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CHANCE-2

Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA

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Year of Publication: 2021

Authors: Yongjun Wang, Xia Meng, Anxin Wang, ..., for the CHANCE-2 Investigators

Journal: The New England Journal of Medicine

Citation: N Engl J Med 2021;385:2520-30.

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2111749

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2111749

Clinical Question

In patients with minor ischemic stroke or high-risk TIA who carry CYP2C19 loss-of-function alleles, does ticagrelor + aspirin reduce 90-day stroke risk compared with clopidogrel + aspirin?

Study Overview

Objective

Ticagrelor-aspirin versus clopidogrel-aspirin in preventing recurrent stroke in patients with minor ischemic stroke or TIA carrying CYP2C19 loss-of-function alleles.

Study Summary

In patients with minor ischemic stroke or high-risk TIA who have CYP2C19 loss-of-function allele, ticagrelor-aspirin reduced stroke recurrence compared to clopidogrel-aspirin over 90 days.
No significant difference in moderate or severe bleeding, though total bleeding events were more frequent with ticagrelor.
Benefits were more prominent early after stroke onset and across metabolizer subgroups.

Intervention

Ticagrelor 180 mg loading dose followed by 90 mg twice daily for 90 days vs. Clopidogrel 300 mg loading dose followed by 75 mg daily for 90 days. All patients received aspirin for the first 21 days.

Bottom Line

Among 6,412 Chinese patients with minor stroke/TIA who were CYP2C19 LOF carriers, ticagrelor-aspirin reduced 90-day stroke from 7.6% to 6.0% (HR 0.77; 95% CI 0.64-0.94; P=0.008). Severe/moderate bleeding was identical (0.3% vs 0.3%), but total any-bleeding doubled (5.3% vs 2.5%). Point-of-care genotyping averaged 80.3 minutes — operationally feasible.

        Major Points
        23% relative risk reduction: ticagrelor-aspirin reduced stroke from 7.6% to 6.0% (HR 0.77; 95% CI 0.64-0.94; P=0.008).
Genotype-guided selection feasible at scale: 11,255 screened, 57% were LOF carriers, POC genotyping averaged 80.3 minutes.
Consistent across metabolizer subgroups: intermediate (HR 0.78; 0.63-0.97) and poor metabolizers (HR 0.77; 0.50-1.18).
No increase in severe/moderate bleeding: 0.3% vs 0.3% (HR 0.82; P=0.66).
Any bleeding doubled: 5.3% vs 2.5% (HR 2.18; 95% CI 1.66-2.85) — mostly mild/nuisance.
30-day stroke also reduced: 4.9% vs 6.4% (HR 0.75; 0.61-0.93). Curves diverged in first week.
Vascular composite reduced: stroke/TIA/MI/vascular death 7.2% vs 9.2% (HR 0.77; 0.65-0.92).
No benefit in prior stroke/TIA patients: HR 1.07 (0.72-1.60) vs HR 0.70 (0.57-0.88) without prior events.
Aspirin limited to 21 days in both arms, then monotherapy through Day 90.
6,412 patients, 202 Chinese sites, double-blind, placebo-controlled. 100% 90-day follow-up.

      

Design

Study Type: Randomized, double-blind, placebo-controlled superiority trial

Randomization: 1

Blinding: Double-blind with matching placebos. 1:1 within 24h of symptom onset.

Enrollment Period: September 23, 2019 to March 22, 2021

Follow-up Duration: 90 days (primary); 12 months total planned

Centers: 202

Countries: China

Sample Size: 6412

Analysis: Intention-to-treat. Cox proportional hazards with centers as random effect. 90% power to detect 25% RRR at planned P=0.048 (0.05 adjusted for one interim analysis via O'Brien-Fleming spending function). Because no alpha was expended at the interim, the final analysis used a two-sided alpha of 0.05.

Inclusion Criteria

Age ≥40 years.
CYP2C19 loss-of-function allele (*2 or *3) carrier confirmed by point-of-care genotyping.
Acute nondisabling ischemic stroke (NIHSS ≤3) OR high-risk TIA (ABCD² ≥4).
Able to start trial drug within 24 hours of last known normal.

Exclusion Criteria

Received IV thrombolysis or mechanical thrombectomy.
Surgery requiring drug cessation scheduled.
mRS 3-5 (moderate-severe disability).
History of intracranial hemorrhage or amyloid angiopathy.
DAPT in prior 72 hours.
Current heparin or oral anticoagulation.
Presumed cardiac source of embolus (AF, prosthetic valve, endocarditis).
Contraindication to ticagrelor, clopidogrel, or aspirin.

Baseline Characteristics

Characteristic	Ticagrelor-Aspirin (N=3,205)	Clopidogrel-Aspirin (N=3,207)
Age median (IQR)	65.0 (57.0-71.7)	64.6 (56.9-71.1)
Female	1,090 (34.0%)	1,080 (33.7%)
Hypertension	2,356 (73.5%)	2,374 (74.0%)
Diabetes	1,033 (32.2%)	1,009 (31.5%)
Dyslipidemia	888 (27.7%)	895 (27.9%)
Previous ischemic stroke	669 (20.9%)	681 (21.2%)
Current smoker	995 (31.0%)	986 (30.7%)
CYP2C19 intermediate metabolizer	2,486 (77.6%)	2,515 (78.4%)
CYP2C19 poor metabolizer	719 (22.4%)	692 (21.6%)
Qualifying — Ischemic stroke	2,577 (80.4%)	2,581 (80.5%)
Qualifying — TIA	628 (19.6%)	626 (19.5%)
NIHSS median (stroke)	2 (IQR 1-3)	2 (IQR 1-3)
Time onset to randomization median	13.5h (IQR 9.0-20.3)	14.3h (IQR 8.9-20.7)
Symptomatic intracranial stenosis	841/2,969 (28.3%)	798/2,951 (27.0%)

Arms

Field	Ticagrelor + Aspirin	Control
Intervention	Ticagrelor 180 mg loading Day 1, then 90 mg BID Days 2-90. Open-label aspirin 75-300 mg Day 1, then 75 mg/day for 21 days. Ticagrelor monotherapy Days 22-90.	Clopidogrel 300 mg loading Day 1, then 75 mg/day Days 2-90. Open-label aspirin 75-300 mg Day 1, then 75 mg/day for 21 days. Clopidogrel monotherapy Days 22-90.
Duration	90 days	90 days

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
New ischemic or hemorrhagic stroke at 90 days	Primary	243/3,207 (7.6%)	191/3,205 (6.0%)	0.77	0.008
Stroke within 30 days \| 95% CI: 0.61-0.93	Secondary	205 (6.4%)	156 (4.9%)	HR 0.75
Vascular composite (stroke/TIA/MI/vascular death) \| 95% CI: 0.65-0.92	Secondary	293 (9.2%)	229 (7.2%)	HR 0.77
Ischemic stroke \| 95% CI: 0.65-0.95	Secondary	238 (7.4%)	189 (5.9%)	HR 0.78
Disabling stroke (mRS >1) \| 95% CI: 0.77-1.36	Secondary	92 (2.9%)	97 (3.1%)	HR 1.02
Ordinal stroke/TIA shift (common OR) \| 95% CI: 0.66-0.94	Secondary	shift: fatal 8 (0.2%) / severe 21 (0.7%) / moderate 63 (2.0%) / mild 151 (4.7%) / TIA 40 (1.2%) / none 2924 (91.2%)	shift: fatal 4 (0.1%) / severe 30 (0.9%) / moderate 63 (2.0%) / mild 94 (2.9%) / TIA 34 (1.1%) / none 2980 (93.0%)	Common OR 0.79
Ordinal — Fatal stroke (mRS 6)	Secondary	8 (0.2%)	4 (0.1%)
Ordinal — Severe stroke (mRS 4-5)	Secondary	21 (0.7%)	30 (0.9%)
Ordinal — Moderate stroke (mRS 2-3)	Secondary	63 (2.0%)	63 (2.0%)
Ordinal — Mild stroke (mRS 0-1)	Secondary	151 (4.7%)	94 (2.9%)
Ordinal — TIA	Secondary	40 (1.2%)	34 (1.1%)
Ordinal — No stroke or TIA	Secondary	2924 (91.2%)	2980 (93.0%)
Severe/moderate bleeding (GUSTO)	Adverse	11 (0.3%)	9 (0.3%)	HR 0.82 (0.34-1.98)	0.66
Fatal bleeding	Adverse	3 (0.1%)	3 (0.1%)	HR 0.97 (0.20-4.81)
Intracranial hemorrhage	Adverse	6 (0.2%)	3 (0.1%)	HR 0.49 (0.12-1.96)
Any bleeding	Adverse	80 (2.5%)	170 (5.3%)	HR 2.18 (1.66-2.85)
Mild bleeding	Adverse	69 (2.2%)	161 (5.0%)	HR 2.41 (1.81-3.20)
All-cause death	Adverse	18 (0.6%)	9 (0.3%)	HR 0.50 (0.22-1.11)

Subgroup Analysis

Consistent across intermediate (HR 0.78; 0.63-0.97) and poor metabolizers (HR 0.77; 0.50-1.18). Age <65: HR 0.68 (0.51-0.90); ≥65: HR 0.88 (0.67-1.14). No benefit in prior stroke/TIA: HR 1.07 (0.72-1.60). No benefit in prior antiplatelet: HR 1.30 (0.69-2.44). Without intracranial stenosis: HR 0.62 (0.47-0.81).

Criticisms

Chinese population only (98% Han) — lower CYP2C19 LOF prevalence in Western populations (~25% vs ~60%).
Excluded cardioembolic, moderate-severe stroke, thrombolysis/thrombectomy patients.
Any bleeding doubled (5.3% vs 2.5%) — driven by mild bleeding, dyspnea, arrhythmias.
12-month data not yet published; only 90-day outcomes reported.
Benefit driven by early first-week divergence.
Cost-effectiveness of genotype-guided strategy not evaluated.
No direct comparison to genotype-unselected DAPT (original CHANCE).
Higher premature drug discontinuation with ticagrelor (320 vs 216).

Funding

Supported by the Ministry of Science and Technology of the People's Republic of China, the Beijing Municipal Science and Technology Commission, the Chinese Stroke Association, and grants from the National Science and Technology Major Project (2017ZX09304018). Shenzhen Salubris Pharmaceuticals provided ticagrelor, clopidogrel, and placebos at no cost and with no restrictions. Chongqing Jingyin Bioscience provided the GMEX point-of-care genotyping system and technical support at no cost and with no restrictions.

Based on: CHANCE-2 (The New England Journal of Medicine, 2021)