Prevention of venous thromboembolism in the hospitalized medical patient
ABSTRACT
Hospitalized acutely ill medical patients are at high risk for venous thromboembolism (VTE), and clinical trials clearly demonstrate that pharmacologic prophylaxis of VTE for up to 14 days significantly reduces the incidence of VTE in this population. Guidelines recommend use of low-molecular-weight heparin (LMWH) or unfractionated heparin (5,000 U three times daily) for VTE prophylaxis in hospitalized medical patients with risk factors for VTE; in patients with contraindications to anticoagulants, mechanical prophylaxis is recommended. All hospitalized medical patients should be assessed for their risk of VTE at admission and daily thereafter, and those with reduced mobility and one or more other VTE risk factors are candidates for aggressive VTE prophylaxis. Based on results from the recently reported EXCLAIM trial, extended postdischarge prophylaxis with LMWH for 28 days should be considered for hospitalized medical patients with reduced mobility who are older than age 75 or have a cancer diagnosis or a history of VTE.
HOW DO THE PROPHYLAXIS OPTIONS STACK UP?
What the ACCP recommends
Current ACCP guidelines recommend the use of either LMWH or low-dose UFH (5,000 U subcutaneously two or three times daily) as a Grade 1A recommendation for VTE prophylaxis in patients with medical conditions and risk factors for VTE.9 This represents the guidelines’ highest level of recommendation, ie, one that is based on randomized controlled trials (RCTs) without important limitations. In contrast, the 2006 International Consensus Statement, developed as a collaborative effort among expert bodies on VTE, specified a more narrow dosing recommendation for UFH in this patient population (5,000 U three times daily, not twice daily) as well as specifying 40 mg once daily as the recommended dose of enoxaparin and 5,000 IU once daily as the recommended dose of dalteparin.11
For medical patients with risk factors for VTE who have a contraindication to anticoagulant prophylaxis, the ACCP guidelines recommend the use of graduated compression stockings or intermittent pneumatic compression devices as a Grade 1C+ recommendation (“no RCTs but strong RCT results can be unequivocally extrapolated, or overwhelming evidence from observational studies”9).
Current ACCP guidelines do not address the use of fondaparinux in their recommendations for VTE prophylaxis in medical patients.
Getting a handle on bleeding risk
Patient characteristics that exclude pharmacologic thromboprophylaxis due to bleeding risk are generally limited to active bleeding or coagulopathy, as demonstrated by a platelet count less than 50,000 cells/µL or an international normalized ratio greater than 1.5. Additionally, bleeding risk should be carefully assessed if an invasive procedure is planned during a patient’s hospital stay.
It is worth noting that the anticoagulant doses used for VTE prophylaxis are a fraction of those used for treatment of VTE. Thus, if a patient would be treated with full-dose anticoagulation if VTE developed, then that patient should be eligible for VTE prophylaxis.
Because the use of mechanical forms of prophylaxis in medical patients is not truly evidence-based, mechanical prophylaxis should be reserved for medical patients who have a contraindication to anticoagulants, or for use in combination with anticoagulants in patients at very high risk of VTE.
UFH vs LMWH
Two meta-analyses have compared UFH with LMWH for VTE prevention in medical patients.12,13 In a recent analysis that included 10 trials directly comparing the two therapies, 14 trials comparing UFH with control, and 11 trials comparing LMWH with control, Wein et al found a lower risk of DVT with LMWH than with UFH (relative risk, 0.68 [95% CI, 0.52 to 0.88]) but no difference between the therapies in mortality or bleeding risk.12 In an earlier and smaller analysis, Mismetti et al found no significant differences between UFH and LMWH in preventing DVT or death but did find a significant reduction in major bleeding episodes with LMWH versus three-times-daily UFH (52% relative reduction; P = .049).13
Randomized trials also reveal that enoxaparin 40 mg once daily is as efficacious as UFH 5,000 U three times daily for VTE prevention in medical patients.14,15 The above analysis by Wein et al12 and an additional meta-analysis by King and colleagues16 found that three-times-daily dosing of UFH is more efficacious than twice-daily dosing of UFH, but at the expense of more bleeding, including major bleeding.
Economic considerations
Because of differences in drug acquisition costs between UFH and the LMWH agents, several economic evaluations have compared the use of these therapies for prophylaxis in medical patients at risk of VTE.
In an analysis of hospital costs for medical patients receiving VTE prophylaxis from more than 330 US hospitals for the period 2001–2004, Burleigh et al found that mean total hospital costs were higher for patients who received UFH than for those who received LMWH ($7,615 vs $6,866) even though mean drug costs were higher for LMWH ($791 vs $569 for UFH).17 A reduction in hospital length of stay appeared to contribute to the overall savings with LMWH; other contributors may have included costs associated with heparin-induced thrombocytopenia (HIT) in UFH recipients or the extra nursing time required for administering UFH in two or three daily doses.
Leykum et al used a decision analysis model to estimate the economic effect of substituting enoxaparin for UFH in hospitalized medical patients for whom VTE prophylaxis is indicated.18 Cost data were based on Medicare reimbursement rates as well as drug and laboratory costs for a multi-institutional health system. The model assumed HIT incidence rates of 2.7% with UFH and 0.3% with enoxaparin. It also assumed the cost of a daily dose to be $4 for UFH versus $84 for enoxaparin. From the payer perspective, the model showed that substituting enoxaparin for UFH would reduce the overall cost of care by $28.61 per day on a per-patient basis, despite enoxaparin’s higher acquisition cost, and would save $4,550 per quality-adjusted life-year by reducing the incidence of HIT.
Another cost analysis confirms the association between HIT and increased hospital costs. Creekmore et al retrospectively analyzed data from 10,121 adult medical patients who received VTE prophylaxis at the University of Utah Hospital in Salt Lake City from August 2000 to November 2004.19 They found that an admission during which HIT developed incurred a mean cost of $56,364, compared with $15,231 for an admission without HIT. Because LMWH was associated with a lower incidence of HIT compared with UFH (0.084% vs 0.51%, respectively), LMWH reduced the incremental cost of VTE prophylaxis by $13.88 per patient compared with UFH.
THE EXCLAIM TRIAL: IS THERE A ROLE FOR EXTENDED PROPHYLAXIS?
Although the previously discussed studies have clearly demonstrated the benefit of in-hospital VTE prophylaxis for acutely ill medical patients, none has rigorously examined extended-duration out-of-hospital prophylaxis in these patients. This represents an important gap in the literature, since a substantial proportion of VTE develops in the outpatient setting within 3 months of a hospitalization, and most outpatient VTE episodes occur within 1 month of a preceding hospitalization.20
To begin to fill this gap, the Extended Clinical Prophylaxis in Acutely Ill Medical Patients (EXCLAIM) trial was conducted to compare extended-duration LMWH prophylaxis with a standard LMWH prophylaxis regimen in acutely ill medical patients using a prospective, multicenter, randomized, double-blind, placebo-controlled design.21
Patients and study design
Patients were eligible for enrollment if they were aged 40 years or older and had recent immobilization (≤ 3 days), a predefined acute medical illness, and either level 1 mobility (total bed rest or sedentary state) or level 2 mobility (level 1 with bathroom privileges). The predefined acute medical illnesses consisted of New York Heart Association class III/IV heart failure, acute respiratory insufficiency, or other acute medical conditions, including post-acute ischemic stroke, acute infection without septic shock, and active cancer.
All patients received open-label enoxaparin 40 mg subcutaneously once daily for 10 ± 4 days, after which they were randomized to either enoxaparin 40 mg subcutaneously once daily or placebo for an additional 28 ± 4 days.
The primary efficacy end point was the incidence of VTE events, defined as asymptomatic DVT documented by mandatory ultrasonography at the end of the double-blind treatment period (28 ± 4 days) or as symptomatic DVT, symptomatic PE, or fatal PE at any time during the double-blind period. Symptomatic DVT was confirmed by objective tests; PE was confirmed by ventilation-perfusion scan, computed tomography, angiography, or autopsy.
Secondary efficacy end points were mortality at the end of the double-blind period, at 3 months, and at 6 months, as well as the incidence of VTE at 3 months.
The primary safety outcome measure was the incidence of major hemorrhage during the double-blind period; secondary safety measures were rates of major and minor hemorrhage, minor hemorrhage, HIT, and serious adverse events.
