR less than 110 beats/minute with persistent AF in the following instances:
(a) Stable LV function (LVEF greater than 40%)
(b) Asymptomatic or acceptable symptoms
(c) Of note: Might be associated with reversible decline in ventricular performance over
time (called tachycardia-associated cardiomyopathy)
iii. Treatment options
Table 54. Nonacute Setting and Chronic Maintenance Rate Control Therapy of AF
Loading Dose Maintenance
Drug Onset Major Adverse Effects
(Oral) Dose (Oral)
Rate Control
25–100 mg Hypotension, bradycardia, heart failure
Metoprolol Same as maintenance 4–6 hours
twice daily and asthma exacerbation, heart block
Propranolol (for Hypotension, bradycardia, heart failure
60–90 80–240 mg in
thyrotoxicosis- Same as maintenance and asthma exacerbation, heart block
minutes divided doses
associated AF)
120–360 mg/day Hypotension, heart failure
in divided doses; exacerbation, heart block
Diltiazem Same as maintenance 2–4 hours
slow release
available
120–360 mg/day Hypotension, heart failure
in divided doses; exacerbation, heart block, digoxin
Verapamil Same as maintenance 1–2 hours
slow release interaction
available
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Table 54. Nonacute Setting and Chronic Maintenance Rate Control Therapy of AF (continued)
Loading Dose Maintenance
Drug Onset Major Adverse Effects
(Oral) Dose (Oral)
Rate control in patients with heart failure and without accessory pathway
Digoxin toxicity; GI, neurologic and
0.125–0.375 mg/ electrophysiologic changes
Digoxin 0.5 mg/day 2 days
day Goal concentrations for AF are higher
(typically, 1–2 ng/mL) than for HFrEF
800 mg/day for 1 week See Table 574
Amiodarone 600 mg for 1 week 1–3 weeks 200 mg/day
400 mg for 4–6 weeks
AF = atrial fibrillation; GI = gastrointestinal; HFrEF = heart failure with reduced ejection fraction.
Originally published in: Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with
atrial fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice
Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for
the Management of Patients With Atrial Fibrillation). Circulation 2006;114:700-52. Published online before print August 2, 2006.
(a) β-Blockers (above is not a complete list of options)

(1) Added mortality benefit in post-MI and LV systolic dysfunction
(2) Younger patients may not tolerate because they are unable to quickly increase HR
during exercise.
(b) Nondihydropyridine calcium channel blockers: Avoid in LV dysfunction.
(c) Digoxin
(1) Not usually used as monotherapy
(2) Controls rate only at rest with increased vagal tone
(3) Consider in patients with HF.
(d) Amiodarone:
(1) Can be used as rate control when not responding to AV node blockers. Decreases
number of AF episodes; therefore, more tolerable to the patient
(2) Note: Can cause conversion to normal sinus rhythm, so need to ensure no clot is
present before use or patient has to receive anticoagulation therapy
(e) AV nodal ablation with pacemaker pacing
(f) Suggested reference: RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) study
(1) Noninferiority trial of lenient rate control (resting HR less than 110 beats/minute)
versus strict rate control (resting HR less than 80 beats/minute with moderate
exercise) in patients with permanent AF
(2) No statistically significant difference for CV death or hospitalization for HF, stroke,
systemic embolism, bleeding, and life-threatening arrhythmic events
(3) Lenient rate control is more convenient; fewer outpatient visits and examinations
are needed.
(4) Of note, only 67% of patients obtained strict rate control, and the mean resting HR
at the end was 93 ± 9 beats/minute in the lenient control group.
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Cardiology I
b. Rhythm control
i. Prevention of AF may stop the progression to persistent or permanent AF.
ii. Indication
(a) Symptomatic patients despite adequate rate control
(b) Hemodynamically unstable condition
(c) Patients with HF
(d) AF secondary to a trigger or substrate (e.g., ischemia, hyperthyroidism) that has been corrected
(e) Not an option for permanent AF
iii. Pharmacologic cardioversion
(a) Class Ic
(1) Flecainide
(2) Propafenone
(3) Note: Avoid in patients with structural heart disease.
(b) Class III
(1) Sotalol—Not efficacious for conversion to sinus rhythm, but beneficial in prevention
of recurrence
(2) Amiodarone—More effective than other agents; 61%–86% success rate
(3) Dofetilide
(4) Dronedarone – Although included in the guidelines, adverse effects and black box
warnings have all but eliminated this agent as a therapeutic option: Increased risk
of HF and death in patients with recent symptomatic HF), liver toxicity, interstitial
lung pneumonitis, pulmonary fibrosis
(c) “Pill-in-the-pocket” cardioversion for hemodynamically stable, recurrent symptomatic
paroxysmal AF
(1) Single oral loading dose of propafenone or flecainide may terminate AF in
ambulatory outpatients already taking a β-blocker, diltiazem, or verapamil (to
prevent rapid AV conduction if atrial flutter occurs).
(2) Prior safety of the agent should have been shown for the patient in-hospital.
(3) Patients may not have sinus or AV node dysfunction, bundle-branch block, QT-
interval prolongation, Brugada syndrome, or structural heart disease.
iv. Maintenance of sinus rhythm: When comparing rate control with rhythm control, there was
no difference in mortality, stroke, or quality of life (NEJM 2002;347:1825-33), and study
confirmed that chronic anticoagulation therapy is needed in either rate or rhythm control.
Moreover, rhythm control had a statistically significant increase in hospitalizations and
adverse drug effects.
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Figure 1. Rhythm control for recurrent paroxysmal or persistent atrial fibrillation.

Drugs listed in alphabetic order, not in order of suggested use.
LVH = left ventricular hypertrophy.
Originally published in: Wann LS, Curtis AB, January CT, et al.; writing on behalf of the 2006 ACC/AHA/ESC Guidelines for the Management
of Patients With Atrial Fibrillation Writing Committee. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial
fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation./American Heart Association Task Force
on Practice Guidelines. Circulation 2011;123:104-23.
(2) ANDROMEDA
(A) Dronedarone versus placebo in patients hospitalized with severe HF (NYHA
class III or IV) and severe LV systolic dysfunction (LVEF around 35% or less)
(B) Patients given dronedarone had a 2-fold increase in mortality related to
worsening of HF.
(3) ATHENA
(A) Dronedarone decreased the incidence of hospitalization caused by CV events.
(B) Dronedarone reduced the incidence of death in patients with AF.
(4) DIONYSOS
(A) Patients taking dronedarone for the prevention of recurrent AF were half as
likely to remain in sinus rhythm as patients taking amiodarone.
(B) However, these patients were less likely to discontinue antiarrhythmic therapy
because of adverse effects.
(5) PALLAS
(A) Evaluated the use of dronedarone compared to placebo in patients with
permanent AF and at least one other ASCVD risk factor
(B) Study was discontinued early because of the significant excess of CV events in
the dronedarone group compared to placebo.
c. Direct current cardioversion (DCC)
i. Indication
(a) When rapid ventricular response does not respond to pharmacologic measures
(b) When patient is hemodynamically unstable
(c) When patient finds symptoms unacceptable
(d) Contraindicated with digitalis toxicity and hypokalemia
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Cardiology I
ii. DCC alone

iii. DCC with pharmacologic enhancement; pretreatment with amiodarone, flecainide,
propafenone, sotalol, or dronedarone and continue. Useful to prevent recurrence of AF
d. Ablation for AF or surgical Cox maze III (“maze”) procedure
i. Two types of ablation: Ablation of focal triggers in and around pulmonary veins (called
pulmonary vein isolation) and ablation at the site of origin of trigger (preferred, because the
patient is left in NSR) versus ablation of the AV node with implant of pacemaker (controls only
the HR and the patient remains in AF)
ii. Maze procedure is done only if patient has AF and is undergoing cardiothoracic surgery for
another reason such as coronary artery bypass grafting surgery or valve repair/replacement.
iii. Ablation is currently first-line therapy or an alternative to antiarrhythmic therapy to prevent
recurrent AF.
iv. Good option for patients who are symptomatic with little or no left atrial enlargement
v. Ablation is indicated for the following:
(a) Symptomatic paroxysmal (class I recommendation) or persistent AF (class IIa
recommendation) intolerant of at least one antiarrhythmic drug or
(b) Symptomatic paroxysmal AF (class IIa recommendation) before the initiation of
antiarrhythmic drugs (first line)
vi. Risk of AF recurrence is highest 6–12 months post ablation.
vii. Patients are at risk of TE (stroke or PE) during and for at least 6 weeks after ablation because
of damaged left atrial endothelium and placement of transseptal sheaths and electrode
catheters during the procedure, as well as left atrial stunning.
viii. Suggested reference
Heart Rhythm 2012;9:632-96: A report of the Heart Rhythm Society (HRS) Task Force on
Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European
Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology
(ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the ACC,
AHA, the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons
(STS). Endorsed by the governing bodies of the ACCF, the AHA, the ECAS, the EHRA, the STS,
the APHRS, and the HRS
e. Preventing thromboembolism in AF
i. See Thromboembolism chapter for stroke prevention in AF.
ii. Antithrombotic therapy after AF ablation
(a) Therapeutic warfarin anticoagulation maintained pre, during, and post ablation
(b) Newer oral anticoagulant switched to warfarin about 1 month before ablation, and
therapeutic warfarin anticoagulation maintained pre and during ablation; then patient’s
medication switched back to newer oral anticoagulant once INR is less than 2
(c) Limited experience with maintaining newer oral anticoagulant until 24 or 48 hours before
procedure or maintaining during procedure and no warfarin or LMWH bridge
(d) LMWH bridging has been abandoned secondary to excessive bleeding risk.
(e) Consensus recommendation from 2012 HRS AF ablation guidelines is that all patients
undergoing AF ablation receive therapeutic anticoagulation with warfarin or a newer
oral direct thrombin inhibitor or factor Xa inhibitor for at least 2 months post procedure,
regardless of CHADS2 score. A longer duration of anticoagulation for high-risk patients
is strongly encouraged, with discontinuation done in the setting of ambulatory continuous
rhythm monitoring for AF recurrence.
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f. Prevention of thromboembolism when undergoing cardioversion

i. Patients in stable condition in AF for less than 48 hours
(a) Sinus rhythm obtained and no risk factors for AF: Anticoagulation unnecessary
(b) Sinus rhythm obtained and risk factors for AF
(1) Oral anticoagulation after cardioversion; duration of 4 weeks
(2) Consider long-term anticoagulation after cardioversion if stroke risk factors and/or
risk of AF recurrence/presence of thrombus
ii. Patients in stable condition in AF for 48 hours or more
(a) Anticoagulation at least 3 weeks before (prevents new thrombi and permits any potential
thrombi to organize and adhere to the atrial wall, where they will likely not embolize before
sinus rhythm is restored) and 4 weeks after (normal atrial contraction may not return for 2
weeks, and any newly formed thrombi may embolize) electric or pharmacologic cardioversion
(b) Alternatively, cardioversion can be performed immediately after a TEE revealing no left
atrial/left atrial appendage clot in the setting of current therapeutic anticoagulation with
UFH/LMWH/warfarin or, more recently, at least 2–4 hours after the first dose of a newer
oral anticoagulant (see Thromboembolism chapter for time to Cmax).
iii. Hemodynamically unstable, immediate cardioversion required, and in AF 48 hours or more
(a) A TEE can be used to evaluate for thrombus in the left atrium or left atrial appendage.
(b) Intravenous heparin (fully anticoagulated) or LMWH before cardioversion
(c) Oral anticoagulation after cardioversion; duration of 4 weeks
iv. Hemodynamically unstable, immediate cardioversion required, and in AF less than 48 hours:
Cardioversion administered without delay for anticoagulation
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Cardiology I
Figure 2. Cardioversion of hemodynamically stable AF, the role of TEE, and subsequent anticoagulation strategy.
AF = atrial fibrillation; DCC = direct current cardioversion; LA = left atrium; LAA = left atrial appendage; OAC = oral anticoagulant; SR = sinus
rhythm; TEE = transesophageal echocardiogram.
Reprinted with permission from the European Society of Cardiology. Originally published in: Camm AJ, Kirchhof P, Lip GYH, et al. Guidelines
for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).
Eur Heart J 2010;31:2369-429.
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Cardiology I
Patient Cases

T.T. is a 55-year-old-man with a medical history significant for coronary artery disease, NYHA class III
HF, LVEF 35%, two cardioembolic strokes, and diabetes mellitus who presents to the clinic today with new
palpitations, fatigue, shortness of breath, and dizziness for the past 3 weeks. A 12-lead ECG shows AF with an
HR of 101 beats/minute and a QTc of 420 milliseconds. The patient is currently taking carvedilol 12.5 mg twice
daily, lisinopril 20 mg/day, aspirin 81 mg/day, and insulin glargine 20 units at bedtime. His blood pressure is
120/80 mm Hg. Laboratory testing shows the following: SCr 0.80 mg/dL, hemoglobin 14.0 g/dL, and INR 1.0.
14. Which option best reflects the HR goal for T.T.?

A. Less than 150 beats/minute.
B. Less than 110 beats/minute.
C. Less than 80 beats/minute.
D. Not specified in a practice guideline.
15. Which is the best course of action to treat T.T. currently?

A. Perform DCC to obtain NSR.
B. Increase carvedilol dose to 25 mg orally twice daily, and add rivaroxaban 20 mg orally daily with food.
C. Add dofetilide 250 mcg orally twice daily and rivaroxaban 20 mg orally daily with food.
D. Increase carvedilol dose to 25 mg orally twice daily, add dofetilide 250 mcg orally twice daily, and
add rivaroxaban 20 mg orally daily with food.
H.W. is a 50-year-old man with symptomatic paroxysmal AF and HTN. He is seen in the arrhythmia clinic,
where he is refusing ablation. His current medications include apixaban 5 mg orally twice daily, enalapril
10 mg orally twice daily, hydrochlorothiazide 25 mg orally daily, and metoprolol tartrate 50 mg orally twice
daily. His laboratory test results are normal (with apixaban coagulation effects), BP 120/70 mm Hg, and HR
75 beats/minute. He has no LV hypertrophy on ECG, and his QTc is 400 milliseconds. His LVEF is 65% on
echocardiography, and he has no evidence of clot. He attests to high medication adherence.
16. Which option best reflects the HR goal for H.W.?

A. Less than 150 beats/minute.
B. Less than 110 beats/minute.
C. Less than 80 beats/minute.
D. Not specified in a practice guideline.
17. A decision is made to start rhythm control for H.W. Which would be the best antiarrhythmic drug to treat
H.W. currently?
A. Amiodarone.
B. Dofetilide.
C. Dronedarone.
D. Flecainide.
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B. Atrial Flutter (Domain 1, Tasks 1, 2, 5, 6, 7; Domain 3, Tasks 2, 3)

1. Classifications
a. Type I flutter: Classic form (“saw-tooth” P waves in inferior leads)
b. Type II flutter: Atypical atrial flutter circuits, often faster
2. Epidemiology
a. Less common than AF; however, there are many similarities
b. Occurs in 25%–35% of patients with AF
c. Presentation (type I flutter): 250–350 atrial beats/minute
d. Symptoms
i. Dyspnea
ii. Fatigue
iii. Palpitations
iv. Chest discomfort
v. Exercise-induced fatigue
vi. Worsening HF
3. Pathophysiologic mechanisms
a. Reentry within the atrial wall
i. Type I flutter: Macroreentrant circuit depends on the cavotricuspid isthmus.
ii. Type II flutter: Less common lesion-related macroreentrant (surgical scar)
b. Causes: Can be precipitated by forms of organic heart disease that cause atrial stretch
i. Hypertension
ii. Chronic obstructive pulmonary disease
iii. Valvular disorders
iv. Dilated or hypertrophic cardiomyopathy
v. Cardiac disease
vi. Surgery
vii. Ischemia/infarction
4. Complications: Embolic risk. The risk of stroke is lower than with AF.
5. Treatment (treated similarly to AF)
a. Preventing thromboembolism
i. Risk of embolism is lower.
ii. No appropriate trials to evaluate anticoagulation; therefore, AF guidelines extend to atrial
flutter (see above Atrial Fibrillation and Thromboembolism sections)
b. Direct current cardioversion
c. Ablation: First-line treatment because it most effectively increases quality of life
d. Pharmacologic (limited data to evaluate antiarrhythmic medications)
i. AV nodal–blocking agents; more difficult-to-control rate
ii. Class Ia and Ic drugs
iii. Class III drugs
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Cardiology I
Table 55. Recommendations for Long-term Management of Atrial Flutter

Clinical Status/Proposed Therapy Recommendationa
First-episode and well-tolerated atrial flutter 1. Cardioversion
2. Catheter ablation
Recurrent and well-tolerated atrial flutter 1. Catheter ablation
2. Dofetilide
3. Amiodarone, sotalol, flecainide, quinidine, propafenone
Poorly tolerated atrial flutter 1. Catheter ablation
Atrial flutter appearing after use of class Ic agents or 1. Catheter ablation
amiodarone for treatment of atrial fibrillation
Symptomatic non–cavotricuspid isthmus-dependent 1. Catheter ablation
flutter after failed antiarrhythmic drug therapy
a
Recommendations are numbered by classification of supporting evidence.
Originally published in: Blomstrom-Lundqvist C, Scheinman MM, Aliot EM, et al. ACC/AHA/ESC guidelines for the management of patients
with supraventricular arrhythmias – executive summary: a report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines, and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop
Guidelines for the Management of Patients With Supraventricular Arrhythmias.). J Am Coll Cardiol 2003;42:1493-531.
XII. VENTRICULAR ARRHYTHMIAS
A. VT with Pulse (Domain 1, Tasks 1, 2)

1. Classification
a. ECG morphology (monomorphic or polymorphic)
b. Duration (sustained or nonsustained)
c. Location
d. Hemodynamic significance (stable, unstable, pulseless)
e. Mechanism (reentrant, automatic)
2. Epidemiology
a. ECG: Typically wide QRS
b. Rate: Greater than 100 beats/minute
c. The mortality risk correlates with the degree of structural heart disease.
d. Symptoms
i. Dyspnea
ii. Syncope
iii. Palpitations
3. Pathophysiologic mechanism
a. Impulse is generated from increased automaticity of a single point in either the left or the right
ventricle or is caused by a reentry circuit within the ventricle.
b. Nonsustained VT—Three or more consecutive premature ventricular contractions (PVCs) lasting
less than 30 seconds and terminating spontaneously
c. Sustained VT—Three or more consecutive PVCs at a rate greater than 100 beats/minute lasting
more than 30 seconds and/or lasting less than 30 seconds but requiring termination because of
hemodynamic compromise
d. Causes
i. Idiopathic
ii. Sleep apnea
iii. Myocardial scarring from previous MI: Scar cannot conduct electrical activity,
causing a potential circuit around it.
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Cardiology I
iv. Coronary artery disease

v. Hypertrophic cardiomyopathy
vi. Nonischemic cardiomyopathies
vii. Electrolyte abnormalities
viii. Right ventricular dysplasia

B. Chronic Treatment (Domain 1, Tasks 3, 4, 5, 6)
1. Nonsustained VT
a. EF greater than 40% and asymptomatic; usually does not require therapy
b. Symptomatic; β-blockers or amiodarone
c. EF less than 40%; amiodarone
2. Sustained VT
a. Implantable cardioverter defibrillator
b. If VT reoccurs after ICD placement or if ICD is not an option
i. Ablation
ii. Sotalol
iii. β-Blocker plus amiodarone
iv. Amiodarone
v Correct underlying cause.
XIII. PHARMACIST ROLE IN ARRHYTHMIA MANAGEMENT (Domain 2, Tasks 1, 5)
A. Medication Reconciliation
B. Patient Education (medications, signs and symptoms of stroke)

Available resources: www.hrsonline.org/Patient-Resources/Patient-Information-Sheets#axzz2qrUgkpeG
C. Anticoagulation Management for AF/Atrial Flutter
D. Evaluate for Drug Interactions.
E. Ensure that 12-lead ECG is obtained and QTc interval determined for appropriate antiarrhythmic agents
causing torsades de pointes.
F. Prevent adverse drug events by ensuring the drug’s appropriateness according to the patient’s
comorbidities and medication profile.
G. Identify Adverse Drug Events with Frequent Monitoring.

1. Subjective questioning
2. Laboratory draws
H. Historian: Identify the Medications the Patient Has Taken in the Past to Treat the Arrhythmia. Make
recommendations according to the patient’s past treatments and current disease states.
I. Ensure Continuity of Care.
J. Keep Nurses and Physicians Up to Date on Current Cardiac Medication Literature and Ongoing Trials.
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K. Ensure Medications Can Be Obtained by the Patient According to Cost and/or Formulary.
L. Facilitate Prior Authorizations from Insurance Company.
M. Create Collaborative Agreements or Standing Orders.
XIV. ANTIARRHYTHMIC MEDICATIONS (Domain 1, Tasks 2, 3)
Table 56. Oral Antiarrhythmic Medications (classification, mechanism, drugs, and indication)
Vaughan-
Williams Indicationsa Drugs Mechanism of Action
Classification
AF, atrial flutter, paroxysmal Channel blocked: Na
supraventricular tachycardia, (intermediate association
ventricular arrhythmias and dissociation), K, Ach, α
Quinidine
a
Disopyramide – Only paroxysmal ECG manifestations:
supraventricular tachycardia May ↑ sinus rate;
↑ QT (not dose related);
↑ QRS high dose
Ia
Channel blocked: Na
(intermediate association
and dissociation), K, Ach
Disopyramide ECG manifestations:
May ↑ sinus rate;
↑ QT (not dose related);
↑ QRS high dose
Ventricular arrhythmias Channel blocked: Na
(fast association and dissociation)
Ib Mexiletine
a
Used most commonly as add-on to ECG manifestations: May ↓ sinus rate,
amiodarone and not as sole agent generally do not affect QRS or QT
AF and atrial flutter, paroxysmal Channel blocked: Na
supraventricular tachycardia, (slow association and dissociation), β
Propafenone
ventricular arrhythmias ECG manifestations:
May ↓ sinus rate; ↑ PR, ↑ QRS
Ic a
May precipitate atrial flutter in Channel blocked: Na
patients with AF if no rate-controlling (slow association and dissociation)
agent coadministered Flecainide
ECG manifestations:
May ↓ sinus rate; ↑ PR, ↑ QRS
AF, atrial flutter, paroxysmal Channel blocked: β, indirect CaECG
ß-Blockers
II supraventricular tachycardia, manifestations: ↓ Sinus rate
(i.e., metoprolol)
ventricular arrhythmias
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Cardiology I
Table 56. Oral Antiarrhythmic Medications (classification, mechanism, drugs, and indication) (continiued)
Vaughan-
Williams Indicationsa Drugs Mechanism of Action
Classification
Amiodarone: Supraventricular and Channel blocked: K, Na, Ca, β, α, Ach
ventricular arrhythmias Amiodarone ECG manifestations: ↓ Sinus rate,
Dronedarone: Paroxysmal or persistent ↑ PR, ↑ QRS, ↑ QT
atrial fibrillation and atrial flutter Channel blocked: K, Na, Ca, β, α, Ach
Sotalol: Ventricular arrhythmias; Dronedarone ECG manifestations: ↓ Sinus rate,
maintenance of AF and flutter ↑ PR
III Dofetilide: Supraventricular
Channel blocked: K, β
arrhythmias; atrial flutter and
Sotalol ECG manifestations: ↓ Sinus rate,
fibrillation conversion
may ↑ PR, ↑ QT (dose related)
Channel blocked: K
Dofetilide ECG manifestations: ↑ QT
(dose related)
AF, atrial flutter, paroxysmal Diltiazem Channel blocked: CaECG
IV
supraventricular tachycardia Verapamil manifestations: ↓ Sinus rate
AF Channel blocked: Positive inotropic
effect, enhanced vagal tone, and
Additional
Digoxin decreased ventricular rate to fast
agents
atrial arrhythmias
ECG manifestations: ↓ Sinus rate
a
Including off-label uses.
Ach = acetylcholine; AF = atrial fibrillation; Ca = calcium; ECG =, electrocardiographic; K = potassium; Na = sodium.
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Cardiology I
Table 57. Antiarrhythmic Medications (oral class I and III agents only) Properties and Dosing
Mechanism of Action, Pharmacokinetics,
Drug Contraindications, Adverse Effects, Dosing
Drug Interactions
Class Ia – Na+ channel blockers
Quinidine MOA: Strong vagolytic and anticholinergic Sulfate (extended release): 300 mg PO every
(Quinidex, properties, 8–12 hours
Quinaglute) Na+ and K+ channel blockage Gluconate (extended release): 324–648 mg PO
PK: Half-life 5–9 hours every 8–12 hours
Substrate CYP3A4
Inhibitor CYP2D6
AEs: Nausea/vomiting/diarrhea (30%)
TdP (first 72 hours, not dose related)
“Cinchonism”: CNS symptoms, tinnitus
Thrombocytopenia, rash, pruritus
DIs: Warfarin, digoxin
Disopyramide MOA: Potent Na+ and M2 blockade, Ach; strong Initial dose 400–800 mg/day in
(Norpace, negative inotrope divided doses; IR every 6 hours,
Norpace CR, PK: Half-life 4–8 hours CR every 12 hours
Rythmodan, Substrate CYP3A4 Maximum 1200–1600 mg/day
Rythmodan- Dose adjustment required for renal insufficiency
CIs: Glaucoma
LA)
AEs: Anticholinergic adverse effects
TdP
ADHF
Class Ib – Na+ channel blockers
Mexiletine MOA: Inactive Na+ channel blocker VT maintenance: 200–300 mg
(Mexitil) PK: Half-life 12–20 hours every 8 hours
Substrate CYP2D6, CYP1A2 Maximum of 1200 mg/day
Inhibitor CYP1A2
CIs: Third-degree AV heart block
AEs: GI upset (administer with food); CNS: Tremor,
dizziness, ataxia, nystagmus
Class Ic – Na+ channel blockers (***avoid with HF or post MI)
Propafenone MOA: Na+ and Ca2+ channel blocker; ß-blocker AF conversion: 600 mg (IR) PO × 1
(Rythmol) PK: Half-life 10–25 hours (efficacy 45% in 3 hours)
Substrate CYP2D6, CYP1A2
Inhibitor CYP2D6 AF maintenance:
IR: 150–300 mg PO every 8 hours
CIs: HF NYHA III–IV, liver disease, valvular
SR: 225–425 mg PO every 12 hours
disease (TdP), CAD, VT
AEs: Metallic taste, dizziness
DIs: Propafenone may ↑ digoxin concentrations,
may decrease warfarin metabolism, has β-blocker
properties and pharmacokinetic interaction increasing
β-blocker concentrations – Need to monitor HR
and reduce β-blocker dose if necessary to prevent
symptoms/heart block
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Table 57. Antiarrhythmic Medications (oral class I and III agents only) Properties and Dosing (continued)
Drug Interactions
Class Ic – Na+ channel blockers (***avoid with HF or post MI) (continued)
Flecainide MOA: Strong Na+ channel blockade; vagolytic, AF conversion: 300 mg PO × 1
(Tambocor) anticholinergic, and negative inotrope (efficacy 50% in 3 hours)
PK: Half-life 10–20 hours
Substrate CYP2D6 AF maintenance: 50–200 mg PO bid
Inhibitor CYP2D6
CIs: HF, CAD, valvular/LV hypertrophy (TdP)
AEs: Dizziness, tremor, HF exacerbation, VT, atrial
flutter (in patients with AF)
DI: May increase digoxin concentrations; flecainide
concentrations increased by haloperidol, cimetidine,
and fluoxetine
Class III – K+ channel blockers
Amiodarone MOA: K+, Na+, Ca2+ channel blocker, ß-blocker AF/VT conversion/maintenance: 600–800 mg/
(Cordarone, PK: Half-life 26–107 days (chronic oral dosing), day in divided doses until 10 g total; then
Pacerone) large volume of distribution (high affinity for 100–400 mg/day maintenance
adipose tissue)
*** Maintenance doses are often started before
Substrate CYP3A4, CYP1A2, CYP2C9 the patient completes the 10-g loading dose.
Inhibitor CYP3A4, CYP2D6, CYP2C9, CYP1A2,
CYP2C19, intestinal P-glycoprotein
CIs: Iodine hypersensitivity, hyperthyroidism, third-
degree AV heart block
AEs: Pulmonary fibrosis (1.7% in outpatient setting),
thyroid dysfunction (2%–23%),
hepatotoxicity (3%–20%), neurologic toxicity (4%–
9%), TdP (< 1%), AV block (14%), photosensitivity
(3%–10%), visual disturbances (4%–9%), sinus
bradycardia
***The 2007 HRS amiodarone guidelines and

prescribing information recommend the following:
Baseline thyroid panel and liver function tests
repeated every 6 months; chest radiography and
physical examination at baseline and repeated every
3 to 6 months with a high-resolution CT scan if new
symptoms of pulmonary toxicity appear such as
dyspnea, cough, or chest radiograph changes
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Cardiology I
Drug Interactions
Class III – K+ channel blockers (continued)
Amiodarone Since the 2007 guidelines were published, new AEs of AF/VT conversion/maintenance: 600–800 mg/
(Cordarone, optic neuritis and neuritis leading to blindness were day in divided doses until 10 g total; then
Pacerone) added to prescribing information and require regular 100–400 mg/day maintenance
ophthalmologic examinations (including funduscopy
and slit lamp examination) *** Maintenance doses are often started before
the patient completes the 10-g loading dose.
***Most AEs are dose-dependent; reduce to lowest
effective dose
***Does not increase mortality in HF
DIs:
Warfarin (reduce dose by 25%–50%, recheck INR
accordingly), digoxin (reduce dose by 50%), statins
(simvastatin 20 mg maximal dose)
Dabigatran effects increased but not clinically
relevant,dabigatran
Sotalol MOA: K+ channels, blocks ß1- and ß2-receptors AF conversion: No effect!
(Betapace) PK: Renally eliminated
AF maintenance:
Half-life 30–40 hours
Dose 80–160 mg
CIs: Baseline QTc > 0.45 seconds or CrCl < 40 mL/ Twice daily; CrCl > 60 mL/minute
minute in atrial arrhythmias only Daily; CrCl 40–60 mL/minute
AEs: HF exacerbation, bradycardia, AV heart block, Contraindicated; CrCl < 40 mL/minute
bronchospasm, TdP 3%–8% within 3 days of
initiation VT maintenance:
Dose 80–160 mg
***Ideally initiated in hospital, because of Twice daily; CrCl > 60 mL/minute
proarrhythmia Daily; CrCl 30–60 mL/minute
DIs: Has β-blocker properties, so the dose of Every 48 hours; CrCl 10–30 mL/minute
concomitant β-blockers may need tapering after Every 72 hours; CrCl > 10 mL/minute
sotalol initiation; monitor HR
Dofetilide MOA: K+ channel blocker only AF conversion/maintenance:
(Tikosyn) PK: Renal and hepatic elimination (CrCl > 60 mL/minute)
Half-life 6–10 hours 500 mcg PO twice daily
Substrate CYP3A4 (CrCl 40–60 mL/minute)
250 mcg PO twice daily
(CrCl 20–40 mL/minute)
CIs: Baseline QTc > 0.44 seconds or CrCl 125 mcg PO twice daily
< 20 mL/minute Contraindicated CrCl < 20 mL/minute
*If initiated after amiodarone failure, need a

3-month washout period
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Cardiology I
Drug Interactions
Class III – K+ channel blockers (continued)
Dofetilide AEs: TdP (0.8%; 4% if not renally dosed), REMS:
(Tikosyn) dizziness, diarrhea ***Ensuring dofetilide is prescribed only
by certified prescribers, dispensed only by
***Does not increase mortality in HF certified dispensers (retail pharmacy must be
enrolled in TIPS), and dispensed for use only
DIs: CYP3A4 inhibitors or cation drug transport with documentation of safe use conditions
system inhibitor drugs secreted by the kidney
(ketoconazole, verapamil, trimethoprim, megestrol, ***Educating health care providers about the
dolutegravir, prochlorperazine), HCTZ (should be risks and the need to initiate and reinitiate
discontinued as concentrations of dofetilide increase) therapy in a hospital (at least a 72-hour
stay) that can provide calculations of CrCl,
continuous ECG monitoring, and cardiac
resuscitation; do not initiate if QTc is > 0.44
second or 0.5 second in patients with baseline
conduction abnormalities; obtain QTc 2–3
hours after first five doses, reduce by 50%
if QTc ↑ > 15% (QTc should never exceed
0.5 second or 0.55 second in patients with
baseline conduction system abnormality);
if QTc prolongs by more than 15% or 0.5
second in patients with baseline conduction
abnormalities of baseline after any dosage
adjustment, dofetilide must be discontinued
and deemed treatment failure; before the
patient is discharged, the health care facility
must either provide a free 7-day supply of
dofetilide and the medication guide to patients
or ensure the patient’s take-home prescription
is filled
***Inform the patient about the serious risks

associated with dofetilide therapy (medication
guide mandated)
***Mandates K+, Mg, SCr, and 12-lead ECG

monitoring at least every 3 months
Ach = acetylcholine; ADHF = acute decompensated heart failure; AE = adverse effect; AF = atrial fibrillation; AV = atrioventricular; bid = twice daily;
Ca2+ = calcium; CAD = coronary artery disease; CI = contraindicationt; CNS = central nervous system; CR = controlled release; CrCl = creatinine
clearance; CT = computed tomography; CYP = cytochrome P450; DI = drug interaction; ECG = electrocardiogram; GI = gastrointestinal; HCTZ
= hydrochlorothiazide; HF = heart failure; HR = heart rate; HRS = Heart Rhythm Society; INR = international normalized ratio; IR = immediate
release; IV = intravenously; K+ = potassium; LA = long acting; LV = left ventricular; LVEF = left ventricular ejection fraction; Mg = magnesium; MI
= myocardial infarction; MOA = mechanism of action; Na+ = sodium; NYHA = New York Heart Association; PK = pharmacokinetics; PO = orally;
QTc = corrected QT interval; REMS = Risk Evaluation and Mitigation Strategies; SCr = serum creatinine; SR = sustained release; TdP = torsades de
pointes; TIPS = Tikosyn In Pharmacy Systems; VF = ventricular fibrillation; VT = ventricular tachycardia.
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Cardiology I
Patient Case
18. A 75-year-old man with a history of MI, AF, and stage C HFrEF presents to the clinic 2 weeks after hospital-
ization for VT ablation. His current medications include amiodarone 400 mg/day (after a 5-g loading dose
administered during his recent hospitalization), aspirin 81 mg orally daily, warfarin 5 mg orally daily (INR
2.4), simvastatin 40 mg orally daily, lisinopril 20 mg orally daily, spironolactone 25 mg orally daily, meto-
prolol succinate 100 mg orally twice daily, and digoxin 0.25 mg orally daily. His estimated CrCl is 55 mL/
minute, and other chemistry test and LFT results are normal. Serum digoxin concentration is 1.5 ng/mL. His
BP is 120/70 mm Hg, and HR is 59 beats/minute. Which is the best course of action currently?
A. Decrease his warfarin dose to 2.5 mg orally daily, and decrease his amiodarone dose to 200 mg orally daily.
B. Decrease his simvastatin dose to 20 mg orally daily, and decrease his amiodarone dose to 200 mg orally daily.
C. Decrease his warfarin dose to 2.5 mg orally daily, and decrease his digoxin dose to 0.125 mg orally daily.
D. Decrease his simvastatin dose to 20 mg orally daily, and decrease his digoxin dose to 0.125 mg orally daily.
VALVULAR HEART DISEASE
XV. THROMBOEMBOLISM PREVENTION
A. Prevention of TE in Patients with Valvular Heart Disease or Prosthetic Heart Valves (Domain 1, Tasks 2, 3)
1. Patients with valvular AF are considered at “high risk” of cardioembolic stroke and should receive
anticoagulation and, in some cases, added aspirin.
2. Patients with mechanical valve prosthesis without AF are at high risk of thromboembolic
complications (mainly cardioembolic stroke and valve thrombosis) and require lifelong antithrombotic
prophylaxis.
3. Prosthetic valves are made of various materials that differ in thrombogenicity.
a. Newer materials reduce thrombogenicity, and future materials such as polymerics may reduce
thrombogenicity even more.
b. Bioprosthetic valves are less thrombogenic, but they are not as durable as mechanical valve
prosthesis and are thus more prone to failure, requiring replacement.
c. Because valve position, type, and materials affect thrombogenicity, correct use of anticoagulation
therapy requires a determination of exactly which valve(s) has(have) been replaced and the type
of prosthesis used so that mistakes in anticoagulation are avoided.
4. Risk factors for thrombosis
a. Annual risk of TE ranges from 4% to 23% without prophylaxis.
b. Prophylaxis reduces the risk of TE to less than 2% a year.
c. Risk of TE is highest in the early postsurgical period because of exposed valvular components
(e.g., suturing ring, valve surfaces). After about 3 months, endothelialization occurs, and TE risk
decreases.
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Cardiology I
5. Types of valves
a. Mechanical prosthetic valves
i. Three basic types of mechanical valves: Caged-ball/disk, tilting disk, and bileaflet
Table 58. Types of Mechanical Heart Valves

Valve Type Model
Caged-ball Starr-Edwards
Tilting disk Björk-Shiley
Monostrut
Medtronic-Hall
Omniscience
Omnicarbon
Ultracor
Bileaflet St. Jude
On-X
Carbomedics
Baxter TEKNA
Duromedics
Sorin Bicarbon
ii. Older caged-ball and tilting disk valves are more thrombogenic than bileaflet valves.
iii. Annual TE event rate in patients who receive anticoagulation treatment to an INR of 2.5–4.9
(a) Bileaflet 0.5% a year
(b) Tilting disk 0.7% a year
b. Bioprosthetic valves
i. Bioprosthetic valves use a ring of material from an animal source (e.g., porcine, bovine).
ii. Porcine valves use the tissue valve from pig hearts (usually aortic valves).
iii. Pericardial valves use tissue from the bovine pericardium to make the valve leaflets, which
are supported by a synthetic frame.
iv. Less thrombogenic and less durable than mechanical valves
Table 59. Bioprosthetic Valve Types

Valve Type Model
Porcine Hancock I
Hancock II
Intact
Carpentier-Edwards
Freestyle
Bicor
Pericardial (bovine) Carpentier-Edwards Perimount
Ionescu-Shiley
Mitroflow
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Cardiology I
6. Position of valves: Valve position influences thrombogenicity. Mechanical mitral valves are more
thrombogenic than mechanical aortic valves.
7. Antithrombotic prophylaxis
a. Intravenous adjusted-dose UFH or subcutaneous LMWH can be used postoperatively after valve
insertion as a transition to warfarin and continued until INR is therapeutic and stable.
b. A recent observational study suggests that discontinuation of warfarin after placement of a
bioprosthetic aortic valve is associated with an increased risk of thromboembolism and CV death;
therefore, future guidelines may suggest anticoagulation after aortic bioprosthetic surgery, as
they now do for mitral bioprosthetic valve placement (JAMA 2012;308:2118-25).
c. In the only study reported with mechanical heart valves and a target-specific oral anticoagulant
(phase II, open-label, RE-ALIGN trial), patients treated with dabigatran had increased
thrombotic and bleeding risk, compared with patients treated with warfarin, and the trial was
terminated prematurely. Dabigatran is the only newer oral agent that specifically carries a
contraindication for use in patients with mechanical heart valves.
d. All patients with a mechanical valve should receive lifelong warfarin therapy adjusted to the
recommended INR range.
e. Patients with bioprosthetic valves and AF should receive lifelong anticoagulation therapy.
Although not contraindicated in current (January 1, 2014) product labeling of dabigatran,
rivaroxaban, and apixaban, these agents have not been studied in this group of patients.
f. Patients with either mitral stenosis or a bioprosthetic heart valve were enrolled in the ENGAGE-
AF trial comparing edoxaban and warfarin, but results in this important subgroup have not yet
been presented or published.
Table 60. Chest Guideline Recommendations for Antithrombotic Prophylaxis

Valve Position Bioprosthetic Mechanicala
Aortic Aspirinb Warfarin (INR 2–3)c
Mitral Warfarin (INR 2–3) x 3 Warfarin (INR 2.5–3.5)
months; then aspirinb
a
Recommend adding low-dose aspirin 50–100 mg orally daily for all patients with mechanical valves and low risk of bleeding.
b
Aspirin 50–100 mg/day. Recommend against giving aspirin to patients at high risk of bleeding (e.g., history of GI bleed, age > 80 years).
c
ACC/AHA recommends INR 2.5–3.5 for all caged-ball and tilting disk valves.
GI = gastrointestinal; INR = international normalized ratio.
8. Patients who develop systemic embolism despite a therapeutic INR

a. If patient was not previously taking aspirin, add aspirin 50–100 mg/day.
b. Titrate warfarin to a higher INR range.
Previous INR Range Postsystemic Embolism INR Range

2–3 2.5–3.5
2.5–3.5 3.5–4.5
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Cardiology I
Patient Cases
19. A 78-year-old woman with a history of permanent AF, dyslipidemia, HTN, and prior GI bleed is hospital-
ized with planned St. Jude mechanical aortic valve surgery for aortic stenosis. Diagnostic angiography be-
fore surgery revealed no significant coronary artery disease. Her CrCl is 55 mL/minute, and her medications
at the time of admission for surgery were enalapril 10 mg orally twice daily and atorvastatin 40 mg orally
daily. Which is the best antithrombotic regimen for stroke prevention for this patient after surgery?
A. Aspirin 325 mg orally plus warfarin orally at a goal INR of 2–3.
B. Dabigatran 150 mg orally twice daily.
C. Warfarin at a goal INR of 2.5–3.5.
D. Warfarin orally at a goal INR of 2–3.
20. A 68-year-old patient with a medical history of HTN and bicuspid aortic stenosis and bioprosthetic valve re-
placement 2 years ago presents with AF. Current medications are metoprolol succinate 100 mg orally twice
daily and aspirin 325 mg orally daily. The patient has a HAS-BLED score of 2 and a CrCl of 80 mL/minute.
Which is the best antithrombotic strategy for stroke prevention for this patient currently?
A. Add clopidogrel 75 mg orally daily.
B. Add warfarin at a goal INR of 2.5–3.5.
C. Dabigatran 150 mg twice daily.
D. Discontinue aspirin and add warfarin at a goal INR of 2–3.
XVI. AORTIC STENOSIS (Domain 1, Tasks 2, 3; Domain 3, Task 2)
A. Epidemiology
1. Most common type of valvular heart disease
2. Affects up to 5% of the elderly older than 75 years
3. High risk of SCD in symptomatic patients
4. Most common cause is calcific aortic stenosis.
B. Diagnosis Is Usually Made by Heart Murmur on Physical Examination by Auscultation: Typically,

crescendo-decrescendo systolic ejection murmur radiating to the neck and confirmed by echocardiography
C. Severe Aortic Stenosis: Defined by Doppler echocardiography as a maximum aortic jet velocity greater
than 4 m/second, mean transvalvular pressure gradient greater than 40 mm Hg, and continuity equation
valve area less than 1.0 cm2 or valve area index less than 0.6 cm2
D. Pathophysiology: Pressure Overload Hypertrophy
E. Signs and Symptoms

1. Three classic signs and symptoms: HF, syncope, and angina
2. HF is caused by hypertrophy and the failure to eject blood effectively from the ventricles, leading
to fluid overload; syncope secondary to diminished carotid blood flow and angina secondary to
diminished coronary flow to the hypertrophied heart
3. Typically, symptom-free until late in the disease course
4. Interval from the onset of symptoms to the time of death is around 2 years in patients with HF, 3 years
in those with syncope, and 5 years in those with angina.
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Cardiology I
F. Treatment of Severe Aortic Stenosis

1. Medical management of severe aortic stenosis has a mortality rate of 50% at 1 year.
2. Mechanical or bioprosthetic valve replacement surgery provides symptom relief and mortality
reduction in appropriate candidates.
3. Candidates are screened for surgical acceptability by using the STS (Society of Thoracic Surgeons)
score, which predicts operative and short-term postoperative survival, using a model of 24 variables.
See http://riskcalc.sts.org/STSWebRiskCalc273/de.aspx.
4. Transcatheter aortic valve replacement (TAVR) (nonsurgical placement of a porcine or bovine
aortic valve)
5. Aortic balloon valvuloplasty (now used primarily as a bridge to TAVR or as palliation because
durability is short). Two valves are FDA approved: SAPIEN (Edwards) and CoreValve system
(Medtronic).
G. TAVR with SAPIEN Valve (Edwards): Placed primarily by using a transfemoral approach and, less
preferably, a transapical approach. FDA approved according to the PARTNER trial
1. PARTNER (Placement of AoRtic TraNscathetER Valve) trial was a prospective, unblinded,
multicenter randomized trial that compared medical management with TAVR in patients who were
not considered surgical candidates (cohort B) and with aortic valve replacement (AVR) in patients
deemed high-risk operable (cohort A).
2. Cohort B results: Compared with medical management of TAVR
a. Reduced all-cause mortality by 38% at 1 year (p<0.001)
b. Reduced the composite of all-cause mortality and rehospitalization at 1 year by 38% (p<0.001)
c. 2-fold increased risk of major bleeding (p<0.001)
d. 2-fold increased risk of stroke (p=0.03)
e. Improved quality of life
3. Cohort A results: Compared with AVR
a. Noninferior for 1-year mortality (24.2% vs. 26.8%; hazard ratio 0.93; 95% CI, 0.71–1.22,
p=0.001 for noninferiority)
b. Increased risk of stroke at 1 year (8.3%–4.3%; p=0.04)
c. Reduced bleeding risk at 1 year (14.7% compared with 25.7%; p<0.01)
d. Two-year outcomes showed similar mortality and stroke risk between TAVR and AVR.
e. PARTNER II trial comparing TAVR and AVR in patients at intermediate surgical risk is ongoing,
with expected completion in 2015.
H. Antithrombotic Therapy for Stroke Prevention After TAVR

1. Around 32% of patients undergoing TAVR develop AF within 48 hours of the procedure.
2. Completed randomized trials comparing aspirin alone or with aspirin plus clopidogrel for stroke
prevention after TAVR have been underpowered.
3. 2012 ACCP guidelines recommend aspirin 50–100 mg plus clopidogrel 75 mg daily for at least the
first 3 months after TAVR.
4. PARTNER trial regimen was aspirin 75–100 mg plus clopidogrel 300 mg pre procedure and aspirin
75–100 mg indefinitely plus clopidogrel 75 mg daily for 6 months.
5. No information with newer P2Y12 agents such as prasugrel or ticagrelor
6. Variable practice if patients require anticoagulation for another reason, such as AF. Some centers use
triple antithrombotic therapy, whereas others use anticoagulation plus one antiplatelet.
I. Medical Therapy for the Inoperable Patient or the Symptomatic Patient Awaiting Surgery/TAVR
1. Maintain sinus rhythm if the patient develops AF (administer an antiarrhythmic agent).
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Cardiology I
2. Avoid hypotension.
3. Digoxin for HF and depressed LVEF
4. Angina
a. First-line therapy: β-Blocker
b. Second-line therapy: Calcium channel blocker
c. Avoid long-acting nitrates because reduction in preload may lead to worsening symptoms.
5. Heart failure
a. Cautious use of diuretics (avoid dehydration)
b. First-line β-blocker and ACE inhibitor or ARB (monitor for hypotension and worsening
symptoms with addition of vasodilator)
6. Hypertension
a. First-line β-blocker
b. Second-line ACE inhibitor or ARB
Patient Case
21. A 78-year-old woman who underwent TAVR 1 month ago presents for follow-up at surgical clinic. She de-
veloped postoperative AF and received a 1-week course of amiodarone while hospitalized and aspirin 81 mg
orally daily with warfarin anticoagulation since hospital discharge. She has maintained sinus rhythm since
hospital discharge. Her surgeon wants to discontinue her oral anticoagulation nowcurrently. Which is the
best strategy for stroke prevention currently?
A. Aspirin 325 mg orally daily indefinitely.
B. Aspirin 81 mg orally daily indefinitely.
C. Clopidogrel 75 mg orally daily for 3 months.
D. Aspirin 81 mg orally daily plus clopidogrel 75 mg orally daily for at least 2 months.
PULMOPNARY ARTERIAL HYPERTENSION
XVII. DEFINITION, DIAGNOSIS, AND TREATMENT GOALS (5TH WORLD SYMPOSIUM 2013)
A. Pulmonary Arterial Hypertension (PAH) (Domain 1, Task 1)

1. Pulmonary hypertension (PH) is defined by a mean pulmonary arterial pressure (mPAP) of 25 mm Hg
or greater at rest as measured at right heart catheterization (RHC).
2. PAH is a subpopulation of PH hypertension that includes an end-expiratory pulmonary artery wedge
pressure or LV end-diastolic pressure of 15 mm Hg or less and a pulmonary vascular resistance
greater than 3 Wood units at RHC.
B. Classification (Domain 1, Task 2)

1. Group 1: PAH (includes idiopathic, heritable, drug/toxin induced, connective tissue disease such as
scleroderma, portal HTN, congenital, and human immunodeficiency virus [HIV] infection) (4.2%)
2. Group 2: PH caused by left heart disease (78.7%)
3. Group 3: PH caused by chronic lung disease and/or hypoxia (9.7%)
4. Group 4: Chronic thromboembolic PH (0.6%)
5. Group 5: PH caused by multifactorial mechanisms (6.8%)
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C. Symptoms (Domain 1, Task 2)

1. Dyspnea with exertion (60% of patients), fatigue, chest pain, syncope, weakness (40%) – Caused by
impaired oxygen delivery to tissues and diminished cardiac output
2. Orthopnea, peripheral edema, liver congestion, abdominal bloating, and other signs of right
ventricular hypertrophy and failure occur when disease progresses to involve the heart.
D. Diagnosis and Classification (Domain 1, Task 2)
Table 61. Diagnostic Findings of Pulmonary Arterial Hypertension

Hemodynamic alterations mPAP ≥ 25 mm Hg, PCWP ≤ 15 mm Hg, and PVR > 3 Wood units on RHC
Electrocardiogram Signs of RV hypertrophy, right-axis deviation, and anterior ST- and T-wave
abnormalities consistent with RV strain pattern
Echocardiography Estimated RV systolic pressure elevation, enlarged RV, RV dysfunction
Chest radiography Enlarged pulmonary arteries and diminished peripheral pulmonary vascular
markings, RV enlargement
Physical examination Cool and/or cyanotic extremities, jugular venous distension, pulsatile
hepatomegaly, peripheral edema, ascites
Laboratory testing Elevated BNP concentration
BNP = B-type natriuretic peptide; mPAP = mean pulmonary arterial pressure; PA = pulmonary artery; PCWP = pulmonary capillary wedge
pressure; PVR = pulmonary vascular resistance; RHC = right heart catheterization; RV = right ventricle/ventricular.
Table 62. Classification of Pulmonary Arterial Hypertension Symptoms

WHO/Modified NYHA Classification
Class Definition
I No symptoms (dyspnea, fatigue, syncope, chest pain) with normal daily activities
II Symptoms with strenuous normal daily activities that slightly limit functional status and activity level
Symptoms of dyspnea, fatigue, syncope, and chest pain with normal daily activities that severely
III
limit functional status and activity level
IV Symptoms at rest; cannot perform normal daily activities without symptoms
NYHA = New York Heart Association; WHO = World Health Organization.
E. Treatment Goals (Domain 1, Task 3)

1. Relieve acute dyspnea symptoms: Functional class I or II.
2. Improve exercise capacity: 6-minute walk test of at least 380 (to 440) m.
3. Normalization of right ventricular function: Right atrial pressure less than 8 mm Hg and cardiac
index greater than 2.5 L/minute/m24. Cardiopulmonary exercise testing: Peak oxygen consumption
greater than 15 mL/minute/kg and ventilatory equivalent for carbon dioxide less than 45 L/minute
5. BNP concentration normal
F. For Acute Vasodilator Response Testing (Domain 1, Task 2)

1. Use intravenous epoprostenol, inhaled nitric oxide, or intravenous adenosine.
2. Positive response: Reduction in mPAP of at least 10 mm Hg to an absolute mPAP of
less than 40 mm Hg
3. Positive response predicts mortality reduction with long-term calcium channel blocker
or vasodilator use.
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Cardiology I
XVIII. TREATMENT OF PULMONARY HYPERTENSION (Domain 1, Tasks 3, 4, 5, 6)
A. Reassessment – Should include functional class determination and a 6-minute walk test every 3–6
months, with RHC less often
B. Satisfactory Condition – Functional classes I and II, ambulated 380 m or greater (or 1250 ft) during
6-minute walk test, with a cardiac index of 2.2 L/minute/m2 or greater and an mPAP less than 12 mm Hg
Table 63. Initial PAH Treatment Algorithm

Supportive Care: Treat corrective causes of hypoxemia, and avoid dehydration, pain, fatigue, high altitude,
smoking, pregnancy, iron deficiency, etc.
Oxygen to maintain O2 saturation > 90%, diuretic if peripheral edema or ascites
Supervised exercise activity (avoid strenuous exercise)
Oral anticoagulation, warfarin (INR 1.5–2.5) if IPAH, heritable PAH, or PAH caused by anorexigens, or
associated PAH;
± diuretics ± digoxin
(anticoagulation to prevent catheter thrombosis [IV prostaglandin use] and venous thromboembolism)
Immunizations for influenza and Pneumococcus
Avoid pregnancy: Discuss effective methods of birth control with women of childbearing potential
Positive response to acute vasoreactivity testing
Initiate oral CCB
- If sustained response, continue CCB
- If no sustained response, initiate one or more agents below based on the WHO FC
CCB = calcium channel blocker; INR = international normalized ratio; IPAH = idiopathic pulmonary arterial hypertension; IV = intravenous;
PAH = pulmonary arterial hypertension; WHO FC = World Health Organization functional class.
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Cardiology I
C. Therapy Options
1. Initial therapy with one agent from the endothelin pathway, prostacyclin pathway, or nitric oxide
pathway (most common in practice), followed by sequential combination therapy; or
2. Initial therapy with combination therapy of two agents from different classes/having differing actions
Recommendation Gradea WHO FC II WHO FC III WHO FC IV

I Ambrisentan Ambrisentan Epoprostenol IV b
Bosentan Bosentan
MacitentanbRiociguat MacitentanbRiociguat
Sildenafil Sildenafil
Tadalafil Tadalafil
Epoprostenol IV bIloprost
inhaled
Treprostinil subcutaneous
or inhaled
IIa Iloprost IV Ambrisentan
Treprostinil IV Bosentan
MacitentanbRiociguat
Sildenafil
Tadalafil
Iloprost inhaled and IV
Treprostinil Subcutaneous,
IV, or inhaled
IIb Initial combination therapy Initial combination therapy Initial combination therapy
a
Grade I recommendation is one with strong evidence that is recommended or indicated. Grade IIa recommendation is one where evidence
favors use, and treatment should be considered. Grade IIb recommendation is one where usefulness/efficacy is less well established or is based
on opinion: May be recommended.
b
Morbidity or mortality as a primary end point in a randomized controlled study or a reduction in all-cause mortality (prospectively defined).
IV = intravenous; WHO FC = World Health Organization functional class.
From: 5th World Symposium on Pulmonary Hypertension (sponsored by the European Respiratory Society), 2013; Nice, France. If refractory/
unresponsive, reassess: Consider combination therapy, investigational protocols, atrial septostomy, lung transplantation.
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Table 64. Overview of PAH Treatment Options (5th World Symposium)

Drug/Mechanism/
Indication Dose Adverse Effects Considerations
Calcium channel Varies by agent Hypotension, headache, Should not be used empirically without positive
blockers and patient dizziness, peripheral response to acute vasodilatory response testing
tolerance edema, cardiac Diltiazem, amlodipine, nifedipine most
Class II PAH conduction delay commonly used
(diltiazem) Select agent on the basis of HR at baseline
If tachycardia, choose diltiazem
If bradycardia, choose amlodipine, nifedipine
Epoprostenol 2–40 ng/kg/ Jaw pain, nausea, Continuous IV infusion by pump
(Flolan, Veletri) minute IV vomiting, flushing, Flolan: Unstable at acidic pH and room
Prostanoid headache, muscle temperature (refrigerate or use ice packs before
aches and pain, and during infusion)
Class III–IV PAH catheter-related Veletri: Stable at room temperature
thrombosis, and Drug requires reconstitution in sterile
IV line infections; environment
rebound worsening of Medical emergency if infusion interrupted
symptoms if abruptly (half-life – 6 minutes) – Spare drug cassette and
discontinued infusion pump should be kept available
Treprostinil 1.25- to 40-ng/ Severe erythema and Longer half-life (half-life – 3 hours) – Longer to
(Remodulin, Tyvaso) kg/minute induration (83%) and seek medical attention
Prostanoid subcutaneous injection site pain Premixed, prefilled syringe easier to administer
infusion, IV (85%) limits use; also Local treatments (hot/cold packs or topical
Class III–IV PAH Inhaled headache, nausea, analgesics) can be used to minimize infusion site
diarrhea, rash discomfort
Moving infusion site every 3 days minimizes
irritation
Inhaled iloprost 2.5 × 1; then 5 Mild, transient cough, Requires 6–9 inhalations daily (15 minutes each
(Ventavis) mcg/inhalation flushing, headache, with jet nebulizer)
Prostanoid by nebulizer six syncope Prodose AAD nebulization system required
to nine times Inhaled form has fewer systemic adverse
Class III–IV PAH daily while reactions
awake Use no more than every 2 hours
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Table 64. Overview of PAH Treatment Options (5th World Symposium) (continued)
Drug/Mechanism/
Bosentan 62.5–125 mg PO Peripheral edema Severe drug interactions with glyburide
(Tracleer) twice daily 5%–14%, hypotension (increased LFT results) and cyclosporine
Nonselective Initiate at 62.5 mg 7%, increased LFTs (decreased efficacy of both cyclosporine and
endothelin receptor orally twice daily 11%, flushing 7%– bosentan)
antagonist for 4 weeks; then 14%, palpitations 5%, Monitor LFTs monthly (repeat if >3 times
(ETA and ETB) increase to 125 anemia 3% baseline to confirm; if >5 x baseline,
mg twice daily discontinue; if >3 and ≤5 x baseline, reduce dose
Class II–IV PAH Patients weighing to 62.5 mg daily; repeat LFTs every 2 weeks if
<40 kg should >3 x baseline
receive 62.5 mg Monitor hemoglobin/hematocrit at initiation, 1
twice daily month, 3 months, and every 3 months thereafter
Potential teratogen; if childbearing age, use two
contraceptive methods (reduced efficacy of
hormonal contraceptives); monthly pregnancy
test required; decreases concentrations of
norethindrone and ethinyl estradiol
Bosentan is a substrate of CYP2C9 and CYP3A
Bosentan is an inducer of CYP3A and CYP2C9
Bosentan is a substrate of OATP
Efficacy decreased with inducers, and toxicity
increased with inhibitors of CYP 2C9 and 3A4
Concomitant cyclosporine contraindicated
(bosentan concentrations increased 4-fold
and cyclosporine concentrations decreased by
50), glyburide contraindicated (increased LFT
values, bosentan concentrations decreased 30%
and glyburide increased 40%)
May decrease the concentrations/efficacy of
simvastatin, lovastatin, atorvastatin
Animal data indicate increased concentrations of
bosentan when tacrolimus coadministered
Warfarin coadministration showed no significant
INR changes
Coadministration with sildenafil reduces
sildenafil concentrations by 63% and increases
bosentan concentrations by 50% (no dose change
recommended)
Discontinue bosentan 36 hours before initiating
ritonavir; then initiate bosentan at 62.5 mg daily
or every other day
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Cardiology I
Drug/Mechanism/
Ambrisentan 5–10 mg PO once Peripheral edema 17%, Caution with cyclosporine – Maximal dose is 5
(Letairis) daily hypotension 0%, mg daily
Selective endothelin increased LFT results Contraindicated in patients with idiopathic
receptor antagonist 0%–2.8%, flushing pulmonary fibrosis
(ETA only) 4%, palpitations 5%, Potential teratogen (see above comments)
fluid retention, anemia Measure Hgb at initiation, 1 month, and
Class II–II PAH (decreases in Hgb of periodically thereafter
0.9–1.2 g/dL observed Coadministration with cyclosporine resulted in
within first few weeks 2-fold increases in ambrisentan concentrations –
of initiation) Limit ambrisentan dose to 5 mg orally daily
Macetentana 10 mg PO once Anemia (13%), REMS: Potential teratogen; if childbearing age,
(Opsumit) daily nasopharyngitis/ use two contraceptive methods (reduced efficacy
Nonselective pharyngitis (20%), of hormonal contraceptives); monthly pregnancy
endothelin receptor bronchitis (12%), test required
antagonist (ETA and headache (14%), Periodic Hgb/Hct monitoring (recommended at
ETB) influenza (6%), and initiation and as clinically indicated; studies
urinary tract infection required laboratory tests at baseline, 3 months, 6
(9%) months, and every 6 months thereafter)
Baseline LFTs and, if clinically indicated, signs
of liver failure such as nausea, vomiting, right
upper quadrant pain, anorexia, vomiting,
etc. (trials did not show increased risk of
hepatotoxicity)
Active metabolite contributes 40% of activity

Half-life of parent drug is 16 hours and active
metabolite 48 hours
CYP3A4 and CYP2C19 (lesser) substrate

Avoid strong CYP3A4 inducers (e.g., rifampin)
and strong CYP3A4 inhibitors (e.g., ritonavir,
ketoconazole stated in labeling but also
clarithromycin, itraconazole, posaconazole,
voriconazole)
Sildenafil 20 mg PO Headache, epistaxis, Half-life 4–5 hours
(Revatio) three times daily facial flushing, bluish May augment effects of other vasodilators when
Phosphodiesterase (doses as high or blurry vision, light used in combination (especially prostacyclin,
inhibitor as 80 mg three sensitivity, dyspepsia, α-blockers, amlodipine, other antihypertensives,
times daily have insomnia and alcohol)
Class II–IV PAH been used in Contraindicated in patients receiving nitrates
some trials) Sildenafil is a CYP3A4 substrate
Avoid combined use with strong CYP3A4
inhibitors (e.g., ritonavir, cimetidine,
erythromycin) and inducers (rifampin) (The
FDA lists cimetidine as a weak inhibitor and
erythromycin as a moderate inhibitor)
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Cardiology I
Drug/Mechanism/
Tadalafil 40 mg PO Headache, flushing, Half-life 17.5 hours
(Adcirca) once daily; indigestion, nausea, May augment effects of other vasodilators when
Phosphodiesterase initiate 20 mg backache, myalgia, used in combination (especially prostacyclin,
inhibitor PO once daily nasopharyngitis, α-blockers, antihypertensives, alcohol)
if concomitant respiratory tract Contraindicated in patients receiving nitrates
Class II–IV PAH
ritonavir infection If CrCl = 31–80 mL/minute, initiate 20 mg PO once
daily and titrate as tolerated
If CrCl < 30 mL/minute or hemodialysis, avoid use
If Child-Pugh class A or B, initiate 20 mg PO once
daily and titrate as tolerated
If Child-Pugh class C, avoid use
Tadalafil is a CYP3A substrate
Avoid use with potent CYP3A4 inhibitors
(erythromycin, ketoconazole, itraconazole,
grapefruit juice)/inducers (rifampin,
carbamazepine, phenytoin, phenobarbital)
When initiating ritonavir, discontinue tadalafil
at least 24 hours before starting ritonavir; then
reinitiate tadalafil at 20 mg daily after at least 1
week of ritonavir
Riociguat 1 mg PO three Headache, dyspepsia, P-gp and BCRP substrate (consider lower dose for
(Adempas) times daily up to GERD, gastritis, patients receiving concomitant strong inhibitors;
sGC stimulatorb 2.5 mg PO three nausea, vomiting, cyclosporine is an inhibitor of BCRP)
times daily (can dizziness, hypotension,
For chronic No experience with CrCl < 15 mL/minute
be tapered to bleeding, anemia,
thromboembolic
0.5 mg PO three diarrhea, constipation Contraindicated with nitrates and NO donors
PH and class II–IV
times daily if including specific PDE-5 inhibitors (sildenafil,
PAH
intolerance) tadalafil, vardenafil) or nonspecific PDE-5
inhibitors (dipyridamole, theophylline)
Potential teratogen; if childbearing age, use two
contraceptive methods (reduced efficacy of
hormonal contraceptives); monthly pregnancy
test required
Black box warning regarding embryo/fetal
toxicity: REMS for female patients regardless of
childbearing potential; pharmacies must register
and dispense only to authorized users
a
SERAPHIN study results: Macitentan 10 mg daily reduced the risk of the primary composite end point - Death, atrial septostomy, lung transplantation,
initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of PAH - By 45% compared with placebo with hazard ratioHR
0.55 (97.5% CI, 0.39–0.76; p<0.001). Other results included a significant increase in 6-minute walk of 12.5 m and a reduction in hospitalizations.
b
sGC is an enzyme in the cardiopulmonary vasculature that serves as the receptor for NO. Activation of sGC by NO causes synthesis of cGMP,
regulating vascular tone, proliferation, fibrosis, and inflammatory processes. Riociguat has a dual mechanism of action: (1) Sensitizes sGC to
endogenous NO through stabilization of the sGC-NO complex and (2) direct agonist of sGC (not NO-dependent). Riociguat induces vasodilation
through stimulation of the NO-sGC-cGMP pathway by increasing concentrations of cGMP.
AAD = antiarrhythmic drug; BCRP = human breast cancer resistance protein; cGMP = cyclic guanosine monophosphate; CI = confidence interval;
CrCl = creatinine clearance; CYP = cytochrome P450; ET antagonists = endothelin antagonists; FDA = U.S. Food and Drug Administration; GERD =
gastroesophageal reflux disease; Hct = hematocrit; Hgb = hemoglobin; HR = heart rate; INR = international normalized ratio; IV = intravenous; LFT
= liver function test; NO = nitric oxide; OATP = organic anion transport protein; PAH = pulmonary arterial hypertension; PDE-5 = phosphodiesterase
type-5; P-gp = P-glycoprotein; PO = orally; REMS = Risk Evaluation and Mitigation Strategies; sGC = soluble guanylate cyclase.
Reference: Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol 2013;62(25
suppl):D60-72.
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Cardiology I
Table 65. Cost Comparison of Oral Agents Used to Treat PAH in Nonresponders to CCB Therapy
Drug AWP Unit Price 30-Day Supply
Riociguat (Adempas, Bayer AG) 2.5-mg tablets $100.00/tablet tid $9000.00
Bosentan (Tracleer, Actelion) 125-mg tablets $136.80/tablet bid $8208.00
Macitentan (Opsumit, Actelion) 10-mg tablets $273.60/tablet daily $8208.00
Ambrisentan (Letairis, Gilead) 10-mg tablets $257.93/tablet daily $7737.90
Sildenafil (Revatio, Pfizer) 20-mg tablets $25.72/tablet tid $2314.80
Tadalafil (Adcirca, Lilly) 20-mg tablets $34.85/tablet x 2 tablets daily $2091.00
AWP = average wholesale price; bid = twice daily; CCB = calcium channel blocker; PAH = pulmonary arterial hypertension; tid = three times
daily.
From: Red Book Online [Internet]. Greenwood Village, CO: Truven Health Analytics, 2014. Available at http://www.redbook.com/redbook/
online/. Accessed January 20, 2014
Patient Cases
P.L. is a 35-year-old woman with PAH associated with HIV infection who has dyspnea and fatigue with activities of daily
living but not at rest. Her LFT results are normal, hemoglobin concentration is 13.5 g/dL, and CrCl is 90 mL/minute.
22. Which option best represents the World Health Organization (WHO) functional class in which her PAH
symptoms fall?
A. I.
B. II.
C. III.
D. IV.
23. P.L. is unresponsive to vasodilator testing. Concomitant medications include ritonavir-boosted atazanavir
and tenofovir disoproxil fumarate/emtricitabine. Atazanavir is a CYP3A4 inhibitor. Which is the best first-
line therapy for treatment of PAH in P.L.?
A. Sildenafil.
B. Ambrisentan.
C. Bosentan.
D. Macitentan.
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Cardiology I
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Coll Cardiol 2013;62(suppl):D42-50.
7. McLaughlin VV, Gaine SP, Howard LS, et al. Treat-
ment goals of pulmonary hypertension. J Am Coll Car-
diol 2013;62(suppl):D73-81.
8. Pulido T, Adzerikho I, Channick RN, et al. Macitentan
and morbidity and mortality in pulmonary arterial hy-
pertension. N Engl J Med 2013;369:809-18.
9. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated
clinical classification of pulmonary hypertension. J Am
Coll Cardiol 2013;62(suppl):D34-41.
10. Tackett KL, Stajich GV. Combination pharmaco-
therapy in the treatment of pulmonary arterial hyper-
tension: continuing education article. J Pharm Pract
2013;26:18-28.
11. Tackett KL, Stajich GV. Combination pharmaco-
therapy in the treatment of pulmonary arterial hy-
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Pract 2013;26:18-28.
12. Yao AY. Recent advances and future perspectives in
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Cardiology I
ANSWERS AND EXPLANATIONS TO PATIENT CASES

1. Answer C mends “optional” aspirin for a 10-year risk of 5%–10%.
The clinical probability score for this patient is 4; thus, Only the Chest guidelines recommend aspirin because
he has a high probability of experiencing a DVT (see Ta- the patient is older than 50 years. Dual antithrombotic
ble 3). He presents with swelling of his entire right lower therapy significantly increases bleeding risk. Therefore,
extremity (1 point), erythema, and soreness of his right with unsure benefit and increased risk, aspirin therapy
calf (1 point); he was recently bedridden because he un- should at least be temporarily interrupted while the pa-
derwent knee replacement surgery 2 weeks ago (1 point), tient is receiving anticoagulation.
and he has a history of DVT (1 point). There is no “very
high” risk category. 6. Answer D
The patient’s CHADS2 score is 3: age 75 years or older (1
2. Answer B point), uncontrolled HTN (1 point), and diabetes mellitus
Use of D-dimer testing is effective to rule out VTE in the (1 point). A score of 0 is low risk, 1 is intermediate risk,
setting of a low pretest clinical probability; however, it is and 2 or greater is high risk.
not as useful in cases of high pretest clinical probability.
The diagnosis of DVT should be confirmed by objective 7. Answer: D
testing before anticoagulation therapy is initiated. Al- The patient’s HAS-BLED score is 4: uncontrolled HTN
though venography is the gold standard for diagnosis of (1 point), age older than 75 years (1 point), and prior
DVT, it is rarely used in clinical practice because of tech- bleeding (1 point, concomitant aspirin 1 point). Patients
nical difficulty and risk of adverse effects. A CT scan with scores of 3 or higher are at a high risk of bleeding.
of the chest is used in the diagnosis of PE and not DVT.
Duplex ultrasonography is considered a noninvasive test, 8. Answer A
has very good sensitivity and specificity for DVT, and is OptionAnswer B is incorrect because the patient’s CrCl
therefore considered the diagnostic test of choice. is less than 50 mL/minute, and the correct dose of ri-
varoxaban is 15 mg orally daily. OptionAnswer C is
3. Answer A incorrect because a dabigatran dose of 150 mg twice
Although this is a recurrent DVT for this patient, in- daily is appropriate for a CrCl of 48 mL/minute. Aspirin
definite treatment is not necessary. The previous DVT plus clopidogrel is not an anticoagulant therapy, making
episode was secondary to a reversible risk factor (as is OptionAnswer D incorrect. The patient has only one of
the current DVT) and occurred more than 25 years ago. the factors to dose-adjust apixaban (low body weight);
Treatment for at least 3 months is an evidence-based rec- therefore, the usual dose of apixaban 5 mg twice daily
ommendation. Longer treatment durations could be con- orally is correct. Apixaban is also an appropriate choice
sidered after 3 months, depending on the patient’s prefer- because it is the only agent among the answers to show
ence and whether the patient tolerates the treatment well. lower bleeding risk than warfarin.
4. Answer C 9. Answer: D
Answer C (rivaroxaban 15 mg orally twice daily for 21 The patient’s EF is less than 40%; therefore, she has
days, followed by 20 mg orally daily thereafter) is correct. HFrEF, not HFpEF (LVEF greater than 50%), making
OptionAnswers A, B, and D have either incorrect doses OptionAnswer A and OptionAnswer B incorrect. The
or frequencies. See Tables 7 and 8 for dosing guidelines. patient has symptoms with minimal activity and is there-
fore in NYHA class III rather than II, making Option-
5. Answer D Answer A and OptionAnswer C incorrect. The patient
Many patients do not have an indication for dual anti- has structural heart disease, as evidenced by her reduced
thrombotic therapy. In this case, whether the patient LVEF, and has symptoms; therefore, she does not have
should even receive aspirin for primary prevention is stage-B HF, making OptionAnswer A and OptionAn-
controversial, with the U.S. Preventive Services Task swer C incorrect. The patient has stage-C HF (structural
Force recommending no aspirin at all because this pa- heart disease and symptoms) and reduced EF, making
tient’s 10-year ASCVD risk is less than 10%, whereas Answer D correct.
the AHA/American Diabetes Association(ADA) recom-
2-108
Cardiology I
10. Answer: C 13. Answer: B

The patient’s serum digoxin concentration is within the Because the patient has HFpEF and HTN, the goal is to
target desired for HF (0.4–0.9 ng/mL), making OptionAn- control BP according to established guidelines. He has
swer A incorrect. The patient’s serum potassium concen- no jugular venous distension or peripheral edema, so the
tration is above 5 mEq/L; thus, an MRA should not be diuretic dose should not be increased, making OptionAn-
initiated currently, making OptionAnswer B and Option- swer A incorrect. The MRAs are indicated for HFrEF or
Answer D incorrect. The initial spironolactone dose for a as a fourth-line antihypertensive agent, making Option-
patient with a CrCl of 36 mL/minute is 12.5 mg daily or Answer C incorrect. The JNC 8 (Eighth Joint National
every other day, making OptionAnswer B incorrect. The Committee) recommends a goal BP of less than 140/90
initial eplerenone dose for a patient with a CrCl of 36 mL/ mm Hg. His current HR is high enough to increase the
minute is 25 mg every other day, making OptionAnswer metoprolol dose, making Answer B correct.
D incorrect. The combination of hydralazine and a nitrate
was shown to reduce mortality in the AHeFT trial, and it 14. Answer: D
is recommended by the 2013 ACCF/AHA HF guideline This patient has HFrEF. Patients with unstable HF were
to be added to a β-blocker and ACE inhibitor for cases of excluded from the RACE II trial comparing strict with
persistent symptomatic NYHA class III or IV HF in an lenient rate control; current AF practice guidelines de-
African American patient, making Answer C correct. scribing the goal HR in AF exclude patients with an
LVEF less than 40%, making Answer D correct and Op-
11. Answer: B tionAnswers A, B, and C incorrect.
The patient, who has HFrEF, is receiving a target dose
of an ACE inhibitor. Therefore, adding an ARB is not 15. Answer: B
recommended, and Option Answer A is incorrect. The OptionAnswer A is incorrect because the patient is not
patient is not African American and is not receiving receiving anticoagulation and has not had a TEE show-
an MRA, and the patient has no contraindication to an ing no left atrial clot. OptionAnswer C and Option-
MRA (renal function or potassium); therefore, an MRA Answer D are incorrect because dofetilide is initiated
is preferred to adding hydralazine plus nitrates current- only in hospitalized patients (and after serum, potas-
ly, making Option Answer C incorrect. The estimated sium, and magnesium concentrations are shown to be
CrCl of this patient is 87 mL/minute; therefore, the ini- normal). Answer B is correct because anticoagulation
tial eplerenone dose recommended is 25 mg/day, making is indicated for at least 3 weeks before cardioversion
Option Answer D incorrect. The correct spironolactone in the absence of a TEE. Rate control can be enhanced
dose for a patient with a CrCl of 87 mL/minute is 12.5– with an increased carvedilol dose, which may also be
25 mg/day, making Answer B correct. titrated to a target dose (25 mg orally twice daily) ac-
cording to the patient’s diagnosis of HFrEF.
12. Answer: A
The patient has HF symptoms and an EF greater than 50%; 16. Answer: B
therefore, the patient has HFpEF, making Option Answer This patient has an EF greater than 40%; therefore, the
C and Option Answer D incorrect. The patient has no HF target HR, as specified in the 2011 ACCF/AHA/HRS
symptoms at rest and therefore does not have NYHA class AF guidelines, is less than 110 beats/minute (lenient
IV symptoms, making Option Answer B and Option An- rate control), making Answer B correct and OptionAn-
swer D incorrect. Answer A is correct because the patient swers A, C, and D incorrect.
has HFpEF and symptoms with minimal activity.
2-109
Cardiology I
17. Answer: D 20. Answer: D

This patient has a structurally normal heart. Amiodarone Dabigatran should be avoided in patients with bioprosthetic
is reserved for patients with structurally abnormal hearts valves, making OptionAnswer C incorrect. This patient is
(e.g., reduced LVEF) because of its toxicities with chronic at high risk of stroke because the patient has a bioprosthetic
use, making OptionAnswer A incorrect. The patient is valve plus AF; thus, anticoagulation is indicated, making
currently taking hydrochlorothiazide, which is contra- OptionAnswer A, dual antiplatelet therapy, incorrect. The
indicated with dofetilide; therefore, OptionAnswer B is Chest guidelines recommend an INR of 2–3 for patients
incorrect. Dronedarone has toxicities similar to those of with a bioprosthetic valve and AF; therefore, Answer D is
amiodarone and is therefore reserved for patients whose correct and OptionAnswer B is incorrect.
other agents fail and who are intolerant of amiodarone;
thus, OptionAnswer C is incorrect. According to the 2011 21. Answer: D
ACCF/AHA/HRS AF guidelines, flecainide is a first-line Guidelines recommend that in the absence of a requirement
choice for patients with structurally normal hearts without for anticoagulation (e.g., AF in this patient), dual
QT prolongation, making Answer D correct. antiplatelet therapy with low-dose aspirin and clopidogrel
be given for 3 months after TAVR. This patient received 1
18. Answer: D month of anticoagulation therapy; therefore, an additional
The patient has been receiving amiodarone for weeks; 2 months of dual antiplatelet therapy with low-dose aspirin
therefore, drug interactions are already manifest. The in indicated, making Answer D correct. OptionAnswer A
patient’s INR is within goal so the warfarin dose should not is incorrect because it is single antiplatelet therapy, and
be changed, making OptionAnswer A and OptionAnswer the dose of aspirin is too high. OptionAnswer B and
C incorrect. The patient has not yet received a 10-g OptionAnswer C are incorrect because they represent
loading dose of amiodarone; therefore, the current dose single antiplatelet therapy.
of 400 mg should not be reduced, making OptionAnswer
B incorrect. The serum digoxin concentration is above the 22. Answer: C
goal range for a patient with HF (less than 1.0 ng/mL), and This patient has symptoms with ordinary daily activity, but
the patient’s HR is low; therefore, the digoxin dose should not at rest, making Answer C correct and OptionAnswer
be reduced. The maximal simvastatin dose that should be A (no symptoms), OptionAnswer B (symptoms only at
coadministered with amiodarone is 20 mg (see Table 574). moderate activity), and OptionAnswer D (symptoms at
Therefore, Answer D is correct. rest) incorrect.
19. Answer: D 23. Answer: B

This patient has a history of GI bleeding and therefore Sildenafil (OptionAnswer A), bosentan (OptionAnswer
has a higher risk of bleeding. Anticoagulation is C), and macitentan (OptionAnswer D) should be avoided
indicated because this is a mechanical heart valve. in patients taking CYP3A4 inducers or strong CYP3A4
OptionAnswer B is incorrect because dabigatran is inhibitors and are not preferred in patients taking any
contraindicated in a patient with a mechanical heart inhibitors or substrates for CYP3A4. Ambrisentan has
valve. For mechanical valves in the aortic position, the only one clinically significant drug interaction with
intensity of warfarin recommended is an INR of 2–3; cyclosporine; thus, ambrisentan would be preferred for
therefore, OptionAnswer C is incorrect and Answer D is this patient, for whom the HIV medications must need to
correct. Aspirin is indicated at a dose of 81 mg for stroke be maintained, making Answer B correct.
prevention in all patients who are at low risk of bleeding;
therefore, OptionAnswer A is incorrect.
2-110
Cardiology I
ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS

1. Answer: C current HR is 140 beats/minute; therefore, Option Answer
Warfarin should be overlapped with heparin for at least A is incorrect. The patient’s BP is high enough to tolerate
5 days, making Option Answer A incorrect. The FDA- an increased β-blocker dose. Enalapril does not lower HR,
approved rivaroxaban dose for treatment of a PE is 15 mg and the patient is at goal BP; therefore, Option Answer
twice daily, followed by 20 mg daily; thus, Option An- C is incorrect. Because warfarin is not effective imme-
swer B is incorrect. The dabigatran dose tested in the RE- diately, it would require overlap with warfarin for at least
MEDY and RE-SONATE trials was 150 mg twice daily, 2–3 days before warfarin would become effective, making
and parenteral anticoagulation is required for 5−10 days Option Answer B incorrect.
before starting dabigatran; therefore, Option Answer D
is incorrect. The apixaban dose studied in the AMPLIFY 6. Answer: C
trial was 10 mg twice daily for 7 days, followed by 5 mg Digoxin is not effective for converting or maintaining
twice daily for 6 months; therefore, Answer C is correct. NSR, making Option Answer A incorrect. The guidelines
recommend that patients with structural heart disease
2. Answer: D (e.g., HFrEF) avoid sotalol and flecainide, making Option
Rivaroxaban is a direct-acting factor Xa inhibitor. The Answer B and Option Answer D incorrect.
sensitivity to a change in INR with PT, as well as aPTT
and activated clotting times, is variable; therefore, Option 7. Answer: C
Answer A is incorrect. The best measure of effect of a The 2012 HRS guidelines recommend catheter ablation only
factor Xa concentration is an anti-Xa concentration; thus, for symptomatic patients with persistent or paroxysmal AF
Answer D is correct. who have not responded to or had an arrhythmia recurrence
while receiving one or more antiarrhythmic medications.
3. Answer: C Therefore, the patients in Options Answers A, B, and D have
The patient has valvular heart disease and a bioprosthet- indications for catheter ablation of AF and these answers are
ic valve; therefore, newer oral anticoagulants should be incorrect. The patient in Answer C has permanent AF and
avoided, making Option Answer B incorrect. The Ameri- therefore is not a candidate for ablation.
can College of Chest Physicians recommends warfarin for
the first 3 months, followed by low-dose aspirin for stroke 8. Answer: C
prevention after bioprosthetic mitral valve placement; Liver function tests and a thyroid-stimulating hormone
therefore, Option Answer A, aspirin alone at the time of test are recommended to be done every 6 months, making
hospital discharge, is incorrect. The target INR therapeu- Answer C correct. A lipid panel, SCr, and serum sodium
tic range for a patient with a bioprosthetic valve and re- are not a recommended component of amiodarone moni-
quiring anticoagulation is 2–3, making Answer C correct. toring, making Option Answer A and Option Answer B
incorrect. Pulmonary function testing is recommended
4. Answer: A only if the patient has symptoms; therefore, Option An-
Because of the increased risk of hyperkalemia when a swer D is incorrect.
mineralocorticoid receptor antagonist is added to an ACE
inhibitor, frequent monitoring of potassium—within 3 9. Answer: A
days, at 1 week, and then monthly for the first 6 months— The dose of warfarin should be reduced by 33%–50%
is recommended by the 2013 ACCF/AHA HF guidelines, when amiodarone is added; therefore, Answer A is cor-
making Answer A correct and OptionAnswers B, C, and rect. No dosing adjustments are required with rivaroxa-
D incorrect. ban or atorvastatin when amiodarone is added; therefore,
Option Answer B and Option Answer C are incorrect.
5. Answer: D Although amiodarone has β-blocking activity, the meto-
β-Blockers are the first-line rate control medication rec- prolol dose need not be reduced proactively, but the HR
ommended by the ACCF/AHA/HRS AF guidelines; should be monitored during the early phase of therapy in
therefore, Answer D is correct. The patient requires ad- patients who do not have a pacemaker. Therefore, Option
ditional rate control because the goal HR is less than 110 Answer D is incorrect.
beats/minute for a patient with HFpEF, and the patient’s
2-111
Cardiology I
10. Answer: D
The patient has sinus bradycardia and an HR of 50 beats/
minute. Therefore, increasing the metoprolol dose (Op-
tionAnswer A) and adding diltiazem (Option Answer
B) are incorrect because this would increase the risk of
heart block. Nitrates are contraindicated in severe aortic
stenosis because they are venodilators, reducing preload
and then LV volume, which may lead to worsening myo-
cardial ischemia and hypotension because of reduced
cardiac output, making Option Answer C incorrect. An-
swer D, amlodipine, is a second-line antianginal agent
for a patient with severe aortic stenosis. Amlodipine does
not lower HR but may increase coronary artery blood
flow; it would therefore be preferred in a patient unable
to tolerate other agents secondary to bradycardia.
11. Answer: D
For a patient in sinus rhythm, combination therapy with
low-dose aspirin and clopidogrel is recommended for at
least 3 months in patients undergoing TAVR, making
Answer D correct. There is no published experience with
prasugrel and TAVR, making Option Answer C incor-
rect. Anticoagulation would be indicated only for a pa-
tient with another reason for anticoagulation, such as AF,
and in those situations, there are no specific guideline
recommendations regarding triple therapy with antico-
agulation plus dual antiplatelet therapy or anticoagula-
tion with a single antiplatelet agent. Option Answer A
and Option Answer B contain anticoagulation and are
incorrect because the patient is in sinus rhythm.
12. Answer: C
The only agent that requires LFT monitoring is bosentan,
a selective endothelin antagonist. Therefore, Answer C is
correct, and OptionAnswers A, B, and D are incorrect.
2-112

Cardiology I

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Cardiology I

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Cardiology I

Orly Vardeny, Pharm.D., BCACP

Learning Objectives Self-Assessment Questions

9. A 68-year-old patient with HTN, AF, and HFpEF

10. An 80-year-old woman has HTN, severe aortic ste-

11. According to current practice standards, which is

12. In a patient being treated for pulmonary arterial

I. ANTITHROMBOTIC THERAPY FOR VENOUS THROMBOEMBOLISM

B. Etiology (Domain 1, Task 1)

C. Risk Factors for VTE (Domain 1, Task 2)

Table 1. Risk Factors for VTE in Hospitalized Medical Patients

Table 2. VTE Risk Stratification for Surgical Populations

D. Deep Venous Thrombosis (DVT) (Domain 1, Tasks 1–, 2, 3)

2. Signs and symptoms of DVT

E. Pulmonary Embolism (Domain 1, Tasks 1–, 2, 3)

Table 4. Signs and Symptoms of PE

Table 4. Signs and Symptoms of PE (continued)

Signs and Symptoms of Massive PE

2. Considerations for the use of injectable anticoagulants in the treatment of VTE

Table 7. Injectable Options for the Treatment of Acute VTE

3. Considerations for the use of warfarin in the treatment of VTE

d. Patient counseling points (see Table 36)

II. ANTITHROMBOTIC THERAPY IN ATRIAL FIBRILLATION

6. Tools for nonvalvular atrial fibrillation (NVAF) stroke risk stratification

CHADS2 Stroke Risk Factor Points

Table 10. CHADS2 Score and Recommended Antithrombotic Therapya−c

CHA2DS2-VASc Stroke Risk Factor a Points

Table 11. CHA2DS2-VASc Score and Recommended Antithrombotic Therapya

d. Risk stratification considerations

c. Adjusted-dose warfarin versus newer anticoagulants

Table 12. Major Outcomes of New Anticoagulants vs. Adjusted-Dose Warfarina

8. Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE)

III. ANTITHROMBOTIC AGENTS: PHARMACOLOGIC AND CLINICAL CONSIDERATIONS

A. Unfractionated Heparin (Domain 1, Tasks 2, 3, 4, 7)

B. Low-Molecular-Weight Heparin (Domain 1, Tasks 2, 3, 4, 7)

C. Indirect Factor Xa Inhibitor (synthetic pentasaccharide) (Domain 1, Tasks 2, 3, 4, 7)

Table 13. Comparison of UFH, LMWHs, and Fondaparinux

D. Warfarin (Domain 1, Tasks 2, 3, 4, 5, 6, 7)

Table 14. Elimination Half-lives of Vitamin K–Dependent Clotting Factors

Table 15. Comparison of R- and S-Warfarin

h. Warfarin is 99% bound to plasma proteins (mostly albumin).

Table 16. Warfarin Initiation in Outpatients

7. Maintenance dosing of warfarin therapy

HAS-BLEDa Uncontrolled hypertension (SBP > 160 mm Hg) 1 Score MB/pt-yr

b. The “purple toe syndrome”

Table 20. Clinically Important Warfarin Drug Interactions

Table 21. Vitamin K Content of Select Foodsa

ii. Other dietary and herbal supplements

Table 22. Warfarin Drug Interactions with Dietary Supplements

Unknown Decreased INR Ginseng

Table 23. Warfarin Drug-Disease State Interactions

Table 23. Warfarin Drug-Disease State Interactions (continued)

Clinical Condition Effect on Warfarin Therapy

E. Newer Target-Specific Oral Anticoagulants: Dabigatran (Domain 1, Tasks 2, 3, 4, 5, 6, 7; Domain 3, Tasks 2, 3)

Table 24. Dabigatran Characteristics

Table 25. Dabigatran – Considerations for Use

CrCl > 30 mL/minute: 150 mg orally twice daily

CrCl 15–30 mL/minute: 75 mg orally twice daily

CrCl < 15 mL/minute or receiving dialysis: Not recommended

Hemodialysis (see above)