NEW ORLEANS, Louisiana Some of the most eagerly awaited data from this year's American College of Cardiology (ACC; Bethesda, Maryland) scientific sessions was presented at a late-breaking clinical trials session to an overflow crowd in one of the largest halls available in the sprawling Ernest N. Morial Convention Center that sits alongside the Mississippi River. In a room that to its occupants seemed to be holding virtually all of the estimated 20,000-plus attendees at this year's conference, investigators in the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) presented findings that implantable cardioverter defibrillators (ICD) lowered the risk of sudden cardiac death by 23% over the length of the five-year study compared to a placebo and, surprisingly, proved better than a widely used anti-arrhythmia drug, beating the main goal of the trial.
The SCD-HeFT study, a 2,521-patient trial begun in 1997 under the sponsorship of the National Institutes of Health (NIH; Bethesda, Maryland), divided heart-failure patients into three groups, all three of which received conventional drug therapy. One was a control group that received conventional drugs. Another group received conventional drugs plus an anti-arrhythmia drug, and a third group received conventional drugs plus an ICD. The goal of the study was a 25% drop in mortality from all causes for the groups with ICDs and anti-arrhythmia medication.
The NIH said in a statement that an ICD "significantly reduces deaths in heart failure patients." Michael Cain, MD, president of the North American Society of Pacing and Electrophysiology (NASPE; Natick, Massachusetts), said in another statement that these latest findings "build upon a growing body of evidence demonstrating the efficacy of ICDs for a greater number of Medicare patients, including a broader range than other trials those who have not experienced a heart attack." He added that the research confirms studies such as Guidant's (Indianapolis, Indiana) MADIT II (Multicenter Automatic Defibrillator Implantation II Trial), "which also showed a favorable impact of ICD therapy on total mortality in patients with ischemic disease." Cain went a step further in his comments, saying that in light of the NIH study, NASPE recommends "that CMS [Centers for Medicare & Medicaid Services] expand ICD coverage to those Medicare beneficiaries who meet the criteria established in the MADIT II and SCD-HeFT trials."
The "unexpected" finding of the study was that amiodarone actually increased death rates in patients with severe heart failure. However, it did not do so in patients with moderate heart failure, where it was used as a primary preventative agent against death. According to Gust Bardy, MD, of the University of Washington Medical Center (Seattle, Washington), who presented the SCD-HeFT results, "The study also shows that amiodarone, when used as a prophylactic medication, does not improve survival."
Study results showed that patients who received ICDs had a mortality rate of 17.1% over three years compared to those who received placebo (22.3%) and those who received amiodarone (24%). After five years, patients with ICDs had a mortality rate of 28.9% while the amiodarone and placebo patients had a 34.1% and 35.8% mortality rate, respectively. Bardy said the results were "unequivocal," adding, "if you've got mild to moderate to moderate-severe heart failure, you should get an implantable defibrillator."
Cardiologists attending the ACC meeting hailed the trial as a landmark study likely to greatly increase the use of ICDs. Richard Luceri, MD, director of the Arrhythmia Center at Holy Cross Hospital (Fort Lauderdale, Florida), whose center had the most patient implants in the SCD-HeFT trial, said people should not get caught up in incremental data. "I look at the totality of the study," he told Cardiovascular Device Update in a hallway conversation, "and [a] 23% reduction is a pretty hefty number." He also noted that if this were a study on a beta blocker or statin drug, "everyone would be given it and there wouldn't be any question. The fact that this device costs money [about $25,000 apiece] will give hesitation to some, but in fact, the numbers speak for themselves these are lifesaving."
Luceri said the results are "absolutely consistent" with other trials on ICD use. "The most important aspect of this study is the fact that we took a much broader population base. The entry here was heart failure," he said, whereas, for example, "MADIT I had the sickest patients with the highest risk." He said the way to visualize the expanded patient population was to think of an inverted pyramid, with the MADIT trial at the point and SCD-HeFT at the widest part of the triangle. Between those are the Multicenter Unsustained Tachycardia Trial (MUSTT) and the MADIT II trial. "Not only does [SCD-HeFT] validate the other studies," Luceri said, but as a bonus, "you're catching a giant [patient] population." Another ACC attendee, Emanuel Kostacos, MD, of the University of Pennsylvania (Philadelphia, Pennsylvania) told Reuters: "I think there will be a potential explosion of defibrillator use in all kinds of patients with heart failure."
The findings could lead to wider use of ICDs and more liberal insurance reimbursement for them, expanding the $4 billion market for makers of the devices, such as Medtronic (Minneapolis, Minnesota), a trial sponsor whose devices were used in the study, Guidant and St. Jude Medical (St. Paul, Minnesota). Medtronic had predicted that a positive result could mean 600,000 new patients in the U.S. added to those who would benefit from an ICD. That compares with about 600,000 patients in the U.S. who right now could benefit from the devices. Far fewer actually have ICDs.
While Medtronic and the other players in the field are obviously excited about the potential for an enhanced ICD market, Steve Mahle, president of Medtronic Cardiac Rhythm Management, said in a conference call that the "important thing to remember about this trial is that it greatly enhances physicians' ability to identify and treat heart failure patients at risk for sudden cardiac death." Joseph Smith, MD, chief medical officer of Guidant's Cardiac Rhythm Management business, said the trial "demonstrates the ... benefits of implantable defibrillator therapy in a new and large patient group."
These companies received a boost in their hopes for wider ICD use as a Medicare official said in a conference call with reporters that widely positive results from a major clinical trial supporting broader use of devices are likely to prompt expanded Medicare coverage. "There are clearly going to be identified additional patients who will benefit from these defibrillators," said Sean Tunis, MD, chief medical officer at CMS. Tunis said that he expects an "external request" to reopen the ICD decision process in the next several weeks, but Marshall Stanton, MD, vice president and medical director of Medtronic's CRM business unit, said the company already has been in contact with CMS regarding the study.
Tunis added that if CMS decides to examine extending its coverage for such devices, the process likely would take much less than the normal six to nine months. "These are lifesaving devices, and this is data from an extremely well-designed trial," he said. He added that the trial's finding that ICDs seemed to have more benefit in Class II heart failure patients than in sicker Class III patients also will require a closer look. "If the data parse out the way it looks, it [appears] a relatively less-severely ill population benefits from defibrillators."
St. Jude Medical definitely benefited from the positive results reported from its RHYTHM ICD trial. The company, which released the results at an analyst meeting held at the Hilton Riverside Hotel, said the RHYTHM (Resynchronization HemodYnamic Treatment for Heart Failure Management) trial showed a statistically significant improvement in peak VO2 and exercise duration for patients treated with CRT. Additionally, the company said that all prospectively defined primary safety and efficacy endpoints of the study were successfully met. St. Jude said it believes the trial results will clear the way for regulatory approval of its new Epic HF heart failure/defibrillator device by the mid-May NASPE meeting in San Francisco, California.
The Epic HF would give St. Jude a foothold into the cardiac resynchronization therapy defibrillator (CRT-D) market, and allow it to compete with Guidant and Medtronic, both of which received approval from the FDA for such devices in 2002. The devices, which treat the symptoms of heart failure as well as provide shocks to the heart, if it gets out of sync, now account for around 30% of ICDs sold. At its healthcare conference in early January, JPMorgan (New York) said it expects St. Jude's "highly competitive" CRT devices to capture significant market share from Medtronic and Guidant, and the addition of a CRT-D device would greatly enhance the company's offerings.
The primary efficacy endpoint of the RHYTHM ICD study was improvement in cardiac function as measured by patient peak VO2 during cardiopulmonary exercise testing. The goal of the trial was to improve VO2 after six months. Secondary goals included changes in heart-failure class and results of a six-minute walk test. Patients in the trial, which included about 205 participants at 50 sites, were randomized into two groups. All were given Epic devices, but some had the CRT capability left off, while others had it turned on. At the start of the trial, patients whose CRTs were left off had a peak VO2 of 12.8, compared with 11.2 for those whose CRTs were left on. After six months, the "off" group worsened by 1.4 points, while the "on" group improved by 0.52 points. This easily met the trial's goal, was statistically significant and compared favorably with Guidant and Medtronic's results, St. Jude said. The clinical trial was based on an expectation that the CRT arm of the study would show a 1.6 ml/kg/min improvement in peak VO2 compared with the control group, which did not have the CRT feature activated. The actual observed improvement level for CRT compared to control was 1.93 ml/kg/min.
"This is a significant prospective, randomized study, which adds to the growing body of evidence supporting the therapeutic effectiveness of cardiac resynchronization therapy as an adjunct to optimal medical therapy for heart failure patients," said Eric Fain, MD, senior vice president, development and clinical/regulatory affairs for St. Jude Medical's Cardiac Rhythm Management business, who presented the trial results for the first time during the analyst meeting. "The RHYTHM data stands on its own and is also a strong result compared with others," he added. Fain displayed data showing that Guidant's Contak CD trial had a target peak VO2 level of 2 ml/kg/min and came in at about 1.8 ml/kg/min in the sub-group analysis that looked at Class III/IV patients. Medtronic's InSync ICD trial also had a target of 2 ml/kg/min, and it reported median data that came in at 1ml/kg/min, while the actual mean data reported came in at .08 ml/kg/min. He also noted that the patient population enrolled in this study "was a sicker population than was enrolled in the other companies' trials."
The Epic HF ICD offers negative AV/PV hysteresis with search capability designed to ensure a high percentage of biventricular pacing. St. Jude said it is the world's smallest high-voltage cardiac resynchronization device, designed to make implantation easier while improving patient comfort and cosmetic appearance. The device delivers 30 joules of energy in a physiologic-shaped 36 cc ICD.
The total time of follow-up for the study was 1,525 patient months with an average follow-up time of about 8-1/2 months.
The results of two other St. Jude-sponsored trials the PAVE (Post AV Nodal Ablation Evaluation) and DINAMIT (Defibrillator IN Acute Myocardial Infarction Trial) disclosed during a late-breaking clinical trial session of the ACC meeting showed decidedly mixed results. The data from the PAVE study indicated potential benefits of cardiac resynchronization therapy in non-heart failure patient populations, while the data from the DINAMIT study showed no overall mortality benefit of ICD therapy in patients following a recent acute myocardial infarction.
PAVE is the first large-scale, prospectively randomized study to evaluate biventricular (BV) pacing vs. standard right ventricular (RV)-only pacing in patients undergoing ablate-and-pace therapy for atrial fibrillation (AF). The trial randomized 165 patients undergoing ablate and pace to BV or RV pacing and followed them for six months. In patients with chronic AF treated with AV nodal ablation (targeted destruction of the AV node, the heart tissue that conducts the electrical impulse from the atria to the ventricles), BV pacing produced a statistically significant improvement in cardiac function over standard RV pacing as measured by the six-minute walk test. In these same patients, biventricular pacing also produced a statistically significant improvement in functional capacity over standard right-ventricular pacing as measured by peak VO2 and exercise duration. BV-paced patients experienced fewer deaths during the trial than RV-paced patients.
Based on these results, the PAVE study suggests that BV pacing should be the preferred mode of pacing therapy in patients with chronic AF undergoing AV nodal ablation. "The objective of the PAVE trial was to prospectively compare the effect of BV pacing vs. RV pacing in patients undergoing ablate-and-pace therapy," said Rahul Doshi, MD, of the Sunrise Hospital (Las Vegas, Nevada), the leading enroller of patients in the study. "Our results show a significant benefit of BV pacing over RV pacing in exercise and functional capacity for patients with chronic AF and AV nodal ablation." A previous St. Jude-sponsored trial, DAVID (Dual Chamber And VVI Implantable Defibrillator), had demonstrated the potential detrimental effects of active RV pacing in patients with low ejection fractions who received ICD therapy. The PAVE study looked at the potential benefits of pacemaker-based CRT therapy in a patient population required to receive ventricular pacing, and reinforces the conclusions from DAVID that RV pacing in patients with left-ventricular dysfunction may be detrimental.
Data from the PAVE study have been submitted to the FDA in support of a premarket approval application for the company's Frontier CRT system in post-AV nodal ablation cases. There were about 37,000 ablate-and-pace procedures for AF in the U.S. in 2003, St. Jude said. Health Research International predicts an annual growth rate of 18%, with an estimated 63,000 procedures annually by 2006. St. Jude reaffirmed its previous guidance that it expects FDA approval of the Frontier system by the time of the NASPE meeting in May.
DINAMIT was a prospective randomized trial designed to assess ICD therapy for prevention of death in high-risk patients early after acute myocardial infarction (AMI). Investigators had thought that since ICDs have been shown in large trials to prevent deadly arrhythmias, they might be of benefit if implanted early after heart attack in high-risk patients. Now they are not so sure.
Inclusion criteria for the study included a heart attack within six to 40 days, a left ventricular ejection fraction (LVEF) of less than or equal to 35%, and signs of impaired cardiac autonomic modulation (i.e. depressed standard deviation of sinus RR intervals (less than or equal to 70 ms) or elevated heart rate (mean RR interval less than or equal to 750 ms), and an age range of 18 to 80. In the study, 674 heart attack survivors were randomized to prophylactic (preventive) ICD therapy vs. no therapy, in addition to optimal medical treatment, within four to 40 days after their attack. They were then followed up for up to four years.
When the results were analyzed, it was found that ICD therapy did not decrease all-cause mortality, nor did it significantly decrease arrhythmic mortality in the studied patient population. The study concluded, based on these findings, that ICD therapy is not beneficial in patients with a recent myocardial infarction, even if they have risk factors for arrhythmic death. Other therapeutic strategies need to be identified and investigated to reduce non-arrhythmic mortality in this patient cohort.
"The DINAMIT study showed that ICD therapy can significantly reduce the risk of sudden death in patients with a recent myocardial infarction who are at high risk of arrhythmic death due to extensive myocardial scarring and autonomic imbalance, but that this does not result in reduction in total mortality," said Stefan Hohnloser, MD, professor of medicine at J.W. Goethe University (Frankfurt, Germany), one of the study's principal investigators, during a press briefing. "ICD therapy did not prove to be beneficial in patients early after acute myocardial infarction," said Stuart Connolly, MD, professor of medicine at McMaster University (Hamilton, Ontario), also a principal investigator in the DINAMITstudy. "This is most likely because their burden of myocardial ischemia puts them at risk of cardiac-related mortality from causes other than sudden cardiac death."
Previous large-scale clinical trials of patients with ischemic heart disease, low ejection fractions and a history of AMI demonstrated that this patient group will experience decreased mortality when ICD therapy is utilized. These clinical trials have generally focused on patients whose AMI event occurred greater than six months prior to their ICD implant. The DINAMIT results demonstrate that the overall mortality benefits of ICD therapy in a post-AMI patient population do not extend to those who receive an ICD shortly after their AMI event, as other causes of death offset the observed decrease in arrhythmic mortality. Further analysis of the data from these studies will attempt to find evidence of other factors that lead to the differences in non-arrhythmic deaths.
"This is a neutral finding," Hohnloser said. "Arrhythmic mortality was significantly reduced in the ICD group compared to the control group, but that was counterbalanced by an increase in nonarrhythmic deaths in the U.S." He concluded that these results do not mean that prophylactic ICD therapy has no benefit at all, "but it does indicate that early after a heart attack, ICD therapy has no net benefit in terms of mortality."