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

 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

 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

 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

 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

 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

 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

 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

 Secondary end-points  Death from any cause  Venous thromboembolism  Incident diabetes  Safety end-points  Incident diabetes  Adverse events

 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

 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 , P<0.001)

 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

 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)

 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

 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

 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

 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

 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

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

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

 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: