CORONA
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Clinical Question
Do statins improve survival in patients with ischemic cardiomyopathy?
Bottom Line
Low-dose rosuvastatin does not improve survival among patients with moderate-severe ischemic cardiomyopathy, but may reduce the rate of cardiovascular hospitalizations.
Major Points
Cardiomyopathies are broadly classified as ischemic and non-ischemic, the former a consequence of coronary atherosclerosis. Consequently a majority of patients with ischemic cardiomyopathy receive statins as a part of their HF regimen. The observation that most patients with moderate-severe HFrEF die of progressive HF rather than ACS or other CV events led to the hypothesis that statins may not improve survival among this population. GISSI-HF studied this hypothesis among ischemic and non-ischemic HF patients, while CORONA investigated ischemic HF patients only.
The Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) trial randomized 5,011 patients with ischemic heart failure, NYHA class II-IV symptoms, and LVEF ≤40% (LVEF ≤35% with NYHA class II symptoms) to either rosuvastatin 10mg daily or placebo. It found no significant difference in the primary composite outcome of cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.92; 95% CI 0.83-1.02; P=0.12). Notably, all-cause hospitalizations (a secondary outcome) was significantly reduced in the rosuvastatin group. Together, CORONA and GISSI-HF provide reasonably strong evidence against the routine initiation of statins for moderate-severe ischemic cardiomyopathy. Neither study supports the routine discontinuation of statins among heart failure patients; in particular, because hospitalizations for heart failure were reduced in CORONA's rosuvastatin group, routine discontinuation among ischemic patients may be associated with harm. A randomized controlled trial of statin discontinuation in heart failure is currently underway to help settle this issue.[1]
Guidelines
AHA/ACCF Heart Failure Guidelines (2013, adapted)[2]
- Statins do not provide benefit as an adjunct HF therapy unless another indication for their use (class III, level A)
Design
- Multicenter, double-blind, randomized placebo-controlled trial
- N=5,011
- Rosuvastatin (n=2,514)
- Placebo (n=2,497)
- Setting: 371 sites in 21 countries (Europe, Russia, South Africa)
- Enrollment: 2003-2005
- Follow-up: mean 2.7 years
- Analysis: intention-to-treat
Population
Inclusion Criteria
- Age >60 years
- Ischemic HF
- NYHA class II-IV symptoms
- LVEF <40% (or <35% with NYHA class II symptoms)
- No indication for cholesterol-lowering therapy
- Stable on optimal treatment for >2 weeks prior to randomization
Exclusion Criteria
- Prior statin-induced myopathy or hypersensitivity
- Decompensated HF or need for inotropic support
- MI within past 6 months
- UA or stroke within past 3 months
- PCI, CABG, ICD, or BiV pacemaker within past 3 months or plan to implant
- Prior heart transplant
- Significant uncorrected primary valvular heart disease
- Malfunctioning prosthetic valve
- Hypertrophic cardiomyopathy
- Acute endomyocarditis/myocarditis
- Pericardial disease
- Systemic disease (eg, amyloidosis)
- Liver disease
- Serum Cr >2.5 mg/dL
- Chronic muscle disease or CPK > 2.5x ULN
- Prior cyclosporine
- Life-limiting condition limiting compliance with protocol
- Receipt of <80% placebo tablets during run-in period
Baseline Characteristics
Comparisons are rosuvastatin vs. placebo.
- Mean age: 73 years
- Female: 24%
- NYHA class:
- Class II: 37%
- Class III: 62% vs. 61%
- Class IV: 1.6% vs. 1.4%
- LVEF: 31%
- BMI: 27
- BP: 129/76
- HR: 72
- Current smoker: 8% vs. 9%
- History
- MI: 60%
- Past angina: 72% vs. 73%
- CABG/PCI: 26%
- HTN: 63%
- DM: 29% vs. 30%
- Current afib/flutter: 23% vs. 24%
- Stroke: 12% vs. 13%
- Pacemaker: 12% vs. 10%
- ICD: 2.6% vs. 2.9%
- Labs
- Total cholesterol: 5.4
- LDL: 3.6
- HDL: 1.2
- ApoB:ApoA ratio: 0.87
- Triglycerides: 2 mmol/L
- Cr: 115 µmol/L
- NT-proBNP: 166 vs. 180 pmol/L
- hsCRP: 3.5 mg/L
- Medications
- Loop diuretic: 75% vs. 76%
- Loop or thiazide diuretic: 88% vs. 89%
- Aldosterone antagonist: 39%
- ACE inhibitor: 80%
- ACE inhibitor or ARB: 92% vs. 91%
- Beta-blocker: 75%
- Digitalis: 32% vs. 34%
- Antiarrhythmic: 12%
- Antiplatelet agent: 60% vs. 59%
- Antiplatelet or anticoagulant therapy: 90%
Interventions
- Underwent placebo run-in period to assess compliance
- Randomized to rosuvastatin 10mg daily or matching placebo
- Patients seen at 6 weeks and every 3 months after randomization
- McMaster Overall Treatment Evaulation questionnaire, NYHA class, and muscle symptoms assessed
- CPK and Cr measured at 6 months, 15 months, and then annually
- ALT measured at 3 months and then annually
Outcomes
Comparisons are rosuvastatin vs. placebo.
Primary Outcome
- Composite of cardiovascular death, nonfatal MI, or nonfatal stroke
- 0.12 vs. 0.11 (HR 0.92; 95% CI 0.83-1.02; P=0.12)
Secondary Outcomes
- All-cause mortality
- 0.12 vs. 0.12 (HR 0.95; 95% CI 0.86-1.05; P=0.31)
- Any coronary event
- 0.10 vs. 0.093 (HR 0.92; 95% CI 0.82-1.04; P=0.18)
Hospitalizations
- Patients with ≥1 hospitalization
- 35.6% vs. 38.0% (HR 0.94; 95% CI 0.88-1.01; P=0.09)
- Number of hospitalizations
- 3,694 vs. 4,074 (P=0.007)
- For cardiovascular causes
- 22.9% vs. 25.0% (HR 0.92; 95% CI 0.85-0.99; P=0.04)
- For worsening HF
- 11.3% vs. 12.3% (HR 0.91; 95% CI 0.82-1.02; P=0.11)
- For UA
- 1.1% vs. 1.2% (HR 0.91; 95% CI 0.66-1.27; P=0.56)
- For noncardiovascular reason
- 16.2% vs. 16.5% (HR 0.98; 95% CI 0.89-1.08; P=0.72)
Criticisms
- Relatively low dose of rosuvastatin was used (10mg daily), which may have been insufficient to produce a clinical benefit
- Only one statin was studied (rosuvastatin); unclear whether these results are generalizable to the entire statin family
- Only studied patients whose physicians had not recommended they receive a statin, which is a select group of patients and thus not generalizable to the wider population of patients with ischemic cardiomyopathy receiving statins
Funding
Supported by AstraZeneca. Authors with multiple disclosure.