La terapia antiaggregante nel paziente con stroke Paolo Gresele Dipartimento di Medicina, Sez. Medicina Interna e Cardiovascolare Università di Perugia XXVII Congresso Nazionale FCSA Milano, 20-22 Ottobre 2016
Initial presentation of cardiovascular disease in women and men Cohort of 1,937,310 people over 30 y with 6 years median follow-up 114,859 experienced and incident CV event 66% not MI 47% not coronary George J et al., Circulation 2015:132:1320
Stroke/TIA-Epidemiology Second most frequent cause of death worldwide (~5 million deaths/year) Additional 15 million non fatal cases/year First cause of disability Patients with TIA/stroke have an annual risk of major CV event of 4-11% ~80% strokes have an atherothrombotic etiology ~25% of strokes occur in patients with a previous stroke
One year risk of stroke after TIA or minor stroke A contemporary cohort study 3 months risk of stroke or ACS after TIA/minor stroke (historical cohorts 1997-2003): 12-20% 1 year major CV event rates (contemporary cohort): 13.7% Amarenco P et al., NEJM 2016; 374:1533
SECONDARY PREVENTION Proportional effects of antiplatelet therapy on vascular events in five high risk categories Previous MI % Odds Red. (SE) 25 (4) Acute MI Prev. Stroke/ TIA Acute stroke Other high risk 30 (4) 22 (4) 11 (3) 26 (3) 195 7705/71912 (10.7) 9502/72139 (13.2) 25 (2) 22 (2) Antithrombotic Trialists Collaboration, BMJ 2002, 324: 71-86.
Effect of immediate oral antiplatelet therapy in patients with acute presumed ischemic stroke Recurrent Ischemic/Unknown Stroke - 8 trials - 41,483 participants - ASA 160 to 300 mg/d - Within 48 hours of symptoms Sandercock PAG et a., The Cochrane Collaboration 2014; 3: CD000029
Effect of immediate oral antiplatelet therapy in patients with acute presumed ischemic stroke symptomatic intracranial hemorrhage - 8 trials - 41,483 participants - ASA 160 to 300 mg/d - Within 48 hours of symptoms Sandercock PAG et a., The Cochrane Collaboration 2014; 3: CD000029
Benefit of aspirin on recurrent stroke depending on time period after the acute event RISK OF RECURRENT ISCHEMIC STROKE HR 0.42 (0.32-0.55) P<.0001 HR 0.60 (0.41-0.86) P<.006 HR 0.87 (0.84-1.12) P=NS Pooled data from 15,778 participants in 12 trials of aspirin vs control in secondary prevention Rothwell PM et al., Lancet 2016, 388:365
Meta-analysis of the effect of aspirin vs control on 14-day risk of recurrent stroke depending on the degree of initial neurological deficit Mild Moderate Severe Rothwell PM et al., Lancet 2016, 388:365
Cumulative risk (%) CAPRIE Trial Clopidogrel vs aspirin in 19,185 pts with prior MI, Stroke, PAD Relative-risk reduction (%) RRR=8.7% ARR=0.51% NNT=196 Aspirin RRR=7.3% ARR=0.56% NNT=179 MI STROKE Clopidogrel PAD All patients p=0.043 Time since randomisation (mo) Aspirin better Clopidogrel better CAPRIE Steering Commitee, Lancet 1996, 348: 1329.
Ticagrelor vs aspirin in Acute Stroke or TIA The SOCRATES Trial STROKE, MI OR DEATH P=0.07 MAJOR BLEEDING: 0.5% TICA; 0.6% Aspirin -13,199 patients nonsevere stroke/high-risk TIA within 24 hrs -no trombolysis, no cardioembolic -TICAGRELOR: 180 LD, 90 bid maintainance; ASA: 300 LD, 100 oid maintainance Johnston SC et al., NEJM 2016; 375:35
MATCH Study Aspirin 75 mg/d on top of Clopidogrel 75 mg/d in high-risk patients with prior (3 mo) ischemic stroke or TIA Cumulative event rate* 0.20 0.16 0.12 0.08 0.04 EFFICACY Placebo + Clopidogrel ASA + Clopidogrel ARR=1% RRR=6.4% (p=0.244) Cumulative event rate (%) 4 3 2 1 SAFETY Placebo and clopidogrel Aspirin and clopidogrel p=0.029 0.00 0 3 6 9 12 15 18 Months of follow-up 0 0 3 6 9 12 15 18 Time since randomization (months) *IS, MI, VD, Rehospitalization for acute ischemia Primary intracerebral hemorrhage Diener HC et al. Lancet 2004;364:331-7
Probability of recurrent stroke Aspirin or aspirin plus clopidogrel in patients with recent lacunar stroke The SPS3 Trial HR 0.92 (0.72-1.2) p=ns -3020 pts with recent lacunar stroke -follow-up: 3.4 years -Major hemorrhage: 2.1 vs 1.1%/year, p<0,001 -All cause mortality increased: HR 1,52, p=0,004 SPS3 Investigators, NEJM 2012, 367:817-25
Clopidogrel plus aspirin vs aspirin in acute minor stroke/tia The CHANCE Trial INCIDENCE OF RECURRENT STROKE - NNT: 29 - Moderate/severe bleeding: 0.3% CLOP/ASA, 0.3% ASA -5,170 patients minor stroke/high risk TIA within 24 hrs -Clopidogrel: 300 LD, 75 maintainance -ASA: 75 mg; 90 days Wang Y et al., NEJM 2013;369:11
Aspirin plus clopidogrel as secondary prevention after stroke/tia - a metaanalysis MACE Short-term combination Long-term combination - 8 RCTs - 20,728 patients Ongoing POINT trial - ~6000 TIA/minor stroke within 12 hrs; Clop LD 600 mg, MD 75 mg or placebo +ASA; 90d follow-up Zhang Q et al., Cerebrovasc Dis 2015; 39: 13
Extended release Dypiridamole+ASA vs ASA in Cerebrovascular Disease - Metaanalysis ASA+DIP (n/n) ASA alone (n/n) Risk Ratio (95% CI) Weight (%) RR fixed 95% CI Total Total events 3888 522 3907 636 100-00 0.82(0.74-0.91) No significant increase in bleeding complications favours ASA+DIP favours ASA alone The ESPRIT Study Group, Lancet 2006, 367: 1665.
Extended-Release vs Immediate-Release Dipyridamole plus Aspirin vs Aspirin IMMEDIATE RELEASE DIPYRIDAMOLE EXTENDED RELEASE DIPYRIDAMOLE Verro P et al., Stroke 2008;39:1358
Meta-analysis of the effect of aspirin +dypiridamole vs aspirin alone depending on the time period after the acute event 0-12 weeks >12 weeks 0.76 0.63-0.92 P<0,005 0 0.5 1 1.5 2 2.5 Odds Ratio (95% CI) Rothwell PM et al., Lancet 2016, 388:365
EFEFCT OF TICAGRELOR ON TOP OF ASPIRIN in patients with prior myocardial infarction PEGASUS-TIMI 54 Trial CV Death, MI, Stroke RRR=16% ARR=1.27 NNT=79 P<0.001-21,162 patients with AMI 1 to 3 yrs earlier -all on low-dose aspirin -TIMI Major bleeding: TIC 90x2=2.6%; TIC 60x2=2.3%; PLAC=1.06% (p<0.001) -FATAL and INTRACRANIAL BLEEDING: TIC 90x2=0.63%; TIC 60x2=0.71%; PLAC=0.60% (p=ns) Bonaca MP et al., NEJM 2015;3,72:1791
Effect of adding ticagrelor (60 mg) to aspirin in patients with prior MI on the incidence of stroke subanalysis from the PEGASUS-TIMI 54 trial of 14,112 randomized patients 213 had a stroke Bonaca M et al., Circulation 2016;134:861
MACE Effect of a different antiplatelet regimen in patients with recurrent ischemic stroke while on aspirin Retrospective cohort studies -1884 pts on aspirin: 384 clopidogrel 1500 aspirin Lee M et al., BMJ open 2014;4:e006672-1172 patients undergoing new ischemic stroke -MA=212 (18.1%); SA=246 (21%); AA=714 (60.9%) Kim et al., Stroke 2016;47:128
% of patients taking antiplatelet Antiplatelet drugs use in patients with prior CV events depending on country income CHD STROKE 100 100 80 80 60 60 40 40 20 20 0 Overall High Upper Lower Low Overall High Upper Lower Low 0 Country income Country income Yusuf S et al., Lancet 2011, 378:1231
Conclusions Atherothrombotic stroke is a frequent and serious cardiovascular event Antiplatelet therapy is the cornerstone of treatment for secondary prevention of atherothrombotic and cardiovascular events. Aspirin, given as early as possible after the beginning of symptoms, is effective for patients with atherothrombotic stroke Clopidogrel or aspirin plus ER-dipyridamole are valid alternatives Aspirin plus ER-dipyridamole may be superior to aspirin, especially in the long term treatment More aggressive antiplatelet therapy (aspirin+clopidogrel or ticagrelor) may be useful in patients at high risk An optimal implementation of antiplatelet therapy in long term secondary CV prevention is strongly required