Cure Aggrenox

Slide 1: 

lopidogrel in nstable Angina to Prevent ecurrent vents

Disclaimer : 

Disclaimer This slide kit presents new data to support the rationale for the use of ADP receptor antagonists for unapproved indications. The slide kit has been prepared for medical and scientific purposes. It contains information on a use that is not approved by the FDA and should not be construed as an inducement to use clopidogrel for unapproved indications. Neither Sanofi-Synthelabo Inc., nor Bristol-Myers Squibb Company, nor the partnership recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

Plavix® (clopidogrel bisulfate)Indication : 

Plavix® (clopidogrel bisulfate) Prescribing Information. Please see full prescribing information, available here. Plavix® (clopidogrel bisulfate)Indication Clopidogrel is indicated for the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent myocardial infarction, recent stroke, or established peripheral arterial disease.

Plavix® (clopidogrel bisulfate) : 

Plavix® (clopidogrel bisulfate) Prescribing Information. Please see full prescribing information, available here. Plavix® (clopidogrel bisulfate) Contraindications PLAVIX is contraindicated in patients with active pathologic bleeding such as peptic ulcer or intracranial hemorrhage. As with other antiplatelet agents, PLAVIX should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other drug therapy. As part of the worldwide postmarketing experience with PLAVIX, suspected cases of thrombotic thrombocytopenic purpura (TTP) have been reported at a rate of about 4 cases per million patients exposed. See WARNINGS. In CAPRIE, the most common clinically important side effects were pruritus, purpura, diarrhea, and rash; infrequent events included intracranial hemorrhage (0.4%) and severe neutropenia (0.04%).

Rationale : 

1. Yusuf et al for the OASIS Registry Investigators. Lancet. 1998;352:507-514. 2. Alexander et al on behalf of the PURSUIT Investigators. Am J Cardiol. 1999;83:1147-1151. 3. The SYMPHONY Investigators. Lancet. 2000;355:337-345. 4. Cannon et al for the OPUS-TIMI 16 Investigators. Circulation. 2000;102:149-156. Rationale Despite treatment with aspirin and heparin, the incidence of MI and CV death during hospitalization remains high at 6-8%1 Long term, the incidence of these events remains high at 6-8% per year1 The majority of patients (up to 80%) who enter the hospital with acute coronary syndrome (ACS) are already on aspirin therapy2 The negative findings of the oral GP IIb/IIIa’s underscores the need for alternative strategies to treat ACS 3,4

Study Objectives : 

CURE Study Investigators. Eur Heart J. 2000;21:2033-2041. Study Objectives Primary Evaluate the early and long-term efficacy of clopidogrel vs placebo, both given in addition to aspirin (ASA) and other standard therapies, in preventing ischemic complications in patients with ACS without ST-segment elevation (unstable angina or non-ST-segment elevation MI) Secondary Evaluate the safety of clopidogrel in addition to ASA therapy in patients with ACS

Study Design : 

Clopidogrel 75 mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 6-Month Visit 9-Month Visit 12-Monthor Final Visit 3-Month Visit Discharge Visit 1-Month Visit Patients with Acute CoronarySyndrome (unstable angina or non–ST-segment elevation MI) R Placebo loading dose R = Randomization.* In addition to other standard therapies. The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Study Design 3 months £ double-blind treatment £ 12 months Clopidogrel 300 mg loading dose

Key Inclusion Criteria : 

1. Data on file, Sanofi-Synthelabo Inc.2. CURE Study Investigators. Eur Heart J. 2000;21:2033-2041. Key Inclusion Criteria Age ³ 21 years1 Suspected UA or NSTEMI (no ST  ³ 1.0 mm)2 Presentation £ 24 hours after onset of symptoms2 ECG changes compatible with ischemia or elevated cardiac enzymes or troponin I or T ³ 2 x ULN2

Key Exclusion Criteria : 

1. CURE Study Investigators. Eur Heart J. 2000;21:2033-2041. 2. Data on file, Sanofi-Synthelabo Inc. Key Exclusion Criteria NYHA Class IV heart failure1 Uncontrolled hypertension2 Current use of oral anticoagulants, other antiplatelet agents (including clopidogrel or ticlopidine), or NSAIDs with intention for long-term treatment2 IV GP IIb/IIIa inhibitor within 3 days2 PCI or CABG within 3 months1 History of severe thrombocytopenia or neutropenia2 At high risk for bleeding1 Contraindications to antithrombotic or antiplatelet therapy1

Outcome Definitions : 

Outcome Definitions MI: At least two of the following criteria: chest pain, ECG changes, elevation of cardiac markers or enzymes (troponins, CK, CK-MB) Stroke: Neurological deficit ³ 24 hrs (CT/MRI encouraged) CV Death: Includes any death for which there was no clearly documented non-CV cause Refractory Ischemia: In-hosp: recurrent ischemia on max med Rx + ECG changes + intervention £ 1 day After discharge: Rehosp for UA with ECG changes Severe Ischemia: Changes similar to in-hospital refractory ischemia, but no intervention Recurrent Angina: All other ischemic chest pain in hospital The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

Efficacy Analyses : 

Efficacy Analyses First Primary End PointFirst occurrence of any component of the cluster of: Myocardial infarction Stroke (ischemic, hemorrhagic, or of uncertain type) Cardiovascular death Second Primary End PointFirst occurrence of any component of the cluster of: Myocardial infarction Stroke (ischemic, hemorrhagic, or of uncertain type) Cardiovascular death Refractory ischemia The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

Baseline Characteristics : 

Age (mean) 64.2 64.2 Mean time from pain onset to randomization (hrs) 14.1 14.2 Mean heart rate (beats/min) 73.0 73.2 Mean systolic BP (mm Hg) 134.1 134.4 Female (%) 38.3 38.7 Diagnosis at entry Unstable angina (%) 74.9 74.9 Non–ST-segment elevation MI (%) 25.1 25.1 ECG abnormalities (%) 93.9 93.7 Placebo N = 6303 Clopidogrel N = 6259 Baseline Characteristics The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

Patient History : 

History of MI 32.0 32.4 CABG surgery/PTCA 18.1 17.7 Stroke 3.7 4.4 Heart failure 7.8 7.4 Hypertension 57.8 59.9 Diabetes 22.8 22.4 Current or former smoker 60.9 60.6 PlaceboN = 6303(%) ClopidogrelN = 6259(%) The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Patient History

ECG Abnormality Type : 

History Abnormal ECG 93.9 93.7 ST-segment dep  1 mm 42.0 42.2 ST-segment elevation  1 mm 3.2 3.2 Major T-wave inversion 25.9 25.4 Other T-wave inversion 11.3 11.5 Other abnormalities 10.9 10.7 Placebo(%) Clopidogrel(%) The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. ECG Abnormality Type

Medications After Randomization : 

Aspirin 99.9 99.9 Heparin (UFH, LMWH) 92.4 92.4 Beta-blockers 83.5 84.1 Calcium-channel blockers 48.7 49.8 ACE inhibitors 61.5 61.9 Lipid-lowering agents 64.4 64.5 Placebo(%) Clopidogrel(%) Data on file, Sanofi-Synthelabo Inc. Medications After Randomization

Primary End Point – MI/Stroke/CV Death : 

Clopidogrel + ASA* 3 6 9 Placebo + ASA* Months of Follow-Up P = 0.00009† N = 12,562 0 12 * In addition to other standard therapies.† Data on file, Sanofi-Synthelabo Inc. The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Primary End Point – MI/Stroke/CV Death 20% Relative RiskReduction

MI/Stroke/CV Death Within 30 Days : 

Clopidogrel + ASA* 10 20 30 Placebo + ASA* Days of Follow-Up 0 P = 0.003 N = 12,562 * In addition to other standard therapies. The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. MI/Stroke/CV Death Within 30 Days 21% Relative RiskReduction

Main Efficacy Results – Primary End Point : 

MI, stroke, CV death(primary end point) 11.4% 9.3% 20% 0.00009† MI 6.7% 5.2% 23% STEMI (Q-wave MI) 3.1% 1.9% 40% Stroke 1.4% 1.2% 14% CV death 5.5% 5.1% 7% Relative Risk Reduction P value Outcome Placebo + ASA*N = 6303 Clopidogrel + ASA*N = 6259 * In addition to other standard therapies. † Data on file, Sanofi-Snythelabo Inc. The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Main Efficacy Results – Primary End Point

Main Efficacy Results – Second Primary End Point : 

Relative Risk P value End Point Placebo + ASA* Clopidogrel + ASA* Main Efficacy Results – Second Primary End Point * In addition to other standard therapies.‡ Not significant.§ Secondary end points. Second Primary End Point 18.8% 16.5% 14% P = 0.0005† Refractory ischemia 9.3% 8.7% 7% NS‡ Refractory ischemiain hospital 2.0% 1.4% 32% P = 0.007 Refractory ischemia after discharge 7.6% 7.6% 1% NS‡ Severe Ischemia§ 3.8% 2.8% 26% P = 0.003 Recurrent Angina§ 22.9% 20.9% 9% P = 0.01 Heart Failure§ 4.4% 3.7% 18% P = 0.03 † Data on file, Sanofi-Synthelabo Inc.The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

Beneficial Outcomes With Clopidogrel in Various Subgroups : 

Overall 12562 9.3 11.4 Associated MI 3283 11.3 13.7 No associated MI 9279 8.6 10.6 Male sex 7726 9.1 11.9 Female sex 4836 9.5 10.7 £65 yr old 6354 5.4 7.6 > 65 yr old 6208 13.3 15.3 ST-segment deviation 6275 11.5 14.3 No ST-segment deviation 6287 7.0 8.6 Enzymes elevated at entry 3176 10.7 13.0 Enzymes not elevated at entry 9386 8.8 10.9 Diabetes 2840 14.2 16.7 No diabetes 9722 7.9 9.9 Low risk 4187 5.1 6.7 Intermediate risk 4185 6.5 9.4 High risk 4184 16.3 18.0 History of revascularization 2246 8.4 14.4 No history of revascularization 10316 9.5 10.7 Revascularization after randomization 4577 11.5 13.9 No revascularization after randomization 7985 8.1 10.0 Placebo + ASA* Characteristic No. ofPatients Clopidogrel + ASA* Percentage of Patients with Event Placebo Better Clopidogrel Better Relative Risk (95% CI) 1.2 1.0 0.8 0.6 0.4 * In addition to other standard therapies. The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Beneficial Outcomes With Clopidogrel in Various Subgroups

Beneficial Outcomes With Clopidogrel in Addition to Other Standard Therapies : 

Heparin/LMWH No 950 4.9 7.8 Yes 11612 9.7 11.7 Aspirin < 100mg 1927 8.5 9.7 100-200mg 7428 9.2 10.9 > 200 mg 3201 9.9 13.7 IV GP IIb/IIIa No 11739 8.9 10.8 Yes 823 15.7 19.2 Beta-blockers No 2032 9.9 12.0 Yes 10530 9.2 11.3 ACE Inhibitors No 4813 6.3 8.1 Yes 7749 11.2 13.5 Lipid-lowering No 4461 10.9 13.1 Yes 8101 8.4 10.5 PTCA/CABG No 7977 8.1 10.0 Yes 4585 11.4 13.8 * In addition to other standard therapies. Data on file, Sanofi-Synthelabo Inc. Placebo+ASA* Concomitant N Clopidogrel+ ASA* Placebo Better Clopidogrel Better Relative Risk (95% CI) 0.4 0.6 0.8 1.0 1.2 Medication Beneficial Outcomes With Clopidogrel in Addition to Other Standard Therapies

Thrombolytic and IV GP IIb/IIIa Inhibitor Use After Randomization : 

Relative RiskReduction P value Placebo + ASA*N = 6303 Clopidogrel + ASA*N = 6259 Thrombolytics 2.0% 1.1% 43% 0.43-0.76 < 0.001 IV GP IIb/IIIa Inhib 7.2% 5.9% 18% 0.72-0.93 0.003 CI * In addition to other standard therapies. The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Thrombolytic and IV GP IIb/IIIa Inhibitor Use After Randomization

Definition of Bleeding : 

The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Definition of Bleeding Bleeding was defined as “Major” or “Minor” Major bleeding was defined as follows: life-threatening: fatal, symptomatic intracranial hemorrhage, leading to a drop in hemoglobin of at least 5 g/dL, significant hypotension requiring IV inotropes, requiring surgical intervention, or requiring transfusion of 4 or more units of blood non-life-threatening: substantially disabling, intraocular bleeding leading to vision loss, or requiring at least 2 units of blood Minor any other bleeds that led to interruption of study medication

Bleeding Results : 

Placebo + ASA*N = 6303 Clopidogrel + ASA*N = 6259 Major bleeding 2.7% 3.7% † Life-threatening bleeding 1.8% 2.2% ‡ Non–life-threatening bleeding 0.9% 1.5% § Minor bleeding 2.4% 5.1% End Point * In addition to other standard therapies.† P = 0.001; ‡ P = NS; § P = 0.002;  P < 0.001. The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Bleeding Results

Life-Threatening Bleeding : 

Life-Threatening 1.8 2.2 Fatal 0.2 0.2 5 g/dL drop hemoglobin 0.9 0.9 Hypotension-inotropic therapy 0.5 0.5 Surgery required 0.7 0.7 Hemorrhagic stroke 0.1 0.1  4 Blood units 1.0 1.2 Placebo + ASA*N = 6303 (%) Clopidogrel + ASA*N = 6259 (%) * In addition to other standard therapies. The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Life-Threatening Bleeding

Major Bleeding in IV GP IIb/IIIa Antagonists ACS Trials vs CURE: Within 30 Days : 

Active* Diff Trial N Placebo* CURE: 12562 1.5% 2.0% +0.5% IV GP IIb/ IIIa Trials: PRISM-PLUS 1915 0.8% 1.4% +0.6% PURSUIT 9375 9.1% 10.6% +1.5% CAPTURE 1265 1.9% 3.8% +1.9% * In addition to other standard therapies including aspirin and heparin. The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-97.The PURSUIT Trial Investigators. N Engl J Med. 1998;339:436-443.The CAPTURE Investigators. Lancet. 1997;349:1429-1435. Major Bleeding in IV GP IIb/IIIa Antagonists ACS Trials vs CURE: Within 30 Days

Conclusions : 

Conclusions In the long-term management of patients with ACS (unstable angina/NSTEMI), clopidogrel in addition to aspirin: demonstrated a 20% relative risk reduction in MI, stroke or cardiovascular death with long-term use* (P = 0.00009)† the benefits were demonstrated early (within hours) and continued long term (up to 12 months) the benefits were seen in addition to other standard therapies, including ACEIs, lipid-lowering medication, and beta-blockers Minor bleeding was increased, but there was no increase in life-threatening bleeds (including intracranial bleeds) * Up to 12 months.† Data on file Sanofi-Synthelabo Inc. The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

Mechanism of Action - Aspirin : 

Mechanism of Action - Aspirin

Slide 29: 

Aspirin Efficacy vs Placebo in Patients With Stroke or TIA* Johnson, E.S. et al., Arch Intern Med, 1999; 159: 1248-1253 * Endpoint: stroke, MI, or vascular death.

ASA/DP Capsule : 

ASA/DP Capsule

Odds Reduction in Nonfatal Stroke for 9 of the Original 14 Trials : 

Odds Reduction in Nonfatal Stroke for 9 of the Original 14 Trials Wilterdink, J.L. and Easton, J.D. Arch Neurol, 1999; 56:1087-1092

Slide 32: 

Ingelheim, Germany Privately held Boehringer Ingelheim Pharmaceuticals, Inc U.S. subsidiary in Ridgefield, CT Among top 20 pharmaceutical companies worldwide

Slide 33: 

Leader in stroke and cardiovascular disease Manufactures and distributes t-PA outside of U.S. and Canada for myocardial infarction Current research and development: myocardial infarction unstable angina stroke pulmonary medicine oncology

Aggrenox : 

Aggrenox Combination of extended-release dipyridamole and aspirin Secondary stroke prevention in patients with previous stroke or TIA FDA Approval - November 23, 1999 Available early January Competitively priced $1 million grant to NSA - TIA initiative

AHA Guidelines - Antithrombotic Agents in Patients with TIAs : 

AHA Guidelines - Antithrombotic Agents in Patients with TIAs Event Recommended Therapy Therapeutic Options TIA (atherothrombotic) ASA 50-325 mg/d ER-DP 200mg+ASA 25mg BID Clopidogrel 75mg/d Ticlopidine 250mg BID ASA 50-1300mg/d TIA (atherothrombotic) and ER-DP 200mg+ASA 25mg BID Ticlopidine 250mg BID aspirin-intolerant* or if Clopidogrel 75mg/d Warfarin (INR 2-3) TIA occurs during ASA ASA 50-1300 mg/d therapy# TIA (cardioembolic) Warfarin target INR 2.5 (range 2-3) ASA 50-325mg/d (if contraindications to warfarin) *Neither ER-DP+ASA or ASA alone is recommended for patients who are allergic to aspirin or unable to take low-dose aspirin #The recommended antithrombotic agents have not been specifically tested in patients who have experienced a TIA during ASA therapy

Risk Factor ManagementAmerican Heart Association TIA Guidelines : 

Risk Factor ManagementAmerican Heart Association TIA Guidelines Hypertension should be treated to maintain SBP<140 and DBP< 90, if diabetes, then maintain BP<130/85 Discontinue cigarette smoking Eliminate excessive alcohol use Treat hyperlipidemia with AHA diet and statins with goal LDL<100mg/dL Fasting blood glucose levels<126mg/dL Physical activity Do NOT recommend discontinuation of postmenopausal estrogen replacement therapy

A Pharmacoeconomic Model of Antiplatelet Therapy for Secondary Prevention of Stroke : 

A Pharmacoeconomic Model of Antiplatelet Therapy for Secondary Prevention of Stroke

Slide 38: 

Objective: To calculate the cumulative cost and cost-effectiveness of ASA/ER-DP (Aggrenox) and Clopidogrel (Plavix) compared with aspirin for secondary stroke prevention. Perspective: Payer (government or private insurer) Cohort: 1000 survivors of an initial stroke Time Frame: Two years Economic Measure: Cost per Stroke Averted

Slide 39: 

Baseline stroke recurrence rates* First year post-stroke: 13.2% Second year post-stroke: 6.7% Efficacy Rates Aspirin vs Placebo, Meta-analysis1: 15% Aggrenox vs. Aspirin, ESPS-22: 23.1% Plavix vs Aspirin, CAPRIE3: 8% * Burn et al. Long-term risk of recurrent stroke after a first-ever stroke. The Oxfordshire Community Stroke Project. Stroke 1994;25:333-337. 1Johnson ES, et al. A metaregression analysis of the dose-response effect of aspirin on stroke. Arch Intern Med 1999;159:1248-1253. 2Diener HC, et al. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1-13. 3CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39.

Cost Data : 

Cost Data Estimates for the cost of stroke were obtained from a published study using Medicare data 20% sample of Medicare patients aged 65 or older with a primary diagnosis for stroke Two-year survival and cost of first and recurrent strokes Direct cost of stroke estimate included: Acute care hospitalizations Home health care Rehabilitation hospitalizations Hospital outpatient care Physician services (e.g., office visits) Durable medical equipment Skilled nursing facility (SNF) care Non-SNF nursing home care Outpatient drug utilization Source: Samsa et al. Epidemiology of recurrent cerebral infarction: A Medicare claims-based comparison of first and recurrent strokes on 2-year survival and cost. Stroke 1999;30:1340-1349.

Cost Data : 

Cost Data 1 Red Book for Windows. Vol 11, Micromedex, 1999 2 Data on file, Boehringer Ingelheim Pharmaceuticals, Inc.

Results - Cost Effectiveness Ratio : 

Results - Cost Effectiveness Ratio The results of the analysis are expressed in terms of a cost-effectiveness ratio: Cost per Stroke Averted = Benchmark for cost-effectiveness of stroke therapies: Cost-effectiveness ratio of  $50,000* Two-Year Incremental Cost per Stroke Averted (1999 US$) Difference in total cost (Agg - ASA) Difference in number of strokes prevented (Agg-ASA) * Holloway RG, et al. A systematic review of cost-effectiveness research of stroke evaluation and treatment. Stroke 1999;30:1340-1349.

Conclusions : 

Conclusions Aggrenox is a cost-effective alternative to aspirin for secondary stroke prevention Incremental cost of $28,472 per stroke averted Aggrenox prevents an additional 33 strokes per 1000 patients compared with aspirin Plavix is NOT a cost-effective alternative to aspirin for secondary stroke prevention Incremental cost of $161,316 per stroke averted Plavix prevents an additional 11 strokes per 1000 patients compared with aspirin Viable alternative for aspirin-sensitive patients