Dawn Kleindorfer, MD Associate Professor August 27 th, 2008

Financial Disclosures  Site Principal Investigator, PRoFESS study,  Speaker’s Bureau, Boehringer Ingelheim Non-significant category, per UC guidelines  Member, National Stroke Experts Advisory Panel, Boehringer Ingelheim, 8/08

Outline  Anti-platelet trials for ischemic stroke prevention prior to 2008 CAPRIE, ESPS-2, CHARISMA, MATCH  Review of PRoFESS study results Antiplatelet ARB Neuroprotection  Stroke prevention in TIA patients  Future directions Prasugrel SPS3

Stroke Prevention: So Much More Than Anti-platelets!  Blood pressure  Blood sugar  Lipids  Smoking  Anti-coagulation  Procedures to reduce stroke Carotid endarterectomy ?stenting/others  Education/compliance/warning signs

Absolute Risk vs. Relative Risk  Especially important to consider absolute risk for the antiplatelet trials  Large RRR does not necessarily mean a large absolute benefit for your patient Much easier to get large changes in RR the smaller your risk is! ○ Example: 100% RR takes risk from 0.5% to 1.0%!

Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events (CAPRIE): Trial Design 19,185 patients > 21 yr (mean age 62.5 yr) with established diagnosis of stroke, MI, or PAD Study population Study drugs Clopidogrel (75 mg/day); ASA (325 mg/day) Primary endpoint Composite outcome cluster of ischemic stroke, MI, vascular death Treatment durationTreatment period 3 yr; avg patient follow-up 1.9 yr Study design 384 clinical centers in 16 countries; randomized, blinded Secondary endpoint Outcome clusters of ischemic stroke, MI, vascular death, amputation, death from any cause CAPRIE Steering Committee. Lancet. 1996;348:

CAPRIE: Event Rates in Stroke and PAD Subgroups * Results not statistically significant. † p=0.002 CAPRIE Steering Committee. Lancet. 1996;348:1329­1339. Total number of events (1.9 yr mean follow­up) Stroke* MI* Clopidogrel (stroke n=3,233; PAD n=3,223) Aspirin (stroke n=3,198; PAD n=3,229) 8% RRR 14% RRR 1.2% RRR 37% RRR 1.6% 9.7% 10.6% 1.4% Stroke* MI † 2.5% 3.3% 2.1% Stroke Subgroup PAD Subgroup

European Stroke Prevention Study 2 (ESPS 2): Trial Design 6,602 patients >18 yr (mean age 66.7 yr 2 ) with recent cerebrovascular episode (within 90 days of study entry) Study population Study drugs ASA/ER­DP (25 mg ASA/200 mg ER-DP bid); ER- DP (200 mg bid); ASA (25 mg bid); placebo Primary endpoint Stroke, death, and stroke or death together Treatment duration Treatment period 2 yr; patient follow-up 2 yr Study design 59 clinical centers in 13 European countries; randomized, double­blind, placebo­controlled with a 2 x 2 factorial design Secondary endpoint TIA and other vascular events ESPS 2 Group. J Neurol Sci. 1997;151(suppl):S1­S77. Diener HC, et al. J Neurol Sci. 1996;143:1-13.

ESPS 2 Event Rates P=0.006 Total number of events (2-year follow­up) Stroke ASA/ER-DP ASA 23% RRR (n=1,650) 9.5% 12.5% MI 2.4%2.1% 13% RRR (n=1,649) ESPS 2 Group. J Neurol Sci 1997;151(suppl):S1-S77. P=ns

Management of Atherothrombosis with Clopidogrel in High-risk Patients (MATCH): Trial Design 7,599 patients  40 yr (mean age 66.3 yr) with recent (within 90 days of study entry) TIA or ischemic stroke and a high risk of recurrent ischemic events Study population Study drugs Clopidogrel (75 mg/day) plus aspirin (75 mg/day) vs. clopidogrel (75 mg/day) plus placebo Primary endpoint Ischemic stroke, MI, vascular death or rehospitalization for acute ischemic event or urgent revascularization or TIA Treatment duration Treatment and follow-up period 1.5 yr Study design 507 clinical centers in 28 countries; randomized, double-blind, placebo-controlled Secondary endpoint Outcome clusters of primary endpoints, any death or any stroke Diener HC, et al. Lancet. 2004;364:331­337.

MATCH Events Number of patients with events Clopidogrel + ASA (n=3,797) Clopidogrel (n=3,802) Diener HC, et al. Lancet. 2004;364:331­ MI Stroke 7.9% 8.4% 1.6% Other CV Death 1.9% 1.8% Rehospitalization 4.8% 4.5%

Diener et al. Lancet 2004; 364 (9431): 331–337. MATCH Safety Number (%) with eventDifference (%) (95% Cl) P* Aspirin and clopidogrel (n=3759) Placebo and clopidogrel (n=3781) Life-threatening bleeding 96 (3%)49 (1%)1-26 (0–64 to 1–88)< Fatal bleeding16 (<1%)11 (<1%)0.13 (-0.14 to 0.40) Non-fatal bleeding81 (2%)38 (1%)1.15 (0.59 to 1.71) SIH**40 (1%)25 (1%)0.40 (-0.01 to 0.82) PIH***32 (1%)17 (<1%)0.40 (0.04 to 0.76) Major bleeding73 (2%)22 (1%)1.36 (0.86 to 1.86)< Minor bleeding120 (3%)39 (1%)2.16 (1.51 to 2.81)< * Person‘s chi 2 test. All symptomatic (and thus primary) intracranial haemorrhages were life-threatening bleeds. ** SIH = Symptomatic intracranial haemorrhage *** PIH = Primary intracranial haemorrhage

CHARISMA Subgroups Those with prior symptomatic disease overall did have significant reduction in combined endpoint (RRR 12%). Estimate for prior stroke patients having recurrent stroke was up to 20% RRR (personal comm, Greg Albers, MD) Post-hoc analysis, still borderline significance…. Bhatt, et al, J. Am, Coll. Card, 2007

What is a non-inferiority trial, and why do we need it?  When comparing to active treatment controls  When we suspect that the new tx may not be MORE efficacious, but may be similar AND safer/cheaper/easier, etc

Assumptions made with non-inferiority trials  Assay Sensitivity the assurance that the active control would have been better than placebo (if it had been tested)  Constancy Assumption Historical differences between placebo and active control still hold true ○ Such as better BP and lipid control over time...  Similarity in study groups between trials

What is the “margin” and why should we care?  The non-inferiority margin is like the “confidence interval” for how far apart the two drugs can be before they are considered different  Based on stats and clinical judgement Read: an artificial number!  Based on the data for active control  “Biocreep” Serial comparisons with slightly inferior drugs until the comparator is no better than placebo

Some examples below

Some Anti-hypertensive agents may also be neuro-protective?  ACE inhibitors “ promote vasodilation, limit neurohormonal activation and vasoconstriction during ischemia, improve endothelial function by reducing oxidative stress, slow down the development of atherosclerosis; improve fibrinolytic balance, inhibit platelet activation and reverse negative vascular remodelling ” PROGRESS: stroke patients, RRR 28% for those receiving ACE +/- diuretic ○ Even in normotensive patients HOPE: combined endpoint, 32% RRR for ACE vs. placebo

Neuroprotective continued?  ARBs LIFE: ARB vs. beta blocker. Identical BP control, but ARB had 25% RRR in recurrent events (but MI and CV mortality no different!) SCOPE: ARB vs. placebo MOSES: ARB vs. Ca channel blocker, identical BP control, OR of 0.75 in favor of ARB ? Affects of angiotensin II

 Combined endpoint no different  New onset diabetes no different

Neuroprotection in PRoFESS?  No difference in functional outcomes 3 mo after stroke between antiplatelet agents, or between telemisartan and placebo  No differences in MMSE/dementia incidence across antiplatelet and ARB groups Observation period too short? More detailed cognitive testing required ○ Cognitive substudy

TIA is an emergency!!

Risk of Stroke After TIA? Kleindorfer, et al, Stroke 2006

Who gets stroke after TIA?  No clear race or gender effect  ABCDD prediction model A : age of the patient >60yo B: blood pressure- uncontrolled BP ↑ stroke risk C: clinical picture ○ Motor weakness or speech (weakness 2 points) D: duration- greater than 10 mins = 1 pt >60 minutes 2 pts - D: Diabetes history Johnston, et al, JAMA 2007

TIA Subtype May Predict Future Risk  meta-analysis of 1,709 patients in four population-based studies of stroke: risks of recurrent stroke: were Large artery: 4.0% (95% CI ) at 7 days and 12.6% ( ) at 30 days in patients Small vessel: 0% and 2% (0-4.2) respectively  Another population-based study: risk of stroke in carotid stenosis >50% may be as high as 20% in the 2 weeks after the event

Urgent endarterectomy? Rothwell, et al, Lancet 2004

FASTER Pilot trial  Randomized double blind trial within 24 hrs of TIA or minor stroke  Age >40  Must have weakness or language deficit as part of TIA, lasting > 5 minutes  Followed for 90 days Aspirin Aspirin + Simvastatin Aspirin + Clopidigrel Aspirin + Clopidigrel + Simvistatin Kennedy, et al, Lancet Neurol, 2007

FASTER Pilot Trial  392 patients enrolled, stopped prematurely due to enrollment failure Very few patients not on statins! Only 35 events (33 IS, 2 ICH)  Consistent reduction in events among those with clopidogrel + ASA vs ASA alone within 90 d ↓ all stroke 3.8% ↓ 3.3% all stroke, MI, vasc death ↓ 7.0% all stroke, TIA, ACS, all-cause death  No evidence of benefit of early statin use Kennedy, et al, Lancet Neurol, 2007

EXPRESS TIA Study  To evaluate benefit of rapid TIA/minor stroke evaluation in the U.K.  4/02-9/04 vs. 10/04-3/07  Stroke rates, delays in getting care, delay to getting meds measured

EXPRESS TIA Study  Phase I: TIA/minor stroke clinic appt-based, faxes from primary care Recommendations made regarding care ○ Usually faxed to PMD within 24 hrs Testing arranged during following week  Phase II: Aggressive TIA/minor stroke clinic No appt necessary, immediately send pts when dx made Given ASA in the office, and scripts to go home Head CT in clinic if needed

EXPRESS TIA Study: Process of Care Measures

EXPRESS TIA: Stroke Rates

Prasugrel-TRITON TIMI 38 Trial  13,606 patients, Mod. To high-risk ACS with planned stent  Randomized to prasugrel (60 mg loading then 10mg/d) vs. clopidogrel (300mg loading followed by 75mg/d) for 6-15 mo  Primary endpoint: time to first CV death, MI, or stroke Wiviott, et al, NEJM, 2007

Prasugrel-TRITON TIMI 38  Primary endpoint reduced in prasugrel 9.9% in prasugrel, 12.1% in clopidogrel  Major bleeding higher in prasugrel 2.4% prasugrel, 1.8% clopidogrel Only 0.3% intracranial in either group  Mortality identical, as every CV death prevented with prasugrel off-set by one more bleeding death Wiviott, et al, NEJM, 2007

Stroke Patients in TRITON-TIMI? Serebruany, et al, Cerebrovascular Diseases 2008

SPS-3 Trial  Age > 30, lacunar stroke on MRI, non- disabling stroke 2500 pts targeted, 20% hispanic (1300 in so far)  Primary outcome stroke and bleeding Secondary outcome cognitive decline Aspirin target SBP Aspirin Target SBP < 130 Aspirin + plavix Target SBP Aspirin + plavix Target SBP < 130 NIH Ongoing Clinical Trials Website

Discussion Cases  65yo BF, with HTN, presents with her first ischemic stroke, small vessel subtype. Which antiplatelet at discharge?  72yo WM c HTN, DM, HLD, smoking, presents with his second ischemic stroke, R MCA infarct, on aspirin Which antiplatelet at discharge?

Bottom Line for Stroke Prevention?  Still will be controversial as to which anti- platelet is first line  PRoFESS showed that aggrenox and plavix are equally effective and both are options  Previous data had shown aggrenox is better than aspirin, and more controversially, that plavix is better than aspirin, PRoFESS doesn’t change that

Bottom Line?  Issues such as patient compliance, financial situation, history of headaches, may need to be factored in for each patient  Don’t forget other risk factors! May make a much larger impact than agonizing over antiplatelets….