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Evidence regarding clinical use of microvolt T-wave alternans

2002 † indicates values not explicitly reported, but confidently estimated from other reported information. ICD ventricular


Introduction
Microvolt T-wave alternans (MTWA) testing using the analytic spectral method is a noninvasive means of stratifying patients for the risk of sudden cardiac death (SCD). Many studies conducted in patients without implanted ICDs have found MTWA to be a highly accurate risk stratifier and, in particular, have found that the rate of ventricular tachyarrhythmic events (VTEs) among patients who test MTWA negative is exceedingly low [1][2][3][4][5][6][7] suggesting that ICD therapy may not benefit such patients 8 . As a result, MTWA has been proposed as a means of guiding implantable cardioverter defibrillator (ICD) therapy in patients with risk factors for SCD but without a prior history of sustained VTEs (primary prevention patients).
With the advent of the MADIT II 9 and SCD-HeFT 10 trials, clinical guidelines have recommended prophylactic ICD implantation in patients with left ventricular dysfunction and no prior history of VTEs. As a result, a number of recent clinical trials conducted to evaluate MTWA testing have involved patients with prophylactically implanted ICDs [11][12][13][14][15] . Such trials have generally utilized appropriate ICD therapy (AICDT) as the predominant component of the VTE endpoint. AICDT is defined as an ICD therapy deemed to be appropriate based upon expert review of the stored electrogram recorded immediately prior to the delivery of ICD therapy. MTWA testing has tended to not perform as well in these latter trials involving patients with implanted ICDs.
It had been assumed that, in patients with implanted ICDs, AICDT would be a reliable surrogate for sudden cardiac death. Recent analyses of ICD trials 16,17 have concluded that AICDTs in the ICD arms of the studies exceeded sudden deaths in the control arms by a factor of two to three. These analyses raise questions about the suitability of AICDT as a surrogate endpoint for SCD in clinical trials 18 .
In this paper we analyze clinical trials conducted to evaluate MTWA as a predictor of VTEs in primary prevention patients. We compare trials in which few patients had implanted ICDs (and therefore in which VTE endpoint events included none or few occurrences of AICDT) with trials in which many patients had implanted ICDs and thus AICDTs comprised the majority of the VTE endpoints. We also analyze data from the MADIT II 9 and SCD-HeFT 10 trials to determine what fraction of the reported AICDTs in those studies terminated VTEs that would have been lethal had no ICD been implanted in order to elucidate the findings from the analyses of the MTWA studies.

Identification of Clinical Trials
On November 17, 2007 we conducted a PubMed online search for journal publications which included the word alternans in the title and were published after 1993. From this list we identified prospective clinical trials in which MTWA was measured using the spectral analytic method, involved at least 100 patients with a significant risk factor for sudden cardiac death but not selected on the basis of a known history of sustained VTEs, and had a mean follow-up period of at least 12 months. We excluded studies which included patients who underwent MTWA testing earlier than 14 days after a recent myocardial infarction (MI). One study 19 was excluded because it reported on a subset of patients reported in a later publication. We also included in our analysis data from recent major studies presented at national meetings (ABCD 14 , SCD-HeFT substudy 15 , and MASTER I 13 ) which had not yet been published in journal articles. We defined the Low ICD Group to include trials identified above which reported VTE endpoints in which AICDT events accounted for none or a small fraction (≤ 15%) of the reported VTE endpoints -few patients in these studies had implanted ICDs. We defined the High ICD Group to include trials identified above which reported VTE endpoints in which AICDTs constituted the majority of the reported VTE endpoint events.

Statistical Analysis
In order to compare endpoint data across studies with different follow-up periods, event data were converted to annual event rates (AERs). The annual event rate, λ, was computed from the equation S = e -λ T where S is the survival value at time T. S and T were determined either (i) from the published survival curves (resulting from Kaplan Meier or Cox analyses) by measuring S at the maximum displayed survival time, T or (ii) from published data which reported the fraction, F, of patients in each subgroup who had sustained endpoint events during follow-up and setting S = 1 -F and T to the mean reported follow-up period. The hazard ratio (HR) for two subgroups was obtained by computing the ratio of the derived AERs.
For each subgroup in each study we assumed that the occurrence of endpoint events follow time-dependent binomial statistics and used Bayes theorem to obtain the posterior probability distribution for S conditional on n, p(S/n), where n = (1 -S exp )N, S exp is the experimentally measured value of S, and N is the initial total number of subjects:

Predictive Accuracy of MTWA Testing
Tables 1 and 2 display data from prospective trials conducted to evaluate the predictive accuracy of MTWA testing measured using the spectral analytic method in patients with a significant risk factor for SCD but not selected on the basis of a known prior history of sustained VTEs. The trials presented in these tables all reported ventricular tachyarrhythmic event (VTE) endpoints.   In Table 3 we calculate from analysis of published data the ratio of the annual rate of AICDT to the annual rate of ICD mediated reduction in mortality in the MADIT II and SCD-HeFT trials. This ratio is 3.1 [2.0 6.3]. The ratio implies that only 1 in 3.1 patients (32%) who received AICDT in MADIT II and SCD-HeFT averted a sudden death that would have occurred in the absence of ICD implantation.
In Table 4 we present mortality rates in the MADIT II and SCD-HeFT trials and in MTWA trials involving predominantly patients without implanted ICDS in which the mean LVEF < 0.30 and which reported total mortality endpoint data. In the non-ICD arm of the MADIT II and SCD-HeFt trials, the annual mortality rate was 9.5%. In the entire population of the MTWA trials presented here, the annual mortality rate was 5.4%. In the ICD arm of the MADIT II and SCD-HeFT trials, the annual mortality rate was 7.3%. In the MTWA negative patients in the corresponding MTWA trials the annual mortality rate was only 1.7%. The annual mortality rate among MTWA negative patients who predominantly did not receive ICDs was significantly lower, by a factor of 4.3, than among patients in MADIT II and SCD-HeFT who did receive ICD therapy.

Discussion Predictive Accuracy of MTWA
The above analysis of MTWA trials demonstrates that there is a substantial and consistent difference in the reported VTE predictive accuracy of MTWA testing performed using the spectral analytic method in trials in which the endpoint involved a low or high fraction of AICDTs. In the Low ICD Group, involving patients primarily without implanted ICDs, the hazard ratio was 13.6 for annual VTE rates in MTWA non-negative compared to MTWA negative patients (hazard ratio was 5.2 in studies in which the mean LVEF < 0.30). The hazard ratio increases to 15.3 when only SCD and CA, but not non-lethal sustained VTEs, are included in the endpoint. In contrast, in patients in the High ICD Group, the hazard ratio falls to 1.6.
Similarly, the annual VTE rate in the Low ICD Group is only 0.3% (1.2% in studies in which mean LVEF < 0.30); the annual VTE is 0.3% when only SCD and CA are included in the endpoint. In contrast, the annual VTE rate among MTWA negative patients is 5.4% in the High ICD Group -greater by an order of magnitude.
In our analysis we also demonstrate that in MADIT II 9 and SCD-HeFT 10 only 1 in 3.1 patients (32%) who received AICDT averted a SCD that would have occurred in the absence of ICD implantation. This result is consistent with the reports of other investigators who have also found that the number of AICDTs greatly exceeds the ICD mediated reduction in deaths in clinical ICD trials 16,17 . One explanation for the excess number of AICDTs is that ICDs treat arrhythmias that would have self-terminated had no ICD been implanted. Another possible explanation is that ICDs are themselves arrhythmogenic and induce arrhythmias that they then end up treating 17 . Whatever the mechanism, the large excess of the number of patients receiving AICDT over the number of patients averting SCD indicates that AICDT is an unreliable surrogate for a SCD endpoint in clinical trials 18

MTWA in Non-Ischemic Dilated Cardiomyopathy Patients
In Table 1  patients. This study, while it is included in the summary statistics, appears to be an outlier. One possible explanation for MTWA performance in Grimm 21 compared to the other studies of MTWA in DCM patients might be that in Grimm beta-blockers were withheld for at least 24 hours prior to MTWA testing while 74% of patients took beta-blockers during follow-up. In contrast in ALPHA 7 , Kitamura 3 , and Bloomfield 5 were not withheld prior to MTWA testing. It is known that beta-blockers both reduce the incidence of ventricular tachyarrhythmias andparticularly in patients with non-ischemic cardiomyopathy -suppress MTWA 22,23 . Thus, in Grimm 21 it is possible that the withdrawal of beta-blockers acutely increased the incidence of MTWA without concomitantly increasing VTEs during follow-up because these same patients were taking beta-blockers during follow-up. The results of these studies suggest that it may be advisable to perform MTWA tests in patients while they are on the same pharmacologic regimen as they will be on during follow-up. Only if patients have an indeterminate test because they cannot achieve the minimum heart rate of 105 bpm, would it be advised to withdraw beta-blockers to the extent needed for the patient to achieve this heart rate. (Of note, many patients who on initial exercise testing cannot achieve a heart rate of 105 bpm can do so upon repeating the exercise test after a short rest period.)

Benefit of ICD Therapy in MTWA Non-Negative versus Negative Patients
ICD therapy is associated with its own morbidity and mortality including infection, lead breakage, inappropriate shocks, perforation, device and lead recalls 17 . The early complication rate associated with just the ICD implantation procedure itself has been reported to be 11% including a mortality rate of 1%, exclusive of the complications after hospital discharge such as inappropriate shocks and lead breakage 24  that ICD therapy may have an adverse effect on total mortality in a patient population with an annual arrhythmic mortality of less than 2.6%. Table 4 shows that, in MTWA studies involving patients with LVEF < 0.30, the annual total mortality rate was 57% of that observed in the non-ICD arms of the MADIT II 9 and SCD-HeFT 10 trials. An explanation for this observation is possible referral bias in MADIT II and SCD-HeFT where physicians referring patients into these treatment trials pre-selected patients that they believed would be at higher risk of SCD and thus more likely to benefit from ICD therapy. In the natural history MTWA trials no therapy was mandated so there would be little reason to expect a similar referral bias. Of greater interest is the fact that the mortality rate among the MTWA negative patients presented in Table 4  ischemic heart disease and LVEF ≤ 0.35 of whom 51% received ICDs. In this study the propensity score statistical methodology was used to adjust for factors that affect the decision to implant an ICD. These investigators found that ICD implantation in MTWA non-negative patients was associated with a 55% reduction in all-cause mortality (p < 0.003), but that ICD implantation in an equivalent number of MTWA negative patients had no statistically significant effect on mortality.

MTWA as a Guide to ICD Therapy
In the US, ICD therapy is generally reimbursed by third party insurers for patients with

Conclusion
MTWA testing using the spectral analytic method identifies, among non-ICD patients with risk factors for SCD but with no prior history of sustained VTEs, a group of patients at very low risk for SCD and a group at elevated risk. In prospective trials of ICD therapy the number of AICDTs greatly exceeds the number of SCDs prevented as a result of ICD implantation. In trials involving patients with implanted ICDs these excess AICDTs appear to distribute randomly between MTWA negative and non-negative patients obscuring the predictive accuracy of MTWA for SCD. AICDT is an unreliable surrogate endpoint for SCD.
There is no evidence that ICD therapy provides a mortality benefit for primary prevention patients with a negative MTWA test. In patients with ischemic heart disease and LVEF ≤ 0.35, there is evidence that ICD therapy provides a substantial mortality benefit for MTWA positive or indeterminate patients but not for MTWA negative patients 27 . MTWA testing may serve as a means of guiding ICD therapy to appropriate patients and overcoming the widespread reluctance among patients and referring physicians to accept ICD therapy for appropriate patients. MTWA testing may also provide a means for identifying which patients, with risk factors for sudden cardiac death but with LVEF > 0.35, should undergo further evaluation for preventative therapy.
Because the substantial majority of SCDs occur in LVEF > 0.35 patients 31 , substantial progress in reduction of SCD will only be possible when the high risk patients in this group are identified and treated prophylactically.    Annual Rate of Appropriate ICD Therapy represents the annual rate of increase in the number of patients having had AICDT. Annual Rate of ICD Mediated Reduction in Mortality was obtained by computing the difference in the annual mortality event rates between the non-ICD and ICD arms of each study (see Table 4). Number of patients in SCD-HeFT trial excludes amiodarone arm.