ALPHA Lends Support for TWA Testing in Nonischemic HF

March 26, 2007

March 26, 2007 (New Orleans, LA) - A new study of the noninvasive microvolt T-wave alternans (TWA) test in patients with nonischemic cardiomyopathy shows that the one third of patients who test normal will likely not benefit from an implantable cardiac defibrillator (ICD).

Dr Gaetano M De Ferrari (San Matteo Hospital, Pavia, Italy) presented the findings of the T-Wave Alternans in Patients with Heart Failure Trial (ALPHA) during a late-breaking session here today. He said: "The negative predictive value of the test is the most important finding of this study. Patients with a normal TWA test have a very good prognosis and are unlikely to benefit from ICD therapy."

Panelists at the late-breaking session commended De Ferrari on his study, which they said "was difficult to do." But they pointed out that the group of patients with abnormal TWA tests appeared to be sicker and therefore wondered whether this could have contributed to the findings. De Ferrari said this was true to a certain extent, but multivariate analysis controlling for confounding factors still revealed a significant difference between the two groups in terms of the primary end point--a combination of cardiac death and life-threatening ventricular arrhythmias.

A pure primary-prevention population

De Ferrari explained that patients with heart failure have a high risk of mortality, 50% of which is attributable to sudden death. "However, we implant many ICDs that will never work. We need to better refine the strategy to identify which patients need the device, for medical, psychological, and economic reasons."

The TWA test monitors for minute beat-to-beat variations in the electrocardiographic T-wave during exercise stress testing and is performed using the Cambridge Heart/St Jude Medical's ECG-analysis algorithm for the risk stratification of ICD candidates.

De Ferrari said that although there is considerable evidence that TWA testing is quite effective at identifying ischemic patients at high risk of sudden death, "the data regarding the role of this technique in patients with nonischemic heart failure are limited and conflicting. The search for reliable risk stratifiers [in this patient population] has been very frustrating."

In the ALPHA study, 446 NYHA stage 2 and 3 heart-failure patients with cardiomyopathy of nonischemic origin and left ventricular ejection fraction (LVEF) of less than 40% underwent a TWA test and were followed for 18 to 24 months to assess the rates of the combined primary end point, as well as the secondary end points of total mortality and a combination of arrhythmic death, life-threatening arrhythmias, and hospitalization.

Patients were excluded from entering the study if they had a pacemaker or ICD implanted: "We wanted to have a pure primary-prevention population," De Ferrari explained.

Abnormal test linked to fourfold risk of death, arrhythmias

Of the 446 patients, 65% (n=292) had an abnormal TWA test and 154 had a normal result. According to convention, patients with TWA findings labeled "indeterminate" (n=92) were combined with those who had an abnormal TWA test.

Patients with an abnormal TWA test had a fourfold higher risk of the primary end point--cardiac death and life-threatening arrhythmias (hazard ratio 4.01; p=0.002), De Ferrari said. They also had a fourfold higher total mortality (HR 4.60; p=0.002) and a fivefold higher risk of arrhythmic death, life-threatening arrhythmias, and hospitalization (HR 5.53; p=0.004).

Currently, "all patients with stage 2 and 3 disease with LVEF less than 35% are considered candidates for an ICD. The ALPHA study strongly suggests that one third of these patients will have a normal TWA test and will not benefit from the ICD. Knowing this, we are able to better treat the two thirds of patients that really need the device," De Ferrari said.

Events during follow-up

Event All patients (n=446) Abnormal TWA (n=292) Normal TWA (n=154)
Total mortality 28 25 3
Cardiac death 18 16 2

Arrhythmic death

7 7 0
Symptomatic sustained VT or VF 11 9 2
Hospitalization 85 61 24

VT=ventricular tachycardia; VF=ventricular fibrillation

Provocative but provisional data

Both panelists at the late-breaking session congratulated De Ferrari on the trial but pointed to baseline differences between the two groups. "These data are provocative but provisional because of the imbalances between groups," said Dr Douglas L Mann (Baylor Heart Clinic, Houston, TX).

De Ferrari agreed that those with an abnormal TWA test were, on average, 2.5 years older; slightly more were in NYHA class 3 and had a worse quality of life and had worse LVEF; and there were differences between them in terms of digitalis treatment. "But we did a multivariate analysis controlling for these baseline differences and we still found a significant hazard ratio of 3.2," he noted.

Asked by heartwire what he thought the implications of his study were, De Ferrari said only about 13% of patients who needed ICDs in the US actually got them. "We are not getting to the patients the guidelines suggest we can get to. This is clear. This test is very helpful in identifying the population from whom, for the time being, we can withhold ICDs."

Dr Mariell Jessup (Hospital of The University of Pennsylvania, Philadelphia), the other panelist at the late-breaking session said: "These are very intriguing data. It's not clear to me why the implementation of ICDs is so low. But it's hard to picture how this is going to be solved by TWA testing. . . . There are many, many reasons why people aren't putting defibrillators into patients whom they think might benefit."

Future studies will have to monitor shocks

Mann said the ALPHA findings will need to be confirmed, and De Ferrari agreed. However, the Italian researcher pointed out that large numbers of patients would be required. "We could look at people with EF below 35% and a positive TWA who are implanted with ICDs and then also a study in which those with a negative TWA result are randomized either to ICD or conventional treatment. I don't know if this is possible given the guidelines, but if you could show no survival difference between the implanted and nonimplanted patients if they have a normal TWA test, that would be great."

Mann said another way to assess the situation would be to follow all people with ICDs for shocks, do a TWA test, and then follow them longitudinally to see how predictive the test is. Again, De Ferrari agreed but pointed out that "the number of shocks outnumber the number of sudden deaths by a factor of 3 to 1. That is the advantage of this study--most of our patients did not have ICDs. This is very difficult to repeat. In the future we will have to rely on shocks, which are not the same as sudden death."

St Jude Medical acquires rights to Cambridge Heart's TWA test

Just last week, Cambridge Heart announced a three-year exclusive sales and marketing agreement with St Jude Medical Inc, under which St Jude will be responsible for marketing Cambridge Heart's TWA test (HearTwave II Microvolt T-Wave Alternans System) and sensors to cardiologists and electrophysiologists in North America [1]. Cambridge Heart will continue to market the HearTwave II system to internal medicine and primary-care practices and will manage the installation of systems, the training of new customers, and the servicing of the equipment.

There are an estimated 10 million to 12 million individuals in the US with underlying heart disease who are at significantly higher risk for sudden cardiac death than the general population, and the $300 to $400 TWA test "allows physicians to identify, noninvasively, those who will most likely benefit from ICD therapy," says Dr Laurence Blumberg (vice president of business development, Cambridge Heart). "Our alliance with St Jude Medical, a leader in the $10-billion cardiac rhythm management market, is a critical step in expanding patient and physician awareness and the need for TWA testing," he said.

  1. Cambridge Heart. Cambridge Heart Announces Co-Marketing Agreement with St. Jude Medical and a $12.5 Million Equity Investment [press release]. March 21, 2007. Available at: https://phx.corporate-ir.net/phoenix.zhtml?c=106685&p=irol-newsArticle&ID=976331&highlight=

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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