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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
     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
     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
    Clinical Case Presentation
              Physical Exam

• T 97.8 BP 155/95 P 78 R 16

• General PE within normal limits
       Clinical Case Presentation
                Neurologic 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
     Clinical Case Presentation
                Laboratories
• 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
     Clinical Case Presentation
• Patient admitted for 24h with no
  progression of symptoms

• Mild improvement in weakness

• Discharged home on aspirin 325mg daily
    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
           Clinical Question
• How effective is clopidogrel in secondary
  stroke prevention?
             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.
                  Stroke

• Sudden focal neurologic deficit caused by a
  vascular event

• 80-85% ischemic, 15-20% hemorrhagic
     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
Risk Factors for Ischemic Stroke
Non-modifiable     Modifiable
• Age              •   Hypertension
                   •   Prior stroke or TIA
• Race/ethnicity   •   Cardiac disease
• Gender           •   Diabetes mellitus
• Family History   •   Hyperlipidemia
                   •   Asymptomatic carotid
                       stensosis
                   •   Hyperhomocysteinemia
                   •   Cigarette smoking
                   •   Heavy alcohol use
                   •   Obesity
             Stroke Prevention
• Primary stroke prevention
  Risk factor modification


• Secondary stroke prevention
  Aspirin
  Dipyridamole
  Ticlopidine
  Clopidogrel
   Secondary Stroke Prevention
            Aspirin
• 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%
 Effects of Antiplatelet Therapy in
Patients with Previous Stroke or TIA
   Secondary Stroke Prevention
            Aspirin
• 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
   European Stroke Prevention
            Study 2
          ASA vs.   Dipyrid   Dipyrid+ Dipyrid+
          Placebo   vs.       ASA vs. ASA vs.
                    Placebo   Placebo ASA

RRR(%)     18.1      16.3      37.0     23.1


P value    0.013     0.039     <0.001   0.006
            Thienopyridines
• Ticlopidine (Ticlid)
• Clopidogrel (Plavix)
• Irreversibly inactivate ADP receptor
  function, preventing platelet aggregation by
  way of the GPIIb-IIIa complex
                  Thienopyridines
                  Adverse Effects
              Diarrhea   Rash   Nausea Neutropenia TTP
                                                  Four
                                                  cases/million
Clopidogrel    0.4%      0.5%   0.5%    <1%       exposed

                                                  One case/
                                                  2-4,000
Ticlopidine    6.3%      3.4%   2.6%    1.3%
                                                  exposed
    Major Studies Evaluating
   Ticlopidine in Stroke Setting
• Canadian American Ticlopidine Study
  (CATS) 1989
• Ticlopidine Aspirin Stroke Study (TASS)
  1989
          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
          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
          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
            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
               CATS (Gent et al.)
               Intention-to-treat Analysis


                  RRR(%)     95% CI      P value
Stroke, MI, or     23.3      1.0-40.5     0.02
vascular death
Stroke and         20.5                      0.06
stroke death
         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%
          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
          CATS (Gent et al.)
• Limitations
  – High rates of early discontinuation of drug
  – Risk reduction only significant for composite
    outcome and with wide confidence intervals
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
          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
          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
            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
          TASS (Hass et al.)
      Intention-to-treat Analysis

                 RRR(%)   95% CI     P value
Death or non-     12.0    -2 to 26    0.048
fatal stroke
Fatal and non-    21.0    4 to 38    0.024
fatal stroke
            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%)
          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
          TASS (Hass et al.)
• Limitations
  – High rates of early discontinuation of
    medication
  – Wide confidence intervals
 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)
              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
              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
             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
             CAPRIE Trial
• Methods
  – 19,185 pts randomized:
     • clopidogrel+ASA placebo
     • ASA(325mg)+clopidogrel placebo

  – Follow-up visits every 4 months
             CAPRIE Trial
• Outcomes
  – Primary: composite of ischemic stroke, MI, or
    vascular death

  – Secondary: vascular death, death from any
    cause, stroke, MI, or leg amputation
             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%
 Outcome event cluster and treatment group   First outcome events               Event      Relative-risk         P
                                                                                rate per   reduction (95% CI)
                                                                                year
                                             Non-fatal       Fatal    Total


 Ischaemic stroke, MI, or vascular death
 (primary cluster)
 Clopidogrel (nyrs=17636*)                   631             308      939       5.32%      8.7% (0.3 to 16.5)    0.043
 Aspirin (nyrs=17519)                        700             321      1021      5.83%

 Ischaemic stroke, MI, amputation, or
 vascular death
 Clopidogrel (nyrs=17594)                    677             302      979       5.56%      7.6% (-0.8 to 15.3)   0.076
 Aspirin (nyrs=17482)                        737             314      1051      6.01%


                                             --              350      350       1.90%      7.6% (-6.9 to 20.1)   0.29
                                             --              378      378       2.06%
Vascular death
Clopidogrel (nyrs=17482)
Aspirin (nyrs=17501)                         643             490      1133      6.43%      7.0% (-0.9 to 14.2)   0.081
                                             720             487      1207      6.90%
Any stroke, MI, or death from any cause
Clopidogrel (nyrs=17622)
Aspirin (nyrs=17501)                         --              560      560       3.05%      2.2% (-9.9 to 12.9)   0.71
                                             --              571      571       3.11%



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
                     CAPRIE Trial
       Treatment Effect by Subgroup
                                           RRR
                    Event rate per yr     95% CI          P value
STROKE
   Clopidogrel           7.15%              7.3%           0.26
       Aspirin           7.71%          (-5.7 to 18.7)
MI
      Clopidogrel        5.03%              -3.7%          0.66
          Aspirin        4.84%          (-22.1 to 12.0)
PAD
      Clopidogrel        3.71%              23.8%         0.0028
          Aspirin        4.86%           (8.9 to 36.2)
   Treatment Effects of Patients
        with History of MI
                         RRR
                  (Ischemic stroke, MI,    95% CI
                    or vascular death)

PAD/Stroke with         22.7%             4.9 to 37.2
previous MI
(n=2144)

Any previous MI         7.4%              -5.2 to 18.6
(n=8446)
 Incidence of Adverse Effects
                   Clopidogrel   Aspirin
Rash                 6.02%       4.61%
Diarrhea             4.46%       3.36%
GIB                  1.99%       2.66%
Thrombocytopenia     0.26%       0.26%
Neutropenia          0.05%       0.04%
ICH                  0.35%       0.49%
              CAPRIE Trial
• Conclusions

  – Small risk reduction in composite outcome of
    ischemic stroke, MI, or vascular death

  – Clopidogrel at least as safe as ASA
             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
           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
Bhatt et al.
                 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
            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
                           Bhatt et al.
                    Clopidogrel          Aspirin         RRR(%)       P value
                    (event rate/yr)   (event rate/yr)    (95% CI)

Vascular death,          5.8               9.1             36.3       0.004
MI, or ischemic
                                                        (13.4-53.1)
stroke
Rehospitalization        9.3              11.8             21.3       0.038
for ischemic
                                                        (1.2-37.4)
events
Stroke                   2.6               3.5             25.7       0.237
                                                        (-20-53.1)
MI                       2.4               3.9             38.5       0.037
                                                         (2.5-63)
                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
                Bhatt et al.
• Limitations
  – Date and type of cardiac surgery not specified
  – Wide confidence intervals
  – Limited applicability to stroke pts
 Clopidogrel in Unstable Angina to
 Prevent Recurrent Events (CURE)
                Trial
• Study Design
  – Randomized, double-blinded
  – Assess efficacy of clopidogrel+ASA vs. ASA
    in pts with acute coronary syndrome without
    ST-segment elevation
                 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
               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)
                 CURE Trial
• Exclusion Criteria
  –   ST-segment elevation >1mm
  –   Severe (class IV) heart failure
  –   PTCA/stent or CABG within 3 mos prior
  –   Administration of glycoprotein IIb/IIIa
      inhibitors within 3d prior
                 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
                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
               CURE Trial
• Results
  – Mean treatment duration 9 months
  – Discontinued study medication temporarily
    (>5d):
     • 46.2% of pts in clopidogrel group
     • 45.4% in placebo group
               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
        Use of Thrombolytics and
            IIb/IIIa Inhibitors
                Clopidogrel   Placebo   P value

Thrombolytics      1.1%        2.0%     <0.001

IIb/IIIa           5.9%        7.2%     0.003
inhibitors
Incidence of Main Study Outcomes
               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
   Incidence of Adverse Effects
                   Clopidogrel Placebo   RR     P value

Major Bleeding       3.7%       2.7%     1.38   0.001

Minor Bleeding       5.1%       2.4%     2.12   <0.001

Thrombocytopenia     0.4%       0.4%

Neutropenia          0.1%      0.08%
                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
  – Clopidogrel+ASA associated with an increased
    risk of bleeding complications
                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
Summary of Results from Selected
      Antiplatelet Trials
 Trial    Therapy                      Outcome              RRR    ARR (%)     NNT
                                                            (%)      (event
                                                                    rate/yr)


 ESPS-2   ASA vs. placebo        Fatal/Nonfatal Stroke      18.3      1.3      76


 TASS     Ticlop vs. ASA         Fatal/Nonfatal Stroke      21.0      0.6      167




 CATS     Ticlop vs. placebo   Stroke, MI, vascular death   23.3      3.5      29




 CAPRI    Clopid vs. ASA       Stroke, MI, vascular death   8.7       0.5      200
 E


 CURE     Clopid + ASA vs.       Stroke, nonfatal MI,       18.4      2.8      36
          ASA                    cardiovascular death


                                 Fatal/Nonfatal Stroke      14.3      0.2      413
          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
          Final Conclusions
• Based on CAPRIE trial NNT=200
• $160,000/year to prevent one additional
  vascular event
          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
          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
    Perindopril Protection Against
       Recurrent Stroke Study
           (PROGRESS)

• Randomized, double-blinded
• 6,105 pts randomized to perindopril,
  perindopril+indapamide, or placebo
• Overall 28% RRR in stroke
• Combination therapy with 43% RRR
             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 clopidogrel+ASA or ASA alone
  –   Primary outcome of stroke, MI or vascular
      death
                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
THANK YOU

								
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