Advances in Heart Failure

Venous Thromboembolism in Hospitalized Patients With

Heart Failure
Incidence, Prognosis, and Prevention
Tien M.H. Ng, PharmD; Fausan Tsai, MD; Nudrat Khatri, MBBS;
Mohamad N. Barakat, MD; Uri Elkayam, MD

H eart failure (HF) is a common cardiovascular cause of

hospitalizations in the United States and the most frequent
reason among patients aged 65 years and older.1 A recent report
surgery, trauma, immobility, malignancy, venous compres-
sion, previous VTE, advanced age, pregnancy, medications
(especially estrogen and erythropoiesis stimulating agents),
by the National Hospital Discharge Survey showed an increase obesity, myeloproliferative disorders, and acute medical ill-
in the number of hospital admissions with a diagnosis of HF ness.18 22 Many of these are also apparent in the hospitalized
from 1.3 million in 1979 to 3.9 million in 2004, with 30% to patients with HF. Characteristics of patients from the Acute
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35% of these carrying a primary diagnosis of HF.2 Recent data Decompensated Heart Failure National Registry, which in-
from several large registries of HF hospitalizations have dem- cludes 160 000 patient visits, reported a median age of 75
onstrated in-hospital mortality as high as 4% to 7%.3,4 Contrib- years, active malignancy in 5%, and history of stroke or
uting to this is a significant incidence of VTE among hospitalized transient ischemic attack in 17%.23 Renal insufficiency and
patients with HF.5 In addition, VTE is associated with thromboem- dialysis are also associated with an increased risk for deep
bolic complications, which are associated with long-term sequelae venous thrombosis (DVT) and PE,24 27 and may be present in
including postthrombotic syndromes, venous stasis, venous ulcers,
up to one third of hospitalized patients with HF.23 Ischemic
chronic thromboembolic pulmonary hypertension, and pulmonary
cardiomyopathy is arguably the most common cause of HF in
embolism (PE).68 These conditions are often associated with
the United States. Atherosclerotic disease and risk factors for
edema and chronic pain, which can have a significant impact on
development of obstructive coronary artery disease have also
mobility and quality of life. Recurrent VTE and PE are also
common complications reported in as many as 30% of patients.9 been linked to risk for VTE. In a study of 299 patients with
Published information suggests that despite availability of DVT and no symptomatic atherosclerosis and 150 controls,
effective therapy and existence of practice guidelines,10,11 spontaneous thrombosis was associated with a 2.3-fold in-
there is a significant underutilization of VTE prophylaxis in creased odds of having at least 1 carotid plaque.28 Similarly,
hospitalized patients with HF.1215 Analysis of the Acute in a study comparing 136 patients with peripheral vascular
Decompensated Heart Failure National Registry revealed that disease and 40 controls, the incidence of ultrasound-defined
of 71 376 patients eligible for VTE prophylaxis only 21 847 VTE was higher in the patients with peripheral vascular
(31%) received prophylactic regimen.16 An analysis of the disease (20%) than the controls (4%).29 Additional evidence
PREMIER database showed that although 79% of 34 286 comes from a meta-analysis of 63 552 patients in 21 case-
patients admitted with HF received an order for VTE prophy- control or cohort studies that compared traditional cardiovas-
laxis, only 15.8% received recommended appropriate prophy- cular risk factors and risk for VTE. This study concluded that
lactic regimen in terms of the type of medications, dose, and presence of obesity (odds ratio, 2.33), hypertension (1.51),
duration of therapy.17 These data clearly demonstrate the need diabetes (1.42), smoking (1.18), and dyslipidemia (1.16) were
for increased awareness of prevention of VTE in hospitalized all associated with an increased risk for VTE.29a These
patients with HF. Therefore, the purpose of this article is to cardiovascular risk factors were also common in Acute
review the incidence, clinical significance, and preventive treat- Decompensated Heart Failure National Registry.23 These
ment of VTE in hospitalized patients with HF. traditional risk factors and comorbid conditions have been
shown to be predictive of PE in patients with HF.30
Rationale for VTE Prophylaxis in Patients with HF are also at risk for upper extremity VTE.
Hospitalized Patients With HF Risk factors such as pacemakers/implantable cardioverter
Risk Factors for VTE in HF defibrillators and central venous catheters are commonplace
In general, hospitalized patients can exhibit many of the in patients with HF.23 In an analysis of the US Multicenter
traditional risk factors for the development of VTE including Registry of 5451 patients with ultrasound-confirmed DVT,

From the Heart Failure Program, Division of Cardiovascular Medicine, University of Southern California, Keck School of Medicine and School of
Pharmacy, Los Angeles, Calif.
Correspondence to Uri Elkayam, MD, Division of Cardiology, Heart Failure Program, University of Southern California Medical Center, Keck School
of Medicine, 1200 N State St, Room 7621, Los Angeles, CA 90033. E-mail Elkayam@usc.edu
(Circ Heart Fail. 2010;3:165-173.)
2010 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org DOI: 10.1161/CIRCHEARTFAILURE.109.892349

165
 166 Circ Heart Fail January 2010

presence of an indwelling central venous catheter was the Table 1. Incidence of VTE in Hospitalized Patients With HF
strongest independent predictor of DVT (odds 7.3).31 Study Patient Population Incidence of VTE, %
Finally, there is also evidence to suggest the risk for
Beemath et al42 58 873 000 hospitalized 0.73 PE; 1.03 DVT
thromboembolism, including VTE, in HF may be graded and
patients with HF
correlate to the degree of left ventricular dysfunction. In an
Alikhan et al43 290 hospitalized patients with 14.6
analysis of 103 patients who experienced a stroke in the
HF aged 40 years or older
Survival and Ventricular Enlargement trial, each 5% decre-
Leizorovicz et al44 3706 hospitalized medical 4.96
ment in ejection fraction was associated with an 18% increase
patients aged 40 years or
in the relative risk (RR) of fatal or nonfatal stroke.32 Strik- older (51% HF)
ingly, the same relationship was seen in a post hoc analysis of
Cohen et al45 849 medical patients aged 60 10.5
2114 patients with no history of atrial fibrillation in the years or older (25% HF)
Sudden Cardiac Death in Heart Failure Trial.33 For each 5%
increase in left ventricular ejection fraction, there was an patients who experienced either a DVT or a PE, HF was
associated 18% reduction in risk for thromboembolism. In found to contribute 9.5% of the attributable risk after adjust-
addition, in a case-control study of DVT in a veterans affairs ment for other risk factors.6 In addition, symptoms of PE in
hospital, HF was associated with an overall 2.6-fold increased patients with HF may be largely underestimated and attrib-
risk, which jumped to 38.3-fold higher in patients with an uted to HF manifestations. A postmortem interrogation of
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ejection fraction 20%.21 implantable defibrillators in 83 patients with HF found that

the prime mode of death was not an arrhythmia in 69% of the
Procoagulant State in HF patients, with 16.9% dying of thromboembolic events includ-
Hospitalized patients with HF are at increased risk for VTE, ing PE, stroke, and other forms of peripheral embolization.49
most commonly presenting as DVT and PE, which are An autopsy study in 152 patients with dilated cardiomyopa-
associated with significant morbidity and mortality. Throm- thy revealed either pulmonary or systemic emboli or both in
boembolic risk is due to a variety of mechanisms including more than half of the patients.50
stasis of blood because of dilatation of cardiac chambers,
reduced myocardial contractility, decreased mobility, and Prognosis
increased intracardiac and central venous pressures.34,35 In Importantly, available data suggest that the occurrence of
addition, increase in plasma viscosity,36,37 altered coagulabil- VTE in hospitalized patients with HF is associated with poor
ity,35,36,38 inflammation,39 neurohormonal activation,37 and clinical outcomes. In a pooled analysis of trials evaluating the
endothelial dysfunction40 also contribute to the hypercoagu- role of angiotensin-converting enzyme inhibitors in 7000
lable state.35,36,38,41 patients with HF, PE was identified as the fifth most common
cause of death.51 In a prospective cohort study of 198 severe
Incidence and Risk for VTE in Hospitalized decompensated patients with HF, PE was associated with
Patients With HF longer length of hospital stay (37.571.6 days versus
The incidence of VTE in hospitalized patients with HF has 15.415.0 days, P0.001) and greater death or rehospital-
been described in a retrospective registry and prospective ization at 3 months (72.2% versus 43.9%, P0.02) compared
studies of VTE prophylaxis, which have included a substan- with those without PE.52
tial number of patients with HF on placebo (Table 1).42 46 In In summary, there seems to be a large discrepancy between
retrospective observations suggesting a low incidence of
a retrospective analysis of data from the National Hospital
thromboembolic events and prospective or autopsy studies
Discharge Survey, DVT and PE were diagnosed in 1.03% and
that show a relatively high incidence of clinically occult VTE,
0.73% of patients with HF, respectively.42 Although these
which is likely to contribute to the short- and long-term
figures may seem small, the RRs compared with patients
morbidity and mortality of patients with HF.
without HF were 2.15 for PE and 1.21 for DVT. In addition,
these data most likely represent an underestimation of the true Current Recommendations for Prevention of
prevalence of thromboembolic events in patients with HF VTE in Patients With HF
because of the retrospective study design and the clinically For acutely ill medical patients admitted to hospital with HF,
silent nature of thromboembolic complications. This is sup- the eighth American College of Chest Physicians Guidelines
ported by a higher incidence of complications reported in for the Prevention of Thromboembolism recommend throm-
prospective clinical studies of VTE prophylaxis that included boprophylaxis with either low dose unfractionated heparin
patients with HF. In these studies, the placebo rates of DVT (LDUH), low molecular weight heparin (LMWH), or
ranged from 4.0% to 14.6% in the HF subgroups.43 45 The fondaparinux (all grade 1A), except for patients with contra-
assumption of underestimation by the retrospective registry is indications to anticoagulant thromboprophylaxis for whom an
also supported by the studies that demonstrate that HF is a optimal use of mechanical thromboprophylaxis is recom-
common comorbid condition in patients with VTE. The mended (grade 1A).11
International Cooperative Pulmonary Embolism Registry of
2454 patients with acute PE reported concomitant HF in Evidence for Efficacy of Drug Therapy in HF
10.5% of these patients.47 A similar registry of 5451 DVT LDUH
patients identified congestive HF in 13% of the study popu- No randomized clinical trials have evaluated the efficacy and
lation.15,48 In a population-based, case-control study of 625 safety of LDUH for VTE prophylaxis specifically in HF,
 Ng et al Venous Thromboembolism in Heart Failure 167

although several small studies have included patients with HF HF specific data.58,61 68 A randomized, double-blind con-
(Table 2).5358 Specifically, 2 randomized trials have demon- trolled trial in a high-risk group of 959 hospitalized medical
strated a reduction in incidence of VTE in a subset of patients patients compared enoxaparin 40 mg once daily with LDUH
with HF (26 and 63 patients, respectively) with a regimen of 5000 U three times daily. Enoxaparin was found to be at least
heparin 5000 U given subcutaneously every 8 hours com- as efficacious as LDUH with fewer adverse events. A
pared with placebo or control.53,54 Overall, early randomized randomized, double-blind controlled trial in 442 hospitalized
studies in medical patients support the effectiveness of elderly patients bedridden for acute illness demonstrated
heparin given as 5000 U every 8 or 12 hours for reducing the similar efficacy of enoxaparin 20 mg once daily compared
incidence of VTE (mainly DVT and PE) without an increased with LDUH 5000 U twice daily.64 A large randomized,
risk for bleeding.11,69 double-blind controlled trial of 1590 hospitalized bedridden
patients, aged 50 to 80 years, including 293 patients with HF
LMWH compared enoxaparin 36 mg once daily with LDUH 5000 U
Only 2 randomized studies that evaluated LMWH for prophy- three times daily for 8 to 11 days65 and found enoxaparin and
laxis of VTE in medical patients also reported findings in a LDUH to be equivalent in incidence of VTE. More recently,
subgroup of patients with HF (Table 2).43,44,46,59 61 The Prophy- the Thromboembolism-Prevention in Cardiac or Respiratory
laxis in Medical Patients with Enoxaparin (MEDENOX) trial Disease with Enoxaparin trial, a randomized, open-label
randomized 1102 hospitalized patients, immobilized for 3 controlled study, randomized 451 patients with HF or severe
days, to enoxaparin 20 mg or 40 mg once-daily for up to 14 respiratory illness who were confined to bed for two thirds
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days or placebo.46 The primary end point was DVT detected of each day, to enoxaparin 40 mg once daily or LDUH 5000
by bilateral venography, duplex ultrasonography, or docu- U three times daily.66 Although the results including all
mented PE between days 6 and 14, with a follow-up of 110 patients demonstrated equivalence between the 2 therapies in
days. Of the 1102 patients, 34% were hospitalized for New incidence of venographically detected VTE, in the subset of
York Heart Association class III or IV HF. In these patients, 206 patients with HF, enoxaparin was associated with a
the incidence of VTE was 14.6% (12.3% class III and 21.7% numerically lower incidence of VTE (9.7% versus 16.1%,
class IV). Enoxaparin 40 mg was associated with a significant P0.0139 for equivalence). No patients with HF developed
reduction in incidence of VTE at 2 weeks compared with PE during enoxaparin therapy, whereas 1 patient in the
placebo (4.0% versus 14.6%, P0.02), with the greatest LDUH group was found to have PE on autopsy. In the entire
effect seen in class IV (0.0% versus 21.7%, P0.05).43 The study population, there were no differences between enox-
incidence of adverse events was not specified for the sub- aparin and LDUH in minor and major bleeding; however,
group of patients with HF; but in the total MEDENOX study injection hematoma was more frequent in those who received
population, there was no significant difference between all 3 LDUH. Adverse events related to the drug used occurred less
study groups in death (placebo 13.9% versus enoxaparin 20 often with enoxaparin than with LDUH.
mg 14.7% versus enoxaparin 40 mg 11.4%, PNS), major
bleeding (2.0% versus 1.2% versus 3.4%, PNS), or throm- Fondaparinux
bocytopenia (4.8% versus 3.2% versus 2.8%, PNS) at 110 Fondaparinux, a synthetic indirect factor Xa inhibitor, has
days. also been shown to be effective for VTE prevention in
The value of dalteparin for VTE prophylaxis was evaluated medical patients. The Arixtra for Thromboembolism Preven-
in the PREVENT (Prevention of Venous Thromboembolism tion in a Medical Indications Study, a double-blind trial of
in Acutely Ill Medical Patients) trial, a randomized, double- patients aged 60 years and older, randomized 429 patients to
blind, placebo-controlled multicenter study of 3706 patients, fondaparinux 2.5 mg subcutaneously once daily and 420
aged 40 years and older, hospitalized for an acute medical patients to placebo for 6 to 14 days.45 Overall, fondaparinux
condition.44 The patients were randomized to dalteparin 5000 was associated with a lower incidence of VTE (RR 0.53, 95%
IU or placebo for 14 days and followed up for 90 days. The CI 0.31 to 0.92, P0.029) with no difference in major
primary end point was a combination of symptomatic or bleeding (0.2% with each study treatment). In the subset of
asymptomatic DVT detected by ultrasound, symptomatic PE patients admitted with only HF (New York Heart Association
at day 21, and sudden death by day 21. The number of functional class III or IV), fondaparinux (9.0%, 7 of 78
patients with acute congestive HF, New York Heart Associ- patients) was associated with a reduced incidence of symp-
ation class III or IV, was 52% in the dalteparin group and tomatic or venographically detected VTE compared with
51% in the placebo group. In the entire study cohort, the placebo (12.2%, 10 of 82 patients). It should be noted that
primary end point was lower with dalteparin compared with fondaparinux exhibits a long half-life, which can be pro-
placebo; however, there were no significant differences at day longed in renal insufficiency. Thus, the dose may require
14, 21, or 90 in the incidence of mortality, major bleeding, or adjustment. Because worsening of renal function often occurs
thrombocytopenia. In a retrospective analysis of PREVENT, during hospitalization, it is important to continually reassess
the RR of the primary end point in patients with acute the appropriate dosing of fondaparinux or the choice of
congestive HF was 3.07% in the dalteparin group versus heparin for prophylaxis.
4.23% in the placebo group (RR 0.73; 95% CI 0.44 to 1.21).59
Considerations in Patients With HF and
Studies Comparing LDUH and LMWH Renal Insufficiency
Four randomized clinical trials and 1 retrospective study have The guidelines recommend that renal function be considered
compared LDUH and LMWH with 4 of the studies reporting when making decisions about the use and dose of LMWH,
 168 Circ Heart Fail January 2010

Table 2. Studies of VTE Prophylaxis in Medically Ill Patients, Which Included Patients With HF
VTE Results
VTE Prophylaxis
Study Study Population Study Design Regimens Overall Study Population HF Subgroup
UFH
Gallus53 272 high-risk surgical R, C UFH 5000 U TID vs Medical patients only: DVT: UFH UFH (1/11) 0.91% vs P
and 78 medical patients P 2.6% vs P 22.5%, P0.05 (7/15) 46.7% (P value
not available)
Belch et al54 63 patients with HF or 37 R UFH 5000 U TID vs DVT: UFH 4% vs control 26%,
with chest infection control P0.01
Halkin et al55 1358 patients admitted to Consecutive, alternating UFH 5000 U BID vs Mortality: UFH 7.8% vs control Cardiopulmonary disorder
medical wards of acute treatment assignment control 10.9%, P0.025 (N267): UFH 3.1% vs
care hospital control 4.9% (P value not
available)
Cade56 119 critically ill ICU R, DB, C UFH 5000 U BID vs Critically ill patients: DVT: UFH
patients and 131 medical P 13% vs P 29%, P0.05
patients Medical patients: DVT: UFH 2%
vs P 10%, PNS
Gardlund57 11 693 infectious disease R, C UFH 5000 U BID vs Necropsy-verified PE: UFH 15 HF was a finding on
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department admissions control vs Control 16, PNS; median necropsy in 141 of 383
time to fatal PE: UFH 28 vs (37%) patient deaths
control 12.5 days, P0.007
nonfatal VTE: UFH 70 vs control
116, P0.0012
Mismetti et al58 845 Meta-analysis UFH vs control DVT: RR 0.44 (0.29 to 0.64,
P0.001)
PE: RR 0.48 (0.34 to 0.68,
P0.52)
LMWH
Samama et al46 866 medical patients R, DB, C E 40 mg daily vs E DVT or PE: E 40 mg 5.5% vs E 34% of patients were
older than 40 years 20 mg daily vs P 20 mg 15.0% vs P 14.9%, E hospitalized for NYHA FC
40 mg vs P, P0.001 E 20 mg III or IV HF
vs P, PNS. Death from any
cause: E 40 mg 3.3% vs E 20
mg 4.3% vs P 4.4%
Alikhan et al43 290 patients with HF Post hoc analysis of E 40 mg daily vs E E 40 mg 4.0% vs P
older than 40 years Samama et al 20 mg daily vs P 14.6%, P0.02
NYHA FC III: E 40 mg
5.1% vs P 12.3%,
P0.2
NYHA FC IV: E 40 mg
0% vs P 21.7%, P0.05
Chronic HF: E 40 mg
2.2% vs P 12.1%,
P0.04
Leizorovicz 3706 medical patients R, DB, C D 5000 IU once DVT or PE: D 2.77% vs P Acute HF (N1905),
et al44 aged 40 years and older daily vs P 4.96%, P0.0015 trend favoring D: D
3.07% vs P 4.23%,
PNS
Cohen et al59 All-cause mortality: D 2.35% vs
P 2.32%, PNS
McGarry and 3719 medical patients Retrospective, database E 30 to 60 mg DVT: E 1.9% vs control 6.2%,
Thompson60 aged 40 years and older once daily P0.023
(N162) vs Control PE: E 0.0% vs control 1.0%,
PNS
Death: E 8.0% vs control 7.3%,
PNS
Kanaan et al61 7639 Meta-analysis LMWH vs P DVT: OR 0.92 (0.56 to 1.52, 29.4% patients with HF
P0.75) in entire study population
PE: OR 0.80 (0.22 to 2.89,
P0.73)
VTE: OR 0.89 (0.54 to 1.46,
P0.64)
(Continued)
 Ng et al Venous Thromboembolism in Heart Failure 169

Table 2. Continued
VTE Results
VTE Prophylaxis
Study Study Population Study Design Regimens Overall Study Population HF Subgroup
Comparative
studies of UFH vs
LMWH
Harenberg 166 medical patients R, DB, C UFH 5000 U TID vs DVT: UFH 4.8% vs LWMH 3.4% 23 (13.8%) patients with
et al62 LMWH 1.5 aPTT HF
units once daily
Lechler et al63 959 medical patients R, DB, C UFH 5000 U TID vs DVT: UFH 1.4% vs E 0.2%,
E 40 mg once P0.12, P0.05 for
daily equivalence
Bergmann and 442 elderly patients R, DB, C UFH 5000 U TID vs DVT or PE: UFH 4.6% vs E Incidence of cardiac
Neuhart64 bedridden for acute E 20 mg once 4.8%, P0.0005 for failure was similar
medical illness daily equivalence between patients with
VTE vs patients without
VTE (35% vs 29%,
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PNS)
Harenberg 1590 bedridden patients R, DB, C UFH 5000 U TID vs DVT or PE: UFH 0.51% vs E 293 (18.5%) patients
et al65 aged 50 to 80 years E 36 mg once 0.74%, P0.012 for with HF
daily equivalence
Kleber et al66 206 HF and 245 severe R, O, C UFH 5000 U TID vs DVT or PE: UFH 10.4% vs E 206 patients with HF:
respiratory disease E 40 mg once 8.4%, P0.015 for equivalence UFH 16.1% vs E 9.7%,
patients daily P0.0139 for
equivalence
Incidence of VTE was
higher in patients with
HF (HF 12.6% vs
respiratory disease 6.8%)
McGarry et al67 3316 medical patients Retrospective, database UFH 5000 to DVT or PE: UFH 6.3% vs E 1004 patients with HF
aged 40 years and older 15 000 U/day vs E 1.7%, P0.001 (UFH 810, E 194)
30 to 60 mg/day
Mismetti et al58 4669 Meta-analysis LMWH vs UFH DVT: RR 0.83 (0.56 to 1.24,
P0.37)
PE: RR 0.74 (0.29 to 1.88,
P0.52)
Kanaan et al61 3581 Meta-analysis LMWH vs UFH DVT: OR 0.92 (0.56 to 1.52, 29.4% patients with HF
P0.75) in entire study population
PE: OR 0.80 (0.22 to 2.89,
P0.73)
VTE: OR 0.89 (0.54 to 1.46,
P0.64)
Any prophylaxis
vs no treatment
Dentali et al68 19 958 Meta-analysis UFH or LMWH or F Symptomatic DVT: RR 0.47
vs P or No (0.22 to 1.00)
Treatment Any PE: RR 0.43 (0.26 to 0.71)
Fatal PE: RR 0.38 (0.21 to 0.69)
All-cause mortality: RR 0.97
(0.79 to 1.19)
Factor Xa
inhibitors
Cohen et al45 849 medical patients R, DB, C F 2.5 mg once DVT or PE: F 5.6% vs P 10.5%, 160 patients with HF: F
aged 60 years and older daily vs P P0.029 9.0% vs P 12.2%
Symptomatic VTE: F 0.9% vs P (P value not provided)
2.6%, P0.029
Death: F 3.3% vs P 6.0%,
P0.06
NYHA FC indicates New York Heart Association functional classification; C controlled; D, dalteparin; DB, double-blind; E, enoxaparin; F, fondaparinux; ICU, intensive
care unit; O, open-label; P, placebo; R, randomized; UFH, unfractionated heparin.
 170 Circ Heart Fail January 2010

fondaparinux, and other antithrombotic drugs that are cleared Although no information has been published on the subgroup
by the kidneys, particularly in elderly patients, patients with of patients with HF in the EXCLAIM study, the results of the
diabetes mellitus, and those with a high risk for bleeding study suggest that continuation of VTE prophylaxis may be
(grade 1A). Depending on the circumstances, it may be beneficial in patients with HF who continue to be immobile
necessary to avoid the use of an anticoagulant that bioaccu- after discharge, but this needs to be supported by further
mulates in the presence of renal impairment, use a lower dose investigations.
of the agent, or monitor the drug level or its anticoagulant
effect (grade 1B). Improving VTE Prophylaxis in HF
Despite established guidelines recommending prophylaxis
Nonpharmacologic Approaches to against VTE in the majority of hospitalized patients, multiple
VTE Prevention studies and registries continue to demonstrate underutiliza-
In patients with contraindications to pharmacological prophy- tion.14,77 Postulated reasons include lack of awareness, complex-
laxis, mechanical approaches to VTE prevention may be an ity of the guidelines, lack of standardization or institutional
appropriate alternative. Despite very limited data in the protocols, and perceived bleeding risk. In a cross-sectional study
medically ill population, intermittent pneumatic compression of medical patients older than 40 years, the most common
and elastic compression stockings are commonly used in the documented reasons for avoiding pharmacological prophylaxis
United States.70 The only randomized study in medical were bleeding on admission and hepatic impairment.14 In the
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patients compared graduated compression stockings with no observational Canadian study of VTE prophylaxis in acutely ill
prophylaxis in 80 acute myocardial infarction patients.70a medical patients, cancer was associated with lower use.77 Data
DVT, detected by fibrinogen uptake test, was found in 8 also suggest that rates of prophylaxis may be greater at academic
control patients compared with no patients with stockings. institutions than community-based hospitals.77
Otherwise, the efficacy is extrapolated mainly from surgical Numerous studies have demonstrated the value of 3 main
studies, specifically general and orthopedic surgery7173 interventions related to improving adherence to VTE guide-
where these approaches, when applied the day before or the lines. (1) Computerized programs and physician alerts; (2)
day of surgery, was associated with a reduced incidence of personal alert systems, and (3) educational programs. Com-
VTE. Mechanical approaches when combined with pharma- puterized programs that estimate VTE risk and provide
cological prophylaxis is also associated with greater efficacy electronic reminders to the caring physician have been
than either approach alone.71,72,74 Unfortunately, these surgi-
universally shown to improve the proportion of eligible
cal studies did not stratify patients for DVT risk, thus making
patients who receive pharmacological and mechanical pro-
comparisons with the medically ill, such as patients with HF,
phylaxis.78 84 Although rates of pharmacological prophylaxis
difficult.
generally doubled in most studies, the largest improvement
was in use of mechanical prophylaxis. Importantly, in the
Duration of therapy
randomized and longitudinal observational studies, the elec-
Duration of prophylactic therapy of VTE in studies with
tronic alert system was associated with a significant decrease
hospitalized patients with HF has ranged from 6 to 14 days.
in the incidence of VTE.79,80 In the absence of a computerized
Discharged patients, however, may still remain relatively
immobile and are still at risk of developing VTE because of system, preprinted risk stratification scoring systems to iden-
venous stasis, altered coagulation, and endothelial dysfunc- tify VTE prophylaxis eligible hospitalized patients and per-
tion. The PREVENT and MEDENOX trials showed VTE still sonal or written physician alerts have also been shown to
occurring at 90 and 110 days of follow-up, respectively, improve VTE prophylaxis rates85,86 and reduce the incidence
raising the question of whether extended-duration therapy is of symptomatic VTE.85 In addition, institution or health-
needed.44,46 The EXtended Clinical prophylaxis in Acutely Ill system wide education programs using methods such as
Medical patients (EXCLAIM) study, randomized 5101 hos- in-services, institution guideline development, verbal remind-
pitalized patients (4114 included in final analysis) with ers, weekly audits with reporting, and clinical pharmacy led
varying degrees of immobility starting at least 3 days before education and monitoring have demonstrated efficacy at
randomization for reasons that included cancer, ischemic improving prophylaxis prescribing.8790 Ultimately, a combi-
stroke, HF, respiratory failure, and infections to either sub- nation of these methods may be the best approach. In a
cutaneous enoxaparin 40 mg once daily for an average of 10 systematic review of 30 studies that evaluated various strat-
days on an open-label basis.75,76 The majority of the patients egies for improving VTE prophylaxis in hospitalized patients,
were then randomized, double blindly, to receive either it was concluded that the most effective programs were those
placebo or continued prophylaxis for a mean of 28 additional that incorporated multiple methods, and the poorest effect
days. Continued prophylaxis resulted in a reduction of VTE was seen in response to interventions that only passively
from 4.9% to 2.8% (P0.0011). The significant reduction in disseminated the guidelines.91
VTE persisted out to 90 days (5.3% versus 3.1%, P0.0015). The current ACCP guidelines reflect the earlier findings.
However, there was no effect on all-cause mortality at 6 The guidelines recommend that each institution implement a
months (8.9% versus 10.1%, P0.18). Extended prophylaxis formal strategy to improve adherence to VTE prophylaxis
was associated with an increased incidence of total bleeding and that an institution-wide policy be adopted.11 They also
events (5.7% versus 3.8%, P0.007) and major bleeding recommend use of interventions to increase adherence such
events (0.6% and 0.15%, P0.019) in the enoxaparin group. as computer support systems, preprinted order forms, and
 Ng et al Venous Thromboembolism in Heart Failure 171

periodic audits with feedback. Using only passive methods 13. Peterman CM, Kolansky DM, Spinler SA. Prophylaxis against venous
such as distribution of educational materials is discouraged. thromboembolism in acutely ill medical patients: an observational study.
Pharmacotherapy. 2006;26:1086 1090.
14. Cohen AT, Tapson VF, Bergmann JF, Goldhaber SZ, Kakkar AK, Des-
Conclusions landes B, Huang W, Zayaruzny M, Emery L, Anderson FA Jr. Venous
There is a significant increase in the rate of thromboembolic thromboembolism risk and prophylaxis in the acute hospital care setting
events in hospitalized patients with HF, which seems to be (ENDORSE study): a multinational cross-sectional study. Lancet. 2008;
371:387394.
underrecognized and contributes importantly to the morbidity 15. Piazza G, Seddighzadeh A, Goldhaber SZ. Heart failure in patients with
and mortality in this patient population. Guidelines recom- deep vein thrombosis. Am J Cardiol. 2008;101:1056 1059.
mend that all hospitalized patients with HF who are not at 16. Jois-Bilowich P, Michota F, Bartholomew JR, Glauser J, Diercks D,
high risk for bleeding be treated prophylactically with LDUH, Weber J, Fonarow GC, Emerman CL, Peacock WF IV; Adhere Scientific
Advisory Committee and Investigators. Venous thromboembolism pro-
LMWH, or fondaparinux.11 Recent evidence shows a large phylaxis in hospitalized heart failure patients. J Card Fail. 2008;14:
gap between these guidelines and clinical practice. An effort 127132.
should be made to increase the awareness of both the risk for 17. Amin AN, Lin J, Yang G, Stemkowski S. Examining the rate of appro-
VTE in hospitalized patients with HF and the importance of priate, ACCP-recommended VTE prophylaxis use in heart failure
patients. J Card Fail. 2008;14:S83.
appropriate VTE prophylaxis in the majority of these patients. 18. Alikhan R, Cohen AT, Combe S, Samama MM, Desjardins L, Eldor A,
Janbon C, Leizorovicz A, Olsson CG, Turpie AG. Risk factors for venous
Disclosures thromboembolism in hospitalized patients with acute medical illness:
analysis of the MEDENOX Study. Arch Intern Med. 2004;164:963968.
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for Sanofi-Aventis. 19. Heit JA, Silverstein MD, Mohr DN, Petterson TM, OFallon WM, Melton
LJ III. Risk factors for deep vein thrombosis and pulmonary embolism: a
population-based case-control study. Arch Intern Med. 2000;160:
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 Venous Thromboembolism in Hospitalized Patients With Heart Failure: Incidence,
Prognosis, and Prevention
Tien M.H. Ng, Fausan Tsai, Nudrat Khatri, Mohamad N. Barakat and Uri Elkayam
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Circ Heart Fail. 2010;3:165-173

doi: 10.1161/CIRCHEARTFAILURE.109.892349
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