Mega JL, et al. “Rivaroxaban in Patients with Recent Acute Coronary Syndrome”. The New England Journal of Medicine. 2012. 366(1):9-19.
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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)
- Death from Cardiovascular Causes:
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.
Literature Review
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.
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