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 warfarin8,9 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.
