Title: Rosuvastatin for Primary Prevention in Older Persons With Elevated C-Reactive Protein and Low to Average Low-Density Lipoprotein Cholesterol Levels: Exploratory Analysis of a Randomized Trial
Topic: Prevention/Vascular
Date Posted: 5/7/2010
Author(s): Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM.
Citation: Ann Intern Med 2010;152:488-496.
Clinical Trial: No
Related Resources
Trial: Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)
Study Question: Randomized data on statins for primary prevention in older persons are limited, and the relative hazard of cardiovascular disease associated with an elevated cholesterol level weakens with advancing age. What is the efficacy and safety of rosuvastatin in persons 70 years or older?
Methods: A secondary analysis was conducted in JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), a randomized, double-blind, placebo-controlled trial in which the 17,802 participants were randomly assigned with low-density lipoprotein (LDL) cholesterol levels less than 130 mg/dl and high-sensitivity C-reactive protein (CRP) levels of 2.0 mg/L or more without cardiovascular disease. Participants were randomly assigned to receive 20 mg of rosuvastatin daily or placebo. The primary endpoint was the occurrence of a first cardiovascular event (myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes).
Results: In the 70 years or older group, the median age was 74 years (interquartile 72-77, range 70-97 years). Compared to those 50-69 years old, a higher percentage of older participants were women or had hypertension, and lower percentages were obese or smoked cigarettes, relative to younger participants. A total of 5,695 (32%) of trial participants were 70 years or older and accrued 49% (n = 194) of the 393 confirmed primary endpoints. The rates of the primary endpoint in this age group were 1.22 and 1.99 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio, 0.61; 95% confidence interval [CI], 0.46-0.82; p < 0.001). Corresponding rates of all-cause mortality in this age group were 1.63 and 2.04 (hazard ratio, 0.80; CI, 0.62-1.04; p = 0.090). Although no significant heterogeneity was found in treatment effects by age, absolute reductions in event rates associated with rosuvastatin were greater in older persons. The relative rate of any serious adverse event among older persons in the rosuvastatin versus placebo group was 1.05 (CI, 0.93-1.17).
Conclusions: In apparently healthy older persons without hyperlipidemia but with elevated high-sensitivity CRP levels, rosuvastatin reduces the incidence of major cardiovascular events. Effect estimates from this exploratory analysis with age cut-point chosen after trial completion should be viewed in the context of the overall trial results.
Perspective: Previous studies have shown only modest benefits of statins in the elderly without coronary heart disease, and that the risk attributable to total and LDL-C is less than in younger persons. Impressively, the estimated number of older persons who needed treatment for 4 years to prevent one primary endpoint was 24 compared with 36 in the younger age group. There are important differences in JUPITER including identifying a higher risk cohort by including the criteria of a CRP >2 mg/L (despite an LDL-C <130 mg/dl), and the 20 mg dose of rosuvastatin, which has a much greater effect on both LDL-C and CRP than standard statin dosing. Melvyn Rubenfire, M.D., F.A.C.C.
Title: Renal Outcomes With Different Fixed-Dose Combination Therapies in Patients With Hypertension at High Risk for Cardiovascular Events (ACCOMPLISH): A Prespecified Secondary Analysis of a Randomized Controlled Trial
Topic: Prevention/Vascular
Date Posted: 5/7/2010
Author(s): Bakris GL, Sarafidis PA, Weir MR, et al., on behalf of the ACCOMPLISH Trial Investigators.
Citation: Lancet 2010;375:1173-1181.
Clinical Trial: No
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Trial: Avoiding Cardiovascular Events Through COMbination Therapy in Patients LIving With Systolic Hypertension (ACCOMPLISH)
Study Question: What is the comparative efficacy of initial antihypertensive therapy with benazepril plus amlodipine versus benazepril plus hydrochlorothiazide on progression of chronic kidney disease?
Methods: ACCOMPLISH was a double-blind randomized trial undertaken in five countries (USA, Sweden, Norway, Denmark, and Finland). A total of 11,506 patients with hypertension who were at high risk for cardiovascular events were randomly assigned via a central, telephone-based interactive voice response system in a 1:1 ratio to receive benazepril (20 mg) plus amlodipine (5 mg; n = 5,744) or benazepril (20 mg) plus hydrochlorothiazide (12.5 mg; n = 5,762), orally once daily. Drug doses were force-titrated for patients to attain recommended blood pressure goals. Progression of chronic kidney disease, a prespecified endpoint, was defined as doubling of serum creatinine concentration or end-stage renal disease (estimated glomerular filtration rate <15 ml/min/1.73 m2 or need for dialysis). Analysis was by intention to treat.
Results: The trial was terminated early (mean follow-up 2.9 years [standard deviation 0.4]) because of superior efficacy of benazepril plus amlodipine compared with benazepril plus hydrochlorothiazide. There were 113 (2.0%) events of chronic kidney disease progression in the benazepril plus amlodipine group compared with 215 (3.7%) in the benazepril plus hydrochlorothiazide group (hazard ratio, 0.52; 0.41-0.65; p < 0.0001). The most frequent adverse event in patients with chronic kidney disease was peripheral edema (benazepril plus amlodipine, 189 of 561, 33.7%; benazepril plus hydrochlorothiazide, 85 of 532, 16.0%). In patients with chronic kidney disease, angio-edema was more frequent in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. In patients without chronic kidney disease, dizziness, hypokalemia, and hypotension were more frequent in the benazepril plus hydrochlorothiazide group than in the benazepril plus amlodipine group.
Conclusions: The authors concluded that initial antihypertensive treatment with benazepril plus amlodipine should be considered in preference to benazepril plus hydrochlorothiazide since it slows progression of nephropathy to a greater extent.
Perspective: This trial shows that in patients with hypertension at high risk for cardiovascular events, combination treatment with benazepril plus amlodipine reduces progression of chronic kidney disease more effectively than does benazepril plus hydrochlorothiazide. This benefit was also seen when cardiovascular or all-cause mortality was assessed. A limitation of the study is that the trial was not powered as a chronic kidney disease outcome study. A prospective adequately powered trial in patients with more advanced proteinuric nephropathy is needed to establish the superiority between these two different antihypertensive combination treatments on progression of chronic kidney disease. Debabrata Mukherjee, M.D., F.A.C.C.