1. Title slide

2. 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.

3. 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.

4. 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.

5. 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 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.

6. 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.

7. Baseline Characteristics
Placebo Pravastatin
Mean Age (years)
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.

8. 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.

9. 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 %
LDL-C %
HDL-C + 4.9%
Trig %
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.

10. 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 5 1 2 3
Years
Shepherd J et al. Lancet 2002;360:1623–30.

11. 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.

12. 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.

13. 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..

14. 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
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..

15. Diagnosed Cancers in PROSPER
More patients on pravastatin were diagnosed with cancer during the 3.2 year follow-up (Odds Ratio = 1.26; CI: )
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:
1 Pfeffer et al. Circulation 2002;105:2341–46
Shepherd J et al. Lancet 2002;360:1623–30..

16. 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.

17. 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..

18. 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.

19. Incidence of Skeletal Muscle and Hepatic Adverse Events
Placebo Pravastatin
CK > 10X ULN 0 0
Myalgia
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..

20. 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.

21. 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.

22. 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

23. 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.

24. 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