STOCKHOLM — Results of an extension of the landmark Cardiac Resynchronization in Heart Failure trial show an impressive further widening of the device therapy's mortality advantage over optimal medical management with longer follow-up, John G.F. Cleland, M.D., reported at the annual congress of the European Society of Cardiology.
“CARE-HF provides overwhelming evidence that cardiac resynchronization therapy reduces all-cause mortality, sudden death, and death due to worsening heart failure,” said Dr. Cleland, chairman of the study's steering committee and head of cardiology at Castle Hill Hospital, Kingston-upon-Hull, England.
Other new CARE-HF findings presented at the conference included an echocardiographic study providing important new insights into the device therapy's mechanism of action, as well as a favorable cost-effectiveness analysis that concluded cardiac resynchronization therapy (CRT) costs slightly over $24,000 per quality-adjusted life year (QALY) gained.
CARE-HF was a prospective randomized trial involving 813 patients at 82 medical centers in 12 European countries. Participants had left ventricular (LV) systolic heart failure with an ejection fraction of 35% or less and New York Heart Association class III or IV disease despite optimal pharmacotherapy. They also had to have cardiac dyssynchrony as reflected by a QRS interval of at least 120 msec. They were randomized to optimal medical management alone or with CRT and followed for a mean of 29.4 months.
The main results were presented earlier this year at the annual meeting of the American College of Cardiology and have been published (N. Engl. J. Med. 2005;352:1539–49). At the time, many observers were surprised by the significant 36% reduction in all-cause mortality with CRT and were uncertain how the therapy resulted in an apparent reduction in arrhythmic death. After all, prior CRT trials had shown only a trend toward reduced mortality that did not achieve significance.
The CARE-HF steering committee authorized a 7-month extension of follow-up during which an additional 34 deaths occurred in the control arm and 19 in the CRT arm. The incidence of all-cause mortality after 36.4 months of follow-up was 24.7% with CRT and 38.1% in controls, for a 40% relative risk reduction favoring device therapy. The absolute mortality difference between the two study arms had grown from 9.7% to 13.4%.
Device therapy also conferred a 45% reduction in deaths due to worsening heart failure and a 46% decrease in sudden deaths—even though no study participant had an implantable cardioverter defibrillator (ICD).
Luigi Tavazzi, M.D., presented an analysis of serial echocardiographic studies in 735 CARE-HF participants over 29 months. The results show CRT improved cardiac function in a number of ways.
After 3 months, intraventricular mechanical delay was reduced by half in the CRT group compared with control patients and remained stable thereafter. Mitral regurgitation markedly decreased. LV ejection fraction rose by an absolute 11.2% by study's end with CRT in patients with nonischemic heart failure and by 6.0% in those with an ischemic etiology. LV end diastolic and systolic volumes each showed a net decrease of about 30 mL at 3 months, 45 mL at 18 months, and 60 mL at 29 months with CRT.
“I think that one of the main unresolved issues regarding CRT now seems to be resolved: CRT results in reverse remodeling that is sustained long term both in patients with ischemic and nonischemic heart failure,” observed Dr. Tavazzi, professor of cardiology at the University of Pavia (Italy).
Nick Freemantle, Ph.D., professor of clinical epidemiology and biostatistics at the University of Birmingham (England), said his analysis showing CRT cost less than 20,000 Euros per QALY compares favorably with the recent U.K. National Institute for Clinical Effectiveness analysis of bare metal stents for revascularization, which came in at about 24,000 Euros per QALY. A recent Canadian study estimated that carvedilol for heart failure costs 13,000 Euros per QALY.
Discussant Karl Swedberg, M.D., was particularly impressed by the new echocardiographic insights into CRT's effects on cardiac function. Especially noteworthy was the reduction in LV end systolic volume, as this is a key measure of optimal myocardial contractility.
“The change was not small. It suggests the clinical benefits that we see are due to improved myocardial contractility and remodeling,” said Dr. Swedberg, professor of medicine at the University of Goteborg (Sweden).
CRT is recommended for many heart failure patients in the 2005 European Society of Cardiology guidelines. The remaining question, given CRT's demonstrated ability to prevent sudden death, is: Which patients need a far more costly ICD or combined CRT/ICD device?
“That discussion will now continue,” he predicted.
CARE-HF was sponsored by Medtronic Inc., for which Dr. Cleland has been a consultant and speaker. Dr. Tavazzi and Dr. Freemantle are also consultants to Medtronic.