CURE

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Yusuf S, et al. "Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation". The New England Journal of Medicine. 2001. 345(7):494-502.
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Clinical Question

In patients with UA/NSTEMI, does the addition of clopidogrel reduce CV mortality, MI, or stroke?

Bottom Line

In patients with UA/NSTEMI, dual antiplatelet therapy with clopidogrel and aspirin reduced CV mortality, non-fatal MI, or stroke but increased the rate of major bleeding.

Major Points

Early trials such as the VA Cooperative Study (1983) and ISIS-2 (1988) demonstrated that aspirin, which inhibits platelets through irreversible cyclooxygenase blockade, decreases mortality in UA/NSTEMI. Clopidogrel, a newer antiplatelet agent that irreversibly binds to the P2Y12 ADP receptors, has been suggested to have better outcomes. CURE was designed to evaluate if clopidogrel would further improve outcomes from ACS when added to ASA.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial randomized 12,562 patients with UA/NSTEMI to either dual antiplatelet therapy with aspirin plus plavix or to aspirin alone immediately upon presentation. At a mean follow-up of 9 months, dual antiplatelet therapy was associated with a significant reduction in the composite primary endpoint of CV mortality, nonfatal MI, or stroke, largely due to fewer MIs. However, the addition of clopidogrel was associated with increased rate of major bleeding.

Guidelines

ACCF/AHA NSTE-ACS (2014, adapted)[1]

  • Aspirin 162-325 mg without enteric coating at presentation then ASA 81-162 mg PO qday continuously, unless aspirin is contraindicated (class I, level A)
    • If aspirin is contraindicated, treat with clopidogrel with a loading dose then a maintenance dose continually (class I, level B)
  • If treated with an early invasive strategy or an ischemia-guided strategy, treat for ≤12 months with clopidogrel or ticagrelor (class I, level B)
    • In this instance, it's reasonable to use ticagrelor over clopidogrel (class IIa, level B)

Design

  • Multicenter, double-blind, parallel group, randomized, placebo-controlled trial
  • N=12,562 patients with UA/NSTEMI
    • Clopidogrel (n=6,259)
    • Placebo (n=6,303)
  • Setting: 482 centers in 28 countries
  • Enrollment: 1998-2000
  • Mean follow-up: 9 months
  • Analysis: Intention-to-treat
  • Primary outcome: composite of CV mortality, non-fatal MI, or stroke

Population

Inclusion Criteria

  • Hospitalization within 24 hours of symptom onset
  • EKG changes or elevated cardiac enzymes

Exclusion Criteria

  • ST elevations on EKG
  • Severe heart failure
  • Coronary revascularization in previous 3 months
  • Use of GP IIb/IIIa inhibitors in previous 3 days
  • Use of oral anticoagulants
  • High risk for bleeding
  • Contraindications to antithrombotic or antiplatelet therapy

Baseline Characteristics

  • Age: 64.2 years
  • Male: 61.5%
  • Time from onset of pain until randomization: 14.1 hours
  • Heart rate: 73.1 bpm
  • SBP: 134.2 mmHg
  • Diagnosis
    • UA: 74.9%
    • NSTEMI: 26.1%
  • PMH:
    • MI: 32.2%
    • CABG or PTCA: 17.9%
    • Stroke: 4.0%
    • Heart failure: 7.6%
    • HTN: 58.8%
    • DM: 22.6%
    • Current or former smoker: 60.8%
  • EKG changes:
    • Any: 93.8%
    • ST depression ≥1 mm: 42.1%
    • TWI ≥2 mm: 25.7%

Baseline Medications

  • ASA: 66.1%
  • B-blocker: 58.6%
  • ACE-inhibitor: 37.0%
  • Lipid-lowering agent: 25.4%
  • Heparin or LMWH: 72.7%
  • CCB: 28.3%
  • IV nitrate: 45.7%

Interventions

  • Randomized to clopidogrel vs. placebo:
    • Clopidogrel 300 mg loading dose followed by clopidogrel 75 mg daily for 3 to 12 months
    • Placebo daily for 3 to 12 months
  • All patients were administered aspirin 75 to 325 mg daily.
  • Follow-up at 1 month and then 3 month intervals

Outcomes

Comparisons are clopidogrel vs. placebo.

Primary Outcomes

Composite of CV mortality, non-fatal MI, or stroke
9.3% vs. 11.4% (RR 0.80; 95% CI 0.72-0.90; P<0.001; NNT=48
Composite of CV mortality, non-fatal MI, stroke or refractory ischemia
16.5% vs. 18.8% (RR 0.86; 95% CI 0.79-0.94; P<0.001)

Secondary Outcomes

Composite of CV mortality or non-fatal MI
8.6% vs. 10.5% (RR 0.81; 95% CI 0.72-0.91; P<0.001)
CV mortality
5.1% vs. 5.5% (RR 0.93; 95% CI 0.79-1.08)
MI
5.2% vs. 6.7% (RR 0.77; 95% CI 0.67-0.89)
Q-wave MI: 1.9% vs. 3.1% (RR 0.60; 95% CI 0.48-0.76)
Non-q-wave MI: 3.5% vs. 3.8% (RR 0.89; 95% CI 0.74-1.07)
Stroke
1.2% vs. 1.4% (RR 0.86; 95% CI 0.63-1.18; P=NS)
Refractory ischemia
8.7% vs. 9.3% (RR 0.93; 95% CI 0.82-1.04)
During hospitalization: 1.4% vs. 2.0% (RR 0.68; 95% CI 0.52-0.90; P=0.007)
Non-CV mortality
0.7% vs. 0.5% (RR 0.91; 95% Ci 0.60-1.39)

Additional Analyses

Other severe ischemia during hospitalization
2.8% vs. 3.8% (RR 0.74; 95% CI 0.61-0.90; P=0.003)
Other recurrent angina during hospitalization
20.9% vs. 22.9% (RR 0.91; 95% CI 0.85-0.91; P=0.01)
Revascularization during hospitalization
20.8% vs. 22.7% (RR 0.91; P=0.03)
Heart failure during hospitalization
3.7% vs. 4.4% (RR 0.82; 95% CI 0.69-0.98; P=0.026)

Subgroup Analysis

The benefits of clopidogrel were consistent among multiple subgroups, including age, ST changes, enzyme elevations, different doses of aspirin, baseline use of lipid-lowering agents, beta-blockers, heparin, or ACE inhibitors, and revascularization.

Adverse Events

Any bleeding
8.5% vs. 5.0% (RR 1.69; 95% CI 1.48-1.94; P<0.001; NNH=29)
Major bleeding[2]
3.7% vs. 2.7% (RR 1.38; 95% CI 1.13-1.67; P=0.001)
Requiring transfusion ≥2 units: 2.8% vs. 2.2% (RR 1.30; 95% CI 1.04-1.62; P=0.02)
Life threatening*: 2.2% vs. 1.8% (RR 1.21; 95% CI 0.95-1.56; P=0.13)
*Fatal, causing 5 g/dl drop in Hb, requiring surgery, causing hemorrhagic stroke, requiring inotropic agents or requiring transfusion ≥4 units
Minor bleeding[2]
5.1% vs. 2.4% (RR 2.12; 95% CI 1.75-2.56; P<0.001)

Criticisms

  • The change of inclusion criteria after the first 3,000 patients were enrolled makes the study a meta-analysis of two studies rather than a single study.[3]
  • Addition of bleeding to the primary endpoint would make the outcome lose significance.[3]
  • Clopidogrel wasn't given to all undergoing PCI, although this is standard of care now.[3]
  • The protocol was more conservative than that used in many academic centers; for example, GP IIb/IIIa inhibitors were discouraged, and rates of PCI were lower than observed in many US centers.[4]
  • The use of clopidogrel may delay CABG, the effect of which is unclear.[4]
  • Patients were more high-risk, with ischemia on EKG and/or positive cardiac markers, compared to most UA/NSTEMI patients.[4]

Funding

Supported by Sanofi-Synthelabo and Bristol-Myers Squibb. Authors with multiple disclosures.

Further Reading

  1. Amsterdam EA, et al. "2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes." Journal of the American College of Cardiology. 2014;epublished 2014-09-23. Accessed 2014-09-24.
  2. 2.0 2.1 TIMI major and minor bleeding in Table 2; Mehran, R et al. "Standardized bleeding definitions for cardiovascular clinical trials: A consensus report from the bleeding academic research consortium." Circulation; 2011: 123: 2736-2747.
  3. 3.0 3.1 3.2 NEJM Letters to the editor
  4. 4.0 4.1 4.2 Gerschutz GP, Bhatt DL. "The CURE trial: using clopidogrel in acute coronary syndromes without ST-segment elevation." Cleve Clin J Med. 2002 May;69(5):377-8.