Evidensen för profylax med lågmolekylärt heparin (LMWH) hos immobiliserade patienter med risk för trombos

Fråga: Vi har haft diskussioner på medicinavdelningen kring evidensen för profylax med lågmolekylärt heparin (LMWH) hos immobiliserade patienter med risk för trombos (exv strokepatient). Vissa ansåg att det skulle användas en begränsad tid medan andra att det bör användas så länge behov finns. Jag undrar härmed om ni har möjlighet att se över evidensläget kring detta?

Svar: The European (1) and American (2, 3) guidelines have issued similar recommendations and suggestions for prevention of thrombosis in immobile patients with acute ischemic stroke (1-3), and in acutely ill hospitalized medical patients (4) with restricted mobility and at high risk of thrombosis.

Venous thromboembolism (VTE) prevention in patients with acute ischemic stroke, and in patients with hemorrhagic stroke, and restricted mobility, the guidelines (1-3) suggest prophylactic-dose SC unfractionated heparin (UFH) or various low-molecular-weight heparin (LMWH) or intermittent pneumatic compression devices over no prophylaxis. Prophylactic-dose LMWH is suggested over prophylactic-dose UFH (1-3). For hemorrhagic stroke, however, patients who prefer to avoid a theoretically increased risk of rebleeding with heparin would favor mechanical prophylaxis with intermittent pneumatic compression devices over pharmacologic prophylaxis (2, 3).

Meta-analyses have provided estimates of the relative effects of prophylactic-dose anticoagulation for VTE prophylaxis in patients with acute ischemic stroke and restricted mobility (5, 6). Heparin prophylaxis, in comparison with no heparin prophylaxis, results in 33 fewer symptomatic DVTs, five fewer pulmonary emboli, and five additional major hemorrhages (three intracranial and two extracranial) per 1,000 treated patients (2). The prophylactic use of LMWH compared to UFH following ischemic stroke is associated with a reduction in both VTE and pulmonary embolism (PE) (5, 6). Patients with additional risk factors for VTE are more likely to benefit from heparin thromboprophylaxis, whereas patients with risk factors for bleeding are less likely to benefit (2).

The guideline for acutely ill medical patients (congestive heart failure, severe respiratory disease, or acute infectious, rheumatic, or inflammatory conditions) who are immobilized and have one or more additional VTE risk factors (4) used data from three systematic reviews, that included several RCT, to assess the anticoagulant prophylaxis (7-9). Prophylactic anticoagulant regimens included LMWHs, UFH, and fondaparinux. Based on these data, the guidelines (4) suggests that thromboprophylaxis is effective in reducing symptomatic DVT and fatal PE in acutely ill, hospitalized, immobilized medical patients who have characteristics similar to those enrolled in the assessed RCTs.

In patients with acute ischemic stroke, and in acutely ill hospitalized medical patients with restricted mobility, pharmacologic and mechanical prophylaxis should be initiated as early as possible, within 48 h after onset of stroke, and should be continued throughout the hospital stay or until the patient has regained mobility (2–4). Prophylactic-dose heparin should not be used within the first 24 h after administration of thrombolytic therapy (2-4).

The duration of use of prophylaxis in RCTs ranged from 6-21 days or discharge from hospital, whichever came first (4-6). Based on the RCTs, the guidelines (4) considered that providing prophylaxis for 6 to 21 days, until full mobility is restored or until discharge from hospital, whichever comes first, is a reasonable approach. The guidelines (2-4) suggest against extending the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay.

Optimal duration for VTE prophylaxis in stroke patients with prolonged immobility is not well defined. The Extended Prophylaxis for Venous Thromboembolism in Acutely Ill Medical Patients With Prolonged Immobilization (EXCLAIM) study is the only published RCT of extended duration thromboprophylaxis in hospitalized medical patients (10). The study population consisted of 6,085 hospitalized patients aged 40 years with acute medical illness (e.g., heart failure, respiratory insufficiency, infection) and reduced mobility. All patients received initial open-label enoxaparin (40 mg daily for 10 ± 4 days) and were then randomized to receive extended duration enoxaparin (40 mg daily for 38 ±4 days) or placebo. Extended-duration enoxaparin, compared with placebo, reduced the incidence of overall VTE (composite of asymptomatic and symptomatic events) and symptomatic proximal DVT but failed to exclude benefits or harm for fatal PE and overall mortality. The risk of major bleeding was significantly increased with extended-duration enoxaparin, and there were four intracranial bleeding events (one fatal) in the extended enoxaparin group compared with none in the placebo group. In terms of absolute effects, extended-duration enoxaparin prevented six fewer symptomatic proximal DVT per 1,000 at a cost of five more major bleeding events per 1,000. The authors (10) concluded that the benefits of extended-duration enoxaparin seemed to be restricted to women, patients older than 75 years, and those with level 1 immobility (requiring total bed rest or being sedentary without bathroom privileges). However, some clinicians argued for continued prophylaxis for patients with persistent immobility (11, 12).

In chronically immobilized persons residing at home or at a nursing home, the guideline (3) suggest against the routine use of thromboprophylaxis.

1. Dennis M, Caso V, Kappelle LJ, Pavlovic A, Sandercock P; European Stroke Organisation. European Stroke Organisation (ESO) guidelines for prophylaxis for venous thromboembolism in immobile patients with acute ischaemic stroke. Eur Stroke J. 2016 Mar;1(1):6-19.
2. Lansberg MG, O'Donnell MJ, Khatri P, Lang ES, Nguyen-Huynh MN, Schwartz NE, Sonnenberg FA, Schulman S, Vandvik PO, Spencer FA, Alonso-Coello P, Guyatt GH, Akl EA. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e601S-e636S.
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