C lopidogrel for H igh A therothrombotic R isk and I schemic S tabilization, M anagement and A voidance ( 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 16 ASA 12 8 Clopidogrel 4 0 0 3 6 9 12 15 18 21 24 Months of follow-up 27 30 33 36 *MI, ischemic stroke or vascular death † Intent-to-treat analysis (n=19,185)

CAPRIE Steering Committee.

Lancet

1996; 348: 1329 –1339.

8.7% † RRR (p=0.043)

CAPRIE: Clopidogrel Superior to ASA in Sub-Population with Prior CABG

1, 2 RRR 36.3% p=0.004

10 8 2 0 6 4 RRR 8.7% p=0.043

5.8% 5.3% 9.1% 5.8% ASA Clopidogrel All CAPRIE (n=19,185) 1 Prior CABG (n=1480) 2 *MI, ischemic stroke, vascular death

1. CAPRIE Steering Committee.

Lancet

2. Bhatt DL et al.

Circulation

1996; 348: 1329 –1339.

2001; 103: 363  368.

CAPRIE: Clopidogrel Provided Amplified Benefit in Patients with Diabetes

1 38 † 21 † p=0.106

9 † p=0.042

25 21.5% 20 p=0.096

17.7% 15.6% 17.7% ASA Clopidogrel 15 12.7% 11.8% 10 5 0 Patients without diabetes (n=15,233) Patients with diabetes (n=3866) Patients treated 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 Benefit in Patients with High Vascular Risk

1 RRR 14.9% p=0.045

12 10 RRR 8.7% p=0.043

10.2% 8.8% 8 6 4 5.8% 5.3% 2 0 All CAPRIE patients (n=19,099) Prior history of major acute event (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.

ASA Clopidogrel

CURE: Early and Long-Term Benefits of Clopidogrel in ACS Patients

1 0.14

0.12

0.10

0.08

0.06

0.04

0.02

0 0 3 Placebo † (n=6303) 6 Months of follow-up Clopidogrel † (n=6259) 9 12 20% RRR p <0.001

*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 Patients

1 4.9% 5.0

3.7% 4.0

3.0

3.0% 2.8% 3.4% Placebo* Clopidogrel* 1.9% 2.0

1.0

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

15 MI, stroke, or death – ITT population Placebo* Clopidogrel* 11.5% 10 8.5% 27% RRR P=0.02

5 0 0 3 6 9 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.

12

CHARISMA: Design

Study Objectives

1

•

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 treatment 2

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

Low dose ASA 75



162 mg/day Clopidogrel 75 mg/day (n=7802) Patients age events ≥ 45 years at high risk of atherothrombotic R (n=15603) Double-blind treatment up to 1040 primary efficacy events* 1-month visit Low dose ASA 75



162 mg/day 3-month visit Visits every 6 months Placebo 1 tablet/day (n=7801) Final 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 minor or or one major and two 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 definition intracranial hemorrhage (ICH) 1 ), including fatal bleeding or

Bhatt DL, Topol EJ, et al.

Am Heart J

2004; 148: 263 –268.

1 GUSTO 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.

1 GUSTO 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 Event

1 Ischemic event MI Stroke TIA PAD Median duration (months) 23.3

3.5

2.7

23.3

1. Bhatt DL, Fox K, Hacke W, et al.

Am Heart J

2005; 150: 401.

CHARISMA: Results

Overall Population: Baseline Characteristics

Characteristic Clopidogrel + ASA (n=7802) Age Median (range)* Female Ethnicity Caucasian Hispanic Asian Black Other Inclusion group Documented cardiovascular disease Multiple risk factors Neither criterion Smoking Status Current Former 64.0 (39-95) 29.7

80.4

10.0

5.0

3.2

1.5

77.7

21.3

1.0

20.1

48.8

*Data for age are in years, all other data expressed as percent Placebo + ASA (n=7801) 64.0 (45 29.8

79.9

10.7

5.0

3.0 1.4

78.1

20.8

1.1

20.3

48.7



93)

Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

Overall Population: Prior Medical History

Characteristic Hypertension Hypercholesterolemia Congestive heart failure Prior MI Atrial fibrillation Prior stroke TIA Diabetes PAD PCI CABG Carotid endarterectomy Peripheral angioplasty or bypass Diabetic nephropathy Clopidogrel + ASA (%) (n=7802) 73.3

73.7

6.0

34.2

3.8

24.9

12.0

42.3

22.6

22.4

19.5

5.4

11.3

12.9

Placebo + ASA (%) (n=7801) 73.9

74.2

5.9

34.9

3.7

24.3

11.9

41.7

22.7

23.1

19.9

5.2

11.0

12.9

Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

Overall Population: Concomitant Medications*

Medication ASA Open-label clopidogrel Diuretics Nitrates Calcium antagonists Beta blockers Angiotensin II receptor blockers ACE inhibitors Other antihypertensives Statins Antidiabetic medications Clopidogrel + ASA (%) (n=7802) 99.7

9.9

48.2

23.2

36.7

55.0

25.5

60.1

12.4

76.8

41.8

*Maximal frequency of usage of each agent at any time during the trial (assessed after baseline and at every follow-up visit) Placebo + ASA (%) (n=7801) 99.7

10.4

47.1

24.1

36.9

55.7

25.9

60.7

12.4

76.9

41.5

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% 6 Clopidogrel + ASA* 6.8% 4 2 RRR: 7.1% [95% CI: -4.5%, 17.5%] P=0.22 0 0 6 12 18 Months since randomization § 24 30 † First Occurrence 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) † 20 Placebo + ASA * 17.9% 15 Clopidogrel + ASA * 16.7% 10 5 RRR: 7.7% [95% CI: 0.5%, 14.4%] p = 0.04

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

Endpoint* - N (%) Clopidogrel Placebo + ASA + ASA (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 Cardiovascular Mortality Myocardial Infarction Ischemic Stroke Stroke Hospitalization ‡ 371 (4.8) 238 (3.1) 374 (4.8) 229 (2.9) 0.99 (0.86, 1.14) 0.90

1.04 (0.87, 1.25) 0.68 147 (1.9) 132 (1.7) 159 (2.0) 160 (2.1) 0.92 (0.74, 1.16) 0.48

0.82 (0.66, 1.04) 0.10

149 (1.9) 185 (2.4) 0.80 (0.65, 0.997) 0.05

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

Safety Outcome* - N (%) GUSTO Severe Bleeding Clopidogrel + ASA (n=7802) Placebo + ASA (n=7801) 130 (1.7) 104 (1.3) Fatal Bleeding Primary ICH 26 (0.3) 26 (0.3) GUSTO Moderate Bleeding 164 (2.1) 17 (0.2) 27 (0.4) 101 (1.3) RR (95% CI) 1.25 (0.97, 1.61) p value 0.09

1.44 (0.79, 2.63) 0.93 (0.54, 1.58) 0.23

0.78

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 (n=12,153) Multiple Risk Factors (n=3,284) 0.88 (0.77, 0.998) 0.046

1.20 (0.91, 1.59) Overall Population* (n=15,603) 0.93 (0.83, 1.05) 0.4

0.6

0.8

Clopidogrel Better 1.2

1.4

1.6

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.

0.20 0.22

Primary Efficacy Outcome (MI/Stroke/CV Death) by Category of Inclusion

Qualifying CAD, CVD or PAD (N=12,153) 10 RRR: 12.5% [95% CI: 0.2%, 23.2%] p=0.046

8 Placebo + ASA* 7.9% 6 4 Clopidogrel + ASA* 6.9% 2 10 8 Multiple Risk Factor (N=3,284) RRR: -20% [95% CI: -58.8%, 9.3%] p=0.20

Clopidogrel + ASA* 6.6% 6 4 2 Placebo + ASA* 5.5% 0 0 6 12 18 24 Months since randomization 30 0 0 6 12 18 24 Months since randomization 30 *All patients received ASA 75-162 mg/day

Bhatt DL. Presented at ACC 2006.

Documented CV Disease Population: Safety Results

Safety Outcome* - N (%) GUSTO Severe Bleeding Fatal Primary ICH Clopidogrel Placebo + ASA + ASA (n=6062) 95 (1.6) 19 (0.3) 19 (0.3) (n=6091) 84 (1.4) 13 (0.2) 21 (0.3) GUSTO Moderate Bleeding 128 (2.1) 79 (1.3) *Adjudicated outcomes by intention to treat analysis RR (95% CI) 1.14 (0.85, 1.52) p value 0.39

1.47 (0.73, 2.97) 0.87 (0.47, 1.60) 0.28

0.65

1.63 (1.23, 2.15) <0.001

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 8 N=9,478 Placebo + ASA 8.8 % Clopidogrel + ASA 7.3 % 6 4 2 0 0 RRR: 17.1 % [95% CI: 4.4%, 28.1%] p=0.01

6 12 18 24 Months since randomization 30

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!!!