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Rivaroxaban in Patients with a Recent Acute Coronary Syndrome

Authors (Top 5): Jessica L. Mega, M.D., M.P.H., Eugene Braunwald, M.D., Stephen D. Wiviott, M.D., Jean-Pierre Bassand, M.D., Deepak L. Bhatt, M.D., M.P.H.

Journal Name: The New England Journal of Medicine

Year: 2012

Volume: 366

Issue: 1

Type of Study: Randomized, double-blind, placebo-controlled, phase 3 trial

DOI/PMID: 10.1056/NEJMoa1112277

Quick Reference Summary

  • In patients with a recent acute coronary syndrome, rivaroxaban significantly reduced the composite primary efficacy end point of death from cardiovascular causes, myocardial infarction, or stroke (8.9% vs. 10.7%; P = 0.008).
  • The twice-daily 2.5-mg dose of rivaroxaban also reduced death from cardiovascular causes (2.7% vs. 4.1%; P = 0.002) and from any cause (2.9% vs. 4.5%; P = 0.002) but increased major bleeding events (2.1% vs. 0.6%; P<0.001).

Core Clinical Question

Does the addition of low-dose rivaroxaban to standard antiplatelet therapy improve cardiovascular outcomes in patients with a recent acute coronary syndrome compared to placebo?

Background

Disease Overview: Acute coronary syndromes (ACS) result from coronary atherosclerosis with superimposed thrombosis, leading to events like myocardial infarction and unstable angina.

Prior Data:

  • Warfarin added to aspirin reduced cardiovascular outcomes but was limited by bleeding risks and administration challenges.
  • Ximelagatran showed cardiovascular benefits post-myocardial infarction but was associated with hepatotoxicity.

Current Standard of Care: Long-term antiplatelet therapy with aspirin and an adenosine diphosphate receptor inhibitor.

Knowledge Gaps Addressed:

  • Persistent thrombin generation post-ACS contributing to recurrent events.
  • Need for effective anticoagulation strategies with manageable safety profiles.

Study Rationale: Evaluate low-dose rivaroxaban, a factor Xa inhibitor, as an adjunctive therapy to improve cardiovascular outcomes with an acceptable safety profile in post-ACS patients.

Methods Summary

Study Design: Double-blind, placebo-controlled, randomized trial.

Setting and Time Period: Conducted from November 2008 through September 2011 at 766 sites across 44 countries.

Population Characteristics: 15,526 patients ≥18 years with a recent ACS (STEMI, NSTEMI, or unstable angina).

Inclusion/Exclusion Criteria:

  • Included: Recent ACS patients stabilized post-initial management.
  • Excluded: Platelet count <90,000/mm³, hemoglobin <10 g/dL, creatinine clearance <30 ml/min, significant GI bleeding within 12 months, previous intracranial hemorrhage, or ischemic stroke/TIA while on aspirin and thienopyridine.

Intervention Details: Twice-daily oral rivaroxaban at 2.5 mg or 5 mg.

Control/Comparison Group: Placebo administered twice daily.

Primary and Secondary Outcomes:

  • Primary Efficacy: Composite of death from cardiovascular causes, myocardial infarction, or stroke.
  • Secondary Efficacy: Death from any cause, myocardial infarction, or stroke.
  • Primary Safety: TIMI major bleeding not related to CABG.

Statistical Analysis Approach: Hazard ratios with 95% confidence intervals using log-rank tests; stratified by thienopyridine use.

Sample Size Calculations: 983 primary efficacy events for 96% power to detect a 22.5% relative reduction.

Ethics and Funding: Approved by regulatory agencies and ethics committees; funded by Johnson & Johnson and Bayer Healthcare.

Detailed Results

Participant Flow and Demographics

  • Enrollment: 15,526 patients randomized equally to rivaroxaban (2.5 mg and 5 mg) or placebo.
  • Baseline Characteristics: Well-matched across groups; mean age ~62 years, 75% male, diverse racial distribution.
  • Compliance: ~94% compliance with study drug across all groups.
  • Discontinuation: ~27-29% discontinued rivaroxaban vs. 26.4% placebo, primarily due to adverse events or patient choice.

Primary Outcome Results

  • Primary Efficacy End Point:
    • Rivaroxaban vs. Placebo: 8.9% vs. 10.7% (HR = 0.84; 95% CI, 0.74–0.96; P = 0.008)
    • Dose-Specific:
      • 2.5 mg: 9.1% vs. 10.7% (HR = 0.84; 95% CI, 0.72–0.97; P = 0.02)
      • 5 mg: 8.8% vs. 10.7% (HR = 0.85; 95% CI, 0.73–0.98; P = 0.03)
  • Components:
    • Death from Cardiovascular Causes:
      • Rivaroxaban: 2.7%
      • Placebo: 4.1% (HR = 0.66; 95% CI, 0.51–0.86; P = 0.002)
    • Death from Any Cause:
      • Rivaroxaban: 2.9%
      • Placebo: 4.5% (HR = 0.68; 95% CI, 0.53–0.87; P = 0.002)
    • Myocardial Infarction: 5.5% vs. 6.6% (HR = 0.69; 95% CI, 0.51–0.93; P = 0.02)
    • Stroke: No significant reduction (HR = 1.24; 95% CI, 0.86–1.78; P = 0.25)

Secondary Outcome Results

  • Death from Any Cause, Myocardial Infarction, or Stroke: 9.2% vs. 11.0% (HR = 0.84; 95% CI, 0.74–0.95; P = 0.006)
  • Stent Thrombosis: 2.3% vs. 2.9% (HR = 0.69; 95% CI, 0.51–0.93; P = 0.02)

Subgroup Analyses

Consistent primary outcome benefits across most subgroups except for patients with a history of stroke or TIA.

Adverse Events/Safety Data

  • Major Bleeding (TIMI): 2.1% vs. 0.6% (HR = 3.96; 95% CI, 2.46–6.38; P<0.001)
  • Intracranial Hemorrhage: 0.6% vs. 0.2% (HR = 1.24; 95% CI, 0.86–1.78; P = 0.25)
  • Fatal Bleeding: 0.3% vs. 0.2% (P = 0.66)
  • Dose Comparison: Lower dose (2.5 mg) had fewer major bleedings than higher dose (5 mg) (1.8% vs. 2.4%; P = 0.12) and significantly fewer TIMI minor bleeding, TIMI bleeding requiring medical attention, and fatal bleeding.

Results Tables

Outcome Intervention Group Control Group Difference (95% CI) P-value
Primary Efficacy Endpoint 8.9% 10.7% HR 0.84 (0.74–0.96) 0.008
Death from Cardiovascular Causes 2.7% 4.1% HR 0.66 (0.51–0.86) 0.002
Death from Any Cause 2.9% 4.5% HR 0.68 (0.53–0.87) 0.002
Major Bleeding (TIMI, non-CABG) 2.1% 0.6% HR 3.96 (2.46–6.38) <0.001
Intracranial Hemorrhage 0.6% 0.2% HR 1.24 (0.86–1.78) 0.25
Fatal Bleeding 0.3% 0.2% HR not significantly increased 0.66

Authors' Conclusions

  • Primary Conclusions: Rivaroxaban significantly reduced the risk of death from cardiovascular causes, myocardial infarction, or stroke in patients with a recent acute coronary syndrome.
  • Interpretation of Results: The 2.5-mg dose provided a survival benefit without significantly increasing fatal bleeding, whereas the 5-mg dose did not show this survival advantage.
  • Clinical Implications: Very-low-dose rivaroxaban can be considered as an adjunctive therapy in post-ACS patients to improve cardiovascular outcomes, balancing efficacy with bleeding risks.
  • Future Research Recommendations: Further studies to optimize dosing strategies and identify patient populations that would benefit most with minimal bleeding risks.

Critical Analysis

A. Strengths

  • Large Sample Size: Included 15,526 patients, enhancing the power and reliability of results.
  • Randomized Controlled Design: Minimizes selection bias and confounding factors.
  • Blinding: Double-blind design reduces performance and detection bias.
  • Diverse Population: Conducted across 44 countries, improving generalizability.
  • Comprehensive Outcomes: Assessed both efficacy (cardiovascular events) and safety (bleeding).

B. Limitations

  • Bleeding Risks: Significant increase in major bleeding events, which may limit the use of rivaroxaban in certain populations.
  • Subgroup Exceptions: Lack of benefit in patients with a history of stroke or TIA, raising concerns about generalizability to this subgroup.
  • Dose-Response Relationship: Higher dose did not confer additional survival benefits but increased bleeding risks.
  • Compliance Discontinuation: Approximately 27-29% discontinuation rate, which could affect long-term applicability.

C. Literature Context

  • The study's findings are consistent with previous phase 2 trials (ATLAS ACS–TIMI 46) showing dose-dependent efficacy and bleeding risks with rivaroxaban.
  • Contrasts with APPRAISE-2, where apixaban increased bleeding without reducing ischemic events, possibly due to different patient populations and dosing.
  • Aligns with the notion that very-low-dose anticoagulation may offer benefits post-ACS with manageable safety profiles.

Clinical Application

  • Practice Change: Incorporating very-low-dose rivaroxaban (2.5 mg twice daily) as an adjunct to standard antiplatelet therapy may enhance cardiovascular outcomes in post-ACS patients.
  • Applicable Populations: Particularly beneficial for ACS patients without a history of stroke or TIA, and where bleeding risks are manageable.
  • Implementation Considerations: Monitoring for bleeding, patient selection to exclude high-bleeding-risk individuals, and integration with existing antiplatelet regimens.

How To Use This Info In Practice

Practitioners should consider adding very-low-dose rivaroxaban to standard antiplatelet therapy for eligible post-ACS patients to reduce cardiovascular events, while carefully monitoring for bleeding complications.

Additional Notes

  • Statistical Significance: Key findings highlighted in bold with confidence intervals provided.
  • Conflicts of Interest: Multiple authors reported consulting fees and grant support from pharmaceutical companies, including Johnson & Johnson and Bayer Healthcare.
  • Funding Sources: Johnson & Johnson and Bayer Healthcare funded the study.
  • Areas of Uncertainty: Optimal patient selection to maximize benefits while minimizing bleeding risks remains to be fully elucidated.
  • Number Needed to Treat/Harm: The primary efficacy end point would be prevented in 1 patient if 56 patients were treated with rivaroxaban for 2 years.