CHANCE

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Wang Y, et al. "Clopidogrel with aspirin in acute minor stroke or transient ischemic attack". The New England Journal of Medicine. 2013. 369(1):11-19.
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Clinical Question

Among patients with acute TIA or minor ischemic stroke, does the early administration of aspirin/clopidogrel reduce rates of subsequent strokes when compared to aspirin monotherapy?

Bottom Line

Among patients with acute TIA or minor ischemic stroke, starting aspirin/clopidogrel within 24h of symptom onset reduces the 90-day stroke incidence without increasing bleeding rates, when compared to aspirin monotherapy.

Major Points

The efficacy of single-agent antiplatelet therapy in patients with recent strokes was established by IST (1997; aspirin) and CAPRIE (1996; clopidogrel). A logical extension was that combination therapy with aspirin/clopidogrel may reduce the rate of subsequent stroke even further. This gave rise to MATCH (2004), which demonstrated that aspirin/clopidogrel reduced stroke rates to a similar degree as plavix monotherapy and conferred an increased risk of bleeding. MATCH was criticized for including patients who would not likely have benefited from antiplatelet therapy as the majority of patients had lacunar infarcts rather than atherothrombotic events. Moreover, the vast majority of antiplatelet trials in stroke have studied patients with recent stroke (ie, <6 months), not patients in the acute stroke setting. Since a large number of subsequent strokes occur early, CHANCE sought to bring dual antiplatelet therapy into the acute setting.

The 2013 Clopidogrel in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial randomized 5,170 Chinese patients with high-risk TIA or minor ischemic stroke within 24 hours of symptom onset to either combination aspirin/clopidogrel or aspirin alone. In the combination group, aspirin was continued for 21 days; all other therapy was continued for 90 days. At 90 days, combination aspirin/clopidogrel was associated with a 3.5% absolute and a 30% relative reduction in subsequent strokes compared to aspirin monotherapy (8.2% vs. 11.7%; NNT=29) driven predominantly by a reduction in ischemic stroke. There was no between-group difference in bleeding rates, which was the trial's primary safety outcome.

The design of the CHANCE trial represents a sea change towards early antiplatelet therapy in CVA management, recognizing that subsequent ischemic events occur early in the post-CVA period. The early use of combination antiplatelet therapy in CHANCE is one of the most significant differences between it and MATCH, and is likely the reason that CHANCE was a positive trial. Despite these promising results, the trial's results lack generalizability to Europe and the US. Chinese patients have a larger proportion of undertreated modifiable stroke risk factors (including diabetes and hypertension), a greater burden of large-vessel cerebrovascular disease, and frequently have polymorphisms in genes regulating clopidogrel metabolism. The NIH-sponsored Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT)[1] trial is currently enrolling, and will investigate a similar approach to dual antiplatelet therapy in US patients. In the interim, clinicians providing care to non-Chinese patients have been advised to enroll patients in trials like POINT, rather than change their clinical practice to align with CHANCE.[2]

Guidelines

2014 AHA/ASA Secondary Stroke Prevention Guidelines [3]

  • For patients with noncardioembolic ischemic stroke or TIA, the use of antiplatelet agents rather than oral anticoagulation is recommended to reduce the risk of recurrent stroke and other cardiovascular events (Class I; Level of Evidence A).
  • Aspirin (50–325 mg/d) monotherapy (Class I; Level of Evidence A) or the combination of aspirin 25 mg and extended-release dipyridamole 200 mg twice daily (Class I; Level of Evidence B) is indicated as initial therapy after TIA or ischemic stroke for prevention of future stroke. (Revised recommendation)
  • Clopidogrel (75 mg) monotherapy is a reasonable option for secondary prevention of stroke in place of aspirin or combination aspirin/dipyridamole (Class IIa; Level of Evidence B). This recommendation also applies to patients who are allergic to aspirin.
  • The selection of an antiplatelet agent should be individualized on the basis of patient risk factor profiles, cost, tolerance, relative known efficacy of the agents,and other clinical characteristics (Class I; Level of Evidence C).
  • The combination of aspirin and clopidogrel might be considered for initiation within 24 hours of a minor ischemic stroke or TIA and for continuation for 90 days (Class IIb; Level of Evidence B). (New recommendation in 2014 Update)
  • The combination of aspirin and clopidogrel, when initiated days to years after a minor stroke or TIA and continued for 2 to 3 years, increases the risk of hemorrhage relative to either agent alone and is not recommended for routine long-term secondary prevention after ischemic stroke or TIA (Class III; Level of Evidence A).
  • For patients who have an ischemic stroke or TIA while taking aspirin, there is no evidence that increasing the dose of aspirin provides additional benefit. Although alternative antiplatelet agents are often considered, no single agent or combination has been adequately studied in patients who have had an event while receiving aspirin (Class IIb; Level of Evidence C).
  • For patients with a history of ischemic stroke or TIA, AF, and CAD, the usefulness of adding antiplatelet therapy to VKA therapy is uncertain for purposes of reducing the risk of ischemic cardiovascular and cerebrovascular events (Class IIb; Level of Evidence C).
  • Unstable angina and coronary artery stenting represent special circumstances in which management may warrant DAPT/VKA therapy. (New Recommendation in 2014 Update)

Design

  • Multicenter, randomized, placebo-controlled trial
  • N=5,170
    • Aspirin (n=2,586)
    • Aspirin/clopidogrel (n=2,584)
  • Setting: 114 centers in China
  • Enrollment: 2009-2012
  • Follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcome: Stroke

Population

Inclusion Criteria

  • Age ≥40 years
  • Either of the following:
    • Minor ischemic stroke (NIHSS score ≤3)
    • High-risk TIA (ABCD2 score ≥4)
  • Symptom onset ≤24 hours

Exclusion Criteria

  • CT/MRI brain with hemorrhage, vascular malformations, tumor, abscess, or other similar non-ischemic brain disease
  • Isolated sensory symptoms, visual changes, dizziness or vertigo without evidence of acute infarction
  • Pre-event Rankin score >2
  • Other need for anticoagulation including AF
  • History of intracranial hemorrhage
  • Need for long-term antiplatelet therapy
  • Anticoagulation therapy in prior 10 days
  • GI bleeding or major surgery in prior 3 months
  • Likely revascularization surgery in following 3 months
  • Planned intervention that would require cessation of study medication
  • TIA or minor stroke from surgical intervention
  • Life expectancy <3 months
  • Females with child-bearing capacity not on contraception without a negative pregnancy test
  • Other investigational drug use

Baseline Characteristics

From the aspirin group.

  • Demographics: Age 62 years, female 34.7%
  • Baseline health data: SBP 150 mmHg, DBP 90 mmHg, BMI 25
  • PMH: HTN 65.1%, DM 21.0%, HLD 10.9%, PE <0.1%, ischemic stroke 20.0%, TIA 3.1%, MI 2.0%, angina 3.4%, HF 1.5%, AF/AFL 1.9%, valvular heart disease 0.4%, ever smoker 42.7%
  • Symptom onset <12h: 49.5%
  • Qualifying event:
    • TIA 28.2%
    • Minor stroke 71.8%
  • Mean ABCD2 score (for TIAs only): 4

Interventions

  • Randomization to one of two groups:
    • Aspirin group received aspirin 75-300mg on day one followed by 75mg daily plus placebo clopidogrel
    • Aspirin/clopidogrel group received clopidogrel 300mg and aspirin 75-300mg on day one, followed by clopidogrel 75mg daily; aspirin was continued at 75mg daily through day 21 and placebo aspirin was given thereafter
  • All patients had a CT and/or MRI performed as part of routine workup
  • Thrombolytics were disallowed

Outcomes

Comparisons are aspirin vs. aspirin/clopidogrel. All outcomes are at 90 days.

Primary Outcome

Stroke
11.7% vs. 8.2% (HR 0.68; 95% CI 0.57-0.81; P<0.001; NNT=29)

Secondary Outcomes

Stroke, MI, CV mortality
11.9% vs. 8.4% (HR 0.69; 95% CI 0.58-0.82; P<0.001)
Ischemic stroke: 11.4% vs. 7.9% (HR 0.67; 95% CI 0.56-0.81; P<0.001)
Hemorrhagic stroke: 0.3% vs. 0.3% (HR 1.01; 95% CI 0.38-2.70; P=0.98)
MI: 0.1% vs. 0.1% (HR 1.44; 95% CI 0.24-8.63; P=0.68)
CV mortality: 0.2% vs. 0.2% (HR 1.16; 95% CI 0.35-3.79; P=0.81)
All-cause mortality
0.4% vs. 0.4% (HR 0.97; 0.40-2.33; P=0.94)
TIA
1.8% vs. 1.5% (HR 0.82; 0.53-1.26; P=0.36)

Subgroup Analysis

There was no interaction for the primary endpoint for age, sex, stroke vs. TIA, ABCD2 score, history of stroke or TIA, HTN, DM, BP on presentation, or recent aspirin use.

Adverse Events

Bleeding
1.6% vs. 2.3% (HR 1.41; 95% CI 0.95-2.10; P=0.09)
Mild: 0.7% vs. 1.2% (HR 1.57; 95% CI 0.88-2.79; P=0.12)
Moderate: 0.2% vs. 0.1% (HR 0.73; 95% CI 0.16-3.26; P=0.68)
Severe: 0.2% vs. 0.2% (HR 0.94; 95% CI 0.24-3.79; P=0.94)

Criticisms

  • Chinese only patients, a population with a much higher rate of stroke (and more large-vessel strokes[2]) than in the US
  • Low treatment of comorbid diseases increasing risk for stroke in the trial population (eg, HTN, DM)
  • Low rate of screened patients included as participants[2]
  • Polymorphisms affecting clopidogrel metabolism are more common in Chinese patients[2]
  • Unknown benefit after 90 days[2]

Funding

Ministry of Science and Technology of the People's Republic of China

Further Reading

  1. Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial homepage. Accessed 2013-07-08.
  2. 2.0 2.1 2.2 2.3 2.4 Hankey GJ. "Editorial: Dual antiplatelet therapy in acute transient ischemic attack and minor stroke." The New England Journal of Medicine. 2013;369(1):82-83
  3. Kernan WN et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014. 45:2160-236.