Calgary EM Journal Club: Dual Anti-Platelet Therapy for Stroke (The CHANCE Trial)

Hi all,

Today is the first installment of a new addition to the site, the Calgary Emergency Medicine Journal Club!

Click here to open the page in full screen width. It will make the tables much easier to read.

You can check out the Calgary EM Journal Club page here, and this will serve as a resource for residents who couldn’t attend the most recent JC, as well as another FOAM resource to those across the globe.

These will be published once per month, and hopefully we can also get some live Twitter involvement going in the future, much like the TempleEM and St. Emlyns JCs.

Without further ado, here is the November 2013 installment of the Calgary EM JC.

Dual Anti-Platelet Therapy for Stroke

Article: Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack

N Engl J Med 2013;369:11-19. DOI: 10.1056/NEJMoa1215340

PICO Question:

In patients with TIA or minor stroke, should combination anti-platelet therapy with ASA+Clopidogrel be used in favor of ASA alone?

Bottom Line:

Combination anti-platelet therapy should be considered in patients with TIA/minor stroke, but more evidence is needed for generalization to a North American population. We also felt this should be reserved for patients with rapidly resolving motor symptoms lasting <5min who would otherwise not be admitted, and only pending urgent outpatient neurologic opinion/workup.

Discussion:

The CHANCE (Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack) trial is a multicenter placebo controlled RCT comparing the use of ASA+Clopidogrel with ASA alone after TIA/stroke.

In patients with previous MI or stroke, daily ASA is an excellent therapy, with a NNT = 200 for secondary prevention of stroke. This study asks if the addition of clopidogrel (Plavix) can improve upon this stroke prevention and if there is an increased bleeding risk with combination therapy.

Overall it was felt that this was an excellent study, with a fantastic NNT of 29 to prevent a stroke at 90 days when comparing A+C with ASA alone.

The key limitation was external validity and the ability to generalize to a North American population was questionable. (See “Are the results clinically applicable” below) It is also unclear as to why ASA was only used for the first 21 days in the ASA+Clopidogrel arm, with placebo ASA on days 22-90. It was surmised by the group that this may reduce the bleeding risk of combination therapy, while capturing the benefits of dual anti-platelet therapy in the period of highest risk (immediately post stroke/TIA).

The follow-up period of 90 days was felt to be too short by some, as 1 year follow-up in other studies has shown no difference in stroke rate. However, those studies did not have as acute an enrolment period (<24 hours) as CHANCE.

Finally, many attendees felt that there was no benefit to starting combination therapy if this would only be stopped by the neurology service a short time later. Though I can understand their sentiment, previous trials enrolling patients in the sub-acute (1-2 week) period post stroke/TIA showed less or no benefit than CHANCE, and thus I would argue the opposite. That is, if we are to start dual anti-platelet therapy, it should be done in the ED, as early therapy (<24 hours) has greater potential benefit than delayed initiation of therapy.

Study #1 Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic AttackN Engl J Med 2013;369:11-19. DOI: 10.1056/NEJMoa1215340
Objective:	To determine whether combination anti-platelet therapy with ASA + Clopidogrel is superior to ASA alone in the secondary prevention of stroke.
Study Design:	Double blind, randomized, placebo controlled trial of 5170 patients with minor stroke (NIHSS ≤ 3) or high-risk TIA (ABCD² score ≥ 4) at 114 Chinese centers. Patients were randomized to receive either ASA/Clopidogrel (ASA was for the first 21 days in this group, with placebo ASA given on days 22-90) or ASA alone for 90 days. Primary outcome was stroke at 90 days (hemorrhagic or ischemic). Secondary outcomes included moderate-severe hemorrhage as defined by the GUSTO classification (*see below), and secondary efficacy outcomes including anew clinical vascular event (ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death), analyzed as a composite outcome and also as individual outcomes.
Are the results valid?	Risk of Bias: Very Low
Are the results valid?	Was randomization described in enough detail as to permit replication? Yes. Randomization was done centrally, using a double-blind, double-dummy design, with site investigators calling into a computer random number generator to be assigned a number corresponding to a medication kit at their site. Was there sufficient concealment of treatment allocation? Yes Were the 2 groups similar at the start of the trial? Yes, table 1 appears equal in many known predictors of outcome. Were health care workers and patients blind to the treatment allocation? Yes Were those assessing the outcome blind to treatment allocation? Yes Did the authors report an intention to treat protocol? Yes Was follow up complete? Yes, of the 5170 randomized patients, 36 were lost to follow up, 20 in the ASA/Clopidogrel group and 16 in the ASA only group.
What are the results?	A+C ASA only HR (95% CI)Stroke 8.2% 11.7% 0.68 (0.57-0.81,p<0.001) MI/stroke/CV death 8.4% 11.9 % 0.69 (0.58-0.82,p<0.001) Ischemic stroke 7.9% 11.4% 0.67 (0.56-0.81,p<0.001) Bleeding events 2.3% 1.6% 1.41 (0.95-2.10,p=0.09) All individual secondary efficacy outcomes (Hemorrhagic stroke, MI, CV death, all-cause mortality, TIA, mild/moderate/severe bleeding) differences were non-statistically significant between the two groups.
Are the results clinically applicable?	This trial had excellent methodology with a NNT=29 for preventing stroke at 90 days for the A+C group compared with ASA alone.The biggest question with this study is external validity, ie: can these results be translated into our North American patient population?The baseline characteristics show that this is a much higher risk population than ours, with median age =62, 23% having had a previous stroke or TIA, and 42.7% smokers/ex-smokers. Also, these patients were all minor stroke (NIHSS ≤ 3) or high-risk TIA (ABCD² score ≥ 4. This raises the question of benefit in the less severe TIA group. Furthermore, this population has more uncontrolled co-morbidities, putting them at higher risk for stroke.
Author’s conclusion:	The authors concluded that “among patients with high-risk TIA or minor ischemic stroke who are initially seen within 24 hours after symptom onset, treatment with clopidogrel plus aspirin for 21 days, followed by clopidogrel alone for a total of 90 days, is superior to aspirin alone in reducing the risk of subsequent stroke events. The combination of clopidogrel with aspirin did not cause more hemorrhagic events in this patient population than aspirin alone”.

*GUSTO bleeding classification: Moderate = bleed requiring transfusion but not hemodynamic compromise; Severe = fatal bleed or bleed requiring transfusion and causing hemodynamic compromise or requiring surgical intervention.

Final Question: Will this change your practice? Let us know in the comments section.

Thanks for reading. As this is the first Calgary EM Journal Club post, feedback and comments are greatly appreciated.

Cheers,

Chris Bond (@socmobem)

Special thanks to Mike Betzner, FRCPC-EM and Ken Milne of TheSGEM.com for their peer-review.