The Role of Low-Molecular-Weight Heparin for DVT Prophylaxis in Acutely Ill Medical Patients

Abstract

Background: The majority of pulmonary embolism mortality occurs in the acutely ill medical patient, thus it  is  of paramount importance to consider prophylaxis against venous thromboembolism in this population.  The goal of this paper was to conduct a systematic  review of the published literature to delineate the role of the low-molecular-weight heparins (LMWH) compounds for deep vein thrombosis (DVT) prophylaxis in acutely ill medical patients.

Methods: A MEDLINE search (July 1966 – May 2000) was conducted to identify all randomized, controlled trials comparing LMWH to control or to low-dose unfractionated heparin (UFH) in hospitalized medical patients that reported the incidence of venous thrombosis as the primary outcome.  Studies that were non-randomized, assessed danaparoid or other heparinoids, or included predominately patients with acute stroke, myocardial infarction or spinal cord injury were excluded from the analysis.

Results: Three studies involving a comparison of LMWH to placebo in a variety of acutely ill medical populations were identified.  Patients not receiving LMWH prophylaxis experienced a high incidence of venous thrombosis (14-28%) as compared to those patients receiving thromboprophylaxis with a LMWH  (5.5-15.5%).  The investigators of eight studies involving a comparison of UFH versus LMWH found no difference in the incidence of venous thrombosis (DVT or pulmonary embolus) or mortality between these groups.  The use of LMWH was associated with a lower reported incidence of both major hemorrhage and thrombocytopenia as compared to that reported for UFH therapy.

Conclusions: Acutely ill medical patients, particularly those with risk factors for venous thrombosis, should receive thromboprophylactic therapy.  Low-molecular-weight heparin  therapy appears to be no more effective than UFH therapy, but may be associated with fewer adverse drug events such as major bleeding.

Introduction

Prevention of thromboembolic disease in hospitalized patients is an important therapeutic issue, as venous thromboembolic disease has become a major public health concern.  Although 10% of hospitalized patient deaths can be attributed to pulmonary embolism, only 25% of these deaths occur in the surgical population.  The majority of pulmonary embolism mortality occurs in the acutely ill medical patient, thus it  is  of paramount importance to consider prophylaxis against venous thromboembolism in this population.

The incidence of venous thromboembolic disease has been well documented in medical patients and ranges from 10-26% in epidemiological studies to 33% in autopsy-based studies. The risk of venous thrombosis is greatest in patients with known risk factors.  In particular, venous thrombosis has been reported to occur in approximately 24% of patients with a myocardial infarction, 42% of patients experiencing a stroke, and as high as 33% of patients admitted to the medical intensive care unit. Other risk factors for venous thromboembolic disease in medical patients include intrinsic factors such as age, obesity, history of venous thromboembolism, and extrinsic factors such as immobilization, cancer, cardiac or respiratory failure, myocardial infarction, paralytic stroke and severe infectious diseases. Various classification systems have also been developed to objectively assess and categorize  (i.e. low, moderate or high) the risk of venous thromboembolic risk in medical patients.

While extensive clinical benefit and cost-effectiveness data exist to support the routine use of thromboprophylaxis in surgical patients, the routine use of thromboprophylaxis against venous thrombosis in general medical patients remains controversial. While certain high-risk medical groups (e.g. paralytic stroke or myocardial infarction) should receive pharmacological prophylaxis, the situation remains less clear for the majority of hospitalized medical patients.

Until recently, the literature pertaining to the prevention of venous thrombosis in acutely ill medical patients has been relatively sparse.  While more than 100,000 surgical patients have been enrolled in venous thrombosis prophylaxis trials,  less than 10,000 medical patients have participated in studies of this nature. Furthermore, those published DVT prophylaxis studies that have involved medical patients have been limited by significant methodological heterogeneity including study design, baseline risk factors for venous thrombosis, and the detection methods employed to identify venous thrombosis.

Unfractionated heparin (UFH) is considered the reference antithrombotic agent for the prevention of venous thromboembolic disease in medical patients.  When compared to placebo in moderate-risk hospitalized patients, this drug has been shown  to reduce  the incidence of venous thrombosis from 10%-26% to 2%-4%.  In  high-risk patients following myocardial infarction,  the incidence of venous thromboembolic disease is reduced from 24% to 7%, while in ischemic stroke patients the incidence of this disease is reduced from 42% to 26%.

Over the last 10 years,  the use of LMWH agents to  prevent or  treat venous thromboses has increased.  Low-molecular-weight heparins have a number of potential advantages over UFH which include once daily administration,  lower incidence of heparin-induced thrombocytopenia, less laboratory monitoring (although aPTT monitoring is not required, periodic CBC monitoring should still be undertaken), and possibly fewer bleeding complications.

Numerous controlled studies have shown  LMWH to be more effective than other thromboprophylactic strategies such as UFH or warfarin in various surgical populations, particularly orthopedic and trauma patients. The incidence of bleeding in some of these surgical studies; however, has been reported to be higher in the LMWH-treated patients. Despite the significantly greater acquisition cost of LMWH as compared to alternatives such as UFH, one U.S.-based pharmacoeconomic study  involving trauma patients has demonstrated that LMWH compounds can be more cost-effective than other antithrombotic alternatives.

Several recent reports of  large randomized controlled trials involving comparisons of LMWH compounds versus placebo or UFH in acutely ill medical patients have been published. The outcomes studied in these trials have included  venous thrombosis (i.e. DVT and PE), drug-related adverse events (i.e. bleeding and thrombocytopenia and patient mortality.  A structured review of these studies should help us to delineate the role of the LWMH compounds for DVT prophylaxis in these acutely ill medical patients.

Methods

A MEDLINE literature search for the period July 1966 to May 2000 was completed to identify randomized, controlled trials comparisons of LMWH to UFH or placebo.  Only those studies involving LMWH doses equivalent to those recommended by the manufacturer and daily UFH doses of 10,000-15,000 IU (when used as a comparator) were included.  Studies that did not involve a recognized method to diagnose deep vein thrombosis (i.e. venography, ultrasonography, impedence phlethysmography, or fibrinogen uptake scanning) were excluded.  Non-randomized studies and those studies that involved an assessment of danaparoid or other heparinoids were also excluded.  Finally, studies that only assessed LMWH prophylaxis after a stroke, myocardial infarction, or spinal cord injury were also excluded from the analyses.

Results

Placebo-Controlled Trials with Low-Molecular-Weight Heparins

We were able to identify three published randomized controlled studies involving a comparison of a LMWH compound to placebo. (Table 1). A double-blind study involving  non-surgical elderly patients revealed a 3-fold higher incidence of  DVT in the group receiving placebo as compared to the group receiving enoxaparin (9.1% vs. 3.0%, p< 0.001).  In a subgroup of the placebo-recipients who were also confined to bed, the incidence of DVT was 20%.  No patients in the LMWH group experienced a pulmonary embolus (PE), as compared to 3 patients in the placebo arm.

In the Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) trial, 1,102 moderate to high risk medical patients were randomized to receive placebo, enoxaparin 20mg daily or enoxaparin 40mg daily. Study participants  had congestive heart failure (New York Heart Association (NYHA) Class III or IV), acute respiratory failure (not requiring ventilatory support), or other specified medical conditions with an additional risk factor for venous thrombosis including age, cancer, previous DVT, or obesity.  All patients were examined for lower DVT by systemic ascending contrast venography between study days 6 and 14, or earlier if a thrombosis was clinically suspected.  Possible cases of pulmonary embolism were diagnosed using standard methods.  Secondary outcomes included major hemorrhage,  heparin-induced thrombocytopenia and death.  In this trial, the incidence of venous thrombosis was significantly lower in the group that received 40 mg of enoxaparin (5.5%) as compared to the group that received placebo (14.9%) (relative risk [RR] 0.37, 97.6% confidence interval [CI], 0.22 to 0.63, p < 0.001).  There was; however, no difference in outcomes between the enoxaparin 20 mg (15.0%, 43 of 287 patients) and placebo groups.  In addition, the incidence of adverse events such as major hemorrhage and heparin-induced thrombocytopenia did not differ between groups.

The third placebo-controlled study identified involved  223 mechanically-ventilated patients with chronic obstructive pulmonary disease. These patients were randomized to receive either daily subcutaneous nadroparin (3,800 anti-Xa IU for patients less than 70 kg; 5,700 anti-Xa IU for patients over 70 kg) or placebo. Therapy was continued until the patient was successfully weaned from mechanical ventilation. Only 169 of 221 (76.4%) patients were assessed at study completion using venography. The incidence of total DVT was significantly lower in patients receiving nadroparin than those receiving placebo (15.5% versus 28.2%, respectively, p = 0.045).  No patients in either treatment arm had a confirmed pulmonary embolus. Neither the incidence of serious hemorrhage (6 patients in the nadroparin arm vs. 3 in the placebo arm) nor thrombocytopenia (10 patients in the nadroparin arm vs. 7 in the placebo arm) differed significantly between groups.

The results of these three studies demonstrate that acutely ill medical patients are at significant risk for developing venous thrombosis during hospitalization.  Use of prophylaxis with at least a moderate dose LMWH (i.e. >4000 anti-Xa IU/day) safely appears to decrease the incidence of venous thrombosis in these patients compared to placebo.

Table 1. Trials Comparing Low – Molecular – Weight Heparins to Placebo in Acutely Ill Medical Patients

Author LMWH Patients DVT PE Death Major Bleed
Dahan 1986 (6) Enoxaparin (6300 IU/d) x 10 days N = 270
Various and elderly
LMWH
4/132
Control
12/131
LMWH
0/135
Control
3/135
LMWH
1/135
Control
6/135
LMWH
1/135
Control
3/135
MEDENOX
1999 (7)
Enoxaparin
(40 mg/d) until DC
N = 1120
CHF, COPD, or other major risk
43/287A
16/291B
40/288 0/287A
0/291B
2/288 15/351A
12/360B
16/362 1/351A
6/360B
4/362
Fraisse 2000 (8) Nadroparin
4100-6150
IU/dC until weaned
N = 221
COPD requiring mechanical ventilation
13/84 24/85 0/108 0/113 18/108 17/113 6/108 3/113

AEnoxaparin 20mg sc daily
BEnoxaparin 40mg sc daily
CAdjusted  to body weight (45-70kg: 3800 IU; 71-110kg: 5700 IU)

Studies Comparing Unfractionated Heparin with Low-Molecular-Weight Compounds

Eight clinical trials were identified involving 4,085 acutely ill medical patients who received prophylaxis with low dose UFH (up to 15,000 IU heparin/day) versus a LMWH. Early mortality was studied as an endpoint in all trials and clinical evidence of PE was assessed in six trials (4033 patients). (Table 2)

Two early studies involving a comparison of UFH (10,000-15,000 IU/day) with nadroparin or dalteparin, respectively, in a population of heterogeneous medical patients, showed no significant difference in the incidence of DVT between groups. The incidence of DVT was relatively low (<4%) in each group, as compared to the incidence range (5%-16%) reported for patients receiving LMWH in other placebo-controlled studies. While the latter study used serial impedence plethysmography (IPG) in addition to ultrasonography to detect deep vein thrombosis, it is unlikely that the combined use of both detection methods would lead to the detection of additional DVT as the sensitivity of each detection method is similar, and evidence does not suggest that sensitivity of either method is improved, particularly in asymptomatic patients, when used together.

The HESIM Group, have conducted the largest published study comparing LMWH to UFH to date. This trial examined the incidence of venous thrombosis, mortality, and bleeding-related outcomes in 1,590 medical inpatients who were randomized to receive either subcutaneous UFH 5,000 IU  three times daily or nadroparin 36 mg once daily.  All subjects were medical inpatients with an identifiable risk for venous thrombosis.  The incidence of thromboembolic events (i.e. combined proximal DVT and PE) did not differ between treatment groups (4 in the UFH group vs. 6 in the with LMWH, p = 0.12. There were 32 deaths in study patients.  Nine of these patients had been randomized to UFH therapy, while 23 received LMWH therapy (p = 0.02).  The incidence of major hemorrhage was low and did not differ between groups.  Four patients in the UFH group developed thrombocytopenia (platelets <80,000/uL) compared to none in the nadroparin-treated patient group.  The low incidence of venous thrombosis in this study population was also attributed to the low sensitivity of compression sonography in asymptomatic patients.

Three studies have been published that involved a comparison of enoxaparin (20 to 40 mg per day) with UFH (10,000,000 IU per day) in a variety of acutely ill medical populations. PRIME randomized 959 hospitalized medical patients to enoxaparin 40mg daily or UFH 5000 IU three times daily. There was no significant difference between any of the study outcomes (DVT, PE, death, or major bleeding) although there was a trend in the UFH treated group towards an increased incidence of PE [4/482 (0.008%) UFH versus 0/477 (0%) enoxaparin] and major bleeds [9/482 (0.02%) UFH versus 2/477 (0.004%) enoxaparin].

The Enoxaparin in Medicine Study Group (EMSG)  conducted in a double-blind study involving a comparison of enoxaparin 20mg daily with UHF 5000 IU twice daily in 439 elderly, hospitalized patients who were bedridden for an acute medical illness. The incidence of DVT in the enoxaparin group [10/207 (4.8%)] was equivalent to that of the UFH group [10/216 (4.6%)].   No difference in the incidence of bleeding complications or mortality was found between the groups .

The Thromboembolism Prevention in Cardiopulmonary Diseases with Enoxaparin (PRINCE) group, compared UFH 5000 IU three times daily to enoxaparin 40 mg daily in 668 medical patients admitted to hospital with either heart failure (NYHA Class III or IV) or severe respiratory disease. Similar to other studies, not all randomized patients were available for serial assessment for venous thrombosis by venography.  This was reported to be typically due to patient refusal, technical problems or death.  The number of thromboembolic events was not significantly different between the enoxaparin (8.4%) and UFH (10.8%)] – treated patients.  In the subgroup of patients with heart failure; however, the incidence of thromboembolic events was significantly higher in the UFH group (16.1% versus 9.7%).  Adverse events including bleeding complications (3.6% heparin vs. 1.5% enoxaparin and injection site hematomas (12.6% heparin vs. 7.2% enoxaparin) appeared to be more common in the UFH treatment arm.

A recent meta-analysis has been published that involves an assessment of these eight trials, in combination with another trial  that was conducted to primarily evaluated the incidence of PE in medical patients.  The authors of this study found no difference between the efficacy of LMWH versus UFH therapy.  When comparing LMWH to UFH therapy, the incidence of DVT (RR 0.83, [95% CI 95%, 0.56 to 1.24, p = 0.37), clinical PE  (RR  0.74,  [95% CI 0.29 to 1.88],  p = 0.52), and mortality (RR  1.07,  [95% CI 0.79 to 1.45], p = 0.66) did not differ  between treatment groups.  LMWH therapy; however, was associated with a lower incidence of major hemorrhage (RR  0.48, [95% CI 0.23 to 1.00], p = 0.049).

Table 2.  Trials Comparing Low Molecular Weight Heparins to Unfractionated Heparin in Acutely Ill Medical Patients

<tdUFH
2/50

Author LMWH/UFH Patients DVT PE Death Major Bleed
Aquino
1990 (20)
Nadroparin
3075 IU vs. UFH 10000000 U x 10d
N = 99
Various and elderly
LMWH
1/49
UFH
1/50
LMWH
0/49
UFH
0/50
LMWH
1/49
UFH
2/50
LMWH
0/49
Haremberg 1990 (21) Dalteparin
2500 IU vs. UFH 15000 IU x 10d
N = 166
Various
3/84 4/82 N/A N/A 3/84 1/82 0/84 1/82
Forette 1995 (22) Nadroparin 3075 IU vs. UFH*10,000000 IU x 28d N = 295
Various and elderly
3/146 3/149 0/146 1/149 6/146 7/149 0/146 4/149
HESIM
1996 (23)
Nadroparin 3100 IU vs. UFH 15000 IU x 10d N = 1590
Elderly and expected bed rest > 10 days(with  additional DVT  risk factor)
6/726 4/710 5/810 6/780 23/810 9/780 5/810 4/780
APTE
1996 (24)
Nadroparin
3075 IU vs. UFH 10000 IU x 90d
N = 256
Various and elderly
0/129 1/127 N/A N/A 8/129 8/127 1/129 4/127
PRIME
1996 (25)
Enoxaparin 4000 IU vs. UFH 15000 IU x 7d N = 959
Various and elderly
1/477 4/482 0/477 4/482 7/477 11/482 2/477 9/482
EMSG
1996  (26)
Enoxaparin 2100 IU vs. UFH 10000 IU x 10d N = 439
Various and elderly
10/207 10/216 1/216 0/223 7/216 8/223 1/216 2/223
PRINCE 1998 (27) Enoxaparin 4200 IU vs. UFH 15000 IU x 10d N = 665
Cardiopulmonary disease (confined to bed; expected hospitalization for > 1 wk)
19/239 22/212 1/239 1/212 28/332 30/333 1/332 1/333

* Adjusted to body weight (40-70kg: 10,000u; > 70kg: 15,000u)

Discussion

Pooled analysis of available studies demonstrates that the baseline risk for lower extremity DVT in acutely ill medical patients is approximately 19%. This incidence is comparable to that observed in general surgery patients, but less than that observed in patients after acute ischemic stroke or orthopedic surgery. The results from the meta-analysis demonstrate a 56% decrease in DVT when either LMWH or UFH is administered to acutely ill medical patients. This decrease is similar to the risk reduction observed in many other medical or surgical populations.

Studies comparing LMWH or UFH to placebo are important to review because they help to establish the magnitude of venous thrombosis risk in acutely ill medical patients as well as quantify the effect of LMWH or UFH prophylaxis on this risk. The high incidence of venous thrombosis in patients not receiving prophylaxis underscores the importance of routine assessment of the risk for venous thromboembolism in patients, and the provision of adequate prophylactic therapy.  In view of the equivalent efficacy of LMWH to UFH prophylactic therapy observed in each of these trials, however, it is somewhat surprising that these large, placebo-controlled trials could be ethically completed. Investigators appeared to justify  the use of a placebo arm by the fact that the incidence of venous thrombosis among such medical patients has not been established, the lack of  a old-standard method of thromboprophylaxis for these patients, and patients with a very high risk of venous thrombosis (e.g. prolonged immobilization, acute stroke) were excluded from each study. Although low-dose UFH is widely used as prophylaxis against thrombosis, it is not a validated control treatment for medical patients.In fact, the few studies supporting its use have been small, data on mortality is conflicting and the recommendations of consensus conferences are not definitive.

Those trials that involved an evaluation of LMWH versus placebo or UFH versus placebo that are available for analysis reveal that UFH/LMWH therapy significantly decreases the incidence of DVT (RR  0.44, [95% CI 0.29-0.64]; p < 0.001) and PE (RR 0.48 [95% 0.34 0.64], p < 0.001), but does not effect mortality (RR 0.98 [95% CI 0.79 to 1.21], p = 0.37). While homogeneity testing in  the meta-analysis performed by Mismetti et al. achieved significance, there is still considerable methodological heterogeneity found between studies. These differences between studies may affect the incidence of venous thrombosis reported.  The reported incidence of venous thrombosis depends not only on the prevalence of the disease, but also on the sensitivity and specificity of the diagnostic test that is used to detect it. In general, clinical symptoms suggestive of a DVT are only present in approximately 50% of patients actually having venous thrombosis. In these patients, venography remains the old standard diagnostic test. However, the need for irradiation, the invasiveness of the test, and the potential to induce thrombosis, all limit the use of venography in clinical practice – particularly for those patients deemed to be at  low or moderate risk for developing venous thrombosis. Despite its expense and complicity,  venography remains the reference method of choice for screening for deep-vein thrombosis in asymptomatic patients.  Many of the older studies used other diagnostic methods to detect DVT such as fibrinogen uptake testing, impedance phlethysmography, or ultrasonography whose sensitivity in asymptomatic patients is low.

Most of the DVT detected in the reviewed studies were asymptomatic in nature and/or distal in location. This diagnosis led to the initiation of full-dose anticoagulation therapy in many patients.  The low propensity of distal DVT to propagate more proximally (e.g. to the lungs) and the potential risks of anticoagulation therapy must be considered when evaluating the results of each study. In clinical practice, few asymptomatic medical patients would be routinely screened for the presence of DVT. Furthermore, at most institutions, duplex ultrasound rather than the significantly more sensitive venography, would be the screening test of choice for all patients regardless of symptomatology.  It remains unclear from these studies how patient outcome would have differed with respect to both incidence of venous thrombosis and mortality had only symptomatic patients been screened and treated if a venous thrombosis was detected. The pooled studies, however, demonstrated a 52% risk reduction in clinical and fatal PE with the use of UFH or LMWH. This fact alone, regardless of the incidence and anatomical location of the DVT that was detected, provides the clinician with strong evidence to consider the use of either of these heparin agents as prophylaxis in clinical practice.

In each of the studies reviewed, there was a significant number of patients that were not able to be assessed.  For example, in the MEDENOX study, 22% of the patients who were randomized into the study were not included in the analysis mostly because of the clinical difficulty in completing venography in these patients. These, in fact, may be patients who are at a relatively higher risk for venous thrombosis.  The inability to assess these patients may have lead to an underestimation of the treatment effect of enoxaparin.

Although the pooled results of available studies suggests that hospitalized medical patients should be considered for prophylactic therapy with either UFH or a LMWH compound, some of the studies, when reviewed individually, do not support this recommendation. This is mainly due to the fact that the baseline risk for venous thrombosis has varied greatly among studies. For example, in some studies, patients were confined to bed while in other trials, the majority of patients were ambulant. In addition, some studies included only mechanically ventilated, medical ICU patients, whereas others excluded this high-risk population.

The negative trials were also characterized by a short duration of thromboprophylaxis. For example, in the MEDENOX study, two fatal pulmonary emboli occurred in the enoxaparin 40 mg treatment group several weeks after prophylaxis had been discontinued. Any conclusions regarding the impact of either of these therapeutic modalities on patient mortality has to be carefully assessed on a study-by-study basis.  It is also important to note that many of the studies were not powered to detect a difference in clinical outcomes such as mortality. While three studies have assessed the ability of thromboprophylaxis to decrease mortality in acutely ill medical patients, the results may be questionable based on the short period of follow-up and the various methodological weaknesses of these studies already described.

While the use of LMWH does not appear to be associated with improved clinical outcomes (i.e. venous thrombosis and patient mortality) as compared to UFH, this newer class of drug does appear to be safer.  LMWH administration was associated with only half the number of major bleeding episodes compared to UFH-treated patients. This is an interesting finding when we consider that DVT prophylaxis with LMWH in various surgical populations has been associated with a greater incidence of bleeding than that observed with UFH. The lower incidence of bleeding observed in trials involving medical patients may be related to the lower LMWH dose that was administered.  After pooling LMWH surgical prophylaxis studies, a clear dose-response effect of LMWH related to bleeding risk has been demonstrated. Patients appear to be at significantly greater risk for experiencing a bleeding episode when the they receive more than 3400 anti-Xa IU of a LMWH per day.  An additional safety advantage of using LMWH rather than UFH prophylaxis is the decreased incidence of heparin-induced thrombocytopenia observed with LMWH use.

Low-molecular-weight heparin therapy can be administered on a once daily basis to patients and thereby will potentially decrease drug administration costs compared to the twice or thrice daily dosing regimens used with UFH.  However, the significantly greater acquisition costs associated with LMWH therapy is unlikely to offset any administration-related savings.  Although a formal pharmacoeconomic analysis of UFH versus LMWH prophylaxis in acutely ill medical patients has yet to be published, economic studies in other populations where UFH and LMWH therapeutic equivalence has been demonstrated (e.g. DVT prophylaxis in general surgery patients) have not revealed LMWH therapy to be cost-effective.

Conclusion

Current literature demonstrates that acutely ill medical patients, (particularly those with respiratory failure or decompensated heart failure), without contraindications to therapy (e.g. active bleeding), should receive pharmacologic thromboprophylaxis.  Substantial evidence now demonstrates that LMWH prophylaxis to be no more efficacious than UFH, except perhaps in patients with decompensated CHF.  A decreased incidence of heparin-related adverse events (i.e. bleeding and thrombocytopenia) and the opportunity for once-daily dosing is certainly enticing, but is still unlikely to make LMWH a cost-effective alternative (over UFH) for DVT prophylaxis in acutely ill medical patients.   Further LMWH versus UFH studies are needed in higher risk medical patients (e.g. mechanically ventilated MICU patients) to further delineate any advantages that this newer class of drugs may have in this population.

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