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CLINICAL RESEARCH: HEART FAILURE

Predicting the Long-Term Effects of Cardiac Resynchronization Therapy on Mortality From Baseline Variables and the Early Response

A Report From the CARE-HF (Cardiac Resynchronization in Heart Failure) Trial

John Cleland, MD, FRCP, FACC^_*,_*, Nick Freemantle, PhD, Stefano Ghio, MD, Friedrich Fruhwald, MD, Aparna Shankar, PhD, Monique Marijanowski, PhD^||, Yves Verboven^|| and Luigi Tavazzi, MD, FESC

^_* Department of Cardiology, University of Hull, Hull, United Kingdom
Department of Primary Care and General Practice, University of Birmingham, Birmingham, United Kingdom
Department of Cardiology, Policlinico S Matteo, Pavia, Italy
Department of Internal Medicine, Medical University of Graz, Graz, Austria
^|| Medtronic Bakken Research Center B.V., Maastricht, the Netherlands.

Manuscript received December 28, 2007; revised manuscript received March 6, 2008, accepted April 3, 2008.

^_* Reprint requests and correspondence: Dr. John G. F. Cleland, Department of Cardiology, University of Hull, Castle Hill Hospital, Castle Road, Cottingham, Kingston upon Hull, HU16 5JQ United Kingdom. (Email: j.g.cleland{at}hull.ac.uk).

Objectives: This study was designed to investigate whether selected baseline variables and early response markers predict the effects of cardiac resynchronization therapy (CRT) on long-term mortality.

Background: Cardiac resynchronization therapy reduces long-term morbidity and mortality in patients with moderate or severe heart failure and markers of cardiac dyssynchrony, but not all patients respond to a similar extent.

Methods: In the CARE-HF (Cardiac Resynchronization in Heart Failure) study, 813 patients with heart failure and markers of cardiac dyssynchrony were randomly assigned to receive or not receive CRT in addition to pharmacological treatment and were followed for a median of 37.6 months. A model including assigned treatment, 15 pre-specified baseline variables, and 8 markers of response at 3 months was constructed to predict all-cause mortality.

Results: On multivariable analysis, plasma concentration of amino terminal pro–brain natriuretic peptide (univariate and multivariable model chi-square test: 105.0 and 48.4; both p < 0.0001) and severity of mitral regurgitation (chi-square test: 44.0 and 17.9; both p < 0.0001) at 3 months, regardless of assigned treatment, were the strongest predictors of mortality. Ischemic heart disease as the cause of ventricular dysfunction (chi-square test: 34.9 and 7.4; p < 0.0001 and p = 0.0066), being in New York Heart Association functional class IV (chi-square test: 18.8 and 9.6; p < 0.0001 and p = 0.0020), or having less interventricular mechanical delay (chi-square test: 29.8 and 8.8; p < 0.0001 and p = 0.0029) at baseline all predicted a worse outcome. However, the reduction in mortality in patients assigned to CRT was similar before (hazard ratio: 0.602; 95% confidence interval: 0.468 to 0.774) and after (hazard ratio: 0.679; 95% confidence interval: 0.494 to 0.914) adjustment for variables measured at baseline and at 3 months.

Conclusions: Patients who have more severe mitral regurgitation or persistently elevated amino terminal pro–brain natriuretic peptide despite treatment for heart failure, including CRT, have a higher mortality. However, patients assigned to CRT had a lower mortality even after adjusting for variables measured before and 3 months after intervention. The effect of CRT on mortality cannot be usefully predicted using such information. (CARE-HF CArdiac Resynchronization in Heart Failure; NCT00170300 [ClinicalTrials.gov] )

Key Words: heart failure • cardiac resynchronization therapy • randomized controlled trial

Abbreviations and Acronyms   CRT = cardiac resynchronization therapy   ESVI = end-systolic volume index   IVMD = interventricular mechanical delay   LV = left ventricle/ventricular   LVEF = left ventricular ejection fraction   MR = mitral regurgitation   NT-proBNP = amino terminal pro-brain natriuretic peptide

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