Pacing the heart, a common and accepted medical practice, may damage patients' hearts, at least in some circumstances, according to a preliminary study that was terminated early because too many patients died. The results of the study, called the DAVID (Dual Chamber and VVI Implantable Defibrillator) trial, were published in the Dec. 25 edition of the Journal of the American Medical Association (JAMA). According to the JAMA article, with patients who need implantable cardioverter defibrillators (ICDs) to control abnormal heart rhythms, simple ventricular backup pacemaker therapy provides better outcomes than supporting the heart rhythm with more sophisticated stimulation of both the right atrium and right ventricle. Indeed, the article said that activating the pacemaker function in the right side of a patient's heart might be throwing off synchronization with the left side, causing the heart to lose efficiency and deteriorate.

Previous evaluations of ICD therapy showed that devices with a simple pacemaker that stimulated the heart only when the heart rate dropped very low saved lives when compared to the best medications. However, newer ICDs include a sophisticated pacemaker designed to maintain an optimal heart rate that is automatically adjusted according to the level of the patient's activities. The DAVID trial was designed to measure the potential incremental benefit of pacing the heart with sophisticated dual-chambered pacing of the right atrial and ventricular chambers compared to right ventricular backup pacing.

Patients enrolled in the DAVID study, which was initiated in 4Q00, represented a typical cross-section of ICD recipients, tending to exhibit mildly symptomatic heart failure (i.e., 88% having New York Heart Association class II or less) and relatively normal interventricular conduction (i.e., 70% having QRS widths of 130 ms or less). Study endpoints included the primary composite endpoint of mortality and hospitalization for worsening heart failure, as well as secondary endpoints such as time to first inappropriate defibrillation therapy and incidence of atrial fibrillation. A total of 37 sites were involved.

Out of the 506 patients implanted with defibrillators in the study, half were programmed to pace their heart at 70 beats per minute as well as to shock both right-side chambers in the event of an arrhythmia. The other half were programmed to shock the right ventricle in the case of an arrhythmia but only to activate the pacemaker function if the heartbeat fell below 40 beats per minute. A normal heartbeat ranges roughly between 50 and 75 beats a minute.

In the study group whose pacemaker function was activated and who were expected to be healthier, 23 died and 43 became ill enough to require hospitalization. In the control group, 15 died and 30 were hospitalized. That was enough for a committee overseeing the study, and the trial was halted on Sept 30 several months early before any more patients were enrolled. The alarming results came as a surprise to the doctors involved in the study.

"The DAVID study produced opposite results from expectations," said Bruce Wilkoff, MD, director of cardiac pacing and tachyarrhythmia devices at the Cleveland Clinic Foundation (Cleveland, Ohio) and chairman of the DAVID steering committee. "About 75% of ICDs implanted in the U.S. include dual-chamber pacemakers, and these are the first randomized data evaluating its impact on congestive heart failure and mortality. Its implications for patients are compelling," he said. Death and/or heart failure hospitalization, the endpoint used to evaluate outcome, revealed that by one year, 26.7% of patients treated with dual chamber pacing had reached the endpoint vs. 16.1% of the patients treated with ventricular backup mode pacing.

The study, which was sponsored by St. Jude Medical (St. Paul, Minnesota) and used its devices exclusively, was limited to comparisons of the two arms on the combined endpoint of mortality and hospitalization for worsening heart failure. Future analysis and publications are still needed to examine differences between the two arms for the other secondary endpoints. "The DAVID results provide important new information that will enhance the clinical management of patients receiving ICD technology," said Michael Coyle, president of St. Jude's Cardiac Rhythm Management business. He also noted that dual-chamber defibrillators have gained widespread use, even in patients who do not require regular pacing support, because of the important diagnostic and discrimination benefits they provide. The study, he added, "shows that careful attention must be paid to the programming of pacemaker functions in ICDs to minimize ventricular pacing in patients who do not require ventricular support."

Scott Papillon, a spokesman for Medtronic (Minneapolis, Minnesota), which also makes defibrillators and pacemakers, said the study can be confusing to patients, and he cautioned against drawing a conclusion that pacing is bad for all risk groups. "What's confusing people, I think, is that the patients in this trial are ICD patients who didn't have bradycardia (abnormally low heart rate) and therefore, didn't have a need for pacing," Papillon told Cardiovascular Device Update. He noted that in the DAVID trial, the investigators didn't leave the pacemakers just for backup "they kind of forced it on some people who really didn't need pacing. They've created a clinical situation that's not typical in normal clinical practice." He also said that the pacing rate in the trial, particularly the 70 beat-per-minute group, is much higher than a normal pacemaker setting, adding that a patient's "at rest" heartbeat would generally be much lower than that. He used the analogy of driving a car on a long trip the entire way in first gear, believing you would get better gas mileage. "Your transmission would go, but you don't blame the transmission because of that." In much the same way, he said you don't blame the ICD device because of how it is programmed. "Physicians know when patients should have pacing and when they shouldn't."

St. Jude said the investigative group would now shift its focus to confirm the mechanism responsible for the increased mortality/hospitalization in the dual-chamber ICD group. And it acknowledged that while it is clear that there was a difference between the two arms as to percentage of time in active ventricular pacing (60% in the dual-chamber arm vs. 1% in the single-chamber arm), it is not clear whether the adverse impact on combined mortality and heart failure hospitalization is the result of pacing in general or right ventricular pacing in particular. To answer that question, St. Jude said it has agreed to sponsor the DAVID II trial, which will utiize the AAI pacing capabilities of the company's Photon ICD platform to re-randomize DAVID study patients to either VVI (ventricular pacing only) or AAI (atrial pacing only) pacing arms. The same clinical endpoints evaluated in DAVID will be maintained for DAVID II, it noted.

"Results of the DAVID study point out the adverse implications of the dominant clinical practice of using the dual-chambered pacing mode in ICD patients, who in fact usually require no more than backup ventricular pacing," Wilkoff said. "These findings will be extremely valuable to the electrophysiology community as we continue to refine our recommendations for allocating and optimally programming the sophisticated pacemaker functions contained in state-of-the-art defibrillators." He said that the investigators look forward to further analyzing these data to assess differences between the two study arms on other important clinical parameters such as time to first inappropriate ICD therapy delivery, in order to further refine their recommendations on use of single-and dual-chamber defibrillators and their associated pacing functions.

Medtronic's Papillon acknowledged that any clinical study that sheds light on how devices should be used most effectively is good, adding the caveat that "this one shows the need for proper programming."

Study may portend changes in treating Afib

A long-held belief that attaining normal heart rhythm in treating atrial fibrillation is no more beneficial than secondary treatments aimed at simply controlling the rate at which the heart beats, according to a new study. The most common treatment for atrial fibrillation is to restore and maintain a normal heart rhythm pharmacologically. But researchers found that establishing a consistent heart rhythm offers no more benefit than the alternative approach, and in fact, could lead to more hospitalizations and adverse drug effects, the researchers concluded.

The study, called the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM), was published in the Dec. 5 issue of the New England Journal of Medicine. It was funded by the National Institutes of Health's National Heart, Lung and Blood Institute (NHLBI; Bethesda, Maryland). It also found that devices, such as implantable pacemakers, offer an effective alternative when drug treatment does not correct the problem. Electrical cardioversions or implanted permanent heart pacemakers were used to correct the rapid heartbeat, noted George Wyse, MD, chair of the AFFIRM steering committee and professor of cardiology at the University of Calgary (Calgary, Alberta). Patients in the study were switched to alternate treatments, such as devices, when clinically indicated, Wyse noted.

"This study has important implications for treatment," Claude Lenfant, MD, director of the NHLBI, said in announcing the results. "It appears that the preferred therapy for many patients with atrial fibrillation may be a strategy to control the heart rate." He added, "The rate control approach may also be less costly due to a difference in the number of hospitalizations."

The study's results could drastically alter the way physicians treat atrial fibrillation. "The AFFIRM study has profound implications for the management of atrial fibrillation. For many physicians, it should fundamentally alter their approach to treatment," said Michael Domanski, MD, a cardiologist with the NHLBI and head of the institute's clinical trials group. Some patients, he acknowledged, may not benefit from the results of the study.

The study was conducted between 1995 and 1999 and involved 4,060 patients at 213 U.S. and Canadian sites. Patients were followed until October 2001. Patients were divided into two groups in the study: a rate control group and a rhythm control group. A total of 1,374 patients in the rhythm control group were hospitalized compared to 1,220 in the rate control group, researchers found. At the end of the study, 356 patients in the rhythm control group died from all causes compared to 310 in the rate control group. Adverse drug effects were more common in the rhythm control group and included bradycardia (abnormally low heart rate) and lung problems.