RXFILES TRIAL SUMMARY A.NGUYEN MAR 2017 – WWW.RXFILES.
CA
PLAVIX ASPIRIN ASPIRIN
CHANCE: Clopidogrel + ASA versus ASA
in patients with acute minor stroke or high-risk transient ischaemic attack (TIA)1
Clopidogrel in High-risk patients with Acute Nondisabling Cerebrovascular Events
BOTTOM LINE
In CHANCE, Chinese patients with minor ischemic stroke NIHSS ≤3 or high-risk TIA ABCD2 ≥4, seen within 24hr symptom onset who
received clopidogrel + ASA x 21 days then clopidogrel alone for a total of 90 days, compared to ASA alone x 90 days:
– had risk of recurrent stroke (NNT=29) without an risk in hemorrhagic events or all-cause mortality
The Canadian Stroke Best Practices Recommendations 2014 are cautious on recommending this routinely for the general
Canadian population, CSBPR’14 (C) and they await the results of the POINT trial (clopidogrel + ASA vs ASA alone x 90 days in North
America, Australia, and Europe).2 The use of ASA alone, clopidogrel alone or dipyridamole + ASA are preferred for secondary
2 CSBPR’14 (A)
stroke prevention.
If choosing to use the results from CHANCE, then patients must be chosen carefully as only a small number (12%) of Chinese
patients may benefit. Therapy must be given within 24 hours of symptom onset, and the dosing regimen followed, for patients
at low risk for bleeds with minor ischemic stroke NIHSS ≤3 or high-risk (for stroke recurrence) TIA ABCD2 ≥4 (also see other inclusion
& exclusion criteria) who did not receive thrombolysis.
BACKGROUND
The risk of stroke is high after TIA or minor stroke, with approximately 20% recurrence rate at 3 months;3 following a TIA most
strokes will occur within the first 2 days.4 Antiplatelet therapy is beneficial as secondary prevention, with ASA as the usual
choice as it’s easily accessible and less expensive. Although combining clopidogrel + ASA reduces recurrent ischemic events in
ACS,5,6 this combination has not been successful and increases the risk of bleeding & mortality when used in stroke patients (e.g.
MATCH, SPS3).7,8 However these trials delayed administering secondary prevention until 1-2 months after the index stroke, and
only few patients with TIA were included. CHANCE was designed to determine if clopidogrel + ASA was better than ASA alone at
reducing risk of recurrent stroke, if given acutely to patients with high-risk TIA or minor ischemic stroke.
TRIAL BACKGROUND
DESIGN: randomized stratified by centre & interval between symptom onset & enrollment <12hr vs. 12-24hr, double-blind, double-dummy, placebo-
controlled, multi-centre n=114, ITT study with concealed allocation conducted in China,
Funding: Ministry of Science and Technology of People’s Republic of China
INTERVENTION: clopidogrel 300mg (day 1), 75mg daily (day 2-90) + ASA 75-300mg (day 1), 75mg daily (day 2-21) vs. ASA 75-300mg (day1), 75mg daily (day 2-90)
Day 1 Day 2-21 Day 22-90
Clopidogrel 300mg (day 1 only) clopidogrel 75mg od
ASA 75-300mg (day 1 only) ASA 75mg od
ASA 75-300mg (day 1 only) ASA 75mg od
INCLUSION: ≥40 years old, acute minor ischemic stroke NIHSS ≤3 or TIA focal brain ischemia with symptom resolution <24hr plus ABCD2 ≥4,
start therapy <24hr symptom onset
EXCLUSION: CT or MRI showing hemorrhage, vascular malformation, tumour, abscess, major nonischemic brain disease; isolated
sensory symptoms, isolated visual changes, isolated dizziness or vertigo without evidence of acute infraction on CT or MRI;
modified Rankin scale >2 (disabling stroke) before index event, NIHSS ≥4, clear indication for anticoagulation, contraindication to
clopidogrel or aspirin, history of intracranial hemorrhage, anticipated requirement for long-term antiplatelets or NSAIDs, heparin
or oral anticoagulation within 10 days before randomization, GIB or major surgery within previous 3 months, planned or probable
revascularization within 3 months after screening, planned survey or interventional treatment requiring cessation of study drug,
TIA or minor stroke caused by angiography or surgery, severe non-cardiovascular coexisting condition with life expectancy <3
months, women not practicing reliable contraception, pregnant women, patient receiving investigational drugs or devices,
received thrombolysis around time of randomization
POPULATION at baseline: n=5170 enrolled (screened 41,561), mean time to randomization 13 hours
2
qualifying event: TIA 27.9%, minor stroke 72.1%; median ABCD score 4 (IQR~4-5); NIHSS baseline score not reported
Main reasons screened patients not enrolled: delay ≥24hr 26.4%, other 15.2%, moderate and major ischemic stroke 10.4%,
9
ICH 7%, low risk TIA 6.5%
Non-modifiable risk factors for stroke or TIA: 66.2% , median age 62 years old, previous ischemic stroke 20%, previous TIA 3.4%
Modifiable risk factors for stroke or TIA: hypertension 65.7%, smoking (past or current) 43%, diabetes 21.1%,
hypercholesterolemia 11.1%
Baseline characteristics were balanced between the two groups
on ASA within 24hr before hospital admission 11.3%
concomitant meds within 90 days: lipid lowering ~42%, antihypertensives ~35%, other ~30%, traditional Chinese medicine ~24%,
antidiabetics ~13%, ASA ~1%, clopidogrel 0.5% 9
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RXFILES TRIAL SUMMARY A.NGUYEN MAR 2017 – WWW.RXFILES.CA
RESULTS follow-up: 90 days
TABLE 1: EFFICACY & SAFETY (confirmed by central adjudication committee unaware of group assignment)
DAY 1: LOADING DOSEǂ
DAY 1: LOADING DOSEǂ DAYS 2-21: CLOPIDOGREL 75MG
DAYS 2-90: ASA 75MG + ASA 75MG DAILY NNT/NNH
CLINICAL ENDPOINTS HR 95% CI ARR/ARI COMMENTS
DAILY DAYS 22-90: CLOPIDOGREL /X 90 DAYS
n=2586 75MG DAILY
n=2584
PRIMARY ENDPOINT
Recurrent stroke 0.68 Kaplan-Meier for 1° endpoint.
11.7% {n=303} 8.2% {n=212} 3.5% NNT 29
(ischemic or hemorrhagic) (0.57 - 0.81) Most of the benefits occurred
0.67 within first few days.
Ischemic stroke 11.4% {n=295} 7.9% {n=204} 3.5% NNT 29
(0.56-0.81)
1.01
Hemorrhagic stroke 0.3% {n=8} 0.3% {n=8} 0% NS
(0.38-2.7)
Fatal or disabling 0.75
6.8% {n=177} 5.2% {n=135} 1.6% NNT 63
stroke (0.6-0.94)
SECONDARY ENDPOINTS
0.82
TIA 1.8% {n=47} 1.5% {n=39} 0.3% NS
(0.53-1.26)
0.69
Stroke, MI, cardiovascular death 11.9% {n=307} 8.4% {n=216} 3.5% NNT 29
(0.58-0.82)
Kaplan-Meier for stroke, MI,
1.44 CV death
MI 0.1% {n=2} 0.1% {n=3} 0% NS
(0.24-8.63)
0.97
Death from all causes 0.4% {n=10} 0.4% {n=10} 0% NS
(0.4-2.33)
Vascular death (due to stroke,
systematic hemorrhage, MI, 1.16
0.2% {n=5} 0.2% {n=6} 0% NS
CHF, PE, sudden death, (0.35-3.79)
arrhythmia)
SAFETY
Moderate-to-severe bleed* 0.3% {n=8} 0.3% {n=7} Not reported 0% NS “Adverse events” and “serious
1.41 adverse events” were similar
Any bleeding 1.6% {n=41} 2.3% {n=60} 0.7% NS
(0.95-2.1) between the two groups.
ǂ Loading dose for ASA alone treatment arm was ASA 75-300mg; loading dose for clopidogrel + ASA treatment arm was clopidogrel 300mg + ASA 75-300mg
*Severe hemorrhage (GUSTO) = fatal or intracranial or other causing hemodynamic compromise requiring blood/fluid/inotropes/surgical intervention
Moderate hemorrhage (GUSTO) = require transfusion but no hemodynamic compromise requiring intervention
STRENGTHS, LIMITATIONS, & UNCERTAINTIES
STRENGTHS: Sample size of 5100 was achieved
There was an event adjudication committee, unaware of group assignment, to confirm efficacy and safety outcomes
The period of time after a stroke is important, as the estimated risk of recurrent stroke is 11.5% at 7 days, 15% at one month,
and 18.5% at 3 months after a minor stroke, and 8%, 11.5% and 17.3% respectively after a TIA.3
In CHANCE, the mean time to randomization was 13 hours. This early enrollment ensured that that there would be lots of
patients at higher risk of recurrent stroke, with the potential to benefit from therapy.
Loss to follow up was low (0.7%)
The rate of discontinuation was low (clopidogrel + ASA 6.4%, ASA 5.6%)
LIMITATIONS: Other risk factors for stroke (ethnicity and family history of stroke) not reported at baseline. However as other baseline
characteristics imbalances were not detected, it is unlikely these were imbalanced.
This study is generalizable to only 12.4% of minor strokes or high-risk TIAs, because initiating therapy had to occur ≤24 hours and
there were strict eligibility criteria.
The following were not reported: baseline NIHSS score, type of contraceptives used (i.e. estrogen containing?), mean loading
dose of aspirin, stroke subtypes
UNCERTAINITIES: Antiplatelet therapy is usually recommended for secondary prevention after stroke or TIA.
If using the results from CHANCE for the first 3 months, can antiplatelet therapy be given indefinitely after 90 days?
The subgroup analysis did not include all risk factors for stroke (missing smoking, hyperlipidemia, ethnicity), so it is unknown
what the hazard ratio for recurrent stroke is in these subgroups.
Is this study only applicable to Chinese patients (e.g. different polymorphisms of CYP-450 affecting clopidogrel metabolism, use
traditional Chinese medicine) treated in China (e.g. suboptimal secondary prevention medications, different standards of care)
ABCD2 was used in CHANCE to identify TIA patients who were at high-risk for another stroke. However a Canadian study found
this tool was not sensitive enough to assess risk, nor did it accurately predict stroke risk.10 Thus the Canadian Stroke Best
Practices Recommendations 2014 do not recommend using ABCD2. This makes it difficult to apply the findings from CHANCE in
Canada when an important entry criterion relies on a tool that is not endorsed.
We await the results of other studies to help guide therapy: dual therapy in non-Chinese patients (e.g. POINT), triple therapy
(e.g. TARDIS), and new antiplatelet or anticoagulant agent s11,12
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RXFILES TRIAL SUMMARY A.NGUYEN MAR 2017 – WWW.RXFILES.CA
RxFILES RELATED LINKS
RxFiles DAPT & Triple Therapy newsletter & chart:
http://www.rxfiles.ca/rxfiles/uploads/documents/DAPT%20and%20Triple%20Therapy%20Newsletter%20and%20Chart.pdf
Canadian Family Physician Journal – RxFiles article on DAPT post stroke: http://www.cfp.ca/content/62/8/640.full.pdf+html?sid=aa5c799f-c58e-
4ca9-ad79-f96a3abe4367
SPS3 Antiplatelet Trial Summary: http://www.rxfiles.ca/rxfiles/uploads/documents/SPS3%20antiplatelet-Trial%20Summary.pdf
SPS3 Systolic Blood Pressure Trial Summary: http://www.rxfiles.ca/rxfiles/uploads/documents/SPS3%20SBP-Trial%20Summary.pdf
MATCH Trial Summary: http://www.rxfiles.ca/rxfiles/uploads/documents/MATCH-Trial%20Summary.pdf
=non-formulary in SK =not covered by NIHB =Exceptional Drug Status in SK =male ACS=acute coronary syndrome CHF= congestive heart failure
GIB=gastrointestinal bleed hr=hour IQR=interquartile range MI=myocardial infarction PE=pulmonary embolism TIA=transient ischaemic attack
ACKNOWLEDGEMENTS: Contributors & Reviews: Lynette Kosar, Brent Jensen, Loren Regier, Jialin Liu, Josh Poteet, Brenna Gallagher Prepared By: Anne Nguyen PharmD
DISCLAIMER: The content of this newsletter represents the research, experience and opinions of the authors and not those of the Board or Administration of Saskatoon Health Region
(SHR). Neither the authors nor Saskatoon Health Region nor any other party who has been involved in the preparation or publication of this work warrants or represents that the
information contained herein is accurate or complete, and they are not responsible for any errors or omissions or for the result obtained from the use of such information. Any use of
the newsletter will imply acknowledgment of this disclaimer and release any responsibility of SHR, its employees, servants or agents. Readers are encouraged to confirm the
information contained herein with other sources. Additional information and references online at www.RxFiles.ca Copyright 2017 – RxFiles, Saskatoon Health Region (SHR)
References
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2013;369(1):11-19.
2. Coutts SB, Wein TH, Lindsay MP, et al. Canadian Stroke Best Practice Recommendations: secondary prevention of stroke
guidelines, update 2014. Int J Stroke. Apr 2015;10(3):282-291.
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Med. Jul 04 2013;369(1):11-19.
10. Perry JJ, Sharma M, Sivilotti ML, et al. Prospective validation of the ABCD2 score for patients in the emergency department with
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11. Hankey GJ. Dual antiplatelet therapy in acute transient ischemic attack and minor stroke. N Engl J Med. Jul 04 2013;369(1):82-83.
12. Sharma M, Khandelwal P. Clopidogrel with aspirin in minor stroke or transient ischemic attack. N Engl J Med. Oct 03
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