1 / 64

Medications for Secondary Prevention of Ischemic Stroke

Medications for Secondary Prevention of Ischemic Stroke. Alison Alleyne, PharmD David Thompson Health Region March 27, 2008. aalleyne@dthr.ab.ca. Outline. Pathophysiology of Ischemic Stroke (IS) Preventing IS  preventing MI Antiplatelets Antithrombotics Statins ACEI & ARBS.

ezekial
Télécharger la présentation

Medications for Secondary Prevention of Ischemic Stroke

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Medications for Secondary Prevention of Ischemic Stroke Alison Alleyne, PharmD David Thompson Health Region March 27, 2008 aalleyne@dthr.ab.ca

  2. Outline • Pathophysiology of Ischemic Stroke (IS) • Preventing IS  preventing MI • Antiplatelets • Antithrombotics • Statins • ACEI & ARBS

  3. Pathophysiology of IS

  4. Terminology • Transient Ischemic Attacks (TIA) • brief episode of neurological dysfunction caused by a focal disturbance of brain or retinal ischemia, with clinical symptoms typically lasting less than 1 h, and without evidence of infarction • Precedes ischemic stroke in 60% of cases • 35% of untreated patients will develop stroke within 5 years of TIA • Stroke • Stable – permanent no expected improvement/deterioration • Improving – return of previously lost neurologic function over days to weeks • Progressing – continues to deteriorate following initial onset of focal deficit

  5. Pathophysiology of Stroke Stroke Primary Hemorrhage (15%) Intraparenchymal Subarachnoid Penetrating artery disease 25% “lacunar” (< 1.5 cm) Cardiogenic embolism 20% A fib Valve disease Ventricular thrombi Others Other causes 5% Prothrombotic states Dissections Arteritis Migraine/vasospasm Drug abuse Others Large Artery Atherosclerotic 20% Hypoperfusion Arteriogenic embolic Cryptogenic 30% (1 of the above, or other cause)

  6. Stroke Begets Stroke Stroke 2002;33:901-6

  7. Difference Between MI and IS

  8. Composite vs Single Endpoints in IS Trials • Can’t assume benefits of therapy from MI-prevention trials to IS-prevention because anatomy is different • primary prevention with ASA is of benefit for MI but not IS • Composite endpoints allow a smaller sample size • however, unless all components of a composite endpoint are affected in the same direction and to a similar degree, their inclusion may not provide the anticipated increase in statistical power. • Including “all cause mortality” is done to try to detect unexpected deleterious effects of treatment, but only prevent other vascular-related deaths and all-cause mortality at ½ the magnitude of stroke prevention (dilutes down results) For stroke/TIA patients, the single endpoint of stroke may be optimal Albers G. Neurology 2000;54:1022-28

  9. Clotting Cascade

  10. A Clot is a Clot is a Clot?

  11. Preventing a Second Event • 26% of patients with stroke (46% of whom had  1 prior event) and 27% of patients with TIA (of whom 75% had  1 prior event) are not taking preventive (antiplatelet or antithrombotic) therapy. Copernicus: The marketing Investment Strategy Group. Patient Flow Analysis of Stroke/TIA Patients. Waltham, Mass: Copernicus, 2006

  12. Antiplatelet Therapy

  13. Antiplatelet Agents • ASA 50-325 mg daily • start within 48h of symptom onset; begin with 160-325mg x 2 weeks • Aggrenox® (ASA 50 mg and 200 mg extended release (ER) dipyridamole) bid • Clopidogrel 75 mg daily • Ticlopidine 250 mg bid BMJ 2002;324:71-86

  14. ASA • IST: 19,000 pts received ASA 300 mg/day (within 48h; median 19h ) vs 2 different doses heparin x 2 weeks • ASA had slightly fewer deaths (9% vs 9.4%), fewer recurrent IS (2.8% vs 3.95% p = 0.03), no excess ICH (0.9% vs 0.8%), and trend toward  death/dependency @ 6 mon (61.2% vs 63.5%) • CAST: 21,000 pts received ASA 160 mg/day vs PL within 48h of stroke and for up to 4 weeks • early mortality decreased (3.3% vs 3.9% p = 0.04) • recurrent IS decreased (1.6% vs 2.1%, p=0.01) ;10% RRR • Antithrombotic Trialists’ Collaboration (ATC): meta-analysis of 287 studies, involving 220,000 pts with previous MI, AMI, previous TIA/stroke, acute IS, other high risk patients • 25% decrease in stroke, MI, vascular death • Meta analysis of 23,00 patients from 21 RCT WITH PRIOR STROKE for mean 29 mon= 22% reduction stroke, MI or vascular death (17.8 vs 21.4% ARR 3.6%) NNT 40 in 3 y

  15. ASA Dose for Stroke Prevention Am J Med 2006;119:198-202

  16. Aggrenox: ESPS-2 ER DP, extended release dipyridamole; ASA, acetasalicylic acid; PL, placebo *p < 0.001; ** p< 0.006; ***p< 0.05 J Neurol Sci. 1996 Nov;143(1-2):1-13

  17. ESPRIT • Randomized open label trial • 2763 pts with TIA/IS within last 6 m (mRS < 3) • Dipyridamole 200 mg bid + ASA 30-325 mg/d vs ASA 30-325 mg daily x 3.5 y • 83% used ER formulation • 34% vs 13% discontinued trial • median dose (75 mg in both gps) higher than daily Aggrenox 50 mg • Death + stroke + MI + major bleed = 13% vs 16% (NNT 33 for 3.5 y or 100 pts for 1 year) • meta-analysis confirms benefit of Aggrenox Lancet 2006;367:1665-73

  18. CAPRIE • Clopidogrel 75 mg/day vs. ASA 325 mg/day in noncardioembolic stroke (34%), MI (33%) or Peripheral Artery Disease (34%) • 19,185 patients over 1.91 years (range, 1-3 y) •  ischemic stroke, MI or vascular death (5.32 vs. 5.83%; 8.7% RRR, p = 0.043) • Initial stroke patients: • 7.3% RRR for composite (CI - 5.7 to 18.7, p=0.26) • 8% RRR for stroke only (CI -7 to 21, p=.28) Lancet 1996;348:1329-39.

  19. MATCH • Clopidogrel + ASA vs. clopidogrel + PL • 7599 pts with previous stroke/TIA • Stroke, MI, vascular death or rehospitalization for acute ischemia: 15.7% vs 16.7 %; RRR 6.4% [95% CI -4.6 to 16.3, p= 0.24] • Increased bleed in combination therapy group, 2.6% vs. 1.3%; ARI 1.3% [95% CI 0.6 to 1.9] Lancet. 2004 Jul 24-30;364(9431):331-7

  20. CHARISMA • R, DB, PC clopidogrel 75 mg/d + ASA (75-162 mg/d) versus ASA + placebo x median 28 months • 15,603 high-risk asymptomatic patients, or symptomatic patients with established CAD, CVD (~25%), or PAD. • also received statins (77%), ACEI (64%), etc as per EBM • MI, stroke or CV death occurred in 6.8% C+A vs 7.3% A (p=0.22) • IS 1.7 vs 2.1%, RR 0.82, CI 0.66-1.04, p = 0.10 • all stroke (nonfatal) 1.9 vs 2.4%, RR 0.8 (CI 0.65-0.997, p = 0.05) • when time to intervention was < 30days, trend towards increased benefit • trend of more severe bleeding in C+A (1.7 vs 1.3%, p=0.09) • moderate bleeding higher in C+A 2.1 vs 1.3% (RR 1.62, CI 1.27-2.1, p<0.0010

  21. TIA or Ischemic Stroke Yes CAD Present? No ASA Clopidogrel ASA Clopidogrel ASA + ER-DP Recurrent TIA/IS Recurrent TIA/IS Recurrent TIA/IS Recurrent TIA/IS Recurrent TIA/IS Clopidogrel Or ASA & Clopidogrel No change, or Assess Risk vs Benefit of combination Tx No change* or  ASA or Clopidogrel or ASA & ER-DP ASA & ER-DP or Clopidogrel* Clopidogrel or ASA & ER-DP*? * assess compliance, adverse effects, drug interactions,etc

  22. Anticoagulants in Non-Cardioembolic IS No benefit, and increased risk of bleeding • SPIRIT: warfarin (INR 3-4.5) vs ASA 30 mg/day • stopped early due to 2.3 fold increase in death • Bleeding increased 1.43 fold per 0.5 increase in INR • WARSS: - warfarin (INR1.2 -2.8) vs ASA 325 mg/day • no difference in prevention of early recurrent IS or death • ESPRIT (warfarin vs ASA arm) • no superiority of warfarin • WASID: warfarin (INR 2-3) vs ASA 1300 mg/day • stopped early, due to increased mortality (4.3% vs 9.7%, p=0.02) and major hemorrhage (3.2% vs 8.3%, p= 0.01) with warfarin • NSD in patients with atherosclerotic intracranial arterial stenosis

  23. Anticoagulation in Nonvalvular Atrial Fibrillation

  24. When to Use Anticoagulation • Cardioembolic stroke • persistent or paroxysmal atrial fibrillation (INR 2-3) • acute MI with left ventricular mural thrombus (INR 2-3) • rheumatic mitral valve disease (INR 2-3) • mechanical prosthetic valve (INR 2.5-3.5) • Cerebral venous sinus thrombosis • Arterial dissections • Hypercoagulable states

  25. Cardioembolic Stroke The left atrial appendage of a woman with atrial fibrillation who suffered a thromboembolic event. Organized 5mm thrombi are apparent. A 5mm thrombus can completely occlude the middle cerebral artery.

  26. Warfarin vs. Placebo in AFib Hart RG. Ann Intern Med 2007;146:857-67

  27. Antiplatelet vs Placebo in Afib Hart RG. Ann Intern Med 2007;146:857-67

  28. Warfarin vs ASA in AF Hart RG. Ann Intern Med 2007;146:857-67

  29. ACTIVE W • 6700 pts with afib and at least 1 risk factor for stroke • warfarin (INR 2-3) vs. ASA 75-100 mg/d + clopidogrel 75 mg/d • Primary endpoint: stroke, systemic embolus, MI or vascular death • stopped early, due to superiority of warfarin group

  30. Safety Outcomes Hart RG. Ann Intern Med 2007;146:857-67

  31. Anticoagulation • Warfarin in nonvalvular afib decreases stroke recurrence from 12% to 4% annually, whereas ASA only decreases risk to 10%. • NNT 11 to prevent 1 stroke in 1 year • Benefit outweighs risk of bleed (even in elderly: • Extracranial bleed: 2.3% per year • ICH in ≥ 60 years: 0.3-1.7% Lancet 1993;342:1255-62

  32. ACC/AHA/ESC Afib Guidelines Prevention must consider: • risk of stroke • bleed risk • ability to safely sustain anticoagulation • patient preference Circulation 2006;114:e257-e354

  33. CHADS2 Score C = Congestive HF (EF<35%) (1 point) H = HT (1 point) A = Age > 75 y (1 point) D = Diabetes (1 point) S = previous Stroke/TIA (2 points) 0 points = ASA 75-325 mg daily 1 point = ASA 75-325 mg daily or warfarin (INR target 2-3)  2 points = warfarin (INR target 2-3)

  34. Risk Assessment

  35. Antithrombotic Therapy for Patients with AFib Circulation 2006;114:e257-e354

  36. Afib--Other Recommendations • If no mechanical valve, can hold treatment for up to 1 week for procedures • Must regularly re-evaluate need for anticoagulation • If pt is > 75 y or has moderate RF but you can’t safely get pt to INR 2-3, consider warfarin targetting INR 1.6-2 • If < 60 years with lone AF, risk/benefit of ASA for primary prevention not established • If patient with afib strokes on warfarin, consider increasing intensity, rather than adding antiplatelet

  37. Suggestions for Anticoagulation in Patients with AF who present with AIS or TIA • Normalize BP before starting anticoagulation • In patients with AF and AIS • do imaging (CT or MRI) to exclude hemorrhage • if no cerebral hemorrhage, begin anticoagulation after 2 weeks (use ASA in the interim) • if cerebral hemorrhage, do not anticoagulate • delay therapy if large cerebral infarction • In patients with AF and TIA • do imaging (CT or MRI) to exclude hemorrhage • if no cerebral hemorrhage, begin anticoagulation as soon as possible Lip GYH. Lancet Neurol 2007;6:981-93 Paciaroni M. Stroke 2007;38:423-30

  38. Antiplatelets and Anticoagulants--Summary Koennecke. CNS Drugs 2004;18:221-41

  39. Statins

  40. SPARCL • 4731 patients with TIA or stroke (excluding cardioembolic stroke) within 1-6 months • LDL 2.6-4.9, no CAD • did not already have indication for statin??? • Atorvastatin 80 mg/d vs PL • Primary Endpoint endpt--first nonfatal or fatal stroke Results • median follow up 4.9y • median LDL 1.9 vs 3.3 N Engl J Med 2006;355:549-59

  41. Type of stroke Hazard ratio (95% CI) with atorvastatin Any 0.84 (0.71-0.99) Fatal 0.57 (0.35-0.95) Nonfatal 0.87 (0.73-1.03) Ischemic 0.78 (0.66-0.94) Hemorrhagic 1.66 (1.08-2.55) SPARCL: Main results N Engl J Med 2006;355:549-59.

  42. Meta-Analysis of Stain Therapy for Stroke Prevention All- stroke prevention: 16% RRR (RR 0.84, CI 0.79-0.91) O’Regan C. Am J Med 2008;121;24-33

  43. Thiazide DiureticsAngiotensin Conventing Enzyme Inhibitors (ACEIs)Angiotensin Receptor Blockers (ARBs)

  44. ALLHAT Health Effects of Diuretics Low-dose thiazide-type diuretic-based treatment in large clinical trials has been shown to reduce the risks of: Event reduction % Stroke 34 Heart failure 42 CHD 28 CVD mortality 24 Total mortality 10 Psaty et al., JAMA 1997;277:739-45 JAMA 2002;288:2981-2997

More Related