CDU Washington Editor

BOSTON – The FDA said in a September 2005 report on implantable cardiac defribrillator (ICD) and pacemaker malfunctions that the annual number of ICDs implanted in the U.S. “increased from fewer than 10,000 implants in 1990 to close to 100,000 in 2002.” However, the medical systems in other Western nations are apparently not quite as aggressive in making use of ICDs.

According to a presentation by Wyn Davies, a consulting cardiologist at St. Mary’s Hospital (London), during the annual meeting of the Heart Rhythm Society (HRS; Washington) held here in May, the rate of ICD implantation in the U.S. exceeds that of the UK by a factor of 10. Another attendee at Heart Rhythm 2006 discussing the subject off the record put the multiplier at a more conservative factor of five, which is still a stark contrast if one assumes that there is no proportional difference in the health status of these two nations.

As a point of comparison, the National Heart, Lung and Blood Institute at the National Institutes of Health (NIH; both Bethesda, Maryland) estimates that about 1 million Americans suffer heart attacks yearly. Given an estimated current U.S. population of about 298 million, the prevalence of heart attacks is about 3.4%. The population of the UK will be about 60.6 million in July, and the UK Department of Health estimates that “275,000 people have a heart attack annually.” This yields a rate of about 4.2%.

Assuming that the rates of myocardial infarction roughly parallel those of sudden cardiac death due to rhythm problems, it would seem that a huge disparity exists between the U.S. and the UK in terms of ICD use, especially given that infarction is a relatively more common occurrence in the UK. If the rates of other heart diseases track those of infarction in both nations, this apparent disparity in the use of ICDs widens.

Regardless of how these numbers actually tumble out, one thing seems incontrovertible: Americans get ICDs at a far greater rate than their counterparts in other Western nations. It might be pertinent to ask whether cardiac arrhythmias are over-treated in the U.S. or under-treated in the UK.

It should be noted up front that many ICDs are installed as a preventive measure for high-risk patients with no history of fibrillation or flutter. Precisely what percentage of ICDs is installed on this basis may be impossible to determine if only because different doctors employ different standards to define such an event. If prophylaxis is not a standard of care in the UK, much of this disparity disappears (the Centers for Medicare & Medicaid Services approved ICD coverage for preventive use in 2005).

So it should be noted that attendance at an event populated by electrophysiologists leaves no doubt that prophylaxis is a very compelling notion for American doctors. On the other hand, the recent disclosure that antibiotics are, or at least were, over-prescribed in the U.S. makes it difficult to avoid the suspicion that ICDs are overused in the U.S.

One of the filtering mechanisms that electrophysiologists use to undergird the decision whether to recommend ICD implantation is that of risk analysis, but this paradigm is, predictably, also the subject of some controversy. One of the debate sessions at the HRS meeting was on this subject.

In that debate, Greg Flaker, MD, director of the electrophysiology lab at the University of Missouri Hospital and Clinics (Columbia) argued that risk analysis creates serious ethical quandaries, while Arthur Moss, MD, professor of medicine at the University of Rochester Medical Center (Rochester, New York), argued the opposite, that risk analysis still has a place in care decisions.

Flaker’s arguments hinged largely on the ethics of denying ICDs to individual patients from subgroups whose members “swim against the data,” while Moss made his case from a systemic standpoint, including the assertion that patients with two or more risk factors experienced a mortality rate of 45% over a three-year span. Moss based his numbers on the Multicenter Automatic Defibrillator Implantation II trial (MADIT II).

Flaker said that “secondary prevention ICD trials have demonstrated a modest mortality reduction,” and he urged the audience to “beware of subgroup” analysis, making the case that it may be dangerous to be a member of a subgroup who generates an outcome that “swims against the data.”

Moss proposed that risk stratification for those with ejection fractions (EFs) less than 30% is still needed, given the downward trend in incremental cost effectiveness for this patient sub-population with demonstrated co-morbidities. Referring to the MADIT II trial, he said that for those with EFs lower than 30%, the three-year non-ICD mortality rate was shown to be 31% and the ICD mortality rate over the same span for the same population was 22%. He concluded that the reduction in mortality was likely to be on the order of 9% and said that a “reasonable inference” was that surgeons had to implant 11 ICDs in order to save the equivalent of one life-year.

Moss presented data that further suggested that “the cost per life-year saved is $235,000” in the three years covered by the MADIT II trial, but that any figures beyond those three years had to be generated by extrapolation and conjecture. He suggested that the mortality rate of 45% over three years in patients with two risk factors was a compelling case for continued risk stratification.

The MADIT II trial, in which Moss participated, was designed in part to examine how patients on conventional drug therapy fared in contrast to those on ICDs and drug therapy, and the Data Safety and Monitoring Board halted enrollment in November 2001 due to the reduced risk of death in patients involved in the study. However, those on ICDs also experienced higher rates of new heart failure and more exacerbated existing heart failure. Moss closed his presentation by insisting that stratification leads to better efficacy and lower systemic cost.

In a brief rebuttal discussion, Flaker insisted that Moss’ data was “unsound” because of the inference that age was more decisive than “physiological data,” and Moss replied that MADIT II did not employ an age cut-off for enrollment. However, in support of his thesis that stratification makes sense, he noted that he found it “paradoxical” that “those younger than 60 got no benefit from ICDs.”

Anne Curtis, MD, president of the Heart Rhythm Society and chief of cardiology at the University of South Florida (Tampa), shed some additional light on the question.

When asked if ICDs are implanted more often than is necessary, Curtis told Cardiovascular Device Update that “I would not agree with that. You could argue that we’re not implanting enough in the United States” due to the difficulty in establishing which patients are really at risk of sudden cardiac death. She confirmed that prophylactic use is not common in the UK, but nonetheless insisted that “Implant rates are still well below” that which could be used to substantial benefit to American patients.

“There are a lot of tools” for risk stratification, Curtis remarked, but they are not powerful enough to enable the kind of distinction that would eliminate installation in patients who are at low or zero risk. She commented that T-wave alternans may prove a more viable risk determination tool than any currently available, but as things stand, doctors simply do not have a tool that lays out risk in an unambiguous fashion.

T-wave alternans is a variation in the T-wave, a relatively inconspicuous feature of heartbeat. However, patient heartbeats must be forced to more than 100 beats per minute to test this phenomenon and the clinical trial data on T-waves is not yet sufficient to establish their predictive power for risk analysis purposes. CMS now pays for, but does not require, T-wave analysis for ICD candidates.

Curtis also pointed out that only 5% of those who experience sudden cardiac death are revived. She asked, “what is our tolerance” for not implanting someone who seems to have no risk but who later has an event?

Anti-tachycardia pacing debated too

Another debate session dealt with anti-tachycardia pacing (ATP), specifically asking whether ATP function should be programmed into all ICDs. Arguing the case for ATP inclusion was Mark Wathen, MD, director of arrhythmia research at Vanderbilt University (Nashville, Tennessee), while Gust Bardy, MD, founder of the Seattle Institute for Cardiac Research (Seattle), made the opposite case.

Wathen led off with the caveat that ICDs are installed to abort cardiac death and that “anything beyond this function has to be considered carefully.” He suggested that the debate is really about whether ATP programming should provide the first line of therapy in advance of full cardiac shock, a subject that moderator Emile Daoud, MD, assistant professor at Riverside Methodist Hospital (Columbus, Ohio), admitted he was not aware was the subject of this much controversy.

Wathen noted that traditional shock is the gold standard, effectively treating more than 99% of cases of ventricular fibrillation and 87-97% of cases of ventricular tachycardia. He also took ventricular flutter off the table in this discussion, as ATP is not effective in dealing with it. Wathen insisted that mortality issues do not plague ATP because no available data ascribes death directly to ATP.

Citing data from the Pacing Reduces Shocks for Fast Ventricular Tachycardia II (Pain Free Rx II) trial, for which he was the lead investigator, Wathen said that the risk of sudden death was essentially the same in both arms, each of which lost two patients (out of a total enrollment of more than 600 randomized subjects).

Some of the concerns about the use of ATP revolve around the prospect that it could fail to restore normal rhythm and delay a restorative shock. However, Wathen said that available data showed that the success rate of shock was identical with and without prior ATP. He further made the case that ATP “is the superior therapy” in part because it reduces the pain experienced by patients. However, ATP did cut down on the shock events for fast ventricular tachycardia (fast VT), reducing shocks from 67% in the control arm to 20% in the treatment arm of the Pain Free Rx II study.

Bardy’s opening salvo consisted of the assertion that the “use of surrogates” can be misleading. He pointed out that cardiologists typically do not know what killed most of their patients, partly because most ICDs are not extracted from the deceased and returned to the clinician.

Bardy decried the “rampant presumption” in the medical establishment that a faster response to cardiac events is necessarily better, pointing out that the apparent lag in response time by the traditional ICD shock cycle, much of which is incurred in charging, is useful because it allows many transient events to pass without needless shock.

He added that this delay also allows data collection, but said that with the inclusion of ATP function into ICDs, “by definition, you’ve turned [the defibrillator] into a hair trigger.”

Bardy cited the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) results that were published in The New England Journal of Medicine in January 2005. The general finding from this trial was that ICD therapy cut down on all-cause mortality by 23% compared to placebo, and he said that the trial employed “a dumb old shockbox” in a trial that reduced decision-making by electrophysiologists. “The whim of obliterating every abnormality will only get you into trouble,” he insisted.

Bardy pointed out that nearly three of four patients in the Pain Free Rx I trial needed a shock, and described many of the numbers presented by Wathen as “inappropriate statistics” derived from a “fishing exercise.” He concluded that ATP should be reserved “for the frequent flier.”

In the rebuttal discussion, Wathen admitted that “we are overtreating grossly,” but made the case that ATP reduces shocks and can increase the therapeutic value because it reacts more quickly than the typical ICD shock function.

For his part, Bardy stated that “it really bothers me” that the total number of deaths (most of which were not attributed to ATP therapy) in the ATP arm in Pain Free II far outstripped the number of deaths in the control group, 32 to 24. He compared the fatality data to the Vioxx problems, asking where the Medical Data Safety Board was during the conduct of this trial.

Sorin, Medtronic in algorithm fray

Cardiac rhythm management (CRM) devices are widely known to be one of the most promising businesses in the medical device industry, so much so that Dennis Zogbi projected in February that CRM hardware will sell to the tune of nearly $15 billion worldwide by 2010. Despite the promising numbers, the variety of devices designed to fix the faulty heart may have taken even the more jaded observers by surprise by now.

However, given all the diagnostic differentiation seen at gatherings such as the HRS conference, perhaps the variety is not surprising after all. As an example, acquired atrioventricular sinus node block, as measured by the ankle-arm index, has generated a substantial number of papers over the past couple of decades, and it can generate a similar state of distress to humans as imposed by ventricular tachyarrhythmia.

The trick for device makers is engineering a device, such as a defibrillator, that can distinguish between these two events.

The scenario for ventricular tachyarrhythmias is fairly widely understood: several studies have sent the clear message that about 55% of defibrillator patients need help only with the atrium because the ventricle is essentially healthy and the atrioventricular sinus node is still passing the beat, so to speak, from the atrium to the ventricle. This slight majority of patients with no discernable ventricular tachyarrhythmias usually needs no help with ventricular function, but a defibrillator must nonetheless be able provide ventricular stimulus when needed.

Several firms have generated algorithms to deal with this state of affairs, but the Sorin Group (Via Crescentino, Italy) has jumped into the fray with its AAISafeR software, putting the firm in direct competition with Medtronic (Minneapolis) and its Managed Ventricular Pacing (MVP) software.

Both these algorithms seek to cut down on unnecessary ventricular pacing, but Sorin bills AAISafeR as “the first pacing system capable of delivering safe and physiological single chamber therapy while collecting and analyzing dual chamber diagnostic information,” according to the firm’s literature. Sorin’s subsidiary, ELA Medical (Arvada, Colorado), packages its Ovatio series of defibrillators with the AAISafeR software and another algorithm, the PARAD+, which is designed to distinguish slow ventricular tachyarrhythmia and normal-rate ventricular tachyarrhythmia. ELA Medical also has packaged the AAISafeR into its Symphony line of pacemakers.

ELA came to Heart Rhythm 2006 with something to celebrate. The firm snared a premarket approval from the FDA for the Ovatio, which includes single- and dual-chamber ICDs, on May 16, the day before the conference began. ELA touts the DR as consuming only 29cc of space, giving it an advantage over bulkier units with patients in both comfort and cosmetic considerations.

Jonathan Sahu, MD, assistant professor of medicine at Rush Medical College (Chicago), told CDU that AAISafeR keeps needless ventricular pacing to a range of 0.1% to 0.2%, but that Medtronic’s MVP “has a ventricular pacing rate of about 4%.” Sahu said that Sorin’s algorithm “is the best on the market” at present and can cover low ventricular tachycardias. “There is some evidence that we may be underestimating” SVTs, which devices with a high pace preset will tend to miss. However, he reassured that “it doesn’t compromise the patient to set the pace at a low rate” in an effort to catch such events.

Sorin’s literature claims that the AAISafeR program deploys four tests to keep track of AV block by using the right ventricular lead to provide enough data to keep track of any AV node block tendencies. The firm says that “79% of non-selected patients experience 0% right ventricular pacing with this algorithm.”

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