A-1 AHA/ACC Guidelines Update in Patients with Atherosclerotic CV Disease Source: Circulation (2001) 104: 1577–79. Medication Recommendations as Supplements to Lifestyle Modification: –Lipid-lowering therapy to achieve LDL-C of <100mg/dL –Antiplatelet therapy, principally aspirin –Anti-hypertensive therapy to achieve BP of <140/90 –Hypoglycemic therapy to achieve near normal fasting glucose (HbA 1C <7%) –ACE inhibitor –Beta-blocker Medication Recommendations as Supplements to Lifestyle Modification: –Lipid-lowering therapy to achieve LDL-C of <100mg/dL –Antiplatelet therapy, principally aspirin

A-2 Sub-Optimal Usage at Discharge of CV Therapies with Proven Value Source: National Registry of Myocardial Infarction –3. 167,000 patients nationwide, July ’99 to June ’00. Includes CHD patients with no exclusions for contraindications or intolerance to these drugs.

A-3 Cook et al, (1999) Med Gen Med, OTC Aspirin Use in Coronary Heart Disease Under-utilization: Only 51% of patients with known cardiovascular disease reported they were taking aspirin or an ‘equivalent’ Mis-medication: Among patients who thought they were taking aspirin for CHD, 15% were actually taking a non-aspirin analgesic National Survey 26,976 persons >40 years of age 3818 reported prior CVD

A-4 BrandNo. of ProductsASA Doses (mg) Aspergum ® 1227 Norwich ® 2325, 500, 650 Bayer ® 1381, 325, 500 St. Joseph ® 181 Ecotrin ® 381, 325, 500 Halfprin ® 281, 162 Ascriptin ® 581, 325, 500 Bufferin ® 481, 325, 500 Adprin ® 1325 Alka-Seltzer ® 3325, 500 OTC “Aspirin Only” Products

A-5 OTC “No Aspirin” Products Tylenol ® acetaminophen Advil ® ibuprofen Aleve ® naproxen Motrin ® ibuprofen Anacin ® (aspirin-free)acetaminophen Excedrin ® (aspirin-free)acetaminophen

A-6 A typical CHD patient might be taking: –aspirin –ACE inhibitor –beta-blocker –statin A CHD patient with diabetes might also be taking: –oral anti-diabetic agents Following New AHA/ACC Guidelines Necessitates High Pill Burden

A-7 Sources: ACC/AHA Guidelines 2001, NHLBI Chartbook 2000 and Adapted from Foot et al (JACC 2000) U.S. Heart Disease Prevalence Is Projected to Double in the Next Half Century

A-8 Hypothetical 2 x 2 Factorial Pravigard (Buffered Aspirin and Pravastatin Sodium) Trial Design PlaceboPravachol Aspirin Placebo Prava+Aspirin Prava alone Aspirin alone Placebo Is Pravachol+Aspirin more effective than both Aspirin alone and Pravachol alone? Hennekens CH et al. Archives of Internal Medicine, In Press.

A-9 Trial LIPID CARE REGRESS PLAC I PLAC II Totals Number of Subjects*% on Aspirin Primary Endpoint CHD mortality CHD death & non-fatal MI Atherosclerotic progression (& events) ,617 Atherosclerotic progression (& events) *99.7% of Pravachol (pravastatin sodium) treated subjects received 40mg dose Total exposure 79,300 patient years Efficacy and Safety of Pravigard (Buffered Aspirin and Pravastatin Sodium) Based on Meta-analysis of 5 Pravachol trials Hennekens CH et al. Archives of Internal Medicine, In Press.

A-10 Contribution of Trials to Total CHD Patient Years of Exposure Total Exposure = 73,900 Patient Years LIPID 68% CARE 28% REGRESS 2% PLAC-I 1% PLAC-II 1% Hennekens CH et al. Archives of Internal Medicine, In Press.

A-11 Meta-Analysis Comparisons PlaceboPravastatin Aspirin Users Aspirin Non-Users Subgroups Randomized Groups Prava-ASA (n=5888) Prava alone (n=1436) ASA alone (n=5833) Placebo (n=1460) Model 1:Multivariate Cox proportional hazards model Model 2: Same as Model 1 except allows for trial heterogeneity: Bayesian hierarchical Hennekens CH et al. Archives of Internal Medicine, In Press.

A-12 RRR = Relative Risk Reduction Relative Risk (95% CI) RRR Prava+ASA vs ASA alone Prava+ASA vs Prava alone Fatal or Non-Fatal MI CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke Prava+ASA vs ASA alone Prava+ASA vs Prava alone 24% % % % 0.74 Prava+ASA vs ASA alone Prava+ASA vs Prava alone 29% % 0.69 Ischemic Stroke Greater Relative Risk Reduction for Pravigard (Buffered Aspirin and Pravastatin Sodium) Cox Proportional Hazards – All Trials Hennekens CH et al. Archives of Internal Medicine, In Press.

A-13 Model 1 - Absolute Event Rates Fatal and NF-MI PlaceboPravaRRR* 7.6% 8.7% 10.7% 10.8% 31.3% 19.4% * Relative risk reduction based on Cox PH model Aspirin Users Aspirin Non-Users Hennekens CH et al. Archives of Internal Medicine, In Press.

A-14 Ischemic Stroke PlaceboPravaRRR* 2.3% 3.1% 3.5% 29.2% 12.0% * Relative risk reduction based on Cox PH model Aspirin Users Aspirin Non-Users Model 1 - Absolute Event Rates Hennekens CH et al. Archives of Internal Medicine, In Press.

A-15 CHD Death, NF-MI, CABG, PTCA, Ischemic Stroke PlaceboPravaRRR* 22.3% 23.8% 28.5% 27.3% 24.2% 15.4% * Relative risk reduction based on Cox PH model Aspirin Users Aspirin Non-Users Model 1 - Absolute Event Rates Hennekens CH et al. Archives of Internal Medicine, In Press.

A Year Model 2 – Hierarchical, Random Effects Fatal or Non-Fatal MI Placebo Prava alone ASA alone Prava+ASA Cumulative Proportion of Events Hennekens CH et al. Archives of Internal Medicine, In Press.

A Model 2 – Hierarchical, Random Effects Ischemic Stroke Only ASA alone Prava+ASA Year Cumulative Proportion of Events Prava alone Placebo Hennekens CH et al. Archives of Internal Medicine, In Press.

A-18 Reported Safety of the Combination in the Pravachol (pravastatin sodium) Trials No increased incidence of –CK abnormalities –Liver Function Test abnormalities –Gastrointestinal bleeds –Hemorrhagic stroke Hennekens CH et al. Archives of Internal Medicine, In Press.

A-19 Important Safety Information - Pravachol (pravastatin sodium) Pravachol is contraindicated for patients who are pregnant or nursing and in the presence of active liver disease or unexplained persistent transaminase elevations. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of creatine phosphokinase (CPK). Patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. The risk of myopathy during treatment with another HMG-CoA reductase inhibitor is increased with concurrent therapy with erythromycin, cyclosporine, niacin, or fibrates. The combined use of Pravachol and fibrates should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. It is recommended that liver function tests be performed prior to initiating therapy, prior to increasing the dose, and when otherwise clinically indicated. If a patient develops increased transaminase levels, or signs and symptoms of liver disease, more frequent monitoring may be required. Withdrawal of Pravachol is recommended if an increase in AST or ALT of >3x ULN persists. Pravachol is well tolerated. The most common adverse events are rash, fatigue, headache, and dizziness.

A-20 Important Safety Information - Aspirin Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products, in patients with the syndrome of asthma, rhinitis, and nasal polyps, and in nursing mothers. Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye’s syndrome with concomitant use of aspirin in certain viral illnesses. Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. Aspirin can inhibit platelet function leading to an increase in bleeding time. Avoid using aspirin in patients with severe renal failure, severe hepatic insufficiency or a history of active peptic ulcer disease. Patients with sodium-retaining states, such as congestive heart failure or renal failure, should avoid sodium-containing buffered aspirin preparations because of their high sodium content. Pregnant women should only take aspirin if clearly needed, use during the third trimester of pregnancy should be avoided. GI side effects include stomach pain, heartburn, nausea, vomiting, and gross GI bleeding.

A-21 Drug Interactions  Polypharmacy may increase the potential for drug-drug interactions.  The CYP450 3A4 pathway metabolized more than 50% of all prescription drugs.  Neither Pravachol nor aspirin are metabolized by CYP450 3A4 to a clinically significant extent.

A-22 Cardiac Hospital Atherosclerosis Management Program (CHAMP) Population:  Patients with acute myocardial infarction Methods:  University-associated teaching hospital  Before CHAMP (1992 to 1993): no specific treatment algorithms used  During CHAMP (1994 to 1995): physician decision based on national clinical guidelines (ACC/AHA, NCEP Adult Treatment Panels I and II) Endpoints:  Treatment rates and clinical outcome were compared between the 2 groups Population:  Patients with acute myocardial infarction Methods:  University-associated teaching hospital  Before CHAMP (1992 to 1993): no specific treatment algorithms used  During CHAMP (1994 to 1995): physician decision based on national clinical guidelines (ACC/AHA, NCEP Adult Treatment Panels I and II) Endpoints:  Treatment rates and clinical outcome were compared between the 2 groups Fonarow GC et al. Am J Cardiol 2001;87:819–22.

A-23 CHAMP: Treatment Rates Fonarow GC et al. Am J Cardiol 2001;87:819–822. P<0.01, pre-versus post-CHAMP at discharge and at 1 year Discharge1 yearDischarge1 year ASA78%68% 92% 94%  -blocker12%18%61%57% Statin6%10% 86%91% Pre-CHAMPPost-CHAMP 1992/ /1995 (n=256)(n=302) Pre-CHAMPPost-CHAMP 1992/ /1995 (n=256)(n=302)

A-24 Recurrent MI20 (7.8%)10 (3.1%)* Heart Failure12 (4.7%) 8 (2.6%) Hospitalization38 (14.8%)23 (7.6%)* Sudden Death 3 (1.2%) 2 (0.6%) Cardiac Mortality13 (5.1%) 6 (2.0%)* Noncardiac Mortality 2 (0.8%) 2 (0.6%) Total Mortality18 (7.0%)10 (3.3%)* *p < 0.05 Pre-CHAMPPost-CHAMP 1992/ /1995 (n=256)(n=302) Pre-CHAMPPost-CHAMP 1992/ /1995 (n=256)(n=302) Fonarow GC et al. Am J Cardiol 2001;87:819–822. CHAMP: Impact on Clinical Outcomes

A-25 Patients discharged on secondary prevention medications from the hospital demonstrate long- term compliance. This increase in compliance translates into better long-term clinical outcomes. Fonarow GC et al. Am J Cardiol 2001;87:819–822. CHAMP: Significance