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Controlled Rosuvastatin Multinational Trial in Heart Failure (The Positive Negative Trial)

      The recently published Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) was a phase 3, randomized, double-blind, parallel-group, multinational clinical study.
      • Kjekshus J.
      • Apetrei E.
      • Barrios V.
      • Böhm M.
      • Cleland J.G.
      • Cornel J.H.
      • Dunselman P.
      • Fonseca C.
      • Goudev A.
      • Grande P.
      • et al.
      CORONA Group
      Rosuvastatin in older patients with systolic heart failure.
      The trial assessed the efficacy and safety of rosuvastatin (10 mg/day) compared with placebo in patients with compensated systolic heart failure (HF). Patients (n = 5,011) aged >60 years with New York Heart Association class II to IV ischemic HF were randomized to receive rosuvastatin (n = 2,514) or matching placebo (n = 2,497) for a median follow-up period of 32.8 months. The primary end point was the time of the first event of cardiovascular death, nonfatal myocardial infarction (MI), or stroke and occurred in 11.4% of patients treated with rosuvastatin and 12.3% of patients randomized to placebo per year. This slight difference favoring the statin was attributed to the decrease in nonfatal MIs (115 of 141) and ischemic stroke (89 of 104). Moreover, patients treated with rosuvastatin experienced fewer numerical deaths from any cause (728 of 759), including sudden death (316 of 327) and fatal infections (54 of 68); reductions in coronary events (554 of 588) and pulmonary embolism (2 of 8); and absence of aortic aneurism (0 of 5). Importantly, the safety profile of rosuvastatin was superior to placebo with regard to drug discontinuation (490 of 546), the frequency of adverse events (241 of 302), and gastrointestinal fatal bleeding (1 of 9). The spectrum of adverse events was mixed, with serious adverse muscle events favoring rosuvastatin (3 of 11), but nonserious events were less common in the placebo group (144 of 167). The prespecified second analysis revealed a highly significant reduction in the hospitalization rate for cardiovascular causes in the rosuvastatin group (2,193 of 2,564, p <0.001). The CORONA investigators correctly assumed that there would be no benefit of rosuvastatin during the first 10 months after randomization, followed by a 22% reduction in events thereafter, resulting in an 8% overall benefit. The study concluded that rosuvastatin was safe and reduced hospitalization rates, but it did not meet the primary end point or diminish fatalities in patients with compensated systolic HF.
      • Kjekshus J.
      • Apetrei E.
      • Barrios V.
      • Böhm M.
      • Cleland J.G.
      • Cornel J.H.
      • Dunselman P.
      • Fonseca C.
      • Goudev A.
      • Grande P.
      • et al.
      CORONA Group
      Rosuvastatin in older patients with systolic heart failure.
      With regard to the practical assessment of CORONA's results, a few issues are worth mentioning. First, considering the targeted highest risk HF population, the low dose of rosuvastatin, and the very ambitious prespecified primary efficacy end point, the trial was most likely doomed to produce negative results. This is especially true for the anticipated mortality reduction, which has historically been extremely difficult to achieve in HF trials
      The CONSENSUS Trial Study Group
      Effects of enalapril on mortality in severe congestive heart failure Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).
      Scandinavian Simvastatin Survival Study Group
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
      and in real-life clinical scenarios in elderly patients.
      • van Jaarsveld C.H.
      • Ranchor A.V.
      • Kempen G.I.
      • Coyne J.C.
      • van Veldhuisen D.J.
      • Sanderman R.
      Epidemiology of heart failure in a community-based study of subjects aged > or = 57 years: incidence and long-term survival.
      Moreover, the causes of mortality in HF are multifactorial and complex,
      • Freudenberger R.S.
      • Hellkamp A.S.
      • Halperin J.L.
      • Poole J.
      • Anderson J.
      • Johnson G.
      • Mark D.B.
      • Lee K.L.
      • Bardy G.H.
      SCD-HeFT Investigators
      Risk of thromboembolism in heart failure an analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).
      • Pocock S.J.
      • Wang D.
      • Pfeffer M.A.
      • Yusuf S.
      • McMurray J.J.
      • Swedberg K.B.
      • Ostergren J.
      • Michelson E.L.
      • Pieper K.S.
      • Granger C.B.
      Predictors of mortality and morbidity in patients with chronic heart failure.
      and it is somewhat naive to expect any significant prevention of these fatalities exclusively by lipid modulation. However, overall, there were fewer deaths in the statin group, but even more encouraging is the fact that Kaplan-Meier estimates continue to spread, favoring rosuvastatin beyond the follow-up period. It seems that CORONA's results may be better should patients be followed for ≥5 years. Aside from mortality, rosuvastatin slightly but unquestionably improved vascular outcomes, preventing acute events. Fewer nonfatal MIs, strokes, and pulmonary embolisms in combination with a significant decrease in cardiovascular hospitalizations suggest that therapy with statins improves the quality of life in elderly patients with systolic HF. The vascular benefits of rosuvastatin could be attributed not only to the improved lipid profile but to the selective inhibition of protease-activated receptor 1 platelet thrombin receptor, as suggested by the PAR-1 Inhibition by Statins (PARIS) study
      • Serebruany V.L.
      • Miller M.
      • Pokov A.N.
      • Malinin A.I.
      • Lowry D.R.
      • Tanguay J.-F.
      • Hennekens C.H.
      Statins inhibit platelet PAR-1 thrombin receptor in patients with metabolic syndrome: the PAR-1 Inhibition by Statins (PARIS) study.
      and observations from the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.
      • Serebruany V.L.
      • Malinin A.I.
      • Hennekens C.H.
      Statins increase risk of haemorrhagic stroke by inhibition of PAR-1 receptor.
      Therapy with rosuvastatin was associated with fewer infections, including fewer fatal infections, supporting the postulate of statin pleiotropy. The idea that statins may prevent sepsis is not new,
      • Hackam D.G.
      • Mamdani M.
      • Li P.
      • Redelmeier D.A.
      Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis.
      and observational studies suggest fewer hospitalizations
      • Gupta R.
      • Plantinga L.C.
      • Fink N.E.
      • Melamed M.L.
      • Coresh J.
      • Fox C.S.
      • Levin N.W.
      • Powe N.R.
      Statin use and hospitalization for sepsis in patients with chronic kidney disease.
      and better survival
      • Thomsen R.W.
      • Hundborg H.H.
      • Johnsen S.P.
      • Pedersen L.
      • Sørensen H.T.
      • Schønheyder H.C.
      • Lervang H.H.
      Statin use and mortality within 180 days after bacteremia: a population-based cohort study.
      in statin-pretreated patients. The pathogenesis of the anti-inflammatory properties of statins remains a mystery but may be related to the suppression of endotoxin activity by monocytes
      • Niessner A.
      • Steiner S.
      • Speidl W.S.
      • Pleiner J.
      • Seidinger D.
      • Maurer G.
      • Goronzy J.J.
      • Weyand C.M.
      • Kopp C.W.
      • Huber K.
      • et al.
      Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo.
      or the inhibition of cytokines and nitric oxide.
      • Ando H.
      • Takamura T.
      • Ota T.
      • Nagai Y.
      • Kobayashi K.
      Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis.
      Last but not least, the safety profile of rosuvastatin in CORONA was superior to that of placebo. Acknowledging the obvious unmet need to improve outcomes and the quality of life in HF patients, and the fact that rosuvastatin caused no increase but rather a decrease in the adverse event rate and drug discontinuations, in lay terms, CORONA was a positive trial. Indeed, the benefit with rosuvastatin was not striking, and mostly not significant, but the trends consistently followed the right direction. Most likely, the unmet need and lack of safety concerns will increase the use of rosuvastatin in compensated systolic HF despite the lack of a formal approved indication.
      There are important lessons to be learned from CORONA. Considering the results of Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)
      • Cannon C.P.
      • Braunwald E.
      • McCabe C.H.
      • Rader D.J.
      • Rouleau J.L.
      • Belder R.
      • Joyal S.V.
      • Hill K.A.
      • Pfeffer M.A.
      • Skene A.M.
      Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators
      Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
      and the excellent safety profile of rosuvastatin, higher doses of statins should be tested in future randomized HF trials, despite the already impressive reductions in low-density lipoprotein and C-reactive protein achieved in CORONA with rosuvastatin 10 mg/day. On the basis of the time pattern of the outcomes, especially delayed death curve stratification, longer follow-up studies are well justified and warranted. Finally, realistic goals should be implemented, and reasonable outcome benefits should be expected for HF trials in the elderly. If the drug is indeed safe and possesses an obvious unmet clinical advantage, the classic vascular combined end point of cardiovascular death, nonfatal MI, and stroke may be not appropriate, and a composite primary end point focusing on the quality of life should be considered.

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