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Journal Club 9/2013

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Brande Harris

on 16 March 2015

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Transcript of Journal Club 9/2013

Journal Club 9/2013
Brande Harris, D.O.
PRoFESS Trial 2008

Eff ects of aspirin plus extended-release dipyridamole versus
clopidogrel and telmisartan on disability and cognitive
function after recurrent stroke in patients with ischaemic
stroke in the Prevention Regimen for Eff ectively Avoiding
Second Strokes (PRoFESS) trial: a double-blind, active and
placebo-controlled study

Background and Literature Review
Published in Lancet, 2008
Learning Objectives:
1. Understand the pharmacologic difference between ASA, ASA+ER-DP, and clopidogrel
2. Understand the results of the various trials examining secondary prevention of stroke
3. Understand how PRoFESS adds to the current body of literature
4. Discuss various the various treatments and establish a rationale for picking a treatment
ASA+DP is more effective than ASA alone in preventing recurrent stroke without significant increase in major bleeding

(European Stroke Prevention Study and the European/Australasian Stroke Prevention in Reversible Ischaemia Trial)
What are those studies?
Risk of recurrent stroke in people surviving initial stroke or TIA is 5-15%/year, highest risk early

Reducing blood pressure, lowering cholesterol, discontinuing cigarettes improves the risk of those events

Previous studies have shown ASA+DP are effective at stroke prevention as they act through different pathways and are more effective than either alone.
Clopidogrel selectively and irreversibly inhibits binding of ADP to platelet receptor

Modestly more effective than ASA in preventing vascular events -- in patients with previous stroke, MI or PAD.

This is consistent for the subgroup who had previous stroke only
MATCH 2007
Clopidogrel + ASA in symptomatic and asymptomatic high vascular risk patients showed increased risk of bleeding

(Management of Atherothrombosis with Clopidrogel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) and Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance trials)
The Pharmacology
Aspirin: Inhibits platelet cyclooxygenase and thus inhibits generation of thromboxane A2, therefore prevents platelet aggregation

Dipyridamole: Inhibits uptake of adenosine into platelets

Clopidogrel:Inhibitors (ADP)-induced pathway for platelet aggregation

Study Rationale
Indirect comparisons of ASA+DP vs clopidogrel

ASA+DP appears to be superior but no direct comparison has been done yet.

ASA+ERDP is used to prevent stroke in patients with previous ischemic stroke

Clopidogrel approved for reducing rate new ischemic stroke, new MI and other vascular death in patients with history of recent MI, stroke or established PAD

Clopidogrel not specifically studied to reduce the risk of recurrent stroke in patients with previous stroke, but is used for that anyhow.

Therefore head-to-head is indicated
Patient Population
Recruitment period: 9/2003 to 7/2006
patients with ischemic stroke within 90 days

Patient population:
55 years+ with ischemic stroke within 90 days
50-54 years
patient who presented within 90-120 days after qualifying stroke with comorbidities: DM, HTN, smoker at time of stroke, obesity (BMI >/= 30), previous vasc disease (stroke, MI, or PAD), end organ damage (retinopathy, LVH, microalbuminuria), or HLP
Intervention and Comparison
1. ASA 25 mg + 200 mg ER-DP bid

2. clopidogrel 75 mg daily

Secondary randomization: telmisartan 80 mg daily vs placebo
Primary end point was “time to any type of recurrent stroke”

Most important secondary outcome was “time to first occurrence of a composite of vascular events (stroke, MI and vascular death)”
Rate of Developing Endpoints
No significant difference in primary and secondary endpoints between patients on ASA with ER-DP or patients on clopidogrel and those on telmisartan and placebo

The number and type of adverse events were not different among the four treatment arms.
Rate of Cognitive Impairment after Recurrent Stroke
Among the patients who had a recurrent stroke, the percentage of individuals who were cognitively impaired (ie, MMSE score ≤24 points) at the penultimate visit was 28% (144 of 515) in the ASA with ER-DP group and 23% of patients in the clopidogrel group (p=0·06).

Impairment after Recurrent Stroke
Barthel index score (<95 vs ≥95) showed no difference in patients who had recurrent stroke by allocation to antiplatelet treatment or telmisartan versus placebo (table 4).

These results indicate that there is no difference between ASA plus ER-DP and clopidogrel with respect to recovery from recurrent stroke.
Modified Rankin Scale
0 - No symptoms.
1 - No significant disability. Able to carry out all usual activities, despite some symptoms.
2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.
3 - Moderate disability. Requires some help, but able to walk unassisted.
4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.
5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.
6 - Dead.
70 yo female with history of prior stroke with mild residual deficits presents for follow up after TIA to discuss secondary prevention.
1. What are her options?
2. What is the best regimen for her?
1. Lower dose of ASA than considered standard in U.S.
2. Follow up was only 2 years
3. Amount of data actually presented was limited
4. Risk that telmisartan dosing could confound data
Dementia Endpoint
The differences between the groups were not statistically significant (p=0·48 and p=0·14,
Adverse Events
Study Strengths
1. Large multi-multi-national study

2. Only two significant end points with several different measures of patient function

3. Examined patient function instead of morbidity vs mortality
70 yo female, with stroke and now with TIA, what medication do I pick??
Based on this study and with other data, any will do
Know thy patient

Why the lack of clinical benefit?
1. Neither ASA with ER-DP nor clopidogrel are neuroprotective, despite indications from experiments in animals that this might be the case.

2. About half of recurrent strokes were due to small vessel disease, which is less likely to be influenced by neuroprotective therapy.
P 70 yo female with history of stroke
I Plavix
C Aggrenox
O Decrease risk of repeat stroke
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