Thromboprophylaxis in medical-surgical intensive careunit patients

Deborah Cook MD, MSc(Epi)a,b,*, Mark A. Crowther MD, MSc(Epi)a, Jim Douketis MDa,for the VTE in the ICU Workshop Participants

aDepartment of Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5bClinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Received 30 July 2005; revised 29 August 2005; accepted 8 September 2005

1. Randomized trials of anticoagulantprophylaxis

Like most hospitalized patients, critically ill patients are

at risk for deep vein thrombosis (DVT) and pulmonary

embolism (PE). Although many diagnostic and therapeutic

emergencies demand the attention of the clinicians working

in the intensive care unit (ICU), prevention of venous

thromboembolism (VTE) remains an important goal.

Only two published randomized trials have tested

thromboprophylaxis in medical-surgical [1,2]. One dou-

ble-blind, single-center trial allocated 119 medical-surgical

ICU patients at least 40 years of age to unfractionated

heparin (UFH), 5000 U twice daily, or placebo subcutane-

ous injections [2]. Using serial I125-fibrinogen leg scanning

for 5 days, the rate of DVT was 13% in the UFH group and

29% in the placebo group (relative risk 0.45, P b .05).

Rates of bleeding and PE were not reported. In a more

recent multicenter trial [1], 223 patients with an acute

exacerbation of chronic obstructive pulmonary disease

requiring mechanical ventilation for at least 2 days were

allocated to the low-molecular-weight heparin (LMWH)

0883-9441/$ – see front matter D 2005 Published by Elsevier Inc.

doi:10.1016/j.jcrc.2005.09.007

T Corresponding author. Departments of Medicine and Clinical

Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario,

Canada. Tel.: +1 905 525 9140x22900; fax: +1 905 524 3841.

E-mail address: debcook@mcmaster.ca (D. Cook).

nadroparin, 3800 or 5700 IU once daily, or placebo.

Patients had screening compression ultrasound (CUS)

weekly and upon clinical suspicion of DVT; venography

was attempted in all patients. The rate of DVT was 16% in

the nadroparin group and 28% in the placebo group

(relative risk 0.67, P b .05). A similar number of patients

bled in each group (25 vs 18 patients, respectively, P =

.18). Although patients were not screened for PE, no

patients developed proven PE during the trial. Although

these trials have provided a foundation for practice, they

are limited by conduct almost 25 years ago using screening

modalities not in use today [2] or by venographic end point

diagnosis and comparison with placebo, which does not

represent current best practice [1].

Two further trials of some relevance to the critically ill

enrolled medical patients [3,4]. The first trial (MEDENOX)

enrolled hospitalized patients with heart failure, respiratory

failure not requiring mechanical ventilation, or one of the

following if associated with an additional DVT risk factor:

infection without septic shock, musculoskeletal disorder, or

inflammatory bowel disease [3]. Patients were excluded if

they required intubation, had a coagulopathy, or serum

creatinine greater than 150 lmol/L. Patients were random-

ized to receive once daily enoxaparin 40 mg, enoxaparin

20 mg, or placebo for 6 to 14 days. Patients had venography

between days 6 and 14 or as clinically indicated. Compres-

sion ultrasound was performed if venography was not

Journal of Critical Care (2005) 20, 320–323

Thromboprophylaxis in medical-surgical intensive care unit patients 321

feasible. Of 1102 randomized patients, 236 were not

included in the main analysis because the venogram could

not be evaluated (n = 72), was technically unfeasible (n =

12), was not performed (n = 4), or was not performed at the

investigators’ discretion (n = 58) or the patient refused (n =

62) or died (n = 28). Among the remaining 866 patients, the

DVT rate was 6% in patients receiving enoxaparin 40 mg

compared with 15% among patients receiving either

enoxaparin 20 mg or placebo (relative risk 0.37). Major

bleeding occurred in 12, 4, and 7 patients, respectively (P =

NS). Clinically suspected and objectively confirmed PE

developed in 1 patient in the enoxaparin 20 mg group and

3 patients in the placebo group, although PE events were not

evaluated in a standard manner according to a prespecified

protocol. The fact that these patients, although requiring

medical admission to hospital, were not critically ill limits

the generalizability of these findings to the ICU setting.

The second trial (PREVENT) [4] enrolled hospitalized

patients 40 years or older with an acute medical condition

requiring projected hospitalization of 4 or more days, with

3 or more days of prior immobilization. Patients had acute

congestive heart failure, respiratory failure not requiring

mechanical ventilation, infection without septic shock, acute

rheumatological disorders, or inflammatory bowel disease.

Except for patients with cardiac or respiratory failure,

patients had to have an additional DVT risk factor, such as

obesity, hormone replacement therapy, chronic venous

insufficiency, and myeloproliferative syndrome. Patients

were excluded if they required intubation, had a platelet

count less than 100� 109/L, or serum creatinine greater than

2.0 mg/dL. Patients were randomized to receive once daily

dalteparin 5000 IU or placebo for 14 days; if the patient was

discharged before then, medication was continued out of

hospital. The primary end point was a composite of

objectively confirmed symptomatic DVT (proximal or

distal), fatal or symptomatic nonfatal PE, sudden death

(sudden death within 24 hours of symptom onset), and

asymptomatic proximal DVT detected by CUS at day 21. Of

3706 patients enrolled in 26 countries, several were excluded

from the primary end point analysis at day 21 if the

ultrasound was not evaluable (327) or performed (363);

thus, 1518 and 1473 patients in the dalteparin and placebo

groups, respectively, were included. The primary composite

end point event rate was 2.77% (42/1518) in the dalteparin

group and 4.96% (73/1473) in the placebo group (relative

risk 0.55, 95% confidence interval [CI] 0.38-0.80, P =

.0015). Symptomatic PE occurred similarly (relative risk

0.82, 95% CI 0.25-2.67) and there was no difference in

morality at 14, 21, or 90 days (at 21 days, 2.35% vs 2.32%,

P = NS). Two patients in the dalteparin group and one in the

placebo group died of hemorrhage. The fact that the patients

in MEDENOX and PREVENT [3,4] were not critically ill

limits the generalizability of these findings to the ICU

setting. However, both studies support prior observations

that compared with no thromboprophylaxis, LMWH is

superior at avoiding VTE.

2. Randomized trials of mechanicalprophylaxis

There are no randomized trials in medical-surgical

critically ill patients testing the effect of pneumatic

compression devices or antiembolic stockings. However,

pneumatic compression devices have been tested in some

specific ICU populations. For example, among 422 trauma

patients in an unblinded trial, there was a trend toward a

higher rate of DVT in those randomized to pneumatic

compression devices (2.7%) compared with LWMH (0.5%)

(P = .122) [5]. In 2551 cardiac surgery patients studied in

an unblinded trial, those randomized to a combination of

UFH and pneumatic compression devices had a significant-

ly lower PE rate (1.5%) compared with UFH thrombopro-

phylaxis alone (4.0%) (P b .001) [6]. Challenges with

generalizing these data to the ICU setting include the

moderate methodologic quality of these trials, poor com-

pliance with both types of mechanical approaches, lack of

availability of pneumatic compression devices, their dis-

comfort in conscious ICU patients, and the acquisition cost.

A Cochrane Review of 9 randomized trials testing

antiembolic stockings, which included orthopedic, neuro-

surgery, general surgery, obstetrics, and general medical

patients, offers little evidence to guide clinicians about the

merits of mechanical thromboprophylaxis in the ICU

setting [7]. The quality of these trials is generally poor

and the applicability of their results to the ICU setting is

questionable. For example, antiembolic stockings are not

properly sized for critically ill patients; those that are too

large are likely ineffective, whereas those that are too tight

because of obesity, edema, or slippage down the leg can

create a tourniquet effect, with the potential to predispose

to vasoconstriction, retrograde blood flow, and venous

stasis. In addition, the loss of elastance associated with

continued use (with or without washing) is unlikely to

sustain the increased venous return associated with their

initial application.

3. Thromboprophylaxis compliance inmedical-surgical ICU patients

Several prospective single-center utilization reviews

provide evidence about DVT prophylaxis in clinical practice

[8-11]. Prophylaxis was given in 33% of 152 medical ICU

patients in one study and 61% of 100 medical ICU patients

in another [9]. In contrast, in a medical-surgical ICU in

which a clinical practice guideline was in place, DVT

prophylaxis was given in 86% of 209 patients [10]. In

another study of medical-surgical ICU patients that exclud-

ed patients who were receiving therapeutic anticoagulation

and in whom heparin was contraindicated, 63% of 96

patients received DVT prophylaxis [11].

In a 1-day cross-sectional multicenter utilization review,

UFH was used predominantly [12]. We considered a range of

Table 1 Randomized clinical trials of heparin thromboprophylaxis in ICU

Reference Population Diagnosis Control rate Intervention rate NNT

Cade [2] 119 General

ICU patients

Fibrinogen

leg scanning

Placebo 29% UFH 5000

U bid 13%

6

Kapoor et ala [13] 791 MICU patients DUS on d1 and q3d Placebo 31% UFH 5000

U bid 11%

5

Goldhaber et ala [14] 325 MICU patients DUS on d3, 7, 10, 14 UFH 5000 U bid 13% Enoxaparin

30 mg bid 16%

–

Fraisse et al [1] 223 COPD patients

ventilated z48 h

Venography by d21 Placebo 28% Nadroparin ~70

AXa U/kg qd 15%

7

All drugs were administered subcutaneous injection. MICU indicates medical intensive care unit; COPD, chronic obstructive pulmonary disease; DUS,

Doppler compression ultrasound; d1, day 1 of ICU admission; bid, twice daily; AXa, anti-Xa factor activity; qd, once daily; NNT, number needed to treat.a Abstract publication only.

D. Cook et al.322

patients including those with an admission diagnosis of

hemorrhage and the potential for immediate postoperative

bleeding to highlight the dual risks of thrombosis and

bleeding. Two methods of VTE prophylaxis were prescribed

for 20 (22%) of 89 patients. Prophylaxis with UFH or

LMWH was significantly less likely for postoperative ICU

patients requiring mechanical ventilation compared with

patients weaned from mechanical ventilation later in their

ICU course (odds ratio [OR] 0.36, P = .03). Use

of intermittent pneumatic compression devices was signif-

icantly associated with active bleeding (OR 13.5, P = .021)

and an increased risk for future bleeding (OR 19.3, P = .001).

Few multicenter observational studies document the

penetrance of effective thromboprophylaxis in the ICU. In

a 1-day binational cross-sectional utilization review of

medical ICU patients in France and Canada [9], we found

that among 1222 patients (65% of whom were mechanically

ventilated), prophylaxis with UFH was given in 63.9% of

patients, similarly between the two countries. Excluding

patients with contraindications to heparin and those

receiving therapeutic anticoagulation, 91.7% of medical

ICU patients appropriately received prophylaxis with either

UFH or LMWH. Independent predictors of any type of

heparin prophylaxis were invasive mechanical ventilation

(OR 2.4, 95% CI 1.4-4.3) and obesity (OR 3.1, 95%

CI 1.1-8.8). Low-molecular-weight heparin was less likely

to be given to patients with renal failure (OR 0.1, 95%

CI 0.0009-0.9) or those receiving antiembolic stockings

(OR 0.4, 95% CI 0.1-0.9) and much more likely to be

prescribed in French ICUs (OR 9.2, 95% CI 5.0-16.9);

however, among patients receiving LMWH, doses above

those normally used for prophylaxis were more likely to be

prescribed in Canadian ICUs (OR 8.7, 95% CI 2.0-37.6).

Patients who were pregnant or postpartum (OR 7.7, 95% CI

1.3-44.3), had neurological failure (OR 2.1, 95% CI 1.3-

3.4), or were in Canadian ICUs (OR 3.0, 95% CI 2.1-4.4)

were most likely to receive mechanical thromboprophylaxis

(with antiembolic stockings or pneumatic compression

devices), whereas those who were already receiving heparin

were less likely to receive mechanical thromboprophylaxis

(OR 0.5, 95% CI 0.3-0.7).

4. Summary

Only two randomized trials evaluating DVT prophylaxis

in medical-surgical critically ill patients have been pub-

lished. One trial demonstrated that UFH is better than no

prevention (number needed to prophylax with UFH, 5000 IU

twice daily, to prevent one DVT = 6) [2]. The second trial of

exclusively ventilated patients with chronic obstructive

pulmonary disease found that nadroparin is better than no

prevention (number needed to prophylax with weight-

adjusted LWMH to prevent one DVT = 7) [1]. Two further

thromboprophylaxis trials in the ICU published in abstract

form are included in Table 1. One tests UFH vs placebo and

generates similar results [13] to those noted previously [1,2].

The other tests UFH vs LMWH in a trial that was stopped

early and is thus inconclusive, illustrating the challenges of

conducting randomized trials in this field [14].

The use of effective DVT prophylaxis ranges widely,

according to utilization reviews. The variety of prophylactic

approaches used highlights the diverse and dynamic

competing risks of bleeding and thrombosis in heteroge-

neous ICU patients over the course of their critical illness,

thereby underscoring population-based and individual risk-

benefit ratios and delineating the need for large definitive

studies to guide prophylaxis regarding both anticoagulant

and mechanical thromboprophylaxis and their combination.

Anticoagulant thromboprophylaxis methods should be

optimized and individualized based on current and potential

risks of thrombosis and bleeding; indirect comparative

evidence suggests that anticoagulant prophylaxis is more

effective than mechanical prophylaxis. Fortunately, utiliza-

tion reviews do suggest the increasing penetrance of

effective heparin prophylaxis over time [15].

References

[1] Fraisse F, Holzapfel L, Couland JM, et al, and the Association of Non-

University affiliated Intensive Care Specialist Physicians of France.

Nadroparin in the prevention of deep vein thrombosis in acute

decompensated COPD. Am Rev Respir Crit Care Med 2000;161:

1109-14.

Thromboprophylaxis in medical-surgical intensive care unit patients 323

[2] Cade JF. High risk of the critically ill for venous thromboembolism.

Crit Care Med 1982;10:448 -50.

[3] SamamaMM, CohenAT, Darmon JY, Desjardins L, Eldor A, Janbon C,

et al. A comparison of enoxaparin versus placebo for the prevention of

venous thromboembolism in acutely ill medical patients. Prophylaxis in

Medical Patients with Enoxaparin Group. N Engl J Med 1999;

341:793-800.

[4] Leizorovicz A, et al, for the PREVENT Medical Thromboprophylaxis

Study Group. Circulation 2004;110:874-9.

[5] Ginzberg E, et al, for the Miami Deep Vein Thrombosis Study Group.

Randomized clinical trial of intermittent pneumatic compression and

low molecular weight heparin in trauma. Br J Surg 2003;90:1338-44.

[6] Ramos R, Salem PK, Pawlikowski MP, Coordes C, Eisesnberg S,

Leidenfrost R. The efficacy of pneumatic compression stockings in

the prevention of pulmonary embolism after cardiac surgery. Chest

1996;109:82 -5.

[7] Amarigiri SV. Elastic compression stockings for prevention of deep

vein thrombosis. Cochrane Library(3): [Oxford Update Software]; 2001.

[8] Keane MG, Ingenito EP, Goldhaber SZ. Utilization of venous

thromboembolism prophylaxis in the medical intensive care unit.

Chest 1994;106:13-22.

[9] Lacherade JC, et al, for the French and Canadian ICU Directors

Groups. Prevention of Venous Thromboembolism (VTE) in Critically

Ill Medical Patients. A Franco-Canadian Cross-sectional Study. J Crit

Care 2003;18(4):228 -37.

[10] Ryskamp RP, Trottier SJ. Utilization of venous thromboembolism

prophylaxis in a medical-surgical ICU. Chest 1998;113:162-4.

[11] Cook DJ, Attia J, Weaver B, et al. Venous thromboembolic disease: an

observational study in medical-surgical intensive care unit patients.

J Crit Care 2000;15(4):127 -32.

[12] Cook DJ, et al, for the Canadian ICU Directors Group. Prevention of

venous thromboembolism in critically ill surgery patients: a cross-

sectional study. J Crit Care 2001;16(4):161 -6.

[13] Kapoor M, Kupfer YY, Tessler S. Subcutaneous heparin prophylaxis

significantly reduces the incidence of venous thromboembolic events

in the critically ill. Crit Care Med 1999;27(Suppl):A69.

[14] Goldhaber SZ, Kett DH, Cusumano CJ, et al. Low molecular weight

heparin versus minidose unfractionated heparin for prophylaxis against

venous thromboembolism in a medical intensive care unit patients: a

randomized controlled trial. J Am Coll Cardiol 2000;35(Suppl):325A.

[15] Geerts W, Cook DJ, Selby R, Etchells E. Venous thromboembolism

and its prevention in critical care. J Crit Care 2002;17(2):95 -104.