MARINER

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Spyropoulos AC, et al. "Rivaroxaban for Thromboprophylaxis after Hospitalization for Medical Illness". The New England Journal of Medicine. 2018. e-published 2018-08-26:1-10.
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Clinical Question

Among high-risk medically ill patients, does anticoagulation with rivaroxaban 10 mg PO qday reduce the posthospital discharge rate of symptomatic or fatal venous thromboembolism when compared with placebo?

Bottom Line

Among patients discharged from a medical hospitalization with elevated risk for VTE, rivaroxaban 10 mg PO qday x45 days following the discharge was not associated with a significant reduction in VTE or VTE-mortality when compared to placebo. There was a small reduction in incident VTE with rivaroxaban though there were few events in both arms.

Major Points

Patients hospitalized with an acute medical illness may have an increased risk of venous thromboembolism (VTE) that persists for several weeks after hospital discharge. Anticoagulant prophylaxis reduces VTE during hospitalizations and after high-risk surgeries, with rivaroxaban 10 mg PO qday reducing incident VTE in RECORD1[1] and RECORD2[2] for hip and knee replacements, respectively.[3] The role for post-hospitalization prophylaxis following higher-risk medical admissions is of unclear clinical utility and guidelines recommend against prolonging the duration of anticoagulation beyond the period of immobilization or hospitalization in view of limited data and unclear net benefit.[3][4]

The Medically Ill Patient Assessment of Rivaroxaban versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk (MARINER) trial randomized 12,024 patients admitted to a hospital for 3-10 days with an increased VTE risk based on a modified IMPROVE risk score ≥4 (out of 10, higher is greater risk) or 2-3 if D-dimer was >2x the upper limit of normal,[5][6] in a 1:1 ratio to rivaroxaban 10 mg PO qday (or 7.5 if CKD) or placebo following discharge and continued for 45 days.[7] Of note, the study was stopped short of its goal 161 primary events for futility. There was no difference in the primary outcome of symptomatic VTE or VTE-mortality (rivaroxaban 0.83% vs. 1.10%; HR 0.76; 95% CI 0.52-1.09; P=0.14). Major bleeding rates were similar. There was a reduction in symptomatic VTE with rivaroxaban (HR 0.44; 95% CI 0.22-0.89) though there were only 36 symptomatic thrombi among the >12,000 participants and the NNT to prevent one symptomatic VTE was 546. The findings of MARINER suggest that post-discharge provision of rivaroxaban for 45 days is of limited utility among medical patients at increased risk for VTE.

Guidelines

As of September 2018, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, prospective, randomized, double-blind, placebo-controlled, event-driven phase 3 trial
  • N=12,024 randomized in a 1:1 ratio (12,019 included in the intention-to-treat analysis)
    • Rivaroxaban (n=6,007)
      • 10 mg (n=4,909)
      • 7.5 mg (n=1,098)
    • Placebo (n=6,012)
      • 10 mg (n=4,913)
      • 7.5 mg (n=1,099)
  • Setting: 671 participating centers in 36 countries in the US and abroad
  • Enrollment: 2014-2018
  • Follow-up: 75 days (range, 70 to 80 days)
  • Analysis: Intention-to-treat
  • Primary outcome: symptomatic venous thromboembolism or death related to venous thromboembolism

Population

Inclusion Criteria

  • Age ≥ 40 years
  • Hospitalized for 3-10 consecutive days with one of the following conditions:
    • Acute heart failure with a LVEF of ≤ 45%
    • Acute respiratory insufficiency or exacerbation of chronic obstructive pulmonary disease (COPD)
    • Acute ischemic stroke
    • Acute infectious or inflammatory disease, including rheumatic diseases
  • Modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE risk score of ≥ 4 OR IMPROVE score of 2–3 plus D-dimer level > 2 × ULN
  • Thromboprophylaxis with low-molecular-weight heparin or unfractionated heparin during the index hospitalization

Exclusion Criteria

  • Treated with anticoagulant or dual antiplatelet therapy
  • Active cancer
  • History of recent bleeding (within 3 months)
  • High risk of bleeding
  • Contraindicated to rivaroxaban

Baseline Characteristics

Comparisons are rivaroxaban vs. placebo

  • Demographics:
    • Age: 69.7 vs. 69.7 years
    • Male: 52.1% vs. 52.5%
  • Reasons for index hospitalization:
    • Heart failure: 40.6% vs. 39.9%
    • Respiratory insufficiency or exacerbation of COPD: 26.2% vs. 26.8%
    • Ischemic stroke: 14.3% vs. 14.4%
    • Infectious disease: 17.5% vs. 17.4%
    • Inflammatory disease: 1.4% vs. 1.5%
  • Mean duration of index hospitalization: 6.7 vs. 6.7 days
  • Mean duration of in-hospital thromboprophylaxis: 6.2 vs. 6.2 days
  • PMH:
    • History of VTE: 12.7% vs. 12.4%
    • History of cancer: 8.1% vs. 8.9%
    • ICU or CCU stay: 54.3% vs. 53.9%
    • Current lower-limb paralysis or paresis: 18.6% vs. 18.7%
  • Modified IMPROVE VTE risk score:
    • Score of 2: 34.9% vs. 35.8%
    • Score of 3: 31.4% vs. 29.6%
    • Score of ≥ 4: 33.6% vs. 34.5%
  • Medications:
    • Aspirin: 52.6% vs. 50.7%
    • Thienopyridine: 6.0% vs. 6.5%
  • Labs:
    • D-dimer >2 × ULN during index hospitalization: 70.4% vs. 70.5%

Interventions

  • Participants were randomized to a group:
    • Rivaroxaban - 1 of 2 doses:
      • Rivaroxaban 10 mg once daily, for patients with CrCl of ≥50 ml/min
      • Rivaroxaban 7.5 mg once daily, for patients with CrCl of ≥30 to <50 ml/min
    • Placebo
  • The first dose of rivaroxaban or placebo was administered as soon as possible after randomization and not later than the next day.
  • The trial agent was taken with or without food for 45 days.

Outcomes

Comparisons are rivaroxaban vs. placebo

Primary Outcome

Composite of symptomatic VTE or VTE-mortality
50 (0.83%) vs. 66 (1.10%); HR 0.76 (95% CI: 0.52 to 1.09); P=0.14; ARD -0.27% (95% CI: -0.61% to 0.08%)
10 mg once daily: 32 (0.65%) vs. 48 (0.98%); HR 0.67 (95% CI: 0.43 to 1.04)
7.5 mg once daily: 18 (1.64%) vs. 18 (1.64%); HR 1.00 (95% CI: 0.52 to 1.92)

Secondary Outcomes

VTE-mortality
43 (0.72%) vs. 46 (0.77%); HR 0.93 (95% CI: 0.62 to 1.42)
Symptomatic VTE (LE DVT or nonfatal PE)
11 (0.18%) vs. 25 (0.42%); HR 0.44 (95% CI: 0.22 to 0.89)
Symptomatic VTE or death from any cause
78 (1.30%) vs. 107 (1.78%); HR 0.73 (95% CI: 0.54 to 0.97)
Symptomatic VTE, myocardial infarction, nonhemorrhagic stroke, or cardiovascular death
94 (1.56%) vs. 120 (2.00%); HR 0.78 (95% CI: 0.60 to 1.02)
Death from any cause
71 (1.18%) vs. 89 (1.48%); HR 0.80 (95% CI: 0.58 to 1.09)

Safety Outcomes

Major bleeding
17 (0.28%) vs. 9 (0.15%); HR 1.88 (95% CI: 0.84 to 4.23); ARD 0.13% (95% CI: -0.03% to 0.30%)
10 mg once daily: 13 (0.27%) vs. 9 (0.18%); HR 1.44 (95% CI: 0.62 to 3.37)
7.5 mg once daily: 4 (0.37%) vs. 0 (0.00%)
Hemoglobin decrease ≥ 2 g/dl
14 (0.23%) vs. 6 (0.10%); HR 2.33 (95% CI: 0.89 to 6.05)
Transfusion of ≥ 2 units of packed red cells
11 (0.18%) vs. 3 (0.05%); HR 3.66 (95% CI: 1.02 to 13.10)
Critical site bleeding
3 (0.05%) vs. 2 (0.03%); HR 1.50 (95% CI: 0.25 to 8.97)
Fatal bleeding
2 (0.03%) vs. 0 (0.00%)
Nonmajor clinically relevant bleeding
85 (1.42%) vs. 51 (0.85%); HR 1.66 (95% CI: 1.17 to 2.35)
Other bleeding
54 (0.90%) vs. 34 (0.57%); HR 1.59 (95% CI: 1.03 to 2.44)

Subgroup Analysis

Symptomatic VTE or death related to VTE
There were no significant interactions between the trial regimen and subgroups.
Major bleeding
There were no significant interactions between the trial regimen and any subgroup variable, with the exception of the duration of the index hospitalization (P=0.02) and in-hospital receipt of thromboprophylaxis (P=0.03).

Adverse Events

Any adverse event
1,438 (24.0%) vs. 1,490 (24.9%)
Serious adverse event
466 (7.8%) vs. 486 (8.1%)
Adverse event with outcome of death
95 (1.6%) vs. 103 (1.7%)

Criticisms

  • The actual event rate of the primary endpoint in the placebo group (1.1%) was lower than the expected event rate (2.5%), which prompted early termination of the enrollment before accumulation of the prespecified 161 events.
  • The efficacy of rivaroxaban may have been diluted by the inclusion of patients with moderate renal impairment (18% of study population) that received a potentially underdosed regimen.

Funding

  • The study was funded by Janssen Research and Development.
  • Data were collected by Parexel.
  • Coordination of study committees and support for trial execution were provided by CPC Clinical Research, Worldwide Clinical Trials, and the Antithrombotic Trials Leadership and Steering (ATLAS) Group.

Further Reading

  1. Eriksson BI et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N. Engl. J. Med. 2008. 358:2765-75.
  2. Lassen MR et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N. Engl. J. Med. 2008. 358:2776-86.
  3. 3.0 3.1 Kahn SR et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012. 141:e195S-e226S.
  4. Lederle FA et al. Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: a background review for an American College of Physicians Clinical Practice Guideline. Ann. Intern. Med. 2011. 155:602-15.
  5. Gibson CM et al. The IMPROVEDD VTE Risk Score: Incorporation of D-Dimer into the IMPROVE Score to Improve Venous Thromboembolism Risk Stratification. TH Open 2017; 01(01): e56-e65.
  6. IMPROVEDD Risk Score Calculator at WikiDoc.org
  7. Spyropoulos AC et al. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 2011. 140:706-714.