In this study in people with moderate to severe heart failure, adding rosuvastatin to established therapies did not reduce the risk of the combined outcome of death from cardiovascular causes non-fatal MI or non-fatal stroke, compared to placebo.
This trial does not provide sufficient evidence to discourage prescribers from continuing to use evidence-based statins such as simvastatin 40 mg, in people with heart failure and co-existing ischaemic heart disease (such as angina or history of MI). However, it should make them pause before using rosuvastatin ahead of such statins in this or other indications, except in the minority of patients who cannot tolerate any other statin.
What is the background to this?
Statins are generally accepted as integral to the management of people with established ischaemic cardiovascular disease, and those at a 20% or greater than risk of developing it in the next 10 years (see NICE guidance). However, published data from studies testing whether patients live longer or live better with statin treatment (compared to just having their cholesterol levels reduced) have up to now been available only for atorvastatin, pravastatin and simvastatin. Simvastatin 40 mg was shown to have a clearly beneficial effect in the Heart Protection Study, and with its low acquisition cost it is first choice drug and dose for most statin candidates. For more information on statins, see the lipids section of NPC.
Ischaemic heart disease is the commonest cause of heart failure, and many patients with heart failure also receive statins. However, evidence for statins in this group of patients is limited: for example, patients with severe heart failure were excluded from the Heart Protection Study. The 2003 NICE clinical guideline on heart failure states “Patients with the combination of heart failure and known atherosclerotic vascular disease should receive statins only in accordance with current indications.”
This study, sponsored by the manufacturers of rosuvastatin, looked at the effect of rosuvastatin versus placebo in people with moderate to severe heart failure (NYHA class II, III or IV)
What did this study find?
Rosuvastatin 10 mg daily was highly effective at reducing LDL-cholesterol. However, over a median follow-up of 32.8 months, there was no significant effect on the primary outcome (CV death, non-fatal MI or non-fatal stroke): Hazard Ratio [HR] 0.92 (95%CI 0.83 to 1.02), or the secondary outcomes of all cause mortality: HR (95%CI) 0.95 (0.86 to 1.05); any coronary event: HR (95%CI) 0.92 (0.82 to 1.04) or death from cardiovascular causes: HR (95%CI) 0.97 (0.87 to 1.09).
In this study, rosuvastatin was highly effective at reducing LDL cholesterol – from a mean of 3.54 mmol/L to 1.96 mmol/L after 3 months. There were also increases in plasma concentrations of HDL and reductions in triglyceride concentrations. However, these encouraging surrogate outcomes did not translate into positive clinical outcomes for patients. There are good statistical reasons for being very cautious before accepting the secondary outcome of effects on hospital admission rates, when the primary outcome of the study was not statistically significant.
So why might we have seen this disappointing result for rosuvastatin? The study was powered to detect a mean overall reduction in the risk of the primary outcome of 16% or greater in the rosuvastatin group, less of a risk reduction than that seen in most statin trials in coronary heart disease and less than that seen in at least one observational study suggesting benefit from statins in heart failure. It seems unlikely that the problem was simply type 2 error.
An accompanying editorial suggests three possible explanations why rosuvastatin did not seem to help these patients live longer or live better. It could be that statins as a class are not efficacious in people with heart failure who are already receiving evidence-based treatment. For example 90% were receiving an ACE-inhibitor or ARB and 75% were receiving a beta-blocker. It could also be that statins as a class have less incremental benefit in a population of older patients (an average of 73 years in this study) who are at higher risk for other events, which could have “drowned out” any benefits on specific cardiovascular outcomes. However, the PROSPER study of pravastatin 40 mg in older people at high risk of cardiovascular events (proportion with heart failure not stated) found a 34% relative reduction in a similar primary endpoint to CORONA over a similar time. Alternatively, as the editorial states, “it is possible that even though rosuvastatin lowered levels of LDL cholesterol and high-sensitivity C-reactive protein, the drug does not share the same benefits regarding important health outcomes with other statins”
It has recently been announced (29th March) that the JUPITER study, a placebo-controlled primary prevention study of rosuvastatin 20 mg in lower-CV-risk patients, has been terminated early due to observed beneficial effects on CV mortality and morbidity. However, details are not yet available, nor do we know how rosuvastatin would compare with simvastatin 40mg/day.
More information on lipid management, including the arguments for and against fixed cholesterol targets or aiming for a “meaningful drop” in cholesterol concentrations, can be found on the lipids section of NPC. The great majority of patients will achieve a good reduction in their total cholesterol, and meet the Quality and Outcomes Framework (QOF) standard of 5 mmol/L total cholesterol or less, on simvastatin 40 mg a day alone. This is widely tolerated and has a low acquisition cost to the NHS.
Action: This trial does not provide sufficient evidence to discourage prescribers from continuing to use evidence-based statins such as simvastatin 40 mg/day, in people with heart failure and co-existing ischaemic heart disease (such as angina or history of MI). However, it should make them pause before using rosuvastatin ahead of such statins in this or other indications, except in the minority of patients who cannot tolerate any other statin.
Design: double blind RCT. Allocation was concealed
Patients: Patients who were at least 60 years of age and who had chronic NYHA class II, III, or IV heart failure of ischemic cause (as reported by investigators) and an ejection fraction of no more than 40% (no more than 35% in patients in NYHA class II), stable on optimal treatment for at least two weeks, provided that the investigator thought they did not need treatment with a cholesterol-lowering drug. Exclusion criteria included MI in the previous 6 months and PCI in the previous 3 months
Intervention and comparison: rosuvastatin 10 mg daily, or placebo, for a mean of 32.8 months
Outcomes and Results: there was no significant effect on the primary outcome (CV death, non-fatal MI or non-fatal stroke): Hazard Ratio [HR] 0.92 (95%CI 0.83 to 1.02); or the secondary outcomes of all cause mortality: HR (95%CI) 0.95 (0.86 to 1.05); any coronary event: HR (95%CI) 0.92 (0.82 to 1.04) or death from cardiovascular causes: HR (95%CI) 0.97 (0.87 to 1.09).
Sponsorship: the study was supported by AstraZeneca, manufacturers of rosuvastatin.