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Antiplatelet Therapy for Stroke Prevention Lessons Learned from SPS3

14 th Western Stroke Conference. Antiplatelet Therapy for Stroke Prevention Lessons Learned from SPS3. Oscar R. Benavente, MD, FRCPC Professor & Research Director of Cerebrovascular Health and Stroke Division of Neurology Vancouver Stroke Program - UBC. Vancouver. December 1, 2012.

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Antiplatelet Therapy for Stroke Prevention Lessons Learned from SPS3

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  1. 14th Western Stroke Conference Antiplatelet Therapy for Stroke Prevention Lessons Learned from SPS3 Oscar R. Benavente, MD, FRCPC Professor & Research Director of Cerebrovascular Health and Stroke Division of Neurology Vancouver Stroke Program - UBC Vancouver. December 1, 2012

  2. Stroke Facts 15 million stroke / year 6 million deaths 5 million disable • Projected 8 million deaths by 2030 • More than 60% deaths in <70 yrs of age • Reduction of 4%/yr = 6 million fewer deaths in the next 10 yrs

  3. Risk of recurrent stroke, and other vascular events after TIA and stroke stroke, MI or VD MI or CHD stroke Pendlebury et al. Cerebrovascular Dis 2009

  4. Atherothrombosis Is a Polyvascular Disorder: Overlap Between PAD, CAD, and CVD 16.6% N=7013 CVD 8.4% 1.2% 1.6% PAD CAD 4.7% 4.7% 44.6% Patients with one manifestation often have coexistent disease in other vascular beds Bhatt DL et al. JAMA. 2006;295:180-189.

  5. Prevalence of Coronary Artery Disease in Stroke Patients Number of Patients 6602 ESPS-2 1 6431a CAPRIE 2 2435 UK-TIA 3 2500 ESPS-1 4 3069 TASS 5 1072 CATS 6 0 10 20 30 40 a CAPRIE data represent only the stroke subset of patients. b CAD history includes MI, angina, unstable angina, ischemic heart disease. Stroke Patients With CAD (%)b

  6. Mechanisms of Platelet Inhibition by Oral Anti-Platelet Therapies P2Y12 Inhibition: Clopidogrel Ticlopidine Prasugrel Ticagrelor ADP P2Y12 ADP Dipyridamole cAMP PAR-1 CollagenTXA2 Activation PLATELET COX TXA2 GP IIb/IIIa (Fibrinogen receptor) Aspirin

  7. Secondary stroke prevention Major therapeutic advances in the last 30 years Well established interventions

  8. Aspirin = Bayer brand name except in U.S. (From the German acetylspirsaure + chemical suffix – in) First synthesized in pure form by Felix Hoffman of Bayer & Co. in 1897.

  9. H. Dreser. Promoted ASA 1899 F. Hoffman. First synthesized ASA 1897

  10. Acetylsalicylic Acid Due to problems with the original Aspirin powder being counterfeited, it became the first pharmaceutical agent ever sold in pill form in early 1900’s.

  11. Bayer’s Latin America sales team for “Mejoral” – 1940s

  12. Bayer factory in Leverkusen, Germany

  13. 1465 males, one or two ASA / day “Not a single case of detectable coronary or cerebral thrombosis occurred among patients who faithfully have adhered to this regimen” Mississippi Valley Medical Journal. 1953 L. Craven, MD. Glendale, CA

  14. Aspirin • Sir John Vane wins Nobel Prize for describing the effect of aspirin on platelets – 1971 • FDA approved for secondary prevention of MI – 1986 • Aspirin remains the most commonly used drug in the world. About 100 M tablets used daily in U.S.

  15. Categories of oral antiplatelet agents by mechanism of platelet inhibition^ ^Other antiplatelet drugs: indobufen, triflusal Reference: Eikelboom JW, Weitz J et al. Antiplatelet drugs. ACCP 2012 Chest 2012: 141: e89S-119s.

  16. Completed trials of antiplatelet agents in patients with non-cardioembolic stroke 2001-2012

  17. Antithrombotic Trialists’ Collaboration287 randomized trials & >135,000 patients(BMJ 2002; 324: 71) Aspirin reduces vascular events (including stroke) about equally in patients with vascular disease, including: Young and old Men and women Hypertensives and non-hypertensives Diabetics and non-diabetics Relative risk reduction: 22% (13% secondary stroke prevention)

  18. Relative effects of antiplatelet regimens in reducing stroke 13% 7.7% 20% 0 10 20 30 40 50 -10 Relative Risk Reduction %

  19. Relative effects of antiplatelet agents in reducing stroke, MI or vascular death Hankey, G. Lancet Neurol 2010;9:273

  20. CHARISMA: Primary Efficacy Results (MI/Stroke/CV Death)* by Inclusion Criteria Population n RR (95% CI) P Value Documented CV disease 12,153 0.88 (0.77, 0.998) .046 Coronary 5835 0.86 (0.71, 1.05) .13 Cerebrovascular 4320 0.80 (0.65, 0.997) .05 PAD 2838 0.87 (0.67, 1.13) .29 Multiple risk factors 3284 1.20 (0.91, 1.59) .20 Overall population 15,603 0.93 (0.83, 1.05) .22 1.2 1.4 1.6 0.4 0.6 0.8 Clopidogrel better Placebo better * First occurrence of MI (fatal or nonfatal), stroke (fatal or nonfatal), or CV death. Bhatt DL. Presented at: American College of Cardiology Annual Scientific Session; March 11-14, 2006, Atlanta, GA. Bhatt DL et al. N Engl J Med. 2006;354:1706-1717.

  21. Prior Myocardial Infarction, Stroke or Peripheral Artery Disease “CAPRIE-like cohort” Analysis from CHARISMA 10 8 6 4 2 0 0 6 12 18 24 30 N=9,478 8.8% Placebo + ASA 7.3% Clopidogrel + ASA Primary outcome event rate (%) RRR: 17.1 [95% Cl: 4.4%, 28.1%] p=0.01 Months since randomization 14 events are prevented treating 1000 pts for 27 months at a cost of 2 severe bleeds Bhatt et al. JACC vol 49, No 19, 2007 Cardiovascular Death, MI or Stroke

  22. Prior Myocardial Infarction, Stroke or Peripheral Artery Disease “CAPRIE-like cohort” Analysis from CHARISMA 0.5 1 2 Placebo Clopidogrel HR (95% & Cl) p-Value 8.3% 6.6% 0.774 (0.613, 0.978) 0.031 10.7% 8.4% 0.780 (0.624, 0.976) 0.029 8.7% 7.6% 0.869 (0.671, 1.125) 0.285 8.8% 7.3% 0.829 (0.719, 0.956) 0.010 Prior MI 3846 Prior IS 3245 Prior PAD 2838 Entire Cohort Bhatt et al. JACC vol 49, No 19, 2007

  23. Rates of Vascular Death, MI or Stroke at Different Time Intervals from Event to Randomization Clp+ASA ASA HR (95% CI) 0.8 (.6-1) 8.2% 10.5% <= 30 d 0.8 (.6-1.2) 6.7% 8.0% 30 - 300 d 0.8 (.6-1.2) 6.8% 8.0% 300 d - 30 m 0.9(.7-1.3) 6.6% 7.2% > 30 m .0 .5 1.0 1.5 2.0 HazardRatio Bhatt et al. JACC vol 49, No 19, 2007

  24. CHARISMA Trial: effect of clopidogrel + ASA early after TIA/Stroke Stroke: ASA = 46 (6.9%) vs ASA + Cl = 34 (5.1%) HR 0.74, 0.46-1.16 International Journal of Stroke, Feb 2011, 3

  25. PROFESS Stroke Recurrence Note: Slides reproduced accurately based on data orally presented. Not validated with a published source. This data curve have been redrawn. R Sacco. Presented at ESCo 2008.

  26. PROFESS Characterization of First Recurrent Stroke Note: Slides reproduced accurately based on data orally presented. Not validated with a published source. R Sacco. Presented at ESCo 2008.

  27. Terutroban vs aspirin in patients with stroke/TIA: PERFORM trial 19,000 patients in 802 centers in 46 countries Mean follow up 2.3 yrs Terurobran: 11% Aspirin: 11% Primary endpoint: composite stroke, mi, vascular death Bousser, MG. Lancet 2011;337:2013-22

  28. Anticoagulantvs. Aspirin after Non-cardioembolic Brain IschemiaThe Major Randomized Trials

  29. Stroke subtype and response to antithrombotic agents

  30. Secondary Prevention of Small SubcorticalStrokes (SPS3) SPS3 is sponsored by National Institutes of Health NINDS: 2 U01 NS38529-04A1

  31. SPS3 n= 283 n= 366 n= 1677 n= 165 n= 171 n= 186 n= 127 81 clinical sites 8 countries Randomization: March 2003 - April 2011 n= 45

  32. SPS3 SPS3 Design I • Randomized multicenter international trial. • Investigator initiated study. • Lacunar strokes within 180 days, verified by MRI. • No cortical stroke, cardioembolic disease / carotid stenosis. • Randomized to 2 interventions in a factorial design: 1) Antiplatelet therapy (double blind): -aspirin 325 mg + placebo -aspirin 325 mg + clopidogrel 75 mg 2) Target levels of blood pressure control (open label): -”usual” 130-149 mmHg systolic -”intensive” <130 mmHg systolic www.clinicaltrials.gov NCT00059306

  33. Benavente OR; Hart RG, et.al.

  34. SPS3 Primary Outcome: Ischemic & Hemorrhagic Stroke • Aspirin = 138 (2.7 %/yr) • Aspirin + Clopidogrel = 126 (2.5 %/yr) HR 0.92 (0.73, 1.2) p value 0.52

  35. SPS3 Ischemic Stroke • Aspirin = 125 (2.4 %/yr) • Aspirin + Clopidogrel = 105 (2.1 %/yr) HR: 0.85 (0.66, 1.1). p value: 0.21

  36. SPS3 Efficacy Outcomes *Defined as: stroke, MI, vascular deaths.

  37. SPS3 All Cause Mortality • Aspirin = 77 (1.4 %/yr) • Aspirin + Clopidogrel = 113 (2.1 %/yr) HR 1.5 (1.1, 2.0) p value 0.005

  38. SPS3 Major Hemorrhages ASA + Cl HR ASA

  39. SPS3 Major Hemorrhages *Intraparenchymal, spinal # subdural, epidural ^ subarachnoid, other

  40. SPS3 Visualization of index event on MRI

  41. SPS3 MRI Localization of Index Event N=3004 Multiple infarcts 39% Mean size of infarct 1.3 cm (8% >2.0 cm)

  42. SPS3 Etiological Subtypes of Recurrent Ischemic Strokes

  43. SPS3 Conclusions on SPS3 Results • Dual antiplatelet therapy was not more effective than aspirin alone. • Major bleeds were increased. • Unexpectedly, mortality was increased. • These results do not support the use of combination therapy for secondary stroke prevention in patients with lacunar strokes.

  44. Effect of clopidogrel added to aspirin on stroke: metanalysis of 13 RCTs OR=0.81, 95% CI 0.74,0.85 Palacio S, Hart RG et al. International J Stroke 2013 (in press)

  45. Effect of antithrombotic drugs for stroke prevention cannot be meaningfully interpreted without considering ischemic stroke subtypes. • Clopidogrel + aspirin clearly reduces ischemic stroke in atrial fibrillation patients.(ACTIVE A) • Clopidogrel + aspirin does not reduce recurrent lacunar stroke.(SPS3) • Warfarin is far superior to antiplatelet therapy for stroke prevention in atrial fibrillation patients, but not for most other causes.(ACTIVE W, WARSS, WASID) • Combining all causes of ischemic stroke in clinical trials (e.g. CHARISMA) masks clinically important differences.

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