Laura Mucci, Pharm.D. Candidate Mercer University 2012 Preceptor: Dr. Rahimi February 2012

1. Laura Mucci, Pharm.D. Candidate Mercer University 2012 Preceptor: Dr. Rahimi February 2012 Rosuvastatin for primary prevention in older individuals with high C-reactive protein and low LDL levels: exploratory analysis of a randomized trialGlynn RJ, Koenig W, Nordestgaard BG, et al. Ann Intern Med. 2010;152:488-496.

2. Background • Limited data available for use of statins for primary prevention of cardiovascular disease in older adults • The association between elevated cholesterol and CV disease weakens with age • Framingham coronary heart disease risk score for patients with total cholesterol ≥ 250 mg/dL • Age 40 years: men 6 points, women 8 points • Age 75 years: men 1 point, women 2 points

3. Background • Age is the dominant risk factor of first cardiovascular event in people without diabetes • Framingham risk score for persons over age 75 • Men: 13 • Women: 16

4. Methods • Secondary analysis of the JUPITER trial • Funded by AstraZeneca, maker of Crestor • Randomized, double-blind, placebo controlled trial conducted at 1315 sites in 26 countries • 17,802 total participants • Analysis focused on participants aged 70 years or older, which was 5695 participants (32% of total) • Trial took place between March 2003 – August 2008

5. Methods – Eligibility Criteria • Men age 50 years or older • Women age 60 years or older • No prior history of cardiovascular disease or diabetes • LDL cholesterol level < 130 mg/dL • High-sensitivity C-reactive protein level ≥ 2.0 mg/L • 4-week placebo run-in phase to test adherence

6. Methods – Exclusion Criteria • LDL ≥ 130 mg/dL • C-reactive protein level < 2.0 mg/L • Patients with diabetes, prior history of CV disease, hypothyroid, liver disease, triglycerides > 500 mg/dL • Lipid lowering therapy within 6 weeks of randomization • Current use of hormone replacement therapy • Cancer within last 5 years • Poor compliance

7. Methods – Participants Aged ≥ 70

8. Methods • Intervention: participants randomized to 2 groups in a ratio of 1:1 • Crestor (rosuvastatin) 20mg daily • Placebo • Follow-up visits at 13 weeks, then 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months

9. Methods • Primary end-point: occurrence of first cardiovascular event • Myocardial infarction (non-fatal) • Stroke (non-fatal) • Arterial revascularization • Hospitalization for unstable angina • Death from cardiovascular causes

10. Methods • Secondary end-points • Death from any cause • Venous thromboembolism • Incident diabetes • Safety end-points • Incident diabetes • Adverse events

11. Statistical Analysis • Endpoints analyzed with the intention-to-treat principle • Cox proportional hazards model used to estimate treatment effects by age group • Likelihood ratio test of age groups by treatment interaction evaluated possible heterogeneity in the treatment effect by age • Number needed to treat to prevent 1 event based on Kaplan-Meier estimates of cumulative risk at 4 years

12. Results • Median LDL cholesterol in the rosuvastatin group (54 mg/dL) was half that of the placebo group • Median C-reactive protein in the rosuvastatin group (2.3 mg/L) was 36% lower than the placebo group • For all ages, rosuvastatin was associated with a 44% reduction in the primary endpoint (95% CI 0.46-0.69, P<0.001)

13. Results • 32% of trial participants were aged 70 or older • They comprised 49% (194 of 393) of the total primary cardiovascular endpoints • Absolute reduction in the incidence of primary endpoints was 0.77 events per 100 person-years

14. Results – Primary Endpoint

15. Results – Secondary Endpoints

16. Results – Number Needed To Treat • Number of adults ≥ 70 years needed to treat for 4 years to prevent 1 primary end point was 24 (95% CI: 15-57) • Number of adults < 70 years needed to treat for 4 years to prevent 1 primary end point was 36 ( 95% CI: 23-77) • To prevent secondary endpoints: NNT was 17 in those aged ≥ 70 and 27 in those < 70 years (95% CI: 12-33, 17-57, respectively)

17. Results • Clear treatment benefit was seen in older adults with hypertension and those with a Framingham risk > 10% • Older participants assigned to placebo had higher rates of serious adverse events • Older participants in the rosuvastatin group had higher incidences of muscle weakness, stiffness or pain, renal disorder, bleeding, GI disorder, hepatic disorder, and incident diabetes, but none were statistically significant

18. Results - Safety

19. Discussion • Rosuvastatin substantially reduced the incidence of major cardiovascular events • Benefits of rosuvastatin emerged shortly after initiation in older adults • Treatment effects in older adults were consistent with effects in younger adults, but absolute event rates and treatment benefits were greater in older adults

20. Discussion • JUPITER trial differed from previous studies of statins • Enrolled older population • Included stroke in primary endpoints • Participants had normal LDL levels • Participants had higher C-reactive protein levels • Identified a population at risk (high CRP) for stroke and heart disease who benefit from statin use despite low LDL levels

21. Discussion • JUPITER also shows a need to include stroke prevention in evaluations of cost effectiveness • Stroke causes a high personal and financial impact and an increased percentage of total cardiovascular events with age • Practitioners often see comorbidities and proximity to death as barriers to primary prevention treatment in the older population

22. Discussion • JUPITER shows that benefit emerges quickly and absolute risk is high in older adults • Fewer older patients need to be treated to prevent one event • Rosuvastatin was associated with a significant risk reduction in first CV event • Absolute treatment benefit is greater in older adults than younger ones

23. Strengths • Large, randomized, blinded, multi-country trial • Average age of participants was 66 years • Results can be applied to our patients

24. Weaknesses • Results were extrapolated from study, more research may be necessary in this population • Funded by Astra-Zeneca, only have evidence for Crestor

25. Level of Evidence: 1B

26. References • Glynn RJ, Koenig W, Nordestgaard BG, et al. Rosuvastatin for primary prevention in older individuals with high C-reactive protein and low LDL levels: exploratory analysis of a randomized trial. Ann Intern Med. 2010;152:488-496.