Venous Thromboembolism Prophylaxis in Medical Patients

Introduction

Pharmacologic measures to prevent venous thromboembolism were first routinely incorporated into the practice of general surgeons, urologists, and orthopedic surgeons in 1975, after the landmark International Multicentre Trial was published.¹ This randomized trial allocated 4,121 surgical patients either to unfractionated heparin 5,000 U, beginning 2 hours preoperatively and continuing every 8 hours for 7 days, or to no heparin. Among the heparin-treated group, two patients had massive pulmonary embolism (PE) verified upon autopsy, compared with 16 among the no heparin group.

These dramatic differences were reinforced by a subsequent meta-analysis of 15,598 surgical patients in randomized trials of venous thromboembolism prevention with low fixed dose (“minidose”) heparin.² Those assigned to heparin prophylaxis had a two-thirds reduction in predominantly asymptomatic deep vein thrombosis (DVT), a one-third reduction in nonfatal pulmonary embolism, and a marked reduction in fatal PE (19 in heparin patients compared with 55 among controls). Based upon the results of these studies, unfractionated heparin in a dose of 5,000 U twice or three times daily, beginning 2 hours preoperatively, became the standard pharmacologic approach to perioperative prevention of DVT and PE.

Despite the intensive study of venous thromboembolism in thousands of surgical patients, the investigation of DVT and PE developing as a complication among medical patients hospitalized for other primary conditions has languished, except for in stroke and myocardial infarction patients. Several fundamental issues are apparent. First, the incidence of venous thromboembolism among hospitalized patients has not been precisely elucidated. Second, subsets of patients with potentially the greatest risk, such as those in medical intensive care units, warrant special attention. Third, the failure rates of conventional low-dose heparin prophylaxis and mechanical prophylaxis with intermittent pneumatic compression boots have not been adequately defined among contemporary hospitalized medical patients. Fourth, the Food and Drug Administration has not approved low molecular weight heparin (LMWH) for prophylaxis against venous thromboembolism in medical patients. Such approval awaits the design, execution, and analysis of appropriate clinical trials in this understudied population.

An Israeli study undertaken more than two decades ago provided intriguing evidence to support the concept that mortality reduction could be achieved in hospitalized general medical patients with low-dose heparin prophylaxis.³ This hypothesis was tested in 1,358 consecutive patients greater than 40 years of age who were admitted through the emergency department to the medical wards of an acute care hospital. Eligible patients with even numbered hospital records were assigned to receive 5,000 U low-dose heparin twice daily. Those with odd numbered records served as controls. Among patients allocated to heparin, there was a 31% reduction in mortality from 10.9% in the control group to 7.8% in the heparin group. The reduction in mortality in the heparin-treated group was evident from the first day, and the difference increased significantly and consistently with time until the end of the study period. Because the death rate was highest in the first 2 days in both groups, the reduction in mortality in absolute numbers was greatest on those 2 days. However, the relative mortality reduction remained stable throughout the study period.

While low-dose heparin was demonstrated in the 1970s to be effective and safe for the prevention of venous thromboembolism in many thousands of surgical patients, only miniscule studies were carried out among medical patients during that era. For example, the Royal Infirmary in Glasgow studied 100 medical patients hospitalized with heart failure or chest infection.⁴ Patients were randomized to receive either heparin 5,000 U every 8 hours or to receive no specific prophylaxis measures. The diagnosis of DVT was established by iodine-125 fibrinogen leg scanning, which was undertaken in all study patients within 24 hours of hospitalization and repeated every other day for 14 days or until hospital discharge. The results in this group of hospitalized medical patients were dramatic. Among controls, 26% developed DVT, whereas the rate was only 4% among those receiving low-dose heparin.

In a trial in 1986 that focused on octogenarian medical inpatients, a placebo-controlled, randomized, double-blind study⁵ utilized a once daily low molecular weight heparin (Pharmuka 10169, subsequently renamed enoxaparin). The dose was 60 mg injected subcutaneously once daily. The potential development of DVT was assessed by iodine-125 fibrinogen leg scanning in all patients. The trial lasted 10 days, and 270 patients were enrolled. The majority of subjects suffered from heart failure, respiratory diseases, stroke, or cancer. Of 263 evaluable patients, 9% in the placebo group developed DVT, compared with 3% of those receiving LMWH prophylaxis. Except for injection site hematomas, bleeding complications were not appreciably increased in the LMWH group.

A trial involving 11,693 medical patients with infectious diseases randomized patients to receive either 5,000 U of heparin every 12 hours or no prophylaxis.⁶ Although patients were treated for a maximum of 3 weeks, follow-up was carried out for a maximum of 2 months. Heparin prophylaxis delayed the occurrence of fatal PE from a median of 12 days to a median of 28 days. Far more nonfatal thromboembolic complications in the control group (116 vs. 70, p = 0.0012). However, the prespecified primary endpoint was clinically relevant, autopsy-verified PE. In this respect, there was virtually no difference between the two groups: 15 heparin treated and 16 control group patients had autopsy-verified fatal PEs. This large trial, which yielded disappointing results, may have been flawed had the following study design flaws: 1) a lack of statistical power to detect a difference between the two groups in the primary endpoint, 2) the restriction of heparin prophylaxis to 3 weeks, and 3) an inadequate dose of heparin. (Keep in mind that the International Multicentre trial¹ used low-dose heparin every 8 hours, not every 12 hours.)

In the past decade, low molecular weight heparin has supplanted unfractionated heparin for prophylaxis against venous thromboembolism in total hip replacement⁷ and has proved superior both to warfarin^8,9 and to graduated compression stockings¹⁰ for total knee replacement. This does not necessarily mean, however, that low molecular weight heparin will prove superior to unfractionated heparin, warfarin, or graduated compression stockings for prophylaxis of hospitalized medical patients.

The MEDENOX trial of enoxaparin prophylaxis in medical patients completed enrollment of approximately 1,100 subjects in July 1998. Patients were randomized to one of three groups in a double-blind controlled trial: enoxaparin 20 mg once daily, enoxaparin 40 mg once daily, or placebo. The principal endpoint is the incidence of DVT as assessed by contrast venography on approximately day 10 of hospitalization. The results of this crucially important trial which favored enoxaparin 40 mg once daily, will be presented at the August 1999 XVII Congress of the International Society on Thrombosis and Haemostasis.

Also, the Veterans Affairs Cooperative Studies Program has organized a randomized trial to study the effect of low-dose heparin prophylaxis on mortality among hospitalized general medical patients.¹¹ Results will be available in about 5 years.

Intermittent pneumatic compression devices constitute an alternative, nonpharmacologic approach to prevent PE and DVT. Though effective, special care must be taken to ensure that these devices are worn as prescribed.¹² Frequent removal and nonuse can be problematic, especially in patients outside of an intensive care unit. In addition to the mechanical effect of increasing venous blood flow in the legs, these devices appear to cause an increase in endogenous fibrinolysis, due to stimulation of the vascular endothelial wall.^13-15

It is possible that for hospitalized medical patients, combined mechanical and pharmacologic prophylaxis will find a special niche. For example, in certain surgical subspecialties, combined prophylaxis modalities are routinely used. Urologists combine intermittent pneumatic compression boots and adjusted-dose warfarin following radical prostatectomy.¹⁶ Neurosurgeons employ compression boots plus fixed, low-dose heparin in craniotomy patients with malignancies.¹⁷

The medical intensive care unit setting remains one of the last frontiers where the culture of routine venous thromboembolism prophylaxis is not well developed. Prophylaxis should be part of the standard admission orders, just like H₂-blockers or carafate are almost always ordered routinely to prevent stress ulcers. Intensive care unit patients pose special challenges when planning prophylaxis strategies. First, these patients are often bleeding overtly or are admitted with thrombocytopenia. Accordingly, heparin or warfarin are often contraindicated. Second, leg ulcers, wounds, or peripheral arterial occlusive disease will preclude the use of intermittent pneumatic compression devices. With these problems in mind, it is useful to examine the current state of prophylaxis among intensive care unit patients.

In 1994, the Venous Thromboembolism Research Group at Brigham and Women’s Hospital found that only one-third of consecutive patients admitted to the Medical Intensive Care Unit received prophylaxis against PE and DVT.¹⁸ In a subsequent survey of this population, one-third of patients developed DVT, and half of these were proximal leg DVTs. Overall, 56% received prophylaxis.¹⁹ Surprisingly, prophylaxis appeared to have little impact on DVT rates. The overall DVT rate in patients who had received either heparin or pneumatic compression prophylaxis was 34%, compared with 32% in patients who did not receive any prophylaxis. This observation should be interpreted cautiously because these patients were not randomly allocated to prophylaxis.

There is currently no consensus on optimal prophylaxis for medical intensive care unit patients.²⁰ Two prior trials have failed to show the superiority of low molecular weight heparin compared with unfractionated low-dose heparin among hospitalized medical patients.^21,22 These two trials may have administered subtherapeutic doses of LMWH.

We have just completed a multicenter, randomized, controlled trial of heparin 5,000 U twice daily (“miniheparin”) versus enoxaparin 30 mg twice daily among Medical Intensive Care Unit patients. This multicentered study has the principal endpoint of venous thrombosis proven by ultrasound examination. Approximately, almost 300 patients have been enrolled. We expect to present the results of this trial at the August 1999 XVII Congress of the International Society on Thrombosis and Haemostasis.

• References

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