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Efficacy of Clopidogrel in Secondary Stroke Prevention

Efficacy of Clopidogrel in Secondary Stroke Prevention. Catherine K. Buchanan Internal Medicine Resident Grand Rounds January 22, 2002. Clinical Case Presentation. BB is a 62 yo WM with no significant PMH Presents to clinic with c/o difficulty walking

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Efficacy of Clopidogrel in Secondary Stroke Prevention

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  1. Efficacy of Clopidogrel in Secondary Stroke Prevention Catherine K. Buchanan Internal Medicine Resident Grand Rounds January 22, 2002

  2. Clinical Case Presentation • BB is a 62 yo WM with no significant PMH • Presents to clinic with c/o difficulty walking • Day prior, noticed limping on R side followed by difficulty using RUE • Took two aspirin and went to bed • Next morning, again experienced difficulty walking • Denies headache, visual changes, dysphagia, dysarthria or sensory changes

  3. Clinical Case Presentation • PMH: None • SH: Married, 4 children. Full-time professor. Prior tobacco use, quit 30 yrs ago. 2-3 glasses of wine/wk • FH: Father deceased at age 73 of massive stroke. Mother deceased at age 101 of “old age” • Meds: Multivitamin qd • Allergies: NKDA • ROS: As above, otherwise negative

  4. Clinical Case PresentationPhysical Exam • T 97.8 BP 155/95 P 78 R 16 • General PE within normal limits

  5. Clinical Case PresentationNeurologic Exam • Pupils equal and reactive bilaterally • EOM full • Facial strength and sensation intact • Palate elevates symmetrically, tongue midline • Motor strength 5/5 on L, 4-4+/5 on R • Sensation intact throughout to pinprick • DTRs 2+ throughout, toes downgoing bilaterally

  6. Clinical Case PresentationLaboratories • CBC, BMP within normal limits • LDL 110, HDL 34 • ECG: Normal sinus rhythm, no ST/T wave changes • Head CT without contrast: mild atrophy, otherwise normal

  7. Clinical Case Presentation • Patient admitted for 24h with no progression of symptoms • Mild improvement in weakness • Discharged home on aspirin 325mg daily

  8. Clinical Case Presentation • Next day, presented to the ED with worsening right-sided weakness • Repeat Head CT negative • Re-admitted and started on clopidogrel 75mg daily • Carotid Dopplers and TTE normal • Discharged home on continued clopidogrel therapy in place of aspirin

  9. Clinical Question • How effective is clopidogrel in secondary stroke prevention?

  10. Stroke Statistics • Third leading cause of death in the U.S. • Estimated 600,000 strokes annually • Leading cause of disability in adults • Estimated annual cost in 1999 – $51 billion • Estimated 4.6 million stroke survivors in U.S.

  11. Stroke • Sudden focal neurologic deficit caused by a vascular event • 80-85% ischemic, 15-20% hemorrhagic

  12. Transient Ischemic Attack • Focal neurologic deficit lasting <24h, typically 5-20 minutes • Approximately 10-15% with prior TIA • At least 1/3 with untreated TIAs will have stroke within 5 years

  13. Non-modifiable Age Race/ethnicity Gender Family History Modifiable Hypertension Prior stroke or TIA Cardiac disease Diabetes mellitus Hyperlipidemia Asymptomatic carotid stensosis Hyperhomocysteinemia Cigarette smoking Heavy alcohol use Obesity Risk Factors for Ischemic Stroke

  14. Stroke Prevention • Primary stroke prevention Risk factor modification • Secondary stroke prevention Aspirin Dipyridamole Ticlopidine Clopidogrel

  15. Secondary Stroke PreventionAspirin • Antithrombotic Trialists’ Collaboration (2002) • Meta-analysis of 287 randomized studies • Antiplatelet therapy reduced odds of non-fatal stroke by 25% • Aspirin reduced odds of vascular event by 23%

  16. Effects of Antiplatelet Therapy in Patients with Previous Stroke or TIA

  17. Secondary Stroke PreventionAspirin • European Stroke Prevention Study 2 (Diener et al.) • 6,602 pts with recent history of TIA or stroke • Randomized to ASA, dipyridamole, ASA+dipyridamole, or placebo

  18. European Stroke Prevention Study 2

  19. Thienopyridines • Ticlopidine (Ticlid) • Clopidogrel (Plavix) • Irreversibly inactivate ADP receptor function, preventing platelet aggregation by way of the GPIIb-IIIa complex

  20. ThienopyridinesAdverse Effects

  21. Major Studies Evaluating Ticlopidine in Stroke Setting • Canadian American Ticlopidine Study (CATS) 1989 • Ticlopidine Aspirin Stroke Study (TASS) 1989

  22. CATS (Gent et al.) • Study Design • Randomized, double-blinded • Assess effect of ticlopidine vs. placebo in reducing rate of subsequent occurrence of stroke, MI, or vascular death in patients with a recent thromboembolic stroke

  23. CATS (Gent et al.) • Participants • 1,053 pts with thromboembolic stroke >1 wk or <4 mos prior to study entry • 62% male, mean age 65, 78% of pts with first stroke

  24. CATS (Gent et al.) • Methods • Pts randomized to ticlopidine or placebo • Diagnosis based on neurologic evaluation; Head CT required • Follow-up assessments every 4 months • Outcomes • Stroke, MI, or vascular death

  25. CATS (Gent et al.) • Results • Mean treatment duration 1.5 yrs • Mean compliance 90% in placebo and treatment groups • 46% of pts in ticlopidine group and 31% in placebo group discontinued study medication before end of study

  26. CATS (Gent et al.)Intention-to-treat Analysis

  27. CATS (Gent et al.) • Ticlopidine group – increased frequency of severe side effects (8.2% vs. 2.8%) • Neutropenia 2.0% • Rash 14.8% • Diarrhea 21.5%

  28. CATS (Gent et al.) • Conclusions • Moderate risk reduction in composite outcome of stroke, MI, or vascular death • Adverse side effect profile, including rash, diarrhea, and neutropenia

  29. CATS (Gent et al.) • Limitations • High rates of early discontinuation of drug • Risk reduction only significant for composite outcome and with wide confidence intervals

  30. Ticlopidine Aspirin Stroke Study(TASS) • Study Design • Randomized, double-blinded • Compare effects of ticlopidine vs. ASA on the risk of stroke or death in pts with recent transient or mild persistent focal cerebral or retinal ischemia

  31. TASS (Hass et al.) • Participants • 3,069 pts with one or more of TIA, amaurosis fugax, RIND, or minor stroke 3 months prior to entry • 58% male, mean age 65 yrs

  32. TASS (Hass et al.) • Methods • Pts randomized to ticlopidine or ASA (1300mg) • Eligibility of each pt reviewed by neurologist blinded to treatment • Pts evaluated at 4 month intervals • Outcomes • Death from all causes or non-fatal stroke

  33. TASS (Hass et al.) • Results • Mean duration of therapy 2.2 yrs • Compliance: 89% of pts took >75% of study medication >90% of time • 43.1% of pts in ticlopidine group and 36.7% of pts in ASA group discontinued study medication prematurely

  34. TASS (Hass et al.)Intention-to-treat Analysis

  35. TASS (Hass et al.) • Results • Severe neutropenia: • 0.9% of ticlopidine group • 0% in ASA group • Increased frequency of diarrhea and rash • Incidence of bleeding events similar between two groups (10%)

  36. TASS (Hass et al.) • Conclusions • Moderate risk reduction in fatal and non-fatal stroke • Small reduction in risk of non-fatal stroke and death • Increased incidence of adverse effects

  37. TASS (Hass et al.) • Limitations • High rates of early discontinuation of medication • Wide confidence intervals

  38. Studies Evaluating Clopidogrel Use in Stroke Prevention • Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events (CAPRIE) Trial (1996) • Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial (2001)

  39. CAPRIE Trial • Study Design • Randomized, double-blinded • Assess relative efficacy of clopidogrel vs. ASA in reducing risk of ischemic stroke, MI, or vascular death in pts with atherosclerotic vascular disease

  40. CAPRIE Trial • Participants • 19,185 pts with clinical evaluation establishing diagnosis of ischemic stroke, MI, or symptomatic PAD • Mean age 62, 72% male • 20% of pts with history of prior TIA or stroke

  41. CAPRIE Trial • Inclusion Criteria for Stroke Participants • focal neurologic deficit onset >1wk and <6 mos before randomization • neurologic signs persisting >1wk from stroke onset • CT or MRI ruling out hemorrhage or non-relevant disease

  42. CAPRIE Trial • Methods • 19,185 pts randomized: • clopidogrel+ASA placebo • ASA(325mg)+clopidogrel placebo • Follow-up visits every 4 months

  43. CAPRIE Trial • Outcomes • Primary: composite of ischemic stroke, MI, or vascular death • Secondary: vascular death, death from any cause, stroke, MI, or leg amputation

  44. CAPRIE Trial • Results • Mean duration of follow-up 1.9 yrs • Early discontinuation of study drug • 21.3% of clopidogrel pts • 21.1% of ASA pts • Mean compliance in both groups 91%

  45. Outcome event cluster and treatment group First outcome events Event rate per year Relative-risk reduction (95% CI) P Non-fatal Fatal Total 631 700 677 737 -- -- 643 720 -- -- 308 321 302 314 350 378 490 487 560 571 939 1021 979 1051 350 378 1133 1207 560 571 5.32% 5.83% 5.56% 6.01% 1.90% 2.06% 6.43% 6.90% 3.05% 3.11% 8.7% (0.3 to 16.5) 7.6% (-0.8 to 15.3) 7.6% (-6.9 to 20.1) 7.0% (-0.9 to 14.2) 2.2% (-9.9 to 12.9) 0.043 0.076 0.29 0.081 0.71 Ischaemic stroke, MI, or vascular death (primary cluster) Clopidogrel (nyrs=17636*) Aspirin (nyrs=17519) Ischaemic stroke, MI, amputation, or vascular death Clopidogrel (nyrs=17594) Aspirin (nyrs=17482) Vascular death Clopidogrel (nyrs=17482) Aspirin (nyrs=17501) Any stroke, MI, or death from any cause Clopidogrel (nyrs=17622) Aspirin (nyrs=17501) Death from any cause Clopidogrel (nyrs=18377) Aspirin (nyrs=18354) *Patient-years at risk for outcome cluster Table 2: Intention-to-treat analysis – primary and secondary outcome clusters

  46. CAPRIE TrialTreatment Effect by Subgroup

  47. Treatment Effects of Patients with History of MI

  48. Incidence of Adverse Effects

  49. CAPRIE Trial • Conclusions • Small risk reduction in composite outcome of ischemic stroke, MI, or vascular death • Clopidogrel at least as safe as ASA

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