1. Stroke PROTECT - An Overview

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					   Systematic Hospital - based Secondary
                Prevention



     The Stroke PROTECT Program
  Preventing Recurrence Of Thrombo-
 embolic Events through Co-ordinated
              Treatment

UCLA Stroke Center
Secondary Stroke Prevention Lecture Series

•   Overview of the PROTECT Program and
    Antiplatelets in Stroke Prevention

•   Statins and Lifestyle Modification Approaches

•   Stenting and Carotid Endarterectomy

•   Risk Factor Reduction in Hypertension and Atrial
    Fibrillation
 UCLA Stroke Center
Stroke: A Major Public Health Burden
    One stroke occurs in the US every 53 seconds
    Third leading cause of death
    >150,000 deaths per year in US
    >750,000 new strokes per year in US
    >4,400,000 stroke survivors in US
    Leading cause of adult disability
    Most preventable of catastrophic conditions

 UCLA Stroke Center
       Age and Gender-Specific Stroke Incidence:
           Northern Manhattan Stroke Study
                         1,000
                                                                                                                931
                           900            Men                                                             857

                           800            Women
                           700                                                                688
                                                                                  650
                                                                                                    629
                           600
            Annual
          Incidence        500                                                          468
                                                                      392
           Rate per        400

           100,000         300
                           200                             175              184

                           100                                   76
                                 8 4      13 7     42 46
                             0
                                  20-24 25-34 35-44 45-54 55-64 65-74 75-84                           85+
                                                   Age Groups (y)
Sacco R et al. Am J Epidemiol. 1998;147:259-268.
           Cumulative Risk of Stroke

                     Post-TIA (%)      Post-Stroke (%)

      30 days           4–8                     3 – 10
      1 year           12 – 13                  5 – 14
      5 years          24 – 29                25 – 40



                                    Sacco. Neurology. 1997;49(suppl 4):S39.
                                    Feinberg et al. Stroke. 1994;25:1320.
UCLA Stroke Center
                   Prognosis After Transient Ischemic
                              Attack (TIA)
                                       1707 patients with TIA identified by
                                       emergency department physicians
       Probability of Survival




                                 1.0
       Free From Stroke and




                                                                              Stroke 10.5%
          Adverse Events




                                 0.9


                                 0.8
                                                                             Adverse events 25.1%

                                 0.7
                                                                             (stroke, cardiovascular
                                                                             hospitalization, death,
                                 0.6
                                                                             or recurrent TIA)
                                        0   7          30               60            90
                                                            Days After TIA
    Number of Patients at Risk
    Stroke          1001 1577                   1527             1480          1451
    Adverse events 1001 1462                    1361             1293          1248




Johnston SC, et al. JAMA. 2000;284:2901-06.
            Management of Stroke

        The best approach towards
       reducing the immense burden
     that stroke places on our society
            remains prevention



UCLA Stroke Center
      Modifiable Stroke Risk Factors
Medical Conditions      Behaviors
• Hypertension           Cigarette smoking

• Cardiac disease        Heavy alcohol use

• Atrial fibrillation    Physical inactivity

• Hyperlipidemia
• Diabetes mellitus
• Carotid stenosis
• Elevated
  homocysteine
• Prior TIA or stroke
 UCLA Stroke Center
RF Control: Impact on Stroke Prevention

   >750,000 strokes annually in the US

   Preventable strokes
    Hypertension                                                369,000
    Hypercholesterolemia                                        150,000
    Tobacco Use                                                  91,500
    Atrial Fibrillation                                          47,000
    Heavy Alcohol Use                                            35,200

                      --Modified from Gorelick, Neuroepidemiology 1997

 UCLA Stroke Center
                     Emerging Strategies
  Atherosclerosis is responsible for the
  majority of ischemic strokes

   Destabilization of the atheromatous
  plaque is a forerunner of ischemic stroke

   This plaque is now the main focus for
  new directions in prevention and treatment
  of cerebrovascular atherosclerosis
UCLA Stroke Center
 Overlap of Vascular Disease in Patients
         With Atherothrombosis
       Ischemic stroke               Unstable angina                  MI          PAD




                                                        Platelet
                                     Plaque                           Thrombus
                                                       adhesion,
                                     rupture                          formation
                                                    activation, and
                                                     aggregation




                                   Vascular events (MI, stroke, or CV death)


Ness J, Aronow WS. J Am Geriatr Soc. 1999;47:1255-1256. Schafer
AI. Am J Med. 1996;101:199-209.
                Atherosclerotic Plaque
             Stable                                            Unstable


                                           Lumen

                                          Endothelium
                                                           Thrombus
                                               Platelets


                                         Lipid Rich Core


        Thick                                                             Thin
     Fibrous Cap                                                      Fibrous Cap

 Falk E et al. Circulation. 1995;92:657–671.
UCLA Stroke Center
                          Stroke Subtypes



                          Ischemic                           Hemorrhagic
                            85%                                 15%


Large Vessel    Cardioembolic        Lacunar   Other   ICH                 SAH
    35%             25%               20%       5%     10%                 5%




   UCLA Stroke Center
                        Stroke Subtypes

                           Ischemic                           Hemorrhagic
                             85%                                 15%


 Large Vessel    Cardioembolic        Lacunar   Other   ICH                 SAH
     35%             25%               20%       5%     10%                 5%



Frequency of High Risk Atherosclerosis Patients in Stroke
Large vessel       100%         35%
Small Vessel        80%         16%
Cardioembolic       60%         15%
                   Total        66%

UCLA Stroke Center
             The Evidence - Practice Gap

“ Despite compelling scientific evidence and
  national treatment guidelines supporting
  the use of secondary prevention medical
  therapies, these treatments continue to be
  underutilized in CVD patients receiving
  conventional care ”



   Adapted from 27th Bethesda Conference Report   JACC 1997;27:958
UCLA Stroke Center
      The Evidence – Practice Gap in
Implementing 2o Prevention in Stroke Patients

 •   Coverdell Acute Stroke Registries Pilot Data
 •   4 states, 7474 consecutive admissions, 2001-02

     Lipid profile done                                                     42%
     Antithrombotic at discharge                                            89%
     Warfarin for atrial fibrillation*                                      67%
     Smoking cessation counseling                                           24%
     *(Among patients with no MD documented contraindication)

                                                       --Frankel et al, Intl Stroke Conf, 2/03



 UCLA Stroke Center
      The Evidence – Practice Gap in
Implementing 2o Prevention in Stroke Patients

 •   UHC Ischemic Stroke Benchmarking Project
 •   35 Academic Medical Centers, 1206 consecutive
     admissions, 2001

     Antithrombotic at discharge                                89%
     Warfarin for atrial fibrillation*                          57%
     Smoking cessation counseling                               40%
     Patient educated about stroke                              32%
     *(Among patients with no MD documented contraindication)




 UCLA Stroke Center
    Selected Barriers to Translating Clinical
          Trials into Clinical Practice
•   Physician
    » Lack of knowledge of current evidence
    » Time constraints
    » Desire to avoid iatrogenic complications
•   Patient
    »   Polypharmacy
    »   Time
    »   Financial
    »   Intrinsic difficulty of lifestyle change
•   Health system
    » Uninsured and underinsured individuals
    » Care of chronic illness not organized systematically
    » High cost of health care
                                                   --Rich, JAMA 2002

UCLA Stroke Center
                      Incentives for Change

• NCQA/HEDIS/JCAHO/GOA reporting measures
   » Hospitals
   » Managed Care
   » Physicians
• Consumer demand for quality care / report cards
• AHA/ASA/JCAHO Stroke Center designation


 UCLA Stroke Center
      Stroke Treatment System Goals

• Implement initiatives to put evidence-
    based guidelines into action
• Improve the quality of care for patients
    with established cerebrovascular
    disease
• Reduce secondary events - and save
    lives
                     --Adapted from Fonarow, CHAMP, 2003
UCLA Stroke Center
How about a Hospital Based System?


      Problem: Large CVD treatment gap
      and poor patient compliance with
      conventional management
      Solution: In-hospital initiation of
      therapy with excellent treatment rates
      and long term patient compliance

          Simple, Rapid, and Most Importantly Effective
UCLA Stroke Center
          Why a Hospital Based System?

  • Patients
       » Patient Capture Point
       » Have patients/family attention: “teachable moment’
       » Predictor of care in community
  • Hospital Structure
       » Standardized processes/protocols/orders/teams
       » JCAHO
            •   Process Improvement Examples
       » HCFA--Peer Review Organizations

UCLA Stroke Center
                                        --Adapted from Fonarow, CHAMP, 2003
               Stroke/TIA Patient Flow in the Hospital
  Advocate/Champion
          Group                     Inpatient Care
         Practice                                                            Outpatient Care
                                Medical Ward          Quality
                                                      Control
                                 Stroke Unit
          850,000                                                                   Neurologist
                                 NICU/ICU                          660,000
     Acute                                           Discharge
Cerebrovascular            ED    Neurology                                     Primary Care MD
                                                      Nurse
     Event
                                  Medicine
          Discharged                                                                 LOST
           ~25,000               Telemetry           Inpatient
                                                      Rehab
                                 Pharmacy
                                                                       Outpatient
                                                                 15%
                                                                        Rehab
        Protocol development process           Implementation
      UCLA Stroke Center
            Challenges to In-Hospital Initiation of
             Secondary Prevention Strategies

          BARRIERS                                SOLUTIONS
1. Communication gaps -              1. Education and mobilizing case
   neurologists vs PCPs                 management teams
2. Lack of ownership - acute vs      2. Hospital is the capture point for patients
   chronic disease dilemma              with acute disease
3. Poor standardization of orders,   3. Preprinted orders, testing per protocol
   testing

4. Lack of financial incentives      4. Joint Commission, NCQA, PROs will be
                                        measuring and reporting
5. Lack of tools/resources           5. GWTG – Stroke, PROTECT

6. Lack of proof of concept          6. UCLA PROTECT demonstrates improved
                                        treatment rates
   UCLA Stroke Center
                                       --Adapted from Fonarow, CHAMP, 2003
            Challenges to a Hospital Based
                       System
 this will not work in a community hospital          the neurologists will not agree to this
  we can not get a consensus           the primary care physicians will not agree to this
                     the managed care organization will not pay for it
  patients do not want to be on a lot of medications          there is not enough time
                               the lipid panel in not accurate when drawn in the hospital
   it may not be safe to start blood pressure lowering medications in hospitalized patients
it will cost too much            this will benefit the competition

the hospital administration will not pay for it               what about the liability
                           there are exceptions x, y, and z     it will take too much time
  it is too hard to get things through the hospital committee
                        the patients should all be followed in my lipid clinic
 the physicians at my hospital do not like cookbook medicine
                                             we do not have anyone to collect this data
     UCLA Stroke Center
                                                    --Adapted from Fonarow, CHAMP, 2003
UCLA Stroke PROTECT Program


   Novel and aggressive hospital-based quality
   improvement program designed to reduce the
   devastating consequences of recurrent stroke
   through improved use of evidence-based
   secondary prevention treatments



UCLA Stroke Center
                     Hypothesis


•   In-hospital initiation of evidence-based secondary
    stroke prevention therapies would result in improved
    physician adherence, patient compliance, and
    treatment rates both at time of discharge and during
    longer term follow-up.




UCLA Stroke Center
                        Design
•   Focused on achieving 4 behavioral goals + 4
    pharmacologic goals in all cervicocephalic
    atherothrombotic disease patients prior to
    hospital discharge

•   Use of program tools including preprinted orders,
    simple guidelines, and prospective monitoring of
    treatment use

•   Started in 2002 and current template of care at
    UCLA
UCLA Stroke Center
                     Eligibility

 Inclusion Criteria:
 Diagnosis of ischemic stroke or transient ischemic
  attack
 Extent of participation will depend on patients
  stroke sub-type and co-morbid vascular risk
  factors


 Exclusion Criteria :
 Intracranial Hemorrhage

UCLA Stroke Center
                          Program Goals
      Appropriate Hospital Initiation and Maintenance of :
1.   Antithrombotic
2.   ACE Inhibitor/ ARB
3.   Statin
4.   Thiazide diuretic
5.   Exercise Education
6.   Diet Education
7.   Smoking Cessation
8.   Awareness of Stroke Warning signs
     UCLA Stroke Center
                     Antithrombotics
   Treatment of choice for prevention of strokes
   due to large vessel atherosclerotic disease and
   intracranial branch atheromatous (lacunar)
   disease

   Current guidelines recommend daily therapy
   with either aspirin, clopidogrel, or
   aspirin/dipyridamole as first-line agents

                                 Albers et al, Chest 2001
UCLA Stroke Center
                     Statins
FDA New Labeling (based on HPS
study)
» April 17, 2003
» Indicated for patients with “stroke or
  evidence of cerebrovascular disease”

All patients with atherosclerosis, regardless of
baseline LDL unless contraindicated, should
be started on a statin
    ACE Inhibitors/ Angiotensin Receptor
                  Blockers
     All patients with atherosclerosis regardless of
     blood pressure, unless contraindicated should be
     started on an ACEI/ ARB. These agents reduce
     blood pressure & have potent vascular effects
     including:

1. Increased vascular compliance
2. Regression of periarteriolar collagen area and total
   interstitial collagen volume density
3. Reduction in the arteriolar wall area
4. Normalization of resistance artery structure
UCLA Stroke Center
                     Thiazide Diuretics

• “Thiazide-type diuretics should be used in
   drug treatment for most patients with
   uncomplicated hypertension, either alone or
   combined with drugs from other classes”.


• “Recurrent stroke rates are lowered by the
   combination of an ACE inhibitor and thiazide-
   type diuretic”.


UCLA Stroke Center                  JNC 7 Report, JAMA 2003
      Medical Regimen Follow-up

• Continuation of the therapies targeting the
   underlying atherosclerosis disease process
   markedly improves clinical outcome in Stroke
   patients with atherosclerosis.

• The continued beneficial therapies prescribed
   should be strongly reinforced during patient
   follow-up.

UCLA Stroke Center
    Medication Discontinuation Rates
• Various randomized trials of antithrombotic
    agents in secondary stroke prevention have
    shown the efficacy of these agents and
    included data on side effects and dropout
    rates.
•   However, there is a paucity of published data
    on adverse events and discontinuation rates
    following initiation of these agents in a non-
    study setting.

UCLA Stroke Center
 VA Greater Los Angeles Healthcare
              System
         [VAGLAHS] Study



 The Incidence of Discontinuation of Clinical trial
proven Antithrombotic therapies in the Secondary
              Prevention of Stroke

                                     Dergalust et al 2003
  UCLA Stroke Center
        VAGLAHS Study - Objective
• Retrospective quality assurance review to
  determine the frequency with which extended
  release dipyridamole/aspirin, clopidogrel and
  warfarin are discontinued after being initiated
  for secondary stroke prevention and to
  determine the reasons for their
  discontinuation.


UCLA Stroke Center                   Dergalust et al 2003
VAGLAHS Study – Methods/ Design
•   Data was collected for 700 patients VA GLA
    Healthcare system for the period of January 2000 to
    December 2001.
•   528 of the 700 patients met inclusion criteria.
•   All patients had to be diagnosed with a stroke or a
    TIA in the VAGLAHS and were on extended release
    dipyridamole/aspirin, clopidogrel or warfarin for
    secondary stroke prevention
•   Primary Endpoint: Permanent discontinuation of the
    antithombotic agent for any reason
                                          Dergalust et al 2003
UCLA Stroke Center
                                  VAGLAHS Study Results
                                    Duration of Therapy

           Number of patients


                                200
                                150
                                100
                                 50
                                  0
                                         1        2        3        4        5
                                      1=<=6 wks, 2=6 wks-6mo, 3=6mo-12mo, 4=12mo-
                                                      24mo, 5>24mo

UCLA Stroke Center
                                                                          Dergalust et al 2003
                 VAGLAHS Study Results
               Incidence of Discontinuation

• Antithrombotic therapy was discontinued in
    27.57% of the patients
•   Reasons for discontinuation included:
    » Non compliance
    » MD error
    » MD preference
    » Bleeding complications
    » Other adverse effects
    » Patient preference

UCLA Stroke Center                      Dergalust et al 2003
                               VAGLAHS Study Results
   Number of patients
                              Reason for Discontinuation


                        80                       67
                        70
                        60                                                    50
                        50        40
                        40                                                                          21
                        30                                   17
                        20                                                                                           5
                        10
                         0




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UCLA Stroke Center                                                                                              Dergalust et al 2003
    VAGLAHS Study - Conclusions
•   Physician error involved scenarios such as
    insufficient follow-up, inattention to the need for
    refills or prescription renewal, poor communication
    between the specialist and primary care provider,
    and system error.

•   Our study shows that inappropriate discontinuation
    of antithrombotic therapy is not uncommon in a
    stroke-prone population and the most common
    cause for it is non-compliance.
UCLA Stroke Center                          Dergalust et al 2003
                     PROTECT Tools
    Stroke center staff pocket card
    Preprinted Order Sheets
    Clinical Pathways/ Care Maps
    Nursing staff interdisciplinary stroke patient education record
    Patient information packet
    Template letters to primary/ referring physicians
    Lab requisition sheet
    Patient self monitor post discharge log
    Phone and clinic follow-up records
    Data abstraction form
    Stroke PROTECT website

UCLA Stroke Center
      PROTECT Website Contents
•   Program Overview – algorithms, outcome measures, analysis
•   Program Evidence
•   Program Results
•   Getting Started
•   Program Tools - downloadable
•   FAQ
•   Patient Prevention Information
•   Power Point slides - downloadable
•   References
•   Useful links
UCLA Stroke Center
      PROTECT Systematic Implementation of
       Secondary Stroke Prevention Algorithm




UCLA Stroke Center
   PROTECT Outpatient Algorithm




UCLA Stroke Center
      PROTECT - Outcome Measures

   Compliance with program goals documented
           at discharge, days 14, day 90 and at 1 year


    Vascular event (including stroke, TIA, myocardial
   infarction, and peripheral arterial occlusion)
          at day 90, and at 1 year


   Medication treatment complications
     at day 14, day 90 and at 1 year
UCLA Stroke Center
        Impact of PROTECT pilot phase on
          Treatment Rates at Discharge

                              Pre      PROTECT

       100
        90
   P    80
   e    70
   r    60
   c    50
   e    40
   n    30
   t
        20
        10
         0
             Antithrombotic   Statin        ACEI/ARB            Thiazide

                                            --Ovbiagele et al, Stroke 2003
UCLA Stroke Center
                Impact of PROTECT on
             Treatment Rates at Discharge


                     100%

                     90%

                     80%

                     70%

                     60%

                     50%                                                  Pre-PROTECT (09/98 - 02/99)
                                                                          PROTECT (09/02 - 02/03)
                     40%

                     30%

                     20%

                     10%

                      0%
                       Antithrombotic   Statin   ACE-I/ ARB   Thiazides




UCLA Stroke Center
PROTECT - Day 90 Medication Compliance Rates

                 Overall Compliance Rate
                 Compliance Rate in Patients without specific contraindications
                                      100 100    94 96                 94
                             100
                                                                  81                83
                              80
  Percentage




                                                                              62
                             60
                             40
                             20
                              0
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        UCLA Stroke Center
                                                                                         Ovbiagele et al 2003
PROTECT Day 90 Compliance Rates with Lifestyle
        Interventions and all 8 Goals

                        100                                          88             91
                         90             84           84
                                                                                                    78
                         80
                         70
                         60
                         50
  Percentage




                         40
                         30
                         20
                         10
                          0
                                                 e                e
                               n ess          enc            e nc             tio
                                                                                  n
                                                                                            oa
                                                                                               ls
                              e              r              r               a
                           ar           d he           d he             ess              Tg
                      1 Aw           eA           etA              coC              TE
                                                                                       C
                                    s           Di              ac
                    91         e rci                          b                RO
                           Ex                             To             l8
                                                                            P
                                                                        l
                                                                   w /a
                                                              nce
                                                        p lia
        UCLA Stroke Center                         C om
                                                                                                     Ovbiagele et al 2003
                     Clinical Significance
  Initiation and maintenance of proven medical and
  behavioral interventions in order to reduce future
  strokes
  Simultaneous reduction in occurrence of myocardial
  infarction and peripheral arterial occlusion
  Active involvement of the patient, family and primary
  care physician
  Applicability at the community hospital level

UCLA Stroke Center
What’s Involved in Starting a Hospital Based
            Treatment Program

•   Collect baseline data or use existing data source
     » E.g. collect data with discharge nurse, medical student, etc.
•   Appoint team to develop treatment algorithm,
    preprinted orders, discharge forms
•   Present at lectures and staff in-services
     » present results
     » review successes and failures
     » lead discussion regarding recommendations on protocol
       improvement
•   Revise protocol to close Gaps
•   Communicate revisions to key departments
•   Repeat cycle every quarter = CQI
UCLA Stroke Center
Continuous Quality Improvement
        (CQI) Process
                     Assess CVD Treatment
                             Rates




 Implement Refined                           Evaluate
      Protocol                              Assessment




                       Refine Protocol
                             Hospital Based
Continuous Quality Improvement (CQI) Process


                              Mobilize GWTG Initiative
                              •Establish “Buy In”
                              •Identify “Champions”
                              •Build Team




                                                            Plan & Prep Program
 Monitor & Support                                          •Attend CME Program
•Collect & Report f/u Data                                  •Develop Hospital Plan
•Review & Improve Process                                   •Assign Roles & Responsibilities




                              Implement Program
                                  •Establish D/C Protocol
                                  •Collect Baseline Data
                                  •Obtain consensus
What is the AHA“Get With the Guidelines -
           Stroke” Program ?

Implemented by AHA Affiliates/Volunteers who will mobilize
  advocacy networks at the Affiliate level to:
• Implement CME-driven educational programs
• Provide workshops for dissemination of guidelines
• Develop care maps
• Formalize a national discharge protocol
• Implement discharge protocols in hospital setting
• Identify best practices for AHA recognition awards
• Develop and disseminate reports and publications
• Measure changes and report outcomes data
• Drive impact into communities



UCLA Stroke Center
           GWTG Tools and Resources

•   AHA/ASA Guidelines
•   AHA National Discharge Protocol/Discharge Form
    Template
•   Care maps - ED, Ward, etc.
•   CME programs
•   AHA National teleconferences
•   Public Service Announcements
•   National and regional advocates

    UCLA Stroke Center
http://www.americanheart.org/.
     Stroke PROTECT ~ Summary

•   The PROTECT Program has demonstrated for the
    first time that Stroke risk-factor modification and
    treatment can be systematically integrated into the
    treatment provided during stroke hospitalization
    utilizing existing resources and medical personnel

•   PROTECT appears to be considerably more
    effective than conventional guidelines and care.


UCLA Stroke Center
            Formation of the Platelet Plug
                   1   Adhesion                                   3   Aggregation
                                                      Activated Gpllb/llla
                                                                             Fibrinoge
                                                                             n

                Platelets       von Williebrand
                               Factor/Gplb bind

 Collagen
Gpla/lla bind
                            Lipid
                            core


                   2   Activation                                 4   Platelet Plug
Thrombin
     ADP

     5 HT

     TXA2




Kumar A et al. Exp Opin Invest Drugs. 1997;6:1257–1267.
Oral Antiplatelet Agents
Different Mechanisms of Action
      clopidogrel bisulfate                          ADP              dipyridamole
                                                                      dipyridamole
          ticlopidine HCl                                         ADP         phosphodiesterase


                                                   ADP


                                                                            Collagen
    Gp IIb/IIIa                                          Activation         Thrombin
   (Fibrinogen                                                                TXA2
    receptor)                              COX

                                            TXA2
                    aspirin

ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.
Schafer AI. Am J Med. 1996;101:199-209.
  Beyond Aspirin: Antiplatelet Agents for
         Secondary Prevention


• Clopidogrel

• Aspirin/ ER Dipyridamole

• Aspirin + Clopidogrel

UCLA Stroke Center
     Clopidogrel: CAPRIE Study

• Clopidogrel 75 mg vs aspirin 325 mg
• 19,185 patients with recent vascular event
• Primary endpoint: stroke, MI, vascular death
• Mechanism: inhibition of platelet ADP
 receptor
CAPRIE Study
Efficacy of Clopidogrel in Primary Analysis
MI, Ischemic Stroke, or Vascular Death (N=19,185)
                                                                                                 Aspirin 325 mg qd   8.7%*
         16                                                                                                         Overall
                                 Event Rate per Year                                                              Relative Risk
                                                                                             Clopidogrel 75 mg qd
                                                                                                                   Reduction1
          12
                                               5.832

           8
                                                          5.33%2

          4
                                                                               P = 0.0451

          0
               0    3     6     9     1  15 18 21 24 27                       30    33      36
                                      2
                                     Months of Follow-Up

Although the statistical significance favoring clopidogrel bisulfate over aspirin was marginal (P = 0.045, based on orall incidence of
primary outcome events: 9.78% for clopidogrel vs 10.64% for aspirin), and represents the result of a single trial that has not been
replicated, the comparator drug, aspirin, is itself effective (vs placebo) in reducing cardiovascular events in patients with recent MI or
stroke. Thus, the difference between clopidogrel and placebo, although not measured directly, is substantial.
    Outcome Events of the Primary Analysis*

                                                      Clopidogrel           Aspirin
                                                        (n=9599)           (n=9586)

      Ischemic stroke                                          438           461
      (fatal or not)
      MI (fatal or not)                                        275           333
      Other Vascular Death                                     226           226

      Total                                                    939          1020


*For the composite end point of MI, ischemic stroke, and vascular death.
 PLAVIX Prescribing Information.
                     Clopidogrel

•   No increased risk of neutropenia
•   Less bleeding risk vs. aspirin




UCLA Stroke Center
      TTP and Thienopyridines
• General incidence: ~3.7/million
• Mortality with prompt treatment: 10-20%
  » 80-90% prior to plasmapheresis
• Ticlopidine incidence: ~1/1600-5000
• Clopidogrel incidence: ~1/15,000-1/100,000
        ESPS-2: Study Design

• Multicenter, randomized, double-blind trial
• 6602 patients with hx of stroke or TIA
• Primary endpoint: stroke or death at 2 yrs
• 4 tx arms: ASA (25 mg BID)
               ER-Dipyridamole (200 mg BID)
               ASA + ER-Dipyridamole
               Placebo
ESPS-2 Results: Stroke-Free Survival
                                100
  Patients Without Stroke (%)



                                95



                                90                              ASA/ER-DP
                                                                ASA
                                85                              ER-DP
                                                                Placebo
                                80
                                      6     12        18   24
                                      Time (months)
                                   ESPS-2 Results:
                  Notable Side Effects on Treatment
                          100
                                                                            Placebo
 Patients Reporting (%)




                           80                                               ASA
                                                                            ER-DP
                           60                                               ASA/ER-DP

                           40        * *        * *

                           20
                                                                   *   *
                            0
                                Headache   GI Events Dizziness   Bleeding
                                                                  Events

* Significantly associated with treatment according to factorial analysis.
    ACCP Antiplatelet Guidelines
• Acceptable options for initial therapy:
  » Aspirin (50-325 mg qd)
  » ASA + extended release dipyridamole (25-200
    mg bid)
  » Clopidogrel (75 mg qd)




                               Albers et al, Chest 2001
               Rapid and Synergistic Effect of Clopidogrel
                  on top of ASA (Healthy Volunteers)

            Mean reduction of platelet deposition compared with ASA alone
            C300+ASA vs ASA alone     C75+ASA vs ASA alone
       Mean reduction (%)                                              p=NS
       80                                 p=0.01               p<0.001
                                                               vs ASA     p<0.001
       70                                                                 vs ASA
                                    p<0.001
                                    vs ASA
       60
       50
                      p=0.03                  p=0.03
       40                                     vs ASA
       30         p=0.04
                  vs ASA
       20
       10
        0
                     Day 1               Day 1                      Day 10
      -10
                     1.5 hrs             6 hrs                      6 hrs
n=18 for all comparisons                               Cadroy Y et al Circulation 2000;101:2823–2828
                           CURE Trial Design

                           300 mg loading +
                           75 mg o.d. dose
                                                                  Clopidogrel
    Patients with                   Aspirin 75-325mg            (~6,250 patients)
   Acute Coronary
     Syndrome
                       R          3 months  double-blind treatment  12 months
(UA or MI Without ST
     elevation)
                                    Aspirin 75-325mg
                                                                       Placebo
                                                                       1 tab o.d.
                                                                   (~6,250 patients)
      Cumulative Hazard Rates for CV
 CURE
             Death/MI/Stroke
                                 0.14




                                                                 Placebo
                                 0.12
Cumulative Hazard Rates
                                 0.10
       Cumulative Hazard Rates
                                 0.08
                                 0.06




                                                                                     Clopidogrel
                                 0.04
                                 0.02




                                                                       P < 0.001
                                 0.0




                                         0
                                         0      3
                                                3            6
                                                             6                 99              12
                                                                                                12

         # of Pts                                      Months of Foll ow-up
                                                      Months of Follow-up
                   Plac                 6303   5780   4664                    3600             2388
                   Clop                 6259   5866   4779                    3644             2418
                         CURE: Benefit of Clopidogrel in
                         Patients With a History of Stroke
                                                                    RRR 26%            Placebo*
                                                                  (95% CI 0.50-1.10)   Clopidogrel*
                                      25%
                       CV Death (%)




                                                                    22.4
      MI, Stroke, or




                                      20%
                                               RRR 20%
                                             (95% CI 0.71-0.90)              17.9
                                      15%

                                      10%
                                               11.0
                                                       8.9
                                       5%

                                       0%
                                            No Previous Stroke    Previous Stroke
                                               (n=12,055)            (n=506)

*Inaddition to standard therapy (including aspirin).
Plavix® (clopidogrel bisulfate) Prescribing Information.
             CURE Study: Bleeding Results
                                                     Clopidogrel    Placebo
                                                     + Aspirin*    + Aspirin*
                                                      n=6259        n=6303
             Event                                      (%)           (%)        P Value

   Major bleeding                                           3.7       2.7        .001

      Life-threatening                                      2.2       1.8        .13

      Other major bleeding                                  1.6       1.0        .005

   Minor bleeding                                           5.1       2.4       <.001
*Other standard therapies were used as appropriate.
 Plavix® (clopidogrel bisulfate) Prescribing Information.
          Upcoming Prevention Trials
   ESPRIT
        Anticoagulants, ASA plus dipyridamole, and ASA alone
   MATCH
        Clopidogrel plus ASA combination vs clopidogrel plus placebo
         combination
   CHARISMA
        High risk prevention
        Clopidogrel +/— ASA
   Secondary Prevention of Small Subcortical Stroke
    (SPS3)
        Lacunar infarcts
        Factorial design ASA/clopidogrel
        Strokes, vascular events, cognitive decline
   PRoFESS
        ER-dipyridamole/ASA vs clopidogrel plus ASA
       Clinical Impact–Antiplatelet

   Antiplatelet therapy reduces the risk of stroke,
    MI, and vascular death in populations at risk
   Antiplatelet therapy should be applicable to
    most patients with stroke
   Combination therapy of aspirin with other
    antiplatelet agents may be more effective than
    aspirin alone
   Additional trials are underway
         How Bad is a Major Stroke?
         Elders at Risk for Stroke (1183, TTO), --Samsa et al, Am Heart J 1998



    50
    45
                      Worse than death
    40
P
e
    35                                   Equivalent to being well
r   30
c   25
e
n
    20               Equivalent to death
    15
t
    10
     5
     0


UCLA Stroke Center