CORONA: Little Clinical Benefit Seen in First Major Statin Trial in Heart Failure

November 6, 2007 — In the first of several large, randomized explorations of a statin given explicitly for heart failure (HF) to reach the reporting stage, treatment with rosuvastatin (Crestor, AstraZeneca) had no significant effect on cardiovascular outcomes, as measured by the primary-end-point composite of cardiovascular (CV) death, nonfatal myocardial infarction (MI), or stroke [1].
The study, Controlled Rosuvastatin in Multinational Trial in Heart Failure (CORONA), was limited to older patients with moderate to severe systolic HF of ischemic origin "who had already received extensive treatment with drugs for cardiovascular disease," write the authors, led by Dr John Kjekshus (Rikshospitalet University Hospital, Oslo, Norway). The 10-mg-per-day rosuvastatin regimen had no effect on the composite end point, although it produced the expected reductions in low-density-lipoprotein (LDL) cholesterol and C-reactive protein (CRP), they observed. It did, however, significantly reduce the number of hospitalizations from CV causes and from HF.
The findings were published online in the New England Journal of Medicine to coincide with their release to the media attending the American Heart Association 2007 Scientific Sessions, where coauthor Dr Åke Hjalmarson (Salhgrenska University Hospital, Göteborg, Sweden) later formally presented the results [2].
They come after years of tantalizing evidence from retrospective analyses and limited prospective series that statin therapy may improve heart-failure status and outcomes, perhaps, in part, independently of any effects on dyslipidemia, for which the drugs are famously given.
Dr John Kobashigawa (University of California, Los Angeles), who spoke as the formal discussant after Hjalmarson's presentation, observed that patients with heart failure had been largely excluded from the landmark statin secondary-prevention trials and differ in important ways from their populations. Their mortality is three to five times higher, he said, and they have more comorbidities. "The majority of adverse events in heart-failure studies are worsening heart failure and sudden cardiac death, as seen in the CORONA trial, as opposed to statin studies, where MI, unstable angina, and revascularization are the most common." Therefore, he said, the CORONA trial, conducted at centers across Europe, "is the first to provide outcomes data for statin treatment in heart-failure patients."
Dr Raymond Gibbons (Mayo Clinic, Rochester, MN), who wasn't involved in CORONA, agreed that there haven't previously been statin trials focusing on patients with heart failure. "But most of us feel that the other [statin] trials justify their use in heart-failure patients," he told heartwire.
Officiating at the CORONA presentation for the media, Dr Gordon F Tomaselli (Johns Hopkins University, Baltimore, MD) said that while he'd prescribe a statin for a patient with systolic, ischemic heart failure, he might hesitate to do so in such a patient "who had a sufficiently low LDL. I certainly wouldn't be adding the drug for a benefit above and beyond the lipid-lowering capacity of the drug."
Another observer of the trial, Dr Steven Nissen (Cleveland Clinic, OH), said to heartwire that although the primary end point was missed in CORONA, "It doesn't mean you shouldn't give statins to these folks. . . . What we do in America is if you've got ischemic heart disease, we give you a statin. You couldn't have done this trial in the US, because here all these patients are getting statins anyway."
There was no difference in the primary end point, Nissen agreed, probably because in the selected population, death was more likely to be from progressive heart failure rather than ischemic events. "Once you have bad left ventricular dysfunction, you can't escape the mortality of the heart failure itself," he said. "They did prevent recurrent MIs, which is what you'd expect a statin to do. But it was unrealistic, in my view, to expect them to keep you alive once your pump is damaged."
Along those lines, Kobashigawa observed that patients like those in CORONA have a very high annual mortality, about 10%. There were relatively few atherothrombotic events in CORONA, "as expected for heart-failure patients." There may not have been enough opportunity, he said, "for the antiatherothrombotic properties of statins to alter outcomes."
At his formal presentation of the trial, Hjalmarson said the apparent reductions in ischemic events with rosuvastatin, but not in mortality, suggests "that the major etiology of cardiovascular deaths in this older vulnerable population of otherwise well-treated patients with advanced systolic heart failure may be a primary electrical event, related to ventricular dilatation and scarring, rather than to an atherothrombotic event."
Speaking with heartwire, Hjalmarson observed that a subgroup analysis suggested preferential statin benefit in patients who were younger, with less severe heart failure and in better general health. One message of the trial, he said, is "if we treat any patients with statins who have more severe heart failure, perhaps we should go for the younger ones with less severe disease, who are expected to live long enough to benefit from the effects of statins."
CORONA randomized 5011 patients in New York Heart Association (NYHA) class 2-4 with a left-ventricular ejection fraction (LVEF) no higher than 40%, or 35% for those in NYHA class 2, whom the European investigators considered not in need of a cholesterol-modifying drug, to receive the statin or a placebo. They averaged 73 years in age; more than 40% were ≥75, write Kjekshus et al.
Over a median follow-up of 33 months, there were no significant differences in the primary end point or in all-cause mortality, the rate of coronary events (which included sudden death, fatal or nonfatal MI, percutaneous coronary intervention [PCI] or coronary arterial bypass graft [CABG], resuscitated cardiac arrest, and hospitalization for unstable angina), effects on NYHA class, or the rate of newly diagnosed diabetes. But there were significant differences in the number of hospitalizations, and, post hoc, in nonfatal ischemic events.
Number of hospitalizations by cause of hospitalization
Despite the lack of difference in the primary end point, there were significant reductions in levels of CRP; however, they were not decreased to what would be considered a low level, Kobashigawa said. "This does bring into question whether higher doses of rosuvastatin could have additional clinical benefit." He also agreed with Hjalmarson that there were signals of preferential benefit among younger patients who had less severe heart failure, suggesting that giving statins earlier in the natural history of heart failure might produce better results.
In an editorial accompanying the study's online publication, Dr Frederick A Masoudi (University of Colorado, Denver) presents several further potential explanations for the apparent disconnect between the secondary-prevention evidence base and the results of CORONA [3].
"First, statins as a class may not be efficacious in patients with ischemic left ventricular systolic dysfunction who are already receiving evidence-based therapy for heart failure," a group that may be less prone to CV ischemic events compared with those entered into earlier statin secondary-prevention trials. And, as rosuvastatin wasn't necessarily one of the statins tested in those trials, it may not have the same potential clinical benefit despite its having significantly improved lipid parameters and markers of inflammation in CORONA. Finally, Masoudi observes, statins in general may not improve CV outcomes noticeably in an older population, one "at higher risk for competing events."
CORONA was funded by AstraZeneca, from which Kjekshus reports receiving lecture fees and consulting or advisory-board fees. Other coauthors disclose the same relationships in addition to receiving research grants and holding equity interest in the company. Coauthor Dr John Wikstrand is employed by the company as its senior medical advisor. Masoudi reports receiving consulting fees from Amgen, UnitedHealthcare, and Takeda and grant support from Amgen.
Sources
Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007; DOI: 10.1056.nejmoa0706201. Available at: http://www.nejm.org.
Hjalmarson Å. Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)--Results of an outcomes trial in patients with ischemic heart disease and heart failure. American Heart Association 2007 Scientific Sessions; November 5, 2007; Orlando, FL. Late-breaking clinical trials 2.
Masoudi FA. Statins for ischemic systolic heart failure. N Engl J Med 2007; DOI: 10.1056.nejme0707221. Available at: http://www.nejm.org.