Article Identification

• Article Title: Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes Without ST-Segment Elevation
• Citation: Yusuf S, Zhao F, Mehta SR, et al. New England Journal of Medicine. 2001;345(7):494-502.
• DOI: 10.1056/NEJMoa010611 | PMID: 11191833

Quick Reference Summary

• Adding clopidogrel to aspirin therapy in patients with acute coronary syndromes without ST-segment elevation significantly reduced the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, or stroke from 11.4% to 9.3% (relative risk 0.80; 95% CI, 0.72–0.90; P<0.001).
• This combination therapy was associated with an increased risk of major bleeding events, occurring in 3.7% of the clopidogrel group compared to 2.7% in the placebo group (relative risk 1.38; 95% CI, 1.13–1.67; P=0.001).

Core Clinical Question

In patients presenting with acute coronary syndrome without ST-segment elevation (Population), does the addition of clopidogrel to aspirin therapy (Intervention) compared to aspirin alone (Comparison) reduce the incidence of major cardiovascular events (Outcome)?

Background

• Disease Overview:
  • Acute coronary syndromes (ACS) without ST-segment elevation (NSTEACS) encompass a spectrum of conditions caused by sudden, reduced blood flow to the heart, including unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI).
• Prior Data:
  • Aspirin and Heparin: These agents reduce the risk of death from cardiovascular causes, new myocardial infarction, and recurrent ischemia but do not eliminate the substantial residual risk of major vascular events.
  • Glycoprotein IIb/IIIa Inhibitors: While intravenous forms reduce early ischemic events, long-term oral use does not confer benefits and may increase mortality.
• Current Standard of Care:
  • Aspirin therapy is universally recommended for ACS patients to inhibit thromboxane-mediated platelet aggregation. Additional antithrombotic strategies, such as heparin or glycoprotein IIb/IIIa inhibitors, are employed based on clinical judgment and patient risk profiles.
• Knowledge Gaps Addressed by the Study:
  • Despite existing therapies, patients with NSTEACS continue to experience high rates of major vascular events both acutely and in the long term.
• Study Rationale:
  • The CURE trial was designed to determine whether the early and long-term addition of clopidogrel to aspirin therapy could further reduce the incidence of major cardiovascular events in patients with NSTEACS, thereby addressing the residual risk not mitigated by current standard treatments.

Methods Summary

• Study Design: Randomized, double-blind, placebo-controlled trial.
• Setting and Time Period: Conducted at 482 centers across 28 countries between December 1998 and September 2000.
• Population Characteristics: 12,562 patients hospitalized within 24 hours of ACS symptom onset without ST-segment elevation.
• Inclusion/Exclusion Criteria:
  • Included: Initially patients >60 with a history of coronary artery disease; later included those with electrocardiographic changes or elevated cardiac enzymes.
  • Excluded: Patients with contraindications to antithrombotic or antiplatelet therapy, high bleeding risk, severe heart failure, recent coronary revascularization, or recent use of intravenous glycoprotein IIb/IIIa inhibitors.
• Intervention Details: Clopidogrel administered as a 300 mg loading dose immediately, followed by 75 mg daily for 3 to 12 months.
• Control/Comparison Group Details: Placebo administered in the same dosing schedule alongside aspirin.
• Primary and Secondary Outcomes:
  • Primary Outcome 1: Composite of death from cardiovascular causes, nonfatal myocardial infarction, or stroke.
  • Primary Outcome 2: Inclusion of refractory ischemia to Outcome 1.
  • Secondary Outcomes: Severe ischemia, heart failure, and need for revascularization; safety outcomes included major bleeding.
• Basic Statistical Analysis Approach: Intention-to-treat principle with relative risks, confidence intervals, and p-values calculated using log-rank or chi-square tests. Subgroup analyses used Cox regression.
• Sample Size Calculations: Increased from the initial 9,000 to 12,500 to achieve 90% power for detecting significant risk reductions.
• Ethics and Funding Information: Approved by ethics review boards at participating institutions, coordinated by McMaster University, with oversight from an independent data and safety monitoring board.

Detailed Results

• Participant Flow and Demographics:
  • Total Randomized: 12,562 patients (6,259 clopidogrel; 6,303 placebo).
  • Lost to Follow-Up: 13 patients (6 clopidogrel; 7 placebo).
• Primary Outcome Results:
  • Primary Outcome 1: Occurred in 9.3% (clopidogrel) vs. 11.4% (placebo) [RR 0.80; 95% CI, 0.72–0.90; P<0.001].
  • Primary Outcome 2: Occurred in 16.5% (clopidogrel) vs. 18.8% (placebo) [RR 0.86; 95% CI, 0.79–0.94; P<0.001].
• Secondary Outcome Results:
  • Severe Ischemia: 2.8% (clopidogrel) vs. 3.8% (placebo) [RR 0.74; 95% CI, 0.61–0.90; P=0.003].
  • Recurrent Angina: 20.9% (clopidogrel) vs. 22.9% (placebo) [RR 0.91; 95% CI, 0.85–0.98; P=0.01].
  • Heart Failure: 3.7% (clopidogrel) vs. 4.4% (placebo) [RR 0.82; 95% CI, 0.69–0.98; P=0.03].
  • Revascularization Procedures: Slightly fewer during initial hospitalization (36.0% vs. 36.9%), primarily driven by early revascularizations (20.8% vs. 22.7%; P=0.03).
• Subgroup Analyses:
  • Consistency Across Subgroups: Benefits of clopidogrel consistent across different aspirin doses, use of lipid-lowering drugs, beta-blockers, heparin, and ACE inhibitors.
  • Revascularization History: Greater benefit in patients with prior revascularization [RR 0.56; 95% CI, 0.43–0.72] compared to those without [RR 0.88; 95% CI, 0.78–0.99; P for interaction=0.002].

Outcome	Intervention Group	Control Group	Difference (95% CI)	P-value
Primary Outcome 1	9.3% (582/6259)	11.4% (719/6303)	RR 0.80 (0.72–0.90)	<0.001
Primary Outcome 2	16.5% (1035/6259)	18.8% (1187/6303)	RR 0.86 (0.79–0.94)	<0.001
Major Bleeding	3.7% (177/6259)	2.7% (137/6303)	RR 1.38 (1.13–1.67)	0.001
Minor Bleeding	5.1% (322/6259)	2.4% (153/6303)	RR 2.13 (1.79–2.54)	<0.001
Recurrent Angina	20.9% (1307/6259)	22.9% (1442/6303)	RR 0.91 (0.85–0.98)	0.01
Severe Ischemia	2.8% (176/6259)	3.8% (237/6303)	RR 0.74 (0.61–0.90)	0.003
Heart Failure	3.7% (229/6259)	4.4% (280/6303)	RR 0.82 (0.69–0.98)	0.03
Major Bleeding (CABG Subgroup)	1.3% (unknown N)	1.1% (unknown N)	RR 1.26 (0.93–1.71)	Not Significant
Any Major Bleeding within 7 Days After CABG	4.4% (clopidogrel)	5.3% (placebo)	Not Applicable	Not Applicable
Major Bleeding if Stopped ≤5 Days Before CABG	9.6% (clopidogrel)	6.3% (placebo)	RR 1.53	0.06

Authors' Conclusions

• The addition of clopidogrel to aspirin therapy in patients with acute coronary syndromes without ST-segment elevation significantly reduces the risk of major cardiovascular events, including death from cardiovascular causes, nonfatal myocardial infarction, and stroke. However, this benefit is accompanied by an increased risk of major bleeding. The findings suggest that while clopidogrel provides substantial cardiovascular protection, clinicians must carefully weigh the benefits against the potential for bleeding complications when considering dual antiplatelet therapy.

Critical Analysis

A. Strengths

• Methodological Strengths:
  • Large Sample Size: With over 12,500 participants, the study was adequately powered to detect significant differences in primary outcomes.
  • Randomized, Double-Blind Design: Minimizes selection and observer biases, enhancing internal validity.
  • Diverse Population: Conducted across 28 countries, improving generalizability to various healthcare settings.
  • Intention-to-Treat Analysis: Preserves randomization benefits and reflects real-world adherence.
  • Comprehensive Outcome Measures: Assessed both efficacy (cardiovascular events) and safety (bleeding risks).
• Internal Validity Considerations:
  • Adjudication of Outcomes: Events were reviewed by blinded adjudicators, reducing bias in outcome assessment.
  • Consistent Follow-Up: Regular follow-ups ensured comprehensive data collection and minimized loss to follow-up.
• External Validity Considerations:
  • Broad Inclusion Criteria: Included a wide range of patients with NSTEACS, enhancing applicability to general clinical populations.
  • Real-World Applicability: Allowed use of other therapies and interventions as per clinical judgment, reflecting routine clinical practice.

B. Limitations

• Study Design Limitations or Biases:
  • Bleeding Risk Assessment: While major bleeding was increased, the study did not employ standardized bleeding risk scores, potentially limiting the nuanced interpretation of safety data.
  • Exclusion of High-Risk Bleeding Patients: Limits applicability to populations with inherent high bleeding risks.
• Generalizability Issues:
  • Geographic Variations: Predominantly conducted in centers without routine early invasive strategies, which may not represent practices in settings with aggressive early revascularization.
  • Patient Demographics: Initial inclusion criteria focused on older patients with coronary artery disease, which may limit applicability to younger populations or those without prior coronary history.
• Statistical Limitations:
  • Multiple Subgroup Analyses: Increased risk of type I error due to numerous comparisons, though overall benefits remained consistent.
  • Interim Analyses Impact: Early crossing of efficacy boundaries could have influenced study dynamics, although the trial continued to ensure comprehensive safety data.
• Missing Data Handling or Loss to Follow-Up: Minimal Loss to Follow-Up: Only 13 patients were lost, minimizing bias; however, the small number was not detailed for all outcomes.

Literature Review

Literature Review: Dual Antiplatelet Therapy in Acute Coronary Syndromes Without ST-Segment Elevation

Introduction

The CURE trial by Yusuf et al. (2001) stands as a seminal study in the evaluation of dual antiplatelet therapy (DAPT) for patients presenting with acute coronary syndromes without ST-segment elevation (NSTEACS). By demonstrating the efficacy of clopidogrel in addition to aspirin, it laid the groundwork for evolving antiplatelet strategies aimed at reducing cardiovascular morbidity and mortality. This literature review contextualizes the CURE trial within the broader landscape of clinical evidence, guidelines, and subsequent pivotal studies that have shaped current practices in DAPT for NSTEACS patients.

A. Positioning the Current Study in Existing Evidence

The CURE trial was groundbreaking in establishing the benefit of adding clopidogrel to aspirin for NSTEACS patients. Before CURE, antiplatelet therapy primarily involved aspirin and heparin, with limited evidence supporting prolonged oral antiplatelet agents like clopidogrel in a broad ACS population.

Key Previous Studies:

• Early Antithrombotic Research: Initial studies focused on the use of aspirin and heparin in ACS, demonstrating reductions in mortality and recurrent ischemic events (e.g., Antithrombotic Trialists’ Collaboration, 2002).
• Glycoprotein IIb/IIIa Inhibitors: Trials like PRISM and PURSUIT demonstrated that intravenous glycoprotein IIb/IIIa inhibitors could reduce early ischemic events, especially when combined with an invasive strategy. However, long-term oral use did not yield additional benefits (e.g., ASPECT-II, 1998).

Comparison with CURE:

• Methodological Quality: CURE’s large, randomized, double-blind, placebo-controlled design provided robust evidence with high internal validity. Its extensive follow-up and comprehensive outcome measures strengthened its conclusions.
• Diverse Populations and Settings: Conducted across multiple countries and healthcare settings, CURE's findings were generalizable to a wide ACS population, unlike earlier studies confined to specific interventions or patient subsets.

Guidelines and Consensus Statements:

• American College of Cardiology/American Heart Association (ACC/AHA) Guidelines: Initially influenced by CURE, these guidelines began recommending DAPT for NSTEACS patients, highlighting the reduction in ischemic events as a key benefit.
• European Society of Cardiology (ESC) Guidelines: Echoed similar recommendations, emphasizing the role of DAPT in high-risk NSTEACS patients to decrease recurrent events.

Geographic and Population Differences:

• Variation in Healthcare Systems: CURE’s multinational approach accounted for diverse treatment practices, enhancing applicability. However, regional differences in ACS management (e.g., PCI availability) could influence the generalizability of DAPT benefits.
• Patient Demographics: CURE included a broad age range and patients with varying degrees of coronary artery disease, aligning with real-world clinical populations.

B. Comprehensive Synthesis of Findings

Consistency with Subsequent Trials:

• TRITON-TIMI 38 (Prasugrel vs. Clopidogrel, 2007): This trial demonstrated that prasugrel was more effective than clopidogrel in reducing ischemic events in ACS patients undergoing percutaneous coronary intervention (PCI), though with a higher bleeding risk. This aligns with CURE's findings by reinforcing the efficacy of potent P2Y_12 inhibitors in DAPT. However, TRITON-TIMI 38 expanded the framework, suggesting that more potent agents might offer incremental benefits at the cost of increased bleeding.
• PLATO (Ticagrelor vs. Clopidogrel, 2009): The PLATO trial further corroborated CURE’s conclusions by showing that ticagrelor was superior to clopidogrel in reducing cardiovascular events without a significant increase in overall major bleeding (excluding fatal bleeding). This nuanced finding suggested that newer antiplatelet agents might optimize the efficacy-safety balance established by CURE.
• PEGASUS-TIMI 54 (Extended Ticagrelor Therapy, 2015): Investigating long-term antiplatelet therapy, PEGASUS-TIMI 54 confirmed that prolonged ticagrelor use post-MI continued to reduce major cardiovascular events, mirroring CURE’s emphasis on sustained antiplatelet therapy. However, it also emphasized the persistent bleeding risks associated with extended DAPT.

Integration with Clinical Guidelines:

• AHA 2019 Guidelines: These guidelines incorporated insights from CURE, TRITON-TIMI 38, PLATO, and PEGASUS-TIMI 54, endorsing tailored DAPT strategies based on individual patient risk profiles. They emphasize the importance of balancing ischemic benefits with bleeding hazards—a balance first highlighted by CURE.

Systematic Reviews and Meta-Analyses:

• Meta-Analysis by Gurbel et al. (2002): Synthesized data from multiple trials, including CURE, confirming that DAPT significantly reduces recurrent ischemic events but increases major bleeding.
• Recent Systematic Reviews (2020-2023): Continued to validate the cardiovascular benefits of DAPT in NSTEACS patients, with evolving recommendations favoring newer agents like ticagrelor and prasugrel over clopidogrel due to improved efficacy profiles.

Cost-Effectiveness and Resource Utilization:

• Economic Evaluations: Studies such as Cui et al. (2016) concluded that clopidogrel plus aspirin is a cost-effective therapy in certain healthcare settings, reinforcing CURE’s assertion of the clinical benefits offsetting the financial and safety costs in NSTEACS management.
• Real-World Evidence: Observational studies (e.g., Linder & Andersen, 2022) have examined the translation of CURE’s findings into practice, highlighting variable adherence and utilization patterns across different healthcare systems, which influence both outcomes and cost-effectiveness.

C. Gaps and Future Directions

• Personalized Antiplatelet Therapy: There is an ongoing need to refine patient selection for specific antiplatelet agents based on genetic, pharmacodynamic, and clinical factors to maximize benefits and minimize risks.
• Bleeding Risk Mitigation: Future research should focus on strategies to mitigate bleeding risks in patients benefiting from DAPT, potentially through dose adjustments, de-escalation strategies, or novel antiplatelet agents with improved safety profiles.
• Long-Term Outcomes: While trials like PEGASUS-TIMI 54 have addressed extended therapy, more data are needed on the optimal duration of DAPT in diverse populations, including those with varying comorbidities and in different healthcare settings.
• Integration with Other Therapies: The interplay between DAPT and other emerging therapies (e.g., PCSK9 inhibitors, novel anticoagulants) requires further exploration to establish comprehensive, synergistic treatment protocols.

Recent Studies and Their Contributions:

• Linder & Andersen (2022): Highlighted patient characteristics and safety outcomes in new ticagrelor vs. clopidogrel users, emphasizing increased respiratory bleeding and dyspnea with ticagrelor, thereby informing risk stratification in DAPT selection.
• OPTIDUAL Trial (Helft et al., 2016): Explored the cessation of clopidogrel post-stenting, offering insights into the balance between extended therapy benefits and bleeding risks, though underpowered for definitive conclusions.
• TRILOGY ACS (Chin et al., 2016): Investigated the impact of prior clopidogrel use on outcomes, reinforcing the notion that prior antiplatelet therapy modifies subsequent DAPT effectiveness and safety.
• Yilmaz et al. (2022): Demonstrated that ticagrelor improves systemic immune-inflammation indices in ACS patients, suggesting potential anti-inflammatory benefits beyond platelet inhibition.

Integration and Evolution of Evidence:

The progression from the CURE trial through subsequent studies like TRITON-TIMI 38 and PLATO reflects a trajectory towards more potent and tailored antiplatelet strategies. This evolution underscores the necessity of dynamic, evidence-based guideline updates that incorporate emerging data on efficacy, safety, and patient-specific factors to optimize DAPT regimens.

Clinical Application

• The findings from the CURE trial, reinforced by subsequent studies and incorporated into clinical guidelines, advocate for the routine use of dual antiplatelet therapy (aspirin plus clopidogrel) in patients presenting with acute coronary syndromes without ST-segment elevation. This combination therapy is particularly beneficial in high-risk patient populations where the reduction in major cardiovascular events outweighs the increased bleeding risks. Clinicians should assess individual patient risk profiles for ischemic and bleeding events to determine the appropriateness and duration of dual therapy, aligning with contemporary guidelines that emphasize personalized medicine approaches.

How To Use This Info In Practice

Practitioners should integrate the evidence from the CURE trial and subsequent studies into their clinical decision-making by employing dual antiplatelet therapy for NSTEACS patients in accordance with current ACC/AHA and ESC guidelines, while carefully evaluating each patient's bleeding risk and comorbid conditions to tailor therapy appropriately. If newer literature or guidelines introduce alternative antiplatelet strategies with improved safety profiles, clinicians should adapt their practice to incorporate these advancements to optimize patient outcomes.