Carvedilol Hibernating Reversible Ischaemia Trial - CHRISTMAS

Description:

The goal of the CHRISTMAS trial was to assess whether improvement in left ventricular ejection fraction (LVEF) was associated with the volume of hibernating myocardium (viable myocardium with contractile failure) in patients with stable, chronic heart failure (CHF) treated with carvedilol compared with placebo.

Hypothesis:

Improvement in LVEF in response to carvedilol in patients with heart failure and LV systolic dysfunction secondary to ischemic heart disease is affected by the volume of hibernating myocardium.

Study Design

Study Design:

Patients Screened: 489
Patients Enrolled: 387
NYHA Class: Class III 28% in placebo arm and 30% in carvedilol arm
Mean Follow Up: 6 months
Mean Patient Age: mean age 62-63 years
Female: 10
Mean Ejection Fraction: Mean baseline LVEF from radionuclide ventriculography was 29.6% ± 10.6%.

Patient Populations:

Diagnosis of stable CHF with objective evidence of LV systolic dysfunction due to coronary artery disease (New York Heart Association [NYHA] class I-III). Stability was defined as freedom from an acute cardiovascular event for three months, freedom from all-cause admission for one month, and stable treatment for heart failure for at least two weeks.

Exclusions:

NYHA class IV; age <40 years and women of child-bearing age; resting heart rate <60 beats per minute, sitting systolic blood pressure <85 mm Hg, unstable angina, arrhythmias that might interfere with treatment or investigation (e.g., atrial fibrillation), uncontrolled hypertension, obstructive pulmonary disease, poorly controlled diabetes, or clinically relevant renal or hepatic disease, and those receiving nondihydropiridine calcium-channel blockers, beta blockers, or antiarrhythmic agents other than amiodarone

Primary Endpoints:

Change in LVEF, measured by radionuclide ventriculography, in hibernators versus nonhibernators, on carvedilol compared with placebo

Secondary Endpoints:

Change from baseline to final visit in radionuclide-determined LVEF on carvedilol versus placebo, irrespective of hibernation status; relation between volume of hibernating myocardium and mean change in radionuclide determined LVEF; change in regional, echocardiographically determined, contractile dysfunction in hibernating and nonhibernating segments; change in the number of segments with reversible exercise-induced myocardial perfusion defects, on carvedilol versus placebo, irrespective of hibernation status; and comparison of the composite clinical endpoint of death or worsening of heart failure on carvedilol versus placebo

Drug/Procedures Used:

Patients were randomized to carvedilol (n=142), at an initial dose of 3.125 mg twice daily, or matching placebo (n=163). Treatment was titrated at two-week intervals to a maximum of 25 mg twice daily or, in patients ≥85 kg, 50 mg twice daily. During the four-month maintenance phase, patients received the maximum tolerated dose during uptitration. At the end of the trial, patients were started on an open-label beta-blocker at the discretion of the local investigator.

Principal Findings:

LVEF did not significantly change in the placebo arm (mean change -0.4 and -0.4 for nonhibernators and hibernators, respectively), but increased in the carvedilol arm (2.5 and 3.2, respectively; p<0.0001 compared with baseline). Mean placebo-subtracted change in LVEF was 3.2% (95% confidence interval [CI] 1.8-4.7; p=0.0001) overall, and 2.9% (0.7-5.1; p=0.011) and 3.6% (1.7-5.4; p=0.0002) in nonhibernators and hibernators, respectively. The effect of hibernator status on response of LVEF to carvedilol was not significant (0.7%, 95% CI -2.2 to 3.5; p=0.644).

Patients with more myocardium affected by hibernation or by hibernation and ischemia had a greater increase in LVEF on carvedilol (p=0.0002 and p=0.009, respectively). However, few patients on carvedilol had no segments affected by either hibernation or reversible ischemia.

The composite of all-cause mortality and worsening heart failure was similar in the placebo arm (n=37) and carvedilol arm (n=44). Death and worsening heart failure did not differ in hibernators and nonhibernators.

Interpretation:

Among patients with stable CHF, treatment with carvedilol was not associated with a difference in the primary endpoint of an interaction between randomized treatment (carvedilol or placebo) and hibernation status on change in LVEF. Treatment with carvedilol was associated with improvements in LVEF in both nonhibernators and hibernators.

The authors note that the data suggest that pharmacological treatment of ischemic or hibernating myocardium could mediate much of the improvement in LVEF seen with carvedilol.

References:

Cleland JG, Pennell DJ, Ray SG, et al., for the Carvedilol Hibernating Reversible Ischaemia Trial: Marker of Success Investigators. Myocardial viability as a determinant of the ejection fraction response to carvedilol in patients with heart failure (CHRISTMAS trial): randomised controlled trial. Lancet 2003;362:14-21.

Clinical Topics: Heart Failure and Cardiomyopathies, Atherosclerotic Disease (CAD/PAD), Statins, Acute Heart Failure

Keywords: Hibernation, Coronary Artery Disease, Carbazoles, Heart Failure, Stroke Volume, Maximum Tolerated Dose, Propanolamines, Myocardium


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