Article Identification

  • Article Title: Dose Comparisons of Clopidogrel and Aspirin in Acute Coronary Syndromes
  • Citation: The New England Journal of Medicine 2010;363:930-42.
  • DOI: 10.1056/NEJMoa0909475
  • PMID: 20665163

Quick Reference Summary

  • In the CURRENT–OASIS 7 trial, double-dose clopidogrel did not significantly reduce the primary composite outcome of cardiovascular death, myocardial infarction, or stroke at 30 days compared to the standard-dose regimen (4.2% vs. 4.4%; hazard ratio [HR] 0.94; 95% confidence interval [CI], 0.83–1.06; P = 0.30).
  • Double-dose clopidogrel was associated with a significant increase in major bleeding events (2.5% vs. 2.0%; HR 1.24; 95% CI, 1.05–1.46; P = 0.01).

Core Clinical Question

Does double-dose clopidogrel compared to standard-dose clopidogrel, and higher-dose aspirin compared to lower-dose aspirin, reduce the incidence of cardiovascular death, myocardial infarction, or stroke within 30 days in patients with acute coronary syndromes undergoing percutaneous coronary intervention?

Background

  • Disease Overview:
    • Acute coronary syndromes (ACS) encompass a range of conditions associated with sudden, reduced blood flow to the heart, including unstable angina and myocardial infarction (both ST-segment elevation [STEMI] and non-ST-segment elevation [NSTEMI]).
  • Prior Data on the Topic:
    • Clopidogrel, a P2Y12 inhibitor, and aspirin are cornerstone antiplatelet therapies in ACS management.
    • Previous studies have established the benefits of clopidogrel in reducing ischemic events in ACS patients, especially those undergoing PCI.
    • Evidence suggests that higher doses of clopidogrel may achieve more potent and uniform platelet inhibition.
  • Current Standard of Care:
    • Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor (typically clopidogrel) is standard for ACS patients, particularly post-PCI.
    • Aspirin dosing varies geographically, with European guidelines favoring lower doses (≤100 mg daily) and American guidelines recommending higher doses (162-325 mg daily).
  • Knowledge Gaps Addressed by the Study:
    • Optimal dosing strategies for clopidogrel and aspirin in ACS patients undergoing PCI have not been definitively established.
    • Uncertainty exists regarding whether higher doses provide additional clinical benefits and the associated risks, particularly bleeding.
  • Study Rationale:
    • To determine whether increasing the doses of clopidogrel and aspirin can enhance clinical outcomes without unacceptable increases in bleeding risk, thereby optimizing antiplatelet therapy in ACS patients undergoing an early invasive strategy.

Methods Summary

  • Study Design: International, randomized, 2x2 factorial, double-blind for clopidogrel dosing, open-label for aspirin dosing.
  • Setting and Time Period: Conducted between June 2006 and July 2009 across multiple centers globally.
  • Population Characteristics: 25,086 patients presenting with ACS (NSTEMI or STEMI) referred for an early invasive strategy, including coronary angiography and PCI.
  • Inclusion/Exclusion Criteria:
    • Inclusion: Adults ≥18 years with ACS requiring invasive strategy; ECG changes or elevated cardiac biomarkers indicative of ischemia.
    • Exclusion: High bleeding risk, active bleeding, known allergy to clopidogrel or aspirin.
  • Intervention Details:
    • Clopidogrel:
      • Double-Dose: 600 mg loading on day 1, 150 mg daily for days 2-7, then 75 mg daily thereafter.
      • Standard-Dose: 300 mg loading on day 1, 75 mg daily thereafter.
    • Aspirin:
      • Higher-Dose: 300-325 mg daily.
      • Lower-Dose: 75-100 mg daily.
  • Control/Comparison Groups:
    • Double-dose vs. standard-dose clopidogrel.
    • Higher-dose vs. lower-dose aspirin.
  • Primary and Secondary Outcomes:
    • Primary Outcome: Composite of cardiovascular death, myocardial infarction, or stroke at 30 days.
    • Secondary Outcomes: Expanded composites including recurrent ischemia, individual components, stent thrombosis in PCI subgroup, and major bleeding events.
  • Basic Statistical Analysis Approach: Kaplan-Meier survival curves, log-rank tests, Cox proportional-hazards models stratified by aspirin dose and ACS type.
  • Sample Size Calculations: Initially 14,000 for 90% power, increased to 25,000 to maintain 80% power due to lower event rates.
  • Ethics and Funding Information: Approved by ethical committees, funded by Sanofi-Aventis and Bristol-Myers Squibb, with declared conflicts of interest from sponsors.

Detailed Results

  • Participant Flow and Demographics:
    • 25,086 patients randomized.
    • 24,835 (99.0%) underwent coronary angiography.
    • 17,263 (69%) underwent PCI.
    • Non-PCI Patients:
      • 45.0% had no clinically significant coronary artery disease.
      • 23.8% underwent coronary-artery bypass grafting (CABG).
      • 31.2% were not candidates for revascularization.
      • Baseline characteristics were well-balanced across clopidogrel and aspirin dose groups, including age (mean ~61 years), gender (~27% female), diagnosis distribution (NSTEMI/unstable angina 70.7%, STEMI 29.3%), and comorbidities.
  • Primary Outcome Results:
    • Clopidogrel Dose Comparison:
      • Double-dose: 4.2% experienced the primary outcome.
      • Standard-dose: 4.4%.
      • Hazard Ratio: 0.94 (95% CI, 0.83–1.06; P = 0.30) — not statistically significant.
    • Aspirin Dose Comparison:
      • Higher-dose: 4.2%.
      • Lower-dose: 4.4%.
      • Hazard Ratio: 0.97 (95% CI, 0.86–1.09; P = 0.61) — not statistically significant.
  • Secondary Outcome Results:
    • Clopidogrel:
      • No significant differences in expanded composite outcomes.
      • Significant reduction in stent thrombosis in PCI subgroup (1.6% vs. 2.3%; HR 0.68; 95% CI, 0.55–0.85; P = 0.001).
    • Aspirin:
      • Reduced recurrent ischemia with higher-dose aspirin (0.3% vs. 0.5%; HR 0.63; 95% CI, 0.43–0.94; P = 0.02).
      • No significant difference in primary or major outcomes.
  • Adverse Events/Safety Data:
    • Clopidogrel:
      • Major bleeding: Double-dose 2.5% vs. Standard-dose 2.0% (HR 1.24; 95% CI, 1.05–1.46; P = 0.01) — significant increase.
    • Aspirin:
      • Minor bleeding increased with higher-dose (5.1% vs. 4.3%; HR 1.18; 95% CI, 1.05–1.33; P = 0.01).
      • No significant difference in major bleeding events.
Outcome Intervention Group Control Group Difference (95% CI) P-value
Primary Outcome 4.2% 4.4% HR 0.94 (0.83–1.06) 0.30
Major Bleeding (Clopidogrel Dose) 2.5% 2.0% HR 1.24 (1.05–1.46) 0.01
Stent Thrombosis (PCI Subgroup) 1.6% 2.3% HR 0.68 (0.55–0.85) 0.001
Recurrent Ischemia (Aspirin Dose) 0.3% 0.5% HR 0.63 (0.43–0.94) 0.02
Minor Bleeding (Aspirin Dose) 5.1% 4.3% HR 1.18 (1.05–1.33) 0.01

Authors' Conclusions

  • The CURRENT–OASIS 7 trial concluded that in patients with acute coronary syndromes referred for an early invasive strategy, there was no significant difference between a 7-day double-dose clopidogrel regimen and the standard-dose regimen concerning the primary outcome of cardiovascular death, myocardial infarction, or stroke.
  • Additionally, higher-dose aspirin (300–325 mg daily) did not demonstrate superiority over lower-dose aspirin (75–100 mg daily) regarding the primary outcome.
  • However, double-dose clopidogrel was associated with an increased risk of major bleeding, and in the PCI subgroup, it significantly reduced stent thrombosis.

Critical Analysis

A. Strengths

  • Methodological Robustness:
    • Large, multicenter, randomized design enhances the generalizability of findings.
    • 2x2 factorial design efficiently evaluated both clopidogrel and aspirin dosing simultaneously.
  • Internal Validity:
    • Randomization achieved well-balanced baseline characteristics, minimizing selection bias.
    • High follow-up completeness (99.9%) reduces attrition bias.
  • Comprehensive Outcome Assessment:
    • Central adjudication of outcomes ensured consistency and accuracy.
    • Multiple predefined secondary outcomes provided a nuanced understanding of effects.
  • Real-World Applicability:
    • Inclusion of a diverse international population enhances external validity.
    • Stratification by PCI status allows for subgroup analysis pertinent to clinical practice.

B. Limitations

  • Lower Event Rate:
    • The observed primary outcome event rate was lower than anticipated, necessitating an increased sample size and potentially diluting the study’s power to detect significant differences.
  • Heterogeneous Population:
    • A substantial proportion (31.2%) were not candidates for revascularization, and 45.0% had no clinically significant coronary artery disease, which may have influenced overall outcome rates and reduced the ability to detect benefits in targeted subgroups.
  • Short Duration of Double-Dose Clopidogrel:
    • The 7-day duration may have been insufficient to observe long-term benefits, especially since the double-dose was tapered to standard-dose thereafter.
  • Increased Bleeding Risk:
    • The significant increase in major bleeding with double-dose clopidogrel raises concerns about the risk-benefit ratio, particularly in populations at higher bleeding risk.
  • Single Primary Endpoint:
    • Focusing on a composite primary outcome may obscure the effects on individual components, although secondary analyses addressed this to some extent.

Literature Review

Positioning the Current Study in Existing Evidence

The CURRENT–OASIS 7 trial is a significant contribution to the body of evidence surrounding antiplatelet therapy optimization in ACS patients undergoing PCI. Prior to this study, multiple trials had established the efficacy of clopidogrel and aspirin in reducing ischemic events in ACS. The CURE trial demonstrated the benefit of clopidogrel addition to aspirin, while studies like TRITON-TIMI 38 and PLATO examined more potent P2Y12 inhibitors—prasugrel and ticagrelor, respectively—compared to clopidogrel.

Key Previous Studies:

  • CURE Trial (Yusuf et al., 2001): Established the benefit of clopidogrel added to aspirin in reducing cardiovascular events in ACS without ST-segment elevation.
  • TRITON-TIMI 38 (Wiviott et al., 2007): Compared prasugrel to clopidogrel in ACS patients undergoing PCI, finding prasugrel superior in reducing thrombotic events but with increased bleeding.
  • PLATO Trial (Wallentin et al., 2009): Compared ticagrelor to clopidogrel, demonstrating ticagrelor’s superiority in reducing vascular death, MI, or stroke without a significant increase in major bleeding, though non-procedure-related bleeding was higher.

Guidelines and Consensus Statements:

  • American Heart Association (AHA) Guidelines (2019): Recommend DAPT with aspirin and a P2Y12 inhibitor in ACS patients, emphasizing the choice of agent based on bleeding risk and ischemic burden.
  • European Society of Cardiology (ESC) Guidelines: Suggest low-dose aspirin (≤100 mg daily) post-PCI, aligning with the lower-dose aspirin arm in CURRENT–OASIS 7.

Geographic and Population Differences:

European guidelines typically advocate for lower-dose aspirin compared to American preferences for higher-dose regimens. This discrepancy underscores the lack of consensus, which CURRENT–OASIS 7 sought to address by directly comparing aspirin dosing strategies in a randomized trial.

Comprehensive Synthesis of Findings

The CURRENT–OASIS 7 trial’s findings align with the broader landscape of antiplatelet therapy research, particularly highlighting the nuanced balance between thrombotic risk reduction and bleeding complications.

Clopidogrel Dose Comparison:

  • Double-Dose vs. Standard-Dose Clopidogrel:
    • Primary Outcome: No significant difference in the composite endpoint.
    • Stent Thrombosis: Significant reduction in the PCI subgroup, echoing findings from studies like CURE, which indicated the benefits of augmented platelet inhibition.
    • Bleeding Risk: Increased major bleeding, consistent with TRITON-TIMI 38’s observations on prasugrel.

Implications: Doubling clopidogrel dosage does not provide significant benefit in the general ACS population undergoing PCI but increases bleeding risk. This mirrors the shift towards more potent P2Y12 inhibitors (prasugrel, ticagrelor) that offer better ischemic protection with manageable bleeding profiles.

Aspirin Dose Comparison:

  • Higher-Dose vs. Lower-Dose Aspirin:
    • Primary Outcome: No significant difference, aligning with ESC guidelines favoring lower doses.
    • Recurrent Ischemia: Reduction with higher-dose aspirin, although not translating into overall primary outcome improvement.
    • Bleeding Events: Increased minor bleeding with higher-dose aspirin, supporting the preference for lower doses to minimize bleeding risk.

Implications: Lower-dose aspirin remains a viable option, balancing efficacy and safety, particularly in settings where bleeding risk is a concern.

Comparison with Supporting Trials:

  • TRITON-TIMI 38 and PLATO:
    • More potent P2Y12 inhibitors (prasugrel, ticagrelor) demonstrated superior efficacy in reducing ischemic events compared to clopidogrel.
    • CURRENT–OASIS 7’s inability to show significant ischemic benefits with higher clopidogrel doses underscores the superiority of newer agents over dose escalation of clopidogrel.
  • PEGASUS-TIMI 54 (Bonaca et al., 2015):
    • Evaluated long-term ticagrelor use, finding sustained ischemic risk reduction, contrasting with the transient benefits and increased bleeding seen with double-dose clopidogrel.
    • Highlights the importance of both agent potency and treatment duration in optimizing outcomes.

Gaps and Future Directions:

  • Long-Term Outcomes: CURRENT–OASIS 7 focused on a 30-day horizon. Long-term benefits and risks of higher-dose clopidogrel remain unexplored.
  • Subgroup Variability: Enhanced benefit in PCI subgroups suggests the need for tailored dosing based on procedural strategies and individual patient risk profiles.
  • Integration with Newer Agents: As prasugrel and ticagrelor become more prevalent, understanding their comparative effectiveness and safety against clopidogrel dosing strategies is crucial.
  • Population-Specific Data: Differences in pharmacodynamics across ethnic groups (e.g., Japanese vs. Western populations) necessitate targeted studies to optimize dosing universally.
  • Bleeding Risk Mitigation: Developing strategies to minimize bleeding risk while maximizing antithrombotic efficacy remains a priority, potentially through pharmacogenomics or concomitant therapies.
  • Cost-Effectiveness Analyses: Further economic evaluations, particularly in diverse healthcare systems, will aid in resource allocation and guideline formulation.

Clinical Application

  • The findings from the CURRENT–OASIS 7 trial suggest that doubling the dose of clopidogrel for the initial 7 days in ACS patients undergoing PCI does not confer additional protection against cardiovascular death, myocardial infarction, or stroke, while significantly increasing the risk of major bleeding.
  • Consequently, clinicians should adhere to standard-dose clopidogrel regimens unless specific patient factors warrant dose modification.
  • Additionally, the lack of significant benefit with higher-dose aspirin supports current guidelines favoring lower-dose aspirin to balance efficacy with safety.
  • These results reinforce the preference for newer P2Y12 inhibitors like prasugrel and ticagrelor, which have demonstrated superior efficacy in reducing ischemic events without proportionally increasing major bleeding risks.
  • Implementation should consider individual patient profiles, including bleeding risk, ischemic risk, and procedural factors, ensuring adherence to contemporary guidelines and evidence-based practices.

How To Use This Info In Practice

Practitioners should incorporate the findings of CURRENT–OASIS 7 by maintaining standard-dose clopidogrel and lower-dose aspirin in ACS patients undergoing PCI, aligning with recent guidelines that emphasize balancing ischemic benefits with bleeding risks. For patients not adequately responding to standard therapies or those at high ischemic risk, consideration of more potent antiplatelet agents like prasugrel or ticagrelor, as supported by ongoing literature, may be warranted.

References

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