"Combined Effects of Lowering LDL Cholesterol and Blood Pressure on Cardiovascular Disease". The New England Journal of Medicine. 2016. 375:2033-44.
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Contents 1 Clinical Question 2 Bottom Line 3 Major Points 4 Guidelines 5 Design 6 Population 6.1 Inclusion Criteria 6.2 Exclusion Criteria 6.3 Baseline Characteristics 7 Interventions 8 Outcomes 8.1 Primary Outcomes 8.2 Secondary Outcomes 9 Criticisms 10 Funding 11 Further Reading
In an intermediate-risk population without cardiovascular disease, does combined therapy with rosuvastatin, candesartan, and hydrochlorothiazide lower the rate of cardiovascular events more effectively than dual-placebo?
Among individuals without cardiovascular disease but at intermediate risk, combined therapy with rosuvastatin, candesartan, and hydrochlorothiazide significantly reduced cardiovascular events compared to dual placebo.
Elevated blood pressure and LDL cholesterol are both associated with increased cardiovascular risk, leading to the hypothesis that their simultaneous management might lead to substantial reductions in cardiovascular events. This approach aligns with the polypill concept, aiming for broad population-based treatment without targets or monitoring, particularly in middle-aged and older adults.
The HOPE-3 trial used a 2-by-2 factorial design to assess the effects of cholesterol lowering with rosuvastatin and blood pressure lowering with candesartan plus hydrochlorothiazide versus respective placebos in a primary prevention population at intermediate risk. This analysis focused specifically on the combined therapy versus dual-placebo comparison.
As of August 2017, no guidelines have been published that reflect the results of this trial.
Multi-center, randomized, placebo-controlled trial with a 2-by-2 factorial design N=12,705 Rosuvastatin (10 mg per day) and candesartan (16 mg per day) plus hydrochlorothiazide (12.5 mg per day) (n=3180) Dual placebo (n=3168) Setting: 228 centers in 21 countries Enrollment: ClinicalTrials.gov number, NCT00468923 Mean follow-up: 5.6 years Analysis: Intention-to-treat
Inclusion Criteria: Men ≥55 years and women ≥65 years without cardiovascular disease with at least one additional risk factor; women ≥60 years with ≥2 additional risk factors Exclusion Criteria: Presence of cardiovascular disease Contraindications to statins, angiotensin-receptor blockers, angiotensin-converting–enzyme inhibitors, or thiazide diuretics Baseline Characteristics Age: 65.7 years (mean) Female: 46.2% Baseline systolic BP: 138.1 mmHg (mean) Baseline LDL cholesterol: 127.8 mg/dL (mean)
Initial run-in with both active treatments Randomization to one of four groups in a 2x2 design: rosuvastatin (10 mg per day), candesartan (16 mg per day) plus hydrochlorothiazide (12.5 mg per day), double placebo, or one drug plus the other drug's placebo Structured lifestyle advice provided individually
Primary Outcomes First coprimary outcome: Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke Second coprimary outcome: First coprimary outcome plus resuscitated cardiac arrest, heart failure, or revascularization Secondary Outcomes Composite of second coprimary outcome plus angina with evidence of ischemia Death from any cause New-onset diabetes Muscle weakness and dizziness Muscle weakness or pain: More common in combined-therapy group (1.7%) vs. dual-placebo group (0.78%) Dizziness: More common in combined-therapy group (14.2%) vs. dual-placebo group (11.9%)
Further research might be needed to optimize the dosing and combination of therapies for various risk groups.
Funded by Canadian Institutes of Health Research and AstraZeneca.
Full text, including Supplementary Material, at NEJM.org.