Journal Club PresentationJournal Club Presentation

Kendra Marsh, MDKendra Marsh, MDDepartment of Cardiology Department of Cardiology

University of Illinois at ChicagoUniversity of Illinois at Chicago

November 27, 2007November 27, 2007

CORONA TRIALCORONA TRIAL

Controlled Rosuvastatin Controlled Rosuvastatin Multinational Trial in Heart Multinational Trial in Heart

FailureFailure

BackgroundBackground A large percentage of patients with left A large percentage of patients with left

ventricular dysfunction have coronary artery ventricular dysfunction have coronary artery disease.disease.

Few of these patients have myocardial Few of these patients have myocardial infarctionsinfarctions

Statin therapy has been shown to be beneficial Statin therapy has been shown to be beneficial in the treatment of coronary artery disease and in the treatment of coronary artery disease and prevention of myocardial infarction.prevention of myocardial infarction.

Patients with severe LV dysfunction often have Patients with severe LV dysfunction often have lower cholesterol, yet they have worse lower cholesterol, yet they have worse outcomes. outcomes.

Potential harm of Statins in Heart Potential harm of Statins in Heart FailureFailure

Lipoproteins are postulated to remove Lipoproteins are postulated to remove endotoxins that seep in through the endotoxins that seep in through the intestinal wall.intestinal wall.

Decreased synthesis of Co-Enzyme Q10Decreased synthesis of Co-Enzyme Q10A co-factor in the mitochondrial electron A co-factor in the mitochondrial electron

transport chaintransport chainAntioxidantAntioxidant

Decreased production of SelenoproteinsDecreased production of SelenoproteinsResulting in skeletal and cardiac myopathiesResulting in skeletal and cardiac myopathies

Potential Benefit of Statins in Heart Potential Benefit of Statins in Heart FailureFailure

Improves endothelial functionImproves endothelial functionAnti-inflammatory activityAnti-inflammatory activity

HypothesisHypothesis

The beneficial results of Rosuvastatin The beneficial results of Rosuvastatin would out-way any theoretical hazards, would out-way any theoretical hazards, improve survival, reduce morbidity and improve survival, reduce morbidity and increase well being in patients with increase well being in patients with chronic, symptomatic, systolic ischemic chronic, symptomatic, systolic ischemic heart failure. heart failure.

Kjekshus J et al. N Engl J Med 2007;10.1056/NEJMoa0706201

Characteristics of the Patients

Patient Characteristics

MethodMethod

Inclusion criteria Inclusion criteria Population: 19 European countries, Population: 19 European countries,

Russia, South AfricaRussia, South Africa60 years or older60 years or olderNew York Heart Association Class II, III or IVNew York Heart Association Class II, III or IVEjection Fraction less than 40%Ejection Fraction less than 40%Stable medical therapy for 2 weeksStable medical therapy for 2 weeks

MethodMethod Exclusion CriteriaExclusion Criteria

Previous adverse reaction to statin ( myopathy or hypersensitivityPrevious adverse reaction to statin ( myopathy or hypersensitivity Decompensated Congestive Heart FailureDecompensated Congestive Heart Failure Inotropic TherapyInotropic Therapy Myocardial Infarction in the past 6 monthsMyocardial Infarction in the past 6 months Unstable Angina or Stroke within the past 6 monthsUnstable Angina or Stroke within the past 6 months PCI/CABG/ICD/Biventricular pacemaker within 3 monthsPCI/CABG/ICD/Biventricular pacemaker within 3 months Previous or planned heart transplantPrevious or planned heart transplant Uncorrected primary heart valveUncorrected primary heart valve Malfunctioning prosthetic valveMalfunctioning prosthetic valve Pericardial or endocardial disease Pericardial or endocardial disease Abnormal LFT’sAbnormal LFT’s Less than 80% of placebo takenLess than 80% of placebo taken Abnormal Creatinine KinaseAbnormal Creatinine Kinase Poor CompliancePoor Compliance

Study DesignStudy Design

Single blinded placebo-control trial.Single blinded placebo-control trial.Rosuvastatin 10 mg oral vs. PlaceboRosuvastatin 10 mg oral vs. PlaceboFollow up at 6 weeks and 3 monthsFollow up at 6 weeks and 3 months If patient was doing well, follow up at 6 If patient was doing well, follow up at 6

months, 15 months and then yearly.months, 15 months and then yearly.Liver Enzymes were checked at 3 months Liver Enzymes were checked at 3 months

ad then yearlyad then yearly

Target OutcomesTarget Outcomes

Primary Outcomes: CompositePrimary Outcomes: Composite Death (Cardiovascular), Non-fatal MI, Non-fatal strokeDeath (Cardiovascular), Non-fatal MI, Non-fatal stroke

Secondary OutcomesSecondary Outcomes Death, any causeDeath, any cause Any cardiac event: sudden cardiac death, fatal or non Any cardiac event: sudden cardiac death, fatal or non

fatal MIfatal MI Revascularization: PCI, CABGRevascularization: PCI, CABG Hospitalization for unstable anginaHospitalization for unstable angina Worsening CHFWorsening CHF

Statistical AnalysisStatistical Analysis

Anticipated mean Hazard ratio 10.4 %Anticipated mean Hazard ratio 10.4 % Projected time for rosuvastatin to show Projected time for rosuvastatin to show

significant effect, 10 monthssignificant effect, 10 months To achieve a 16% reduction in primary To achieve a 16% reduction in primary

outcomes, a statistical power of 90% was used outcomes, a statistical power of 90% was used to detect such a change.to detect such a change.

Therefore the projected number of patients Therefore the projected number of patients needed was 4950.needed was 4950.

People were enrolled with intention to treat.People were enrolled with intention to treat.

ResultsResults

Figure 1. Kaplan–Meier Estimates for the Primary Outcome, Death from Any Cause, and Any Coronary Event.

DiscussionDiscussion

Rosuvastatin 10mg Qdaily did not reduce Rosuvastatin 10mg Qdaily did not reduce primary outcomesprimary outcomes

Cardiovascular hospitalizations were Cardiovascular hospitalizations were significantly reducedsignificantly reduced

There were no significant adverse events There were no significant adverse events when compared to placebo.when compared to placebo.

LimitationsLimitations

Older patientsOlder patients Potentially statin naive with advanced CADPotentially statin naive with advanced CAD NYHC III, IVNYHC III, IV Perhaps the study should have been extended Perhaps the study should have been extended

over a longer period of timeover a longer period of time Diastolic Dysfunction, Nonishemic Diastolic Dysfunction, Nonishemic

Cardiomyopathy patients not includedCardiomyopathy patients not included Unusually compliant group of patientsUnusually compliant group of patients Selection bias for patients who would have good Selection bias for patients who would have good

follow up.follow up.

Thank you!Thank you!