Noninvasive Microvolt T-Wave Alternans Test for Selective Targeting of Primary-Prevention ICDs Gets More Trial Support

November 16, 2006

November 16, 2006 (Chicago IL) -- In yet another study, though one with a few unique twists, the microvolt T-wave alternans (TWA) test (Cambridge Heart, Bedford, MA) demonstrated an ability to stratify patients with ischemic cardiomyopathy and a low LVEF according to risk for sudden death (SD), confirming its potential as a tool for identifying those most likely to benefit from an implantable cardioverter defibrillator (ICD) [1].

In the prospective, observational Alternans Before Cardioverter Defibrillator (ABCD) trial, presented here yesterday at the American Heart Association 2006 Scientific Sessions, the ECG-like microvolt TWA test's positive and negative predictive values were about the same as those of electrophysiologic (EP) testing, the highly invasive traditional way to assess SD risk, in a series of more than 500 patients followed for two years. But neither method alone was as predictive as their combination, suggesting there may be a role for somehow pairing the two tests to assess some primary-prevention ICD candidates, Dr Ottorino Costantini (Case Western Reserve University, Cleveland, OH) said in his formal presentation of the trial.

The ABCD trial, Costantini said, suggests that "the microvolt TWA test is as effective as EP studies in predicting ventricular arrhythmia events at one year" in patients like those entered--those with CAD, nonsustained ventricular tachycardia (VT), and an LVEF <40%. The test, he said, could improve the device's therapeutic efficacy--measured as number of devices implanted per lives saved--"with minimal risk to patients."

Moreover, he said in his presentation, the ABCD data show "that the two tests have a synergistic value, such that the event rate is highest in those with two abnormal tests, extremely low in patients with two normal tests, and intermediate in patients with discordant tests."

ABCD: Interaction between TWA and EP test results and their relationships to arrhythmic events in 566 patients

Parameter

TWA negative, EP negative

TWA positive, EP negative

TWA negative, EP positive

TWA positive, EP positive

Arrhythmic event rate (%)

2.3

5.0

7.5

12.6*

*p=0.016 vs both tests negative; TWA positive=TWA present or test results indeterminate

The study's goal was to show that the microvolt TWA test could help "get ICDs into the right patients," Dr David S Rosenbaum (Case Western Reserve University, Cleveland, OH) told heartwire . But he'd speculate that in addition, ABCD may help close the gap between the huge number of patients in the US who are currently eligible for primary-prevention ICDs based on LVEF and the smaller number currently receiving them. "Why? Because it's going to empower primary-care physicians to make the decision," he said. "By giving them a test that they can use to screen their patients, they could get a more confident prediction of risk. I think it would improve utilization." Rosenbaum and Costantini are ABCD co-principal investigators.

Is one test enough?

As covered extensively by heartwire , the microvolt TWA test resembles a stress ECG test but uses a proprietary algorithm to monitor for tiny variations in T-wave voltage. In most clinical evaluations, including ABCD, a presence of such TWA or "indeterminate" test findings are considered together as a marker of increased SD risk, while a TWA-negative test indicates a presumably low likelihood that ICD protection will ever be needed.

In one published study of more than 700 low-LVEF patients with CAD, a positive or indeterminate TWA test independently indicated more than twice the risks of all-cause and arrhythmic mortality over a mean of 18 months [2].

In March 2006, the Centers for Medicare and Medicaid Services (CMS) initiated Medicare reimbursement for the TWA test when used to further risk-stratify ICD candidates based on LVEF; a number of private third-party payers have followed the CMS lead. Several companies market TWA tests using different analytic methods, but the agency allowed reimbursement for only the Cambridge Heart product, the most extensively studied. Availability of reimbursement has been a major driver of the test's use.

Dr Stuart J Connolly (McMaster University, Hamilton, ON), who was not involved in ABCD, told heartwire that "what is most interesting [about its results], I think, is that the two tests actually work well together. Neither is particularly compelling as a way to select out the patients who are not going to benefit from an ICD--which is, I think, the goal that [the trialists] set for themselves."

The ABCD investigators, Connolly said, "are pointing us in the right direction. I don't know if this is going to mean that we're all going to start using T-wave alternans and EP studies, I rather doubt that." But the trial underscores the need for new risk-stratification tests, and "they need to be simple and easy to use. And when you put T-wave alternans and EP studies together, and you get two negative results, those patients probably don't need an ICD."

As the Costantini presentation's assigned discussant, Connolly said, "For me, the ABCD trial suggests a sequential approach, using multiple risk factors, with perhaps a T-wave alternans test first and followed up selectively with an EP study, to try to find the patients in whom both tests are negative."

In ABCD, 566 patients with CAD, an LVEF <40%, and a history of nonsustained VT but no sustained ventricular arrhythmias underwent both the microvolt TWA test and an EP study no more than 28 days apart. Their mean LVEF was 28%; 70% were in NYHA class 2-3 heart failure; and statins, beta blockers, and either ACE inhibitors or angiotensin receptor blockers were in use by more than 80% of patients.

The protocol required those with a positive result on either test to be implanted with an ICD. If both tests were negative, Costantini reported, an ICD was recommended but the decision left to the discretion of trialists at individual centers.

ABCD: Rates of positive and negative results for microvolt TWA and EP tests in 566 patients

Parameter

TWA positive*

TWA negative

EP positive

EP negative

Rate (%)

71

29

39

61

*TWA present or test results were indeterminate

No arrhythmic events were observed in 501 patients. The remaining 65 experienced VT/VF, SD, or antitachycardia pacing for VT termination; the event rate was 7.5% at one year and 14% at two years, Costantini reported. The positive predictive value of both tests was about 10% or less, and their negative predictive values were nearly the same, at about 96%.

In ABCD, the EP test's predictive value remained high over two years of follow-up, but the TWA test's predictive value fell off after about 12 to 15 months. That, Costantini said in his presentation, "suggests a potential need for periodic risk stratification in patients."

Repeated TWA testing might well be needed "to be reassured that a low-ejection-fraction patient, from whom you've withheld an ICD because of a T-wave alternans test, continues to be safe," Connolly agreed when interviewed. "As long as it keeps showing up negative, you'd be fine. And that might be reasonable."

Were ABCD patients at especially high-risk?

At a presentation on the ABCD trial held for reporters, Rosenbaum addressed a quirk in the trial's entry criteria, a history of nonsustained VT. It's a potential signal of increased risk that wasn't required in the most recent primary-prevention ICD trials, nor is it part of the device's reimbursement-eligibility criteria.

"You could argue that, on one hand, the patient population that we looked at may be at somewhat higher risk than what the current indications require, because they were enriched by the presence of nonsustained tachycardia. On the other hand, we looked at patients with an ejection fraction cutoff of 40%, rather than 35%, so that might put our population at somewhat lower risk. You could look at it either way," Rosenbaum said. "And based on the event rates in this population.....I think you could estimate that the overall background risk of the population was comparable to those who have been studied in recent primary-prevention trials, despite those subtle differences in design."

Asked by heartwire to comment on the issue, electrophysiologist Dr Andrea Natale (Cleveland Clinic, OH), who wasn't involved in ABCD, seemed to agree. He said the trial's population appeared similar to the range of patients in the US who would qualify for primary-prevention ICD reimbursement. "I think you can apply these results to the broad population," he said.

When interviewed, Connolly said he doubts that nonsustained VT as a study entry requirement elevated the population's risk status. "It's questionable whether that makes any difference anymore."

The ABCD trial was sponsored by St Jude Medical. Rosenbaum reports being a consultant to Cambridge Heart. Connolly said he has received research grants from and has consulted for St Jude Medical and Boston Scientific. Natale reports receiving research grants from Medtronic, Boston Scientific, St Jude Medical, Biotronik, Biosense-Webster, and Acuson and speaking honoraria from Biosense-Webster, Boston Scientific, Medtronic, and St Jude Medical.

  1. Costantini O. The Alternans Before Cardioverter Defibrillator (ABCD) trial: A non-invasive strategy for primary prevention of sudden cardiac death using T wave alternans. American Heart Association 2006 Scientific Sessions; November 15, 2006. Late Breaking Clinical Trials III.

  2. Chow T, Kereiakes DJ, Bartone C, et al. Prognostic utility of microvolt T-wave alternans in risk stratification of patients with ischemic cardiomyopathy. J Am Coll Cardiol 2006; 47:1820-1827.



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