Results from a large-scale clinical trial with AstraZeneca’s Crestor (rosuvastatin) have dashed hopes that the drug would gain a valuable new competitive edge by showing effectiveness in preventing mortality and morbidity in heart failure patients.

Adding rosuvastatin to optimised therapy in patients with advanced systolic heart failure did not significantly improve the primary composite outcome of cardiovascular death, non-fatal myocardial infarction (heart attack) or non-fatal stroke, the long-term CORONA (COntrolled ROsuvastatin multiNAtional Trial in Heart Failure) study found. There were, however, significantly fewer hospitalisations for cardiovascular or other causes in the patients taking rosuvastatin, and the drug was associated with substantial reductions in levels of low-density lipoprotein (LDL) cholesterol.

A successful heart failure outcome would have been the first for any drug in the huge cholesterol-lowering statin class. Analysts had predicted that it could boost revenues of Crestor, a key AstraZeneca brand now facing the threat of premature generic competition, by as much as US$1 billion in the US alone. However, they sided with the UK company in playing down the impact of the CORONA data, saying a heart failure claim had been a long shot for Crestor.

In an editorial in the New England Journal of Medicine, Dr Frederick Masoudi, of the Denver Health Medical Center and University of Colorado, US, said that for the moment clinicians should continue to prescribe stains for patients with ischaemic heart failure and left ventricular systolic dysfunction as “enough uncertainty exists about the mechanisms underlying the primary results of the CORONA study”. The NEJM published the study presented at the annual meeting of the American Heart Association in Orlando, Florida.

“Until further evidence accumulates, we cannot tell to what extent the CORONA study reflects the limitations of the use of statins for patients with heart failure, the problems associated with a particular drug, or the intrinsic challenges of treating older patients with complex co-existing illnesses,” Masoudi cautioned.

CORONA was the first prospective outcomes study to examine the impact of adding a statin to optimised treatment for patients with advanced heart failure, AstraZeneca said. As the researchers led by John Kjekshus of Rikshospitalet University Hospital in Oslo, Norway pointed out, patients with systolic heart failure are generally excluded from statin trials. “Acute coronary events are uncommon in this population, and statins have theoretical risks in these patients,” they added.

The 21-country study recruited 5,011 patients aged 60 years and over with New York Heart Association class II, III or IV ischaemic, systolic heart failure who were on high-level treatment including ACE-inhibitors or angiotensin receptor blockers and beta-blockers. In addition to these therapies, patients were randomised to 10mg rosuvastatin per day or placebo.
Eight per cent reduction

Crestor was associated with an 8% reduction in the combined primary endpoint of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, which failed to reach statistical significance. A total of 692 (11.4%) of patients registered this outcome in the rosuvastatin group, compared with 732 patients (12.3%) on placebo.

The 8% improvement was “primary driven by a decrease in atherosclerotic events, i.e., stroke and myocardial infarctions … which is where statins have been proven to have benefit”, AstraZeneca noted. The majority of deaths, it added, “were due to sudden death, or non-ischaemic causes, which do not appear to be impacted by statin therapy”.

Dr George Kassianos, a UK general practitioner and fellow of the European Society of Cardiology, commented: “This study was conducted in a challenging heart failure population where the benefit of statins was previously unknown. CORONA has highlighted that there is a need for early intervention in the progression of atherosclerosis, preventing one of its worst consequences – heart failure. Furthermore, it is particularly encouraging that we can keep these patients out of hospital.”

According to AstraZeneca, at least 4% of all deaths in the UK are due to heart failure and around 40% of people diagnosed with the condition will die within a year – a worse one-year survival rate than for breast, prostate and bladder cancer.