Efficacy of Clopidogrel in Secondary Stroke Prevention

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Efficacy of Clopidogrel in Secondary Stroke
Prevention

• Catherine K. Buchanan
• Internal Medicine Resident
• Grand Rounds
• January 22, 2002

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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

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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

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Clinical Case PresentationPhysical Exam

• T 97.8 BP 155/95 P 78 R 16
• General PE within normal limits

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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

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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

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Clinical Case Presentation

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

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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

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Clinical Question

• How effective is clopidogrel in secondary stroke
  prevention?

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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.

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Stroke

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

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Transient Ischemic Attack

• Focal neurologic deficit lasting lt24h, typically
  5-20 minutes
• Approximately 10-15 with prior TIA
• At least 1/3 with untreated TIAs will have stroke
  within 5 years

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Risk Factors for Ischemic Stroke

• 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

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Stroke Prevention

• Primary stroke prevention
• Risk factor modification
• Secondary stroke prevention
• Aspirin
• Dipyridamole
• Ticlopidine
• Clopidogrel

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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

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Effects of Antiplatelet Therapy in Patients with
Previous Stroke or TIA
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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,
  ASAdipyridamole, or placebo

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European Stroke Prevention Study 2
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Thienopyridines

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

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ThienopyridinesAdverse Effects
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Major Studies Evaluating Ticlopidine in Stroke
Setting

• Canadian American Ticlopidine Study (CATS) 1989
• Ticlopidine Aspirin Stroke Study (TASS) 1989

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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

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CATS (Gent et al.)

• Participants
• 1,053 pts with thromboembolic stroke gt1 wk or lt4
  mos prior to study entry
• 62 male, mean age 65, 78 of pts with first
  stroke

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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

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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

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

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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

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CATS (Gent et al.)

• Limitations
• High rates of early discontinuation of drug
• Risk reduction only significant for composite
  outcome and with wide confidence intervals

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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

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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

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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

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TASS (Hass et al.)

• Results
• Mean duration of therapy 2.2 yrs
• Compliance 89 of pts took gt75 of study
  medication gt90 of time
• 43.1 of pts in ticlopidine group and 36.7 of
  pts in ASA group discontinued study medication
  prematurely

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

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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

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TASS (Hass et al.)

• Limitations
• High rates of early discontinuation of medication
• Wide confidence intervals

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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)

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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

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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

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CAPRIE Trial

• Inclusion Criteria for Stroke Participants
• focal neurologic deficit onset gt1wk and lt6 mos
  before randomization
• neurologic signs persisting gt1wk from stroke
  onset
• CT or MRI ruling out hemorrhage or non-relevant
  disease

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CAPRIE Trial

• Methods
• 19,185 pts randomized
• clopidogrelASA placebo
• ASA(325mg)clopidogrel placebo
• Follow-up visits every 4 months

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CAPRIE Trial

• Outcomes
• Primary composite of ischemic stroke, MI, or
  vascular death
• Secondary vascular death, death from any cause,
  stroke, MI, or leg amputation

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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

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Patient-years at risk for outcome cluster Table
2 Intention-to-treat analysis primary and
secondary outcome clusters
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CAPRIE TrialTreatment Effect by Subgroup
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Treatment Effects of Patients with History of MI
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Incidence of Adverse Effects
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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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CAPRIE Trial

• Limitations
• Stroke outcome analysis limited to composite
  outcomes
• Primary composite outcome with wide confidence
  interval
• Composite outcome risk reduction in subgroup of
  stroke pts not statistically significant

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Bhatt et al.(2000)

• Study Design
• Retrospective analysis of data from CAPRIE trial
  looking at rehospitalization rates for ischemia
  (angina, TIA, limb ischemia) and bleeding

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Bhatt et al.
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Bhatt et al.

• Conclusions
• Small decrease in risk of rehospitalization for
  further ischemic events (angina, TIA, PAD)
• Decreased risk of rehospitalization for GIB
• Limitations
• All rehospitalizations may not have been reported
• Wide confidence intervals

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Bhatt et al.(2001)

• Study Design
• Retrospective analysis of data from CAPRIE trial
  looking at recurrent ischemic events in pts with
  a history of prior cardiac surgery

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Bhatt et al.
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Bhatt et al.

• Conclusions
• Reduced risk of composite outcome of vascular
  death, MI, or ischemic stroke and MI alone
• Reduced risk of rehospitalization for ischemic
  events

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Bhatt et al.

• Limitations
• Date and type of cardiac surgery not specified
• Wide confidence intervals
• Limited applicability to stroke pts

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Clopidogrel in Unstable Angina to Prevent
Recurrent Events (CURE) Trial

• Study Design
• Randomized, double-blinded
• Assess efficacy of clopidogrelASA vs. ASA in pts
  with acute coronary syndrome without ST-segment
  elevation

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CURE Trial

• Participants
• 12,562 pts admitted with symptoms suggestive of
  acute coronary syndrome
• Mean age 64, 61 male
• 4 with prior history of stroke

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CURE Trial

• Inclusion Criteria
• Presentation within 24h of onset of symptoms
• ECG changes compatible with new ischemia or
  elevated cardiac enzymes or troponin I or T (2X
  normal)

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CURE Trial

• Exclusion Criteria
• ST-segment elevation gt1mm
• Severe (class IV) heart failure
• PTCA/stent or CABG within 3 mos prior
• Administration of glycoprotein IIb/IIIa
  inhibitors within 3d prior

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CURE Trial

• Methods
• Pts randomized to clopidogrel or placebo
• ASA (75-325mg) started simultaneously in both
  groups
• Clopidogrel 300mg, then 75mg daily
• Follow-up assessments every 3 months

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CURE Trial

• Primary Outcomes
• Composite of cardiovascular death, non-fatal MI,
  stroke
• Composite of 1st primary outcome or refractory
  ischemia
• Secondary Outcomes
• Severe ischemia, heart failure, need for
  revascularization

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CURE Trial

• Results
• Mean treatment duration 9 months
• Discontinued study medication temporarily (gt5d)
• 46.2 of pts in clopidogrel group
• 45.4 in placebo group

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CURE Trial

• Results
• Discontinued study medication permanently
• 21.1 of pts in clopidogrel group
• 18.8 in placebo group
• 94-99 compliance with ASA in both groups
• 21.2 of pts underwent PTCA
• vast majority received thienopyridine-type agent

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Use of Thrombolytics and IIb/IIIa Inhibitors
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Incidence of Main Study Outcomes
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CURE Trial

• Results
• 18.4 RRR for composite outcome of non-fatal MI,
  stroke, or death from cardiovascular causes
• 14.3 RRR for stroke
• 22.3 RRR for MI

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Incidence of Adverse Effects
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CURE Trial

• Conclusions
• Moderate risk reduction for composite outcome of
  non-fatal MI, stroke, or cardiovascular death and
  MI alone
• Smaller risk reduction for stroke
• ClopidogrelASA associated with an increased risk
  of bleeding complications

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CURE Trial

• Limitations
• Limited applicability to stroke population
• Breaks in medication treatment and use of unknown
  thienopyridine following PTCA
• Not documented if bleeding events occurred in
  association with other anticoagulant use

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Summary of Results from Selected Antiplatelet
Trials
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Final Conclusions

• Aspirin well-founded as effective agent in
  secondary stroke prevention
• Ticlopidine and clopidogrel effective in
  secondary stroke prevention additional risk
  reduction compared to ASA is modest
• Clopidogrel has safer side effect profile
  compared to ticlopidine

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Final Conclusions

• Based on CAPRIE trial NNT200
• 160,000/year to prevent one additional vascular
  event

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Final Conclusions

• Aspirin effective first-line agent for secondary
  stroke prevention
• Clopidogrel effective and safe alternative for
  those pts intolerant to aspirin
• Clopidogrel should be considered in pts with
  recurrent stroke or TIA on aspirin

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Final Conclusions

• Concurrent use with aspirin requires further
  study in stroke population
• Continued modification of risk factors should
  remain major emphasis
• Further study needed to evaluate the effects of
  antiplatelet therapy in conjunction with risk
  factor modification

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Perindopril Protection Against Recurrent Stroke
Study(PROGRESS)

• Randomized, double-blinded
• 6,105 pts randomized to perindopril,
  perindoprilindapamide, or placebo
• Overall 28 RRR in stroke
• Combination therapy with 43 RRR

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Ongoing Studies

• MATCH (Management of Atherothrombosis with
  Clopidogrel in High-Risk Patients) Trial
• High-risk pts with previous stroke or MI
• Stroke or TIA 90 days prior
• Randomized to clopidogrelASA or ASA alone
• Primary outcome of stroke, MI or vascular death

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Clinical Case

• No further events 2 years out
• Continues daily clopidogrel therapy
• Adheres to strict low sodium, low-fat diet
• 30 minutes daily aerobic exercise
• 25 lb. weight loss
• Average BP 125/80

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