Bayer Pharma AG

Essence of this Article

Short-term thromboprophylaxis is recommended in acutely ill medical patients to reduce the risk of developing venous thromboembolism during hospitalization. Although thromboprophylaxis after major orthopaedic surgery is recommended post-discharge, this is not the case for medically ill patients, in whom thromboprophylaxis is recommended only for the duration of hospitalization or immobilization (or for up to 14 days in some guidelines). Therefore, patients may continue to be at risk of venous thromboembolic events for weeks or months after hospitalization. The benefit of thromboprophylaxis with direct Factor Xa inhibitors and direct thrombin inhibitors after elective hip or knee replacement surgery is now well established; however, it has been more difficult to identify from clinical studies groups of medically ill patients who would benefit from extended thromboprophylaxis.

Thromboprophylaxis in medically ill patients: recent phase III studies

Introduction

The benefits of thromboprophylaxis in acutely ill medical patients were first shown with heparins and fondaparinux.457-460 Current clinical practice guidelines recommend that these anticoagulants are administered in at-risk patients for the duration of hospitalization or immobilization (or for up to 14 days in some guidelines) to prevent the development of venous thromboembolism (VTE), which is associated with poorer outcomes (such as chronic post-thrombotic syndrome, chronic thromboembolic pulmonary hypertension and recurrent VTE) and mortality.461-464 The oral, direct Factor Xa inhibitors apixaban and rivaroxaban are approved and recommended for thromboprophylaxis after elective hip or knee replacement surgery.465-467 Phase III clinical trials involving these agents have been completed in hospitalized, acutely ill medical patients to assess their efficacy and safety in this heterogeneous population (Table 1).468, 469

The ADOPT study

  • ADOPT (Apixaban Dosing to Optimize Protection from Thrombosis) studied acutely ill, hospitalized patients with restricted mobility with either congestive heart failure or respiratory failure; or other medical disorders and at least one additional risk factor for VTE468
  • Apixaban (2.5 mg twice daily for 30 days) did not meet the primary efficacy endpoint of superiority to enoxaparin (40 mg once daily for 6–14 days) for prevention of VTE and VTE-related death (2.71% vs 3.06%; relative risk 0.87; 95% confidence interval [CI] 0.62–1.23; p=0.44)468 The cumulative rates of any symptomatic venous thromboembolism, including death related to venous thromboembolism are shown in Figure 1
  • Apixaban was associated with significantly greater rates of major bleeding compared with the recommended enoxaparin regimen (0.47% vs 0.19%; relative risk 2.58; 95% CI 1.02–7.24; p=0.04)468 Figure 2 shows the Kaplan–Meier curves for major and clinically relevant nonmajor bleeding in both groups

Figure 1 Kaplan–Meier curves for adjudicated symptomatic VTE or VTE-related death during the treatment period

Figure 1 Kaplan–Meier curves for adjudicated symptomatic VTE or VTE-related death during the treatment period (the inset shows the same data on an enlarged y axis).468

Figure 2 Kaplan–Meier curves for the composite of major and clinically relevant nonmajor bleeding events during the treatment period

Figure 2 Kaplan–Meier curves for the composite of major and clinically relevant nonmajor bleeding events during the treatment period (the inset shows the same data on an enlarged y axis).468

The MAGELLAN study

  • MAGELLAN (Multicenter, rAndomized, parallel Group Efficacy safety study for the prevention of venous thromboembolism in hospitalized acutely iLL medical patients comparing rivaroxabAN with enoxaparin) recruited hospitalized patients with a specified acute medical illness – mostly infectious disease, heart failure or renal insufficiency – and reduced mobility
  • Rivaroxaban (10 mg once daily) demonstrated non-inferiority to a standard enoxaparin regimen (40 mg once daily) during the active comparator phase (up to Day 10)469
  • Rivaroxaban demonstrated superior efficacy when extended treatment was compared with placebo (up to Day 35)(Figure 3)469
  • Rates of VTE and VTE-related death were lower with rivaroxaban than with enoxaparin/placebo
  • However, bleeding rates were significantly higher with rivaroxaban across the whole study period469 and, as a result, rivaroxaban did not show a favourable benefit–risk profile (Figure 4)

Figure 3 Extended rivaroxaban demonstrated superior efficacy versus standard therapy (up to Day 35) in MAGELLAN

Figure 3 Extended rivaroxaban demonstrated superior efficacy versus standard therapy (up to Day 35) in MAGELLAN (adapted from Cohen et al 2013)
DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.

Figure 4 Rivaroxaban did not demonstrate a favourable benefit–risk profile in MAGELLAN

Figure 4 Rivaroxaban did not demonstrate a favourable benefit–risk profile in MAGELLAN
*Major plus non-major clinically relevant bleeding. Safety population; treatment-emergent bleeding (adapted from Cohen et al 2013). RR, relative risk.

Subanalyses of MAGELLAN have provided useful additional information:

  • Elevated levels of D-dimer soon after hospital admission constitute an independent risk factor for VTE and may be useful in identifying hospitalized patients who could benefit from extended thromboprophylaxis470
  • Patients with severe heart failure receiving enoxaparin/placebo have a substantially higher risk of developing VTE compared with those with less severe or no heart failure, a finding not seen in patients receiving rivaroxaban. This suggests that rivaroxaban could reduce the risk of VTE in patients with more severe heart failure471

MAGELLAN offered clear evidence that the risk of VTE persists after hospital discharge, long after the currently recommended duration of thromboprophylaxis, but the study did not succeed in identifying a patient cohort that would benefit from extended thromboprophylaxis. Further studies (MARINER, NCT02111564) as well as subgroup analyses may help to define the clinical value of treating medically ill patients.

Table 1: Phase III studies of the direct Factor Xa inhibitors

Factor Xa inhibitor (study) Apixaban (ADOPT468) Rivaroxaban (MAGELLAN469)
Study design Randomized, double blind, phase III studies
Patient population 6528 hospitalized, acutely ill medical patients aged ≥40 years with reduced mobility 8101 hospitalized, acutely ill medical patients aged ≥40 years with reduced mobility
Treatment Oral apixaban 2.5 mg bid ≤30 days post-discharge; placebo injections
vs
s.c. enoxaparin 40 mg od for 6–14 days; placebo tablets
Oral rivaroxaban 10 mg od for 35±4 days; placebo injections
vs
s.c. enoxaparin 40 mg od for 10±4 days; placebo tablets
Primary efficacy endpoint 30-day composite of VTE-related death and fatal or non-fatal PE, symptomatic DVT or asymptomatic proximal-leg DVT Composite of asymptomatic proximal DVT, symptomatic proximal or distal DVT, symptomatic non-fatal PE or VTE-related death, at Days 10 and 35
Principal safety outcome Major bleeding, non-major clinically relevant bleeding and all bleeding reported by investigators Composite of major bleeding and non-major clinically relevant bleeding during treatment and within 2 days following the last dose

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DVT, deep vein thrombosis; od, once daily; PE, pulmonary embolism; s.c., subcutaneous;
VTE, venous thromboembolism.


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