"Combined Effects of Lowering LDL Cholesterol and Blood Pressure on Cardiovascular Disease". The New England Journal of Medicine. 2016. 375:2033-44.PubMed•Full text•PDF

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

Clinical Question

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?

Bottom Line

Among individuals without cardiovascular disease but at intermediate risk, combined therapy with rosuvastatin, candesartan, and hydrochlorothiazide significantly reduced cardiovascular events compared to dual placebo.

Major Points

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.

Guidelines

As of August 2017, no guidelines have been published that reflect the results of this trial.

Design

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

Population

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)

Interventions

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

Outcomes

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%)

Criticisms

Further research might be needed to optimize the dosing and combination of therapies for various risk groups.

Funding

Funded by Canadian Institutes of Health Research and AstraZeneca.

Further Reading

Full text, including Supplementary Material, at NEJM.org.