CHARISMA set by mikesanye

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									Clopidogrel for High Atherothrombotic
   Risk and Ischemic Stabilization,
     Management and Avoidance
             (CHARISMA)
  Deepak L. Bhatt M.D., Keith A. A. Fox M.B.Ch.B., Werner Hacke M.D., Peter B.
 Berger M.D., Henry R. Black M.D., William E. Boden M.D., Patrice Cacoub M.D.,
   Eric A. Cohen M.D., Mark A. Creager M.D., J. Donald Easton M.D., Marcus D.
Flather M.D., Steven M. Haffner M.D., Christian W. Hamm M.D., Graeme J. Hankey
  M.D., S. Claiborne Johnston M.D., Koon-Hou Mak M.D., Jean-Louis Mas M.D.,
  Gilles Montalescot M.D., Ph.D., Thomas A. Pearson M.D., P. Gabriel Steg M.D.,
 Steven R. Steinhubl M.D., Michael A. Weber M.D., Danielle M. Brennan M.S., Liz
Fabry-Ribaudo M.S.N., R.N., Joan Booth R.N., Eric J. Topol M.D., on behalf of the
                            CHARISMA Investigators

                The Cleveland Clinic Foundation
CHARISMA: Rationale
    CAPRIE: Superior Efficacy of Clopidogrel
    versus ASA
                                 Patients with recent ischemic stroke, recent MI or symptomatic PAD


                                  20
                                                                                                                   8.7%† RRR
    Cumulative event rate* (%)




                                                                                                         ASA        (p=0.043)
                                  16

                                                                                                     Clopidogrel
                                  12

                                   8

                                   4

                                   0
                                       0     3     6     9    12    15    18    21   24   27   30   33   36
                                                                 Months of follow-up

                                       *MI, ischemic stroke or vascular death
                                       †Intent-to-treat analysis (n=19,185)


CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339.
    CAPRIE: Clopidogrel Superior to ASA in
    Sub-Population with Prior CABG1, 2
                                                                         RRR 36.3%
                                                                         p=0.004

                             10               RRR 8.7%                   9.1%
      Event rate/year* (%)




                             8                 p=0.043                                 ASA
                                                                                       Clopidogrel
                             6               5.8%                               5.8%
                                                       5.3%

                             4

                             2

                             0
                                             All CAPRIE                  Prior CABG
                                             (n=19,185)1                  (n=1480)2

                                  *MI, ischemic stroke, vascular death

1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339.
2. Bhatt DL et al. Circulation 2001; 103: 363368.
    CAPRIE: Clopidogrel Provided Amplified
                                     1
    Benefit in Patients with Diabetes
                                                                                           38†
                                                                           21†
                                                                                     p=0.106
                                                 9†
                           25                                      p=0.042
                                                                                   21.5%
    Event rate*/year (%)




                                       p=0.096                                                     ASA
                           20                                   17.7%                      17.7%
                                                                          15.6%                    Clopidogrel
                           15        12.7%
                                               11.8%

                           10

                            5

                           0
                                  Patients without    Patients with     Patients treated
                                diabetes (n=15,233) diabetes (n=3866) with insulin (n=1134)

                                *MI, stroke, vascular death or rehospitalization
                                for ischemic events/bleeding
                                †Number of events prevented per 1000 patients

                                per year compared with ASA

1. Bhatt DL et al. Am J Cardiol 2002; 90: 625628.
    CAPRIE: Clopidogrel Provides Amplified
                                               1
    Benefit in Patients with High Vascular Risk
                                                                                RRR 14.9%
                                                                                 p=0.045

                                12                                              10.2%
                                            RRR 8.7%
         Event rate/year* (%)




                                10                                                      8.8%      ASA
                                             p=0.043
                                 8                                                                Clopidogrel
                                            5.8%
                                 6                  5.3%

                                 4

                                2

                                0
                                            All CAPRIE                      Prior history of
                                             patients                     major acute event
                                            (n=19,099)                  (MI or ischemic stroke)
                                                                                (n=4496)
                                     *MI, ischemic stroke or vascular death;
                                     mean duration of treatment was 1.6 years

1. Ringleb PA et al. Stroke 2004; 35: 528–532.
    CURE: Early and Long-Term Benefits of
                               1
    Clopidogrel in ACS Patients
                               0.14                                              Placebo†
                                                                                 (n=6303)                       20% RRR
                               0.12
     Cumulative hazard rate*




                                                                                                                p <0.001
                               0.10

                               0.08                                                         Clopidogrel†
                                                                                            (n=6259)
                               0.06

                               0.04

                               0.02

                                 0
                                      0                   3                6                 9             12
                                                                   Months of follow-up

                                     *MI, stroke or cardiovascular death
                                     †On a background of standard therapy (including ASA)



1. The CURE Investigators. N Engl J Med 2001; 345: 494–502.
    CURE: Relationship Between Major
    Bleeding and ASA Dose in ACS Patients1
                                                                                   4.9%
                          5.0
                                                                           3.7%
                          4.0
     Incidence of major




                                                            3.4%
        bleeding (%)




                                       3.0%          2.8%
                          3.0                                                             Placebo*
                                1.9%                                                      Clopidogrel*
                          2.0

                          1.0

                           0
                                 ≤100 mg              101–199 mg              ≥200 mg
                                 (n=5320)              (n=3109)               (n=4110)

                                           ASA dose (range 75–325 mg)
                                *On a background of standard therapy (including ASA)



1. Peters RJG et al. Circulation 2003; 108: 16821687.
           CREDO: Long-Term (1 Year) Benefits
           of Clopidogrel in PCI Patients
                                    MI, stroke, or death – ITT population
                           15
                                         Placebo*
                                         Clopidogrel*
                                                                                         11.5%
       Combined endpoint




                                                                                                 27% RRR
         occurrence (%)




                           10                                                                     P=0.02
                                                                                         8.5%



                           5




                            0
                                0            3          6            9              12
                                          Months from randomization
* Plus ASA and other standard therapies.
Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420.
CHARISMA: Design
    Study Objectives1
    Primary objective:
    • To assess whether clopidogrel 75 mg daily is superior to placebo
       in preventing the occurrence of major ischemic complications
       (stroke, MI, cardiovascular death) in high-risk patients aged ≥45
       years, receiving a background of standard therapy including low-
       dose ASA

    Secondary objective:
    • To evaluate the safety of clopidogrel, in terms of the incidence of
      fatal or severe bleeding (GUSTO definition*)

       *The Global Use of Strategies To Open occluded coronary Arteries (GUSTO)
       definition for severe bleeding includes intracerebral bleeding or bleeding
       complications resulting in substantial hemodynamic compromise requiring
       treatment2

1. Bhatt DL et al. Am Heart J 2004; 148: 263–268.
2. GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
   CHARISMA Trial Design
                                                                                              Clopidogrel
                                                                                              75 mg/day
                                                                                              (n=7802)
Patients age ≥ 45
years at high risk of                             Low dose ASA 75162 mg/day
atherothrombotic
events
                     R                         Double-blind treatment up to 1040
(n=15603)                                      primary efficacy events*


                                                  Low dose ASA 75162 mg/day
                                                                                              Placebo
                                                                                              1 tablet/day
                                                                                              (n=7801)
                                    1-month          3-month   Visits every 6 months    Final visit
                                      visit            visit                           (Fixed study
                                                                                         end date)



* MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death;
 event-driven trial
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
   Inclusion Criteria
                                       Patients aged ≥45 years
                                                 with
                                    at least one of the following:

                      1) Documented coronary disease
                                  and/or
                  2) Documented cerebrovascular disease
                                  and/or
                      3) Documented symptomatic PAD
                                  and/or
     4) Two major or one major and two minor or three minor risk factors

                                      With written informed consent
                                       Without exclusion criteria

Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
   Inclusion Criteria: Patients with
   Documented CV Disease
• One or more of the following primary criteria must be satisfied:
       – Documented cerebrovascular disease:
           Previous TIA within the past 5 years
           Previous ischemic stroke within the past 5 years
       – Documented coronary disease:
           Stable angina with documented multivessel coronary disease
           History of multivessel percutaneous coronary intervention (PCI)
           History of multivessel CABG
           Previous MI
        Documented symptomatic PAD
           Current intermittent claudication with an ABI ≤0.85
           A history of intermittent claudication together with a previous
            related intervention (amputation, peripheral bypass, angioplasty,
            etc.)


Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
   Inclusion Criteria: Patients with Multiple
   Risk Factors Only
   •    For the risk factor only population, two major or one major and two
        minor or three minor atherothrombotic risk factors must be present

                                                    Major risk factors
                             Type 1 or 2 diabetes (treated with medications)
                                                 Diabetic nephropathy
                                                            ABI <0.9
                                     Asymptomatic carotid stenosis 70%
                                   Presence of at least one carotid plaque
                                                    Minor risk factors
                                       SBP 150 mm Hg (despite therapy)
                                           Primary hypercholesterolemia
                                 Currently smoking (>15 cigarettes per day)
                              Male aged 65 years or female aged 70 years

       ABI= Ankle Brachial Index

Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
   Exclusion Criteria

   •     Requirement for clopidogrel such as:
          – recent acute coronary syndrome without ST-segment elevation
          – investigator’s assessment clopidogrel required long-term

   •     Need for chronic therapy with high dose (> 162 mg/day) ASA or
         non-steroidal anti-inflammatory drug (except COX-2 inhibitors)

   •     Current use of other oral anti-thrombotic medications with
         intention for long term treatment (e.g. OAC)

   •     Planned revascularization procedure (OK after the procedure if no
         open-label clopidogrel is needed)



Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
   Primary Study Endpoints
   Primary efficacy endpoint:
   • The first occurrence of any component of the following cluster:
      – MI (Fatal or Non-fatal)
      – Stroke (Fatal or Non-fatal stroke from any cause)
      – Cardiovascular death (including hemorrhagic death)

   Primary safety endpoint:
   • Severe bleeding (GUSTO definition1), including fatal bleeding or
      intracranial hemorrhage (ICH)




Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
1GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
   Other Study Endpoints
   Principal Secondary Efficacy Endpoint:
   • First occurrence of MI (fatal or non-fatal), stroke (fatal or non-
      fatal), cardiovascular death, or hospitalization for UA, TIA or
      revascularization

   Other Efficacy Endpoints:
   • Individual components of the primary and secondary endpoints

   Other Safety Endpoints:
   • Fatal bleeding
   • Primary intracranial hemorrhage
   • Moderate bleeding (GUSTO definition) 1


Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
1GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
  Bleeding Definitions: GUSTO Criteria
  Severe bleeding:
         • Fatal bleeding
         • Primary or post-traumatic intracranial hemorrhage
         • Substantial hemodynamic compromise requiring treatment
           to sustain cardiac output

  Moderate:
        • Bleeding that required transfusion, but did not result in
          hemodynamic compromise or meet definition for GUSTO
          severe bleeding

  Minor bleeding:
         • Other bleeding, not requiring transfusion or causing
           hemodynamic compromise


GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
    Time Since Qualifying Event1


                 Ischemic event                                  Median duration
                                                                    (months)

                 MI                                                   23.3
                 Stroke                                                3.5
                 TIA                                                   2.7
                 PAD                                                  23.3




1. Bhatt DL, Fox K, Hacke W, et al. Am Heart J 2005; 150: 401.
CHARISMA: Results
   Overall Population: Baseline Characteristics
                                                    Clopidogrel + ASA   Placebo + ASA
     Characteristic                                     (n=7802)           (n=7801)
     Age
       Median (range)*                                 64.0 (39-95)      64.0 (4593)
     Female                                               29.7               29.8
     Ethnicity
       Caucasian                                          80.4              79.9
       Hispanic                                           10.0              10.7
       Asian                                              5.0               5.0
       Black                                              3.2               3.0
       Other                                              1.5               1.4
     Inclusion group
       Documented cardiovascular disease                  77.7              78.1
       Multiple risk factors                              21.3              20.8
       Neither criterion                                   1.0               1.1
     Smoking Status
       Current                                            20.1              20.3
       Former                                             48.8              48.7
     *Data for age are in years, all other data expressed as percent


Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
   Overall Population: Prior Medical History
                                                    Clopidogrel + ASA (%)   Placebo + ASA (%)
     Characteristic                                       (n=7802)               (n=7801)
     Hypertension                                           73.3                  73.9
     Hypercholesterolemia                                   73.7                  74.2
     Congestive heart failure                                6.0                   5.9
     Prior MI                                               34.2                  34.9
     Atrial fibrillation                                     3.8                   3.7
     Prior stroke                                           24.9                  24.3
     TIA                                                    12.0                  11.9
     Diabetes                                               42.3                  41.7
     PAD                                                    22.6                  22.7
     PCI                                                    22.4                  23.1
     CABG                                                   19.5                  19.9
     Carotid endarterectomy                                  5.4                   5.2
     Peripheral angioplasty or bypass                       11.3                  11.0
     Diabetic nephropathy                                   12.9                  12.9



Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
   Overall Population: Concomitant Medications*
                                                    Clopidogrel + ASA (%)   Placebo + ASA (%)
     Medication                                           (n=7802)              (n=7801)
     ASA                                                    99.7                  99.7
     Open-label clopidogrel                                  9.9                  10.4
     Diuretics                                              48.2                  47.1
     Nitrates                                               23.2                  24.1
     Calcium antagonists                                    36.7                  36.9
     Beta blockers                                          55.0                  55.7
     Angiotensin II receptor blockers                       25.5                  25.9
     ACE inhibitors                                         60.1                  60.7
     Other antihypertensives                                12.4                  12.4
     Statins                                                76.8                  76.9
     Antidiabetic medications                               41.8                  41.5
     *Maximal frequency of usage of each agent at any time during
     the trial (assessed after baseline and at every follow-up visit)


Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
    Overall Population: Primary Efficacy Outcome
    (MI, Stroke, or CV Death)†
                                       8                                              Placebo + ASA*
                                                                                           7.3%
           Cumulative event rate (%)




                                       6                                             Clopidogrel + ASA*
                                                                                            6.8%

                                       4

                                                                      RRR: 7.1% [95% CI: -4.5%, 17.5%]
                                       2                                          P=0.22

                                       0
                                           0   6          12        18          24   30
                                                   Months since randomization §


 † FirstOccurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death
 *All patients received ASA 75-162 mg/day
 §The number of patients followed beyond 30 months decreases rapidly to

 zero and there are only 21 primary efficacy events that occurred beyond
 this time (13 clopidogrel and 8 placebo)

Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
    Overall Population: Principal Secondary Efficacy
    Outcome (MI/Stroke/CV Death/Hospitalization)†
                                                                                        Placebo + ASA*
                                          20                                                17.9%
              Cumulative event rate (%)




                                                                                        Clopidogrel + ASA*
                                          15                                                  16.7%


                                          10


                                                                     RRR: 7.7% [95% CI: 0.5%, 14.4%]
                                           5
                                                                                p = 0.04

                                           0
                                               0   6          12        18         24     30
                                                       Months since randomization§
*All patients received ASA 75-162mg/day
†First Occurrence of MI, Stroke, CV Death, or Hospitalization for UA, TIA, or Revascularization

§The number of patients followed beyond 30 months decreases rapidly to
zero and there are only 38 primary efficacy events that occurred beyond
this time (23 clopidogrel and 15 placebo)
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
   Overall Population: Secondary Efficacy
   Results
                                                    Clopidogrel Placebo
                                                      + ASA      + ASA
   Endpoint* - N (%)                                 (n=7802) (n=7801)           RR (95% CI)    p value

   Principle Secondary Endpoint† 1301 (16.7) 1395 (17.9) 0.92 (0.86, 0.995) 0.04

   All Cause Mortality                               371 (4.8)   374 (4.8)    0.99 (0.86, 1.14) 0.90
   Cardiovascular Mortality                          238 (3.1)   229 (2.9)    1.04 (0.87, 1.25) 0.68
   Myocardial Infarction                            147 (1.9)    159 (2.0)    0.92 (0.74, 1.16) 0.48
   Ischemic Stroke                                  132 (1.7)    160 (2.1)    0.82 (0.66, 1.04) 0.10
   Stroke                                           149 (1.9)    185 (2.4)     0.80 (0.65, 0.997) 0.05
   Hospitalization‡                                  866 (11.1) 957 (12.3) 0.90 (0.82, 0.98) 0.02

  *Intention to treat analysis
  †First occurrence of MI (fatal or not), stroke (fatal or not), cardiovascular death
  (including hemorrhagic death), or hospitalization for UA, TIA, or a
  revascularization procedure
  ‡For UA, TIA, or revascularization
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
   Overall Population: Safety Results

                                               Clopidogrel      Placebo
                                                  + ASA          + ASA
   Safety Outcome* - N (%)                      (n=7802)        (n=7801)      RR (95% CI)       p value

   GUSTO Severe Bleeding                            130 (1.7)   104 (1.3)   1.25 (0.97, 1.61)    0.09

        Fatal Bleeding                              26 (0.3)    17 (0.2)    1.44 (0.79, 2.63)    0.23

        Primary ICH                                 26 (0.3)    27 (0.4)    0.93 (0.54, 1.58)    0.78

   GUSTO Moderate Bleeding                          164 (2.1)   101 (1.3)   1.62 (1.27, 2.08) <0.001

   *Adjudicated outcomes by intention to treat analysis
   ICH= Intracranial Hemorrhage




Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
    Primary Efficacy Results (MI/Stroke/CV
    Death) by Pre-Specified Entry Category
Population                                                                    RR (95% CI)       p value

Qualifying CAD, CVD or PAD                                                  0.88 (0.77, 0.998) 0.046
(n=12,153)

Multiple Risk Factors                                                       1.20 (0.91, 1.59)     0.20
(n=3,284)

Overall Population*                                                         0.93 (0.83, 1.05)     0.22
(n=15,603)

                               0.4 0.6 0.8                       1.2 1.4 1.6
                             Clopidogrel Better                  Placebo Better
 * A statistical test for interaction showed marginally significant
 heterogeneity (p=0.045) in treatment response for these pre-specified
 subgroups of patients

Adapted from Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
                                      Primary Efficacy Outcome (MI/Stroke/CV
                                      Death) by Category of Inclusion
                                  Qualifying CAD, CVD or PAD (N=12,153)                                                         Multiple Risk Factor (N=3,284)
                                                                                                                       10       RRR: -20% [95% CI: -58.8%, 9.3%]




                                                                                      Primary outcome event rate (%)
                        10                RRR: 12.5% [95% CI: 0.2%, 23.2%]
                                                                                                                                            p=0.20
 Primary outcome event rate (%)




                                                      p=0.046
                                                                                                                       8                          Clopidogrel + ASA*
                                  8                   Placebo + ASA*                                                                                   6.6%
                                                           7.9%
                                  6                                                                                    6

                                                                 Clopidogrel +ASA*                                     4
                                  4                                                                                                                    Placebo + ASA*
                                                                          6.9%
                                                                                                                                                              5.5%
                                  2                                                                                    2


                                  0                                                                                    0
                                      0        6     12     18       24          30                                         0        6     12     18     24      30
                                            Months since randomization                                                            Months since randomization



 *All patients received ASA 75-162 mg/day
Bhatt DL. Presented at ACC 2006.
   Documented CV Disease Population: Safety
   Results
                                                 Clopidogrel Placebo
                                                    + ASA     + ASA
   Safety Outcome* - N (%)                        (n=6062) (n=6091)          RR (95% CI)        p value

   GUSTO Severe Bleeding                             95 (1.6)    84 (1.4)   1.14 (0.85, 1.52)    0.39

        Fatal                                        19 (0.3)    13 (0.2)   1.47 (0.73, 2.97)    0.28

        Primary ICH                                  19 (0.3)    21 (0.3)   0.87 (0.47, 1.60)    0.65

   GUSTO Moderate Bleeding                          128 (2.1)    79 (1.3)   1.63 (1.23, 2.15) <0.001
   *Adjudicated outcomes by intention to treat analysis




Adapted from Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
      Primary Endpoint (MI/Stroke/CV Death) in
        Patients with Previous MI, IS, or PAD
                                                        “CAPRIE-like Cohort”
                                               10       N=9,478                               Placebo + ASA
              Primary outcome event rate (%)



                                                                                                  8.8 %
                                               8                                              Clopidogrel + ASA
                                                                                                    7.3 %

                                               6


                                               4
                                                                           RRR: 17.1 % [95% CI: 4.4%, 28.1%]
                                                                                        p=0.01
                                               2


                                               0
                                                    0   6        12      18      24      30
                                                            Months since randomization


Bhatt DL. Presented at ACC 2006.
Conclusions

• 7.1% RRR for the primary endpoint (MI/Stroke/CV

  Death) in the overall population did not reach statistical

  significance

• 7.7% RRR for the secondary endpoint which included

  hospitalizations was significant

• The overall outcome was influenced by divergent

  findings in the two main sub-groups enrolled in the trial
Conclusions

• In patients with multiple risk factors only, without
  clearly established CV disease, dual antiplatelet was
  not beneficial - excess in CV mortality as well as an
  increase in bleeding

• In patients with documented CV disease (CAD, CVD, or
  PAD) long-term clopidogrel plus ASA resulted in a
  significant 12.5% RRR in MI/Stroke/CV Death with no
  significant increase in severe bleeding compared to
  ASA alone
Clinical Implications
•   In acute setting, prior studies have shown the benefit of dual antiplatelet
    therapy for 1 year post ACS or PCI

•   For stable patients, CHARISMA suggests differential long-term effects by
    patient type:

     – NOT Recommended for Primary Prevention

     – Benefit in Secondary Prevention (CAD, CVD, or PAD)

         • CV death/MI/stroke - 10 events prevented per 1000 patients treated

         • Balanced by 2 severe GUSTO bleeds per 1000 patients treated

•   These data and future trials will help physicians decide which non-
    acute/stable patients should receive long-term dual antiplatelet therapy
THANK YOU!!!

								
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