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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

80th Scientific Sessions of the American Heart Association

Orlando, Florida / November 4-7, 2007

In a new landmark trial, a statin was neutral for its primary end point. This outcome is a milestone, because it helps define what statins do and do not do to prevent CV events in high-risk patients with advanced heart failure. The trial, called CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), associated effective lipid lowering with numerous benefits in the study population of older patients with systolic heart failure, but the reduction in the primary outcome of major CV events did not reach statistical significance. The study reveals that progressive atherosclerosis, the target of statin therapy, is not the primary cause of these events in heart failure patients. The study conclusions are reinforced by the use of rosuvastatin, a highly effective LDL-lowering agent currently available. In the study, LDL was reduced by 45% and C-reactive protein (CRP) by 37% in those randomized to the statin.

“The CORONA study provides important information for clinicians and scientists worldwide,” reported Dr. Subodh Verma, Cardiac Surgeon, St. Michael’s Hospital and Canada Research Chair in Atherosclerosis, University of Toronto, Ontario. Providing his perspective on the results of this trial, Dr. Verma added, “Heart failure carries a high mortality, and importantly, these events are likely not due to atherothrombosis, but primarily due to pump failure. In these high-risk heart failure patients, the CORONA trial does support a role for LDL reduction to reduce vascular event rates, including myocardial infarction [MI] and stroke, in line with previous trials.”

The patients recruited for the CORONA study were age 60 or older and had moderate to severe ischemic systolic heart failure (New York Heart Association [NYHA] classes II, III or IV). A left ventricular ejection fraction £40% was required for class III or IV heart failure and £35% for class II heart failure. In addition, eligible patients were judged by the investigators to not be in need of a cholesterol-lowering agent at baseline (the average baseline LDL was 3.54 mmol/L). Patients also had to be on stable optimal treatment for at least two weeks prior to entry. Patients were not eligible if they had chronic liver disease, pericardial disease, had experienced a MI in the past six months or stroke in the past three months, wore a pacemaker, or had a previous adverse reaction to a statin.

The 5011 patients who entered the trial, recruited at 371 centres in Europe and South Africa, were randomized to rosuvastatin 10 mg or placebo on top of any other therapy administered. This included diuretics in almost 90% of patients, a renin-angiotensin system inhibitor in more than 90% and a beta blocker in 75%. They were followed for a median 32.8 months. The primary composite outcome was CV death, nonfatal MI, or nonfatal stroke. Secondary outcomes included death from any cause, any coronary event, death from CV causes, and the number of hospitalizations.

Study Results

At study end, rosuvastatin reduced the primary end point by 8% relative to placebo, but the 95% confidence intervals (CI) crossed the line of unity (hazard ratio [HR] 0.92, 95% CI: 0.83-1.02; P=0.12) (Figure 1).

Figure 1. CORONA Primary End Point

When limited just to major thrombotic events of fatal or nonfatal MI and stroke, the risk reduction was 16%, which reached borderline significance (HR 0.84, 95% CI: 0.7-1.0; P=0.05) (Figure 2). The reduction in nonfatal MI reached 20% (116 vs. 145; P<0.05). Hospitalization rates were reduced by approximately 10% (P=0.007) for any cause, by approximately 15% (P<0.001) for a CV cause and by 15% for a heart failure cause (P=0.01) (Figure 3).
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Figure 3. CORONA Hospitalization

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“When designing this study, our expected benefit from rosuvastatin was a 16% reduction in the primary end point. We did not obtain this because CV death accounted for the majority of events, and rosuvastatin did not have a significant effect on this outcome. However, when we look at the atherothrombotic events in the post-hoc analysis, we did see exactly a 16% reduction with rosuvastatin treatment,” reported Dr. Åke Hjalmarson, Sahlgrenska Institute, University of Gothenburg, Sweden.

As anticipated with rosuvastatin, LDL reductions were profound, averaging 45% (P<0.001 vs. baseline or placebo-treated patients whose LDL levels did not change significantly) at three months, 41% at 15 months (P<0.001), and 34% (P<0.001) at the final visit. These reductions permitted patients in the active treatment group to achieve an average LDL of 1.96 mmol/L. Average HDL levels climbed from 1.24 mmol/L to 1.29 mmol/L, an increase of 5%, while average triglyceride levels fell from 2.01 mmol/L to 1.56 mmol/L, a reduction of 22%. There were no significant changes in any of these lipid levels in the placebo group. Average CRP levels fell from 3.1 mg/L to 2.1 mg/L on active treatment, a decline of 31.6%, while they increased from 3.0 mg/L to 3.3 mg/L in the placebo group, a 5% difference that was significant (P<0.001).

CORONA Data Analysis: Expert View

Presenting the results of the CORONA study (Kjekshus et al. N Engl J Med 2007;357(22):2248-61), Dr. Hjalmarson indicated that rosuvastatin was effective for atherothrombotic events, but “we can assume that the main cause of death [in systolic heart failure patients] is a primary electrical event.”

Of the total events in the composite end point, CV death (mostly sudden death) represented 68%. In contrast, MI and stroke were characterized by the investigators as “relatively uncommon.” Although the investigators did anticipate a high rate of CV death, they noted that previous trials have associated statins with protection from sudden death, probably through their ability to prevent structural compromise that precedes electrical instability. Autopsy studies show half of all sudden deaths involve plaque rupture. However, in a heart failure population, the results of CORONA indicate that sudden death is a primary electrical event due to ventricular dilatation and scarring, against which statins would not have an anticipated protective effect.

“The clinical outcomes in this trial were driven mainly by death, which in this population of NYHA class III congestive heart failure (CHF) are typically due to sudden arrhythmias or to progressive CHF. There was a trend to reduced ischemic events which is what we would expect statins to prevent,” observed Dr. Robert C. Welsh, Co-Director of Chest Pain Program and Associate Professor of Medicine, University of Alberta, Edmonton. He indicated that CORONA added substantial information towards the management of heart failure patients by addressing a controversial question.

“The patients enrolled in CORONA had a guideline-based indication to receive aggressive secondary prevention such as that offered to post-MI patients,” Dr. Welsh commented. “But these guidelines were based on post-hoc analyses of past trials in this specific population of symptomatic heart failure. [The lack of previously available prospective data] established the importance of performing this trial.” His interpretation of the CORONA results is that “there is no compelling evidence to initiate therapy with statins” in heart failure patients without a clear increased risk of atherothrombotic events, “but if such patients are currently on statins without side effects, there is no indication to discontinue.”

Tolerability of statins was not an issue in this study. There were fewer adverse events overall (241 vs. 302; P=0.004), fewer adverse events in most categories, and fewer discontinuations (490 vs. 546;
p receiving rosuvastatin when compared to those receiving placebo (Table 1).

Table 1. CORONA Discontinuations

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From baseline to last visit, serum creatinine increased from 115 mmol/L to 125 mmol/L in the group receiving rosuvastatin and from 115 mmol/L to 128 mmol/L in those receiving placebo. The proportion of patients with liver enzyme elevations more than three times the upper limit of normal was smaller in the active treatment group, although not statistically different. Muscle symptoms were not more common on rosuvastatin, a lack of change reinforced by the fact that patients were actively questioned about muscle-related changes. The tolerability is reassuring in this population of advanced heart failure patients, of whom about 60% had a prior MI, 65% had hypertension, and 30% had diabetes.

The results of this study, including the safety, are particularly intriguing on the issue of statins in heart failure because the trial was conducted with the most effective of the LDL-lowering therapies. The reductions in LDL, even at the study dose of 10 mg of rosuvastatin, are greater than those observed with some of the first-generation agents used at maximum doses. Also as indicated by the reduction in CRP in this and other studies, rosuvastatin has a profound anti-inflammatory effect, one of the pleiotropic benefits attributed to statins. Overall, it is reasonable to consider this a definitive test of the risks and benefits of statins in this population.

“This was a neutral study, but unlike many neutral studies, I think it generated very important information about treating CV disease,” observed Dr. Jacques Genest, Head, Division of Cardiology, MUHC-Royal Victoria Hospital and Division of Experimental Medicine, McGill University, Montreal, Quebec. “This provides a framework for understanding the effect of lipid lowering for different types of CV risk.”

According to statistics from the American Heart Association, heart failure represents only 7% of deaths due to CV disease. Coronary heart disease and stroke, for which statins have proven to be highly effective at reducing risk, represent almost 70%. For these, a level of LDL below which no further protection is observed has not yet been reached. For high-risk patients, the current Canadian cholesterol guidelines recommend a LDL <2.0 mmol/L, but in post-hoc analyses of such studies as the Treatment to New Targets (TNT), even lower LDL levels provide additional risk reductions when compared to the current target. However, substantial proportions of moderate-risk patients are not even reaching the 2.5 mmol/L level despite statin therapy. More aggressive use of the most effective agents is needed.

Summary

According to Dr. Robert Roberts, President and CEO, University of Ottawa Heart Institute, Ontario, “The CORONA study was well done and provided a definitive answer. Statins are safe in patients with heart failure. The physician can now rest assured that patients receiving statins to decrease cholesterol can remain on it if heart failure develops. Furthermore, it will not decrease mortality but could decrease the number of hospitalizations.”

In moderate to severe heart failure patients, the CORONA study has indicated that LDL lowering is effective for reducing the risk of atherothrombotic events but not for reducing CV deaths, the majority of which appear to be due to primary electrical events. However, the study also demonstrated that highly effective LDL lowering is not harmful in this patient population. Rather, adverse events were lower on rosuvastatin than on placebo. Hospitalization rates were reduced by approximately 10% for any cause, by approximately 15% for a CV cause, and by 15% for a heart failure cause. Although statins, by preventing atherothrombotic events, are likely to prevent the structural changes that increase risk of late-stage electrical events, CORONA results demonstrate that this benefit is not achieved in patients who already have advanced structural damage. Rather, the protection offered by statins is against atherothrombotic events alone. Findings from CORONA underscore the need for early treatment with a statin to avoid one of the worst consequences of atherosclerosis which is heart failure.