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Rationale CVD is the leading cause of death in people aged 70 years and older PROSPER is the first trial specifically designed to examine the cardiovascular benefits of a statin in elderly subjects at high vascular risk Shepherd J et al. Lancet 2002;360:1623–30.

Proven Risk Reduction with Statins Prevention of First Coronary Events: In middle aged men with elevated TC and LDL-C (WOSCOPS) In middle aged men and women with average TC and low HDL-C (AFCAPS) Prevention of Coronary and Cerebrovascular Events: In middle aged men and women with CHD across a broad range of TC and LDL-C (CARE, LIPID, 4S, HPS) Background slide describes the benefit of statins in landmark clinical trials both in primary and secondary prevention. However, the benefits in an elderly population have not been formally tested. PROSPER is the first prospective statin trial in this population. Shepherd J et al. Lancet 2002;360:1623–30.

Objective To determine whether pravastatin 40 mg will reduce coronary and cerebral events in elderly subjects with either pre-existing vascular disease or with high risk of vascular disease PROSPER Objective The primary objective of PROSPER is to determine the effects of pravastatin 40mg on reducing coronary heart disease or stroke in elderly patients (70-82 years of age) who are at high risk of developing cardiovascular disease or who have cardiovascular disease. Shepherd J et al. Lancet 2002;360:1623–30.

Study Population Glasgow Leiden Cork History or high risk of CVD TC 4–9 mmol/L (155–350 mg/dL) Men and women 70 – 82 years old Cork Leiden The PROSPER trial was conducted at three site: Glasgow, Scotland; Cork, Ireland and Leiden, Netherlands. It was a randomised, doubled blind placebo-controlled study that enrolled men and women between the ages of 70-82. Subjects were further divided into those having established vascular disease and those who were at high risk of vascular disease. Shepherd J et al. Lancet 2002;360:1623–30.

PROSPER: STUDY DESIGN Screening (N=23,770) 4 week single-blind placebo lead-in (N=7056) Pravastatin 40 mg (N=2891) Placebo (N=2913) PROSPER: Study design & Primary Endpoints The following schematic illustrates the study design of PROSPER. As shown, 5803 patients (age 70-82) who are at high risk of developing cardiovascular disease or who have cardiovascular disease will be randomized to pravastatin 40mg or placebo once they have met all inclusion criteria. Patients will be followed for an average of 3.5 years. The primary endpoint will be the combined endpoints or CHD death, Nonfatal MI, Fatal or non-fatal stroke. NOTE: Approximately 50% of participants are women and 50% of participants have existing cardiovascular disease Average Follow-up: 3.2 years Primary Endpoint: CHD Death, Non-fatal MI, Fatal or Non-fatal Stroke Shepherd J et al. Lancet 2002;360:1623–30.

Baseline Characteristics Placebo Pravastatin Mean Age (years) 75.3 75.4 Male (%) 48 48 History of CVD (%) 43 45 Current Smoker (%) 28 26 Hypertension (%) 62 62 Mean SBP/DBP (mmHg) 155/84 155/84 Diabetes (%) 11 11 Baseline characteristic were well balanced between treatment groups. Of note is that the majority of patients in the study had systolic hypertension. Shepherd J et al. Lancet 2002;360:1623–30.

Baseline Lipids Placebo Pravastatin mmol/L (mg/dL) mmol/L (mg/dL) Total-C 5.7 (221) 5.7 (221) LDL-C 3.8 (147) 3.8 (147) HDL-C 1.3 (50) 1.3 (50) Trig 1.5 (133) 1.5 (133) The baseline lipid characteristics were well balanced between groups. Shepherd J et al. Lancet 2002;360:1623–30.

Effects of Pravastatin 40 mg on Lipid Profiles LDL-C mmol/L (mg/dL) 2.0 (77) 2.5 (97) 3.0 (116) 3.5 (135) 4.0 (155) 12 24 36 Pravastatin: On-treatment Pravastatin: Intent-to-treat Placebo Pravastatin 40 mg Effect at 3 Months TC - 23.4% LDL-C - 33.4% HDL-C + 4.9% Trig - 13.3% Pravastatin had an excellent effect on lowering LDL-C. As seen in the graph LDL-C reduction with pravastatin was reduced 33.4% had remained at or near that level throughout the trial period in patients on-treatment (OT). Those patients who were intended to treat (ITT) had a reduced reduction in LDL-C at the end of the trial due to lack of compliance with therapy. In those allocated pravastatin 40mg compared to placebo LDL cholesterol levels at 3 months were reduced by 33.4% to an average of 95 mg/dL. Overall, 81% of the patients receiving pravastatin 40mg reached their NCEP target goal. Seventy percent of elderly subjects with pre-existing vascular disease or diabetes achieved their NCEP target LDL cholesterol goal of 100 mg/dL, and 92% of elderly subjects without pre-existing vascular disease achieved their NCEP target LDL cholesterol goal of 130 mg/dL. Thus, the vast majority of elderly patients in PROSPER achieved their NPCC goal with pravastatin 40mg. In addition, pravastatin was equally effective in reducing cardiovascular events regardless of their baseline LDL cholesterol level (< 132 mg/dL vs. 132-<159 mg/dL vs. > 159 mg/dL; p=0.69). In addition there was a 23.4% reduction in total cholesterol, a 13.3% reduction in triglycerides and a 4.9% increase in HDL-C in subjects given pravastatin. 82% reached NCEP goal Months Shepherd J et al. Lancet 2002;360:1623–30.

CHD Death, Non-fatal MI, Fatal or Non-fatal Stroke Primary Endpoint CHD Death, Non-fatal MI, Fatal or Non-fatal Stroke 20 15% RRR (P = 0.014) Placebo Events = 473/2913 (16.2%) 15 % with event 10 Pravastatin Events = 408/2891 (14.1%) Kaplan-Meier curves for the combined primary endpoint of CHD death, non-fatal MI and fatal and non-fatal stroke is shown. The benefit of pravastatin therapy was seen at a little over 1 year as curves began to diverge. At 3.5 years pravastatin reduced the risk of the primary endpoint by 15% with a significant p value of 0.014. 5 1 2 3 Years Shepherd J et al. Lancet 2002;360:1623–30.

Secondary Endpoints CHD Death or Non-fatal MI Fatal or Non-fatal Stroke - 15 7 19% RRR P = 0.006 P = 0.81 6 Placebo Events = 356/2913 (12.2%) Placebo Events = 131/2913 (4.5%) 5 10 % with event 4 3 5 2 Pravastatin Events = 292/2891 (10.1%) Pravastatin Events = 135/2891 (4.7%) 1 1 2 3 1.0 2.0 3.0 Years Years Shepherd J et al. Lancet 2002;360:1623–30.

Other Outcomes: Stroke and Transient Ischemic Attack Fatal/NF Stroke or Transient Ischemic Attack Transient Ischemic Attack % with event 2 4 6 8 10 1 3 Years Placebo Events = 212/2913 (7.3%) Pravastatin Events = 204/2891 (7.1%) 4% RRR (P = 0.64) 1 2 3 4 5 Placebo Events = 102/2913 (3.5%) Pravastatin Events = 77/2891 (2.7%) 25% RRR (P = 0.051) Years Shepherd J et al. Lancet 2002;360:1623–30.

Tertiary Endpoints There were no significant changes in the following endpoints: All-cause mortality Heart failure requiring hospitalization Revascularization procedures Cognitive function Shepherd J et al. Lancet 2002;360:1623–30..

Fatal Events CHD Stroke All Cause Vascular Non Vascular Events Plac Prava 0.76 CHD 122 94 14 22 1.57 Stroke 0.97 All Cause 306 298 157 135 149 163 0.85 Vascular 1.11 Non Vascular 0.6 0.8 1 2 4 Pravastatin Better Placebo Better Shepherd J et al. Lancet 2002;360:1623–30..

Diagnosed Cancers in PROSPER More patients on pravastatin were diagnosed with cancer during the 3.2 year follow-up (Odds Ratio = 1.26; CI: 1.04 - 1.53) No overall increase in cancer risk was observed in previous pravastatin clinical trial experience with longer duration of follow-up (>112,000 patient years of exposure)1 PPP meta-analysis: N=19,768 Odds Ratio = 1.04; CI: 0.95 - 1.15 1 Pfeffer et al. Circulation 2002;105:2341–46 Shepherd J et al. Lancet 2002;360:1623–30..

Subgroups Treatment effect was homogeneous in the following subgroups: Existing CV disease Gender Smoking Hypertension Tertiles of LDL-C Shepherd J et al. Lancet 2002;360:1623–30.

Primary Endpoint* by Tertiles of LDL-C and HDL-C mg/dL LDL-C 0.88 Interaction P value <132 0.88 132–159 0.7 0.77 >159 HDL-C 0.64 <43 0.93 43–53 0.007 1.09 >53 0.6 0.8 1 2 Pravastatin Better Placebo Better * CHD Death, Non-fatal MI and Stroke Shepherd J et al. Lancet 2002;360:1623–30..

Primary Endpoint* by Tertiles of HDL-C Interaction P value HDL-C <43 0.64 43–53 0.93 0.007 >53 1.09 0.6 0.8 1 2 Pravastatin Better Placebo Better * CHD Death, Non-fatal MI and Stroke Shepherd J et al. Lancet 2002;360:1623–30.

Incidence of Skeletal Muscle and Hepatic Adverse Events Placebo Pravastatin CK > 10X ULN 0 0 Myalgia 32 36 Rhabdomyolysis 0 0 ALT > 3X ULN 1 1 Pravastatin did not cause any significant increase in muscle or liver adverse events in this highly susceptible patient population. Many elderly patients that are on multiple medications have an increased potential for experiencing drug interactions. In the PROSPER trial there was no significant elevations in creatine kinase or alanine transferase levels. In addition there was no differences in myalgia and no reported cases of rhabdomyolysis. Shepherd J et al. Lancet 2002;360:1623–30..

Summary of Results Pravastatin achieved a 15% RRR (p = 0.014) in the primary endpoint (CHD death, non-fatal MI, fatal or non-fatal stroke) over 3.2 years of follow-up Pravastatin significantly reduced CHD events by 19% (p = 0.006) CHD mortality decreased by 24% (p = 0.043) No difference in cognitive function was observed Shepherd J et al. Lancet 2002;360:1623–30.

Conclusions In elderly patients at high risk of CV events, pravastatin 40 mg effectively reduces the risk of coronary disease within 3 years The elderly should be treated with a statin to reduce CV risk Those with pre-existing CV disease or low HDL-C benefit most Pravastatin 40 mg is well tolerated in this elderly population with multiple co-morbidities and concomitant medications Shepherd J et al. Lancet 2002;360:1623–30.

Meta-Analysis of Cancer Incidence From Major Statin Trials Study Statin Placebo WOSCOPS 116/3302 106/3293 CARE 172/2081 161/2078 LIPID 379/4512 399/4502 PROSPER 245/2891 199/2913 ALL Pravastatin studies 912/29424 865/12786 SSSS 90/2221 96/2223 AFCAPS/TexCAPS 252/3304 259/3301 HPS 814/10269 803/10267 LIPS 14/844 18/833 Other Statin studies 1159/16638 1163/16624 All Statin studies 2071/29424 2028/29410 0.25 0.5 0.75 1 1.25 1.5 1.75 2 Shepherd J et al. Lancet 2002;360:1623–30. Statin better Odds ratio Statin worse

Cardiovascular Outcomes Based on Gender Pravastatin (n=1396) Placebo (n=1408) Male CHD death, non-fatal MI and fatal or non-fatal stroke 222 279 CHD death, non-fatal MI 167 219 Fatal and non-fatal stroke 65 70 TIA 38 53 Female (n=1495) (n=1505) CHD death, non-fatal MI and fatal or non-fatal stroke 186 194 CHD death, non-fatal MI 125 137 Fatal and non-fatal stroke 70 61 TIA 39 49 0.25 0.5 0.75 1 1.25 1.5 1.75 2 Statin better Hazard ratio Statin worse Shepherd J et al. Lancet 2002;360:1623–30.

Cardiovascular Outcomes Based on Primary/Secondary Prevention Pravastatin (n=1306) Placebo (n=1259) Secondary Prevention CHD death, non-fatal MI and Fatal or non-fatal stroke 227 273 CHD death, non-fatal MI 166 211 Fatal and non-fatal stroke 74 69 TIA 47 64 Primary Prevention (n=1585) (n=1654) CHD death, non-fatal MI and Fatal or non-fatal stroke 181 200 CHD death, non-fatal MI 126 145 Fatal and non-fatal stroke 61 62 TIA 30 38 0.25 0.5 0.75 1 1.25 1.5 1.75 2 Hazard ratio Shepherd J et al. Lancet 2002;360:1623–30. Statin better Statin worse