Michelle L. Bridenbaker, RN, BSN, CPhT

Disclosures

June 24, 2004

Presenter: Jeanne E. Poole, MD, University of Washington (Seattle) for the SCD-HeFT Investigators

The high incidence of sudden cardiac death (SCD), particularly in patients with impaired left ventricular (LV) function and congestive heart failure (CHF), has been well documented. Patients with CHF are most susceptible to SCD, with a risk 6-9 times higher than that in the general population. Several large, well-designed clinical trials have proven the effectiveness of implantable cardioverter defibrillator (ICD) therapy for both the primary and secondary prevention of SCD across most of the important patient subsets.

The results of the landmark Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), presented at this year's American College of Cardiology 2004 Annual Scientific Session, added further weight to the benefits of ICDs and suggested that the pool of potential candidates for the therapy is much broader than initially estimated.

Despite the findings from the second Multicenter Automatic Defibrillator Implantation Trial (MADIT II),[1] which found that ICD therapy reduced the risk of all-cause mortality by 31% compared with optimal medical therapy in patients with prior myocardial infarction and LV ejection fraction (LVEF) ≤ 30%, regardless of baseline QRS interval, the US Centers for Medicare and Medicaid (CMS) decided not to expand reimbursement coverage for ICDs to account for the entire MADIT II patient population. Instead, they used the results of a posthoc subgroup analysis from the trial that evaluated the effects of QRS duration as measured by surface electrocardiogram (ECG) on mortality and decided to make QRS duration of ≥ 120 ms a requirement for coverage.

CMS has since come under substantial fire from clinicians, who argue that limiting coverage on the basis of QRS duration excludes a substantial number of patients who could otherwise benefit from the therapy. They argue that the decision for the therapy should be left to the discretion of the physician.

The current subgroup analysis from the SCD-HeFT trial, presented at Heart Rhythm 2004 -- 25th Annual Scientific Sessions, evaluated the impact of baseline ECG data on outcome, and the results ultimately challenge CMS's decision to use QRS prolongation as the criterion for treatment reimbursement.

SCD-HeFT: Study Design and Results

SCD-HeFT was a placebo-controlled, randomized, 3-arm study, designed to determine by intention-to-treat analysis whether amiodarone or a single-chamber ICD programmed to shock-only (no back-up pacing) would reduce all-cause mortality when compared with placebo (double-blind to drug therapy) in patients with (ischemic or nonischemic) dilated cardiomyopathy, New York Heart Association (NYHA) Class II and III CHF, and LV dysfunction (EF ≤ 35%). A total of 2521 patients who met the above criteria underwent 12-lead ECG, 6-minute hall walk testing, and Holter monitoring and were then randomized on a 1:1:1 ratio to amiodarone (n = 845), placebo (n = 847), or ICD therapy (n = 829).

Follow-up data were available in 100% of patients. The overall results of the study found that ICD therapy was associated with a highly significant 23% reduction in all-cause mortality compared with placebo (P = .007). In addition, amiodarone was found not to confer any survival benefit over placebo (hazard ratio [HR] 1.06; 97.5% confidence interval, 0.86, 1.30; P = .529). The mortality rate for placebo-controlled patients was 7.2% over 5 years.

ECG Analysis Methods

All 12-lead ECGs were evaluated at the ECG Core Lab in Seattle, Washington, by a physician and a trained nurse. The specific parameters measured included: heart rate and rhythm; the measured intervals of PR, QRS, QT, and corrected QT; as well as morphology assessment (presence of left bundle branch block [LBBB], right bundle branch block [RBBB], or an interventricular conduction defect [IVCD]).

At baseline, all ECG measures were distributed evenly across the 3 treatment groups. In the overall patient population, the median PR and QRS intervals were both 112 ms, respectively; 59% of patients had a QRS < 120 ms, 41% had a QRS ≥ 120 ms, and 19% of patients had a particularly wide QRS interval of > 150 ms (Table 1).

Table 1. Baseline ECG Measures: All Patients
Parameter Median 25th and 75th Percentile or
Patients (n)
Heart rate (bpm) 73 63, 54
AF (%) 7 173
PR (ms) 112 96, 140
QRS (ms) 112 96, 140
< 120 (%) 59 1487
≥ 120 (%) 41 1033
> 150 (%) 19 483
LBBB (%) 22 561
RBBB (%) 5 132
IVCD (%) 17 419
QT (ms) 394 360, 424
QTc (ms) 430 406, 460
QT-QRS (ms) 272 248, 300
AF = atrial fibrillation; IVCD = interventricular conduction defect; LBBB = left bundle branch block; RBBB = right bundle branch block

Baseline ECG measurements were also stratified by disease etiology and NYHA functional class (Table 2).

Ischemic vs Nonischemic

Overall, there was no difference between the proportion of patients with a wide vs narrow QRS interval; however, a particularly wide QRS (> 150 ms) was observed more frequently in nonischemic patients. Median heart rate tended to be slightly higher and the PR and QRS intervals were slightly longer in ischemic vs nonischemic patients. LBBB was found more frequently in nonischemic patients, whereas RBBB and IVCD were more common in ischemic patients. The incidence of AF, as well as the measures of the QT interval, were equivalent between the 2 groups.

NYHA Class II vs Class III

Compared with class II patients, patients in class III had a higher incidence of AF and longer PR and QRS intervals. Class III patients also had a higher baseline heart rate, which the investigators attributed to a lower rate of beta-blocker use. A narrow QRS was observed more frequently in class II patients than in class III, with no difference in wide QRS intervals between the 2 groups (although slightly higher in class III patients). There were no differences in either QRS interval > 150 ms or morphology between the 2 groups.

Table 2. Baseline ECG: Ischemic vs Nonischemic; NYHA Class II vs Class III
Parameter Ischemic
(n = 1310)
Nonischemic (n = 1211) Class II
(n = 1761)
Class III
(n = 760)
Heart rate (bpm) 71 75 71 76
AF (%) 7 7 6 9
PR (ms) 180 176 178 180
QRS (ms) 112 110 110 112
< 120 (%) 59 59 60 57
≥ 120 (%) 41 41 40 43
> 150 (%) 15 232 19 19
LBBB (%) 16 30 22 22
RBBB (%) 8 2 5 6
IVCD (%) 20 13 16 17
QT (ms) 400 388 396 390
QTc (ms) 426 435 427 434
QT-QRS (ms) 276 268 275 266
AF = atrial fibrillation; IVCD = interventricular conduction defect; LBBB = left bundle branch block; NYHA = New York Heart Association; RBBB = right bundle branch block
ECG Outcome Data: Amiodarone vs Placebo

When stratifying the ECG data in the amiodarone vs placebo group by the variables measured above (dichotomized at the mean, except for QRS), the data were consistent with the results of the overall SCD-HeFT trial -- ie, amiodarone was not associated with a survival benefit compared with placebo in any of the subgroups studied. In addition, the lack of benefit associated with amiodarone was present regardless of whether QRS duration was < 120 ms or ≥ 120 ms.

ECG Outcome Data: ICD vs Placebo

The ECG subgroup analyses comparing ICD to placebo also reflected the overall benefit of ICDs reported in SCD-HeFT. There was a slight variance, however, in that patients with a heart rate ≥ 73 bpm and those with AF at baseline were less likely to benefit from ICD therapy. It was also noted, though, that the confidence intervals for the small group of patients who had AF at baseline were quite large. Neither a narrow nor wide QRS interval influenced the benefit of ICD compared with placebo.

Investigators also found that altering the cut-off points for "narrow" and "wide" QRS complexes from ≥ 120 ms and < 120 ms, respectively to > 120 ms and ≤ 120 ms, respectively influenced the HR. Whereas the HR for ICDs in patients with QRS ≥ 120 ms was 0.67 compared with placebo, when the QRS duration was dichotomized instead as > 120 ms, the HR was 0.80. The same changes in HR were also observed when comparing QRS < 120 ms with QRS ≤ 120 ms. Interestingly, when stratifying QRS intervals based on >, =, or < 120, investigators found that patients with QRS measuring exactly 120 ms were those who would reap the greatest benefit from ICDs (Table 3).

Table 3. SCD-HeFT Patient Population: QRS Subanalysis
Patient Group N HR 97.5% CI
< 120 ms 988 0.84 0.62, 1.14
≥ 120 ms 699 0.67 0.49, 0.93
≤ 120 ms 1064 0.74 0.56, 0.99
> 120 ms 612 0.80 0.57, 1.13
< 120 ms 988 0.84 0.62, 1.14
= 120 ms 87 0.21 .08, 0.59
> 120 ms 612 0.80 0.57, 1.13
CI = confidence interval; HR = hazard ratio
MADIT II Patients

Investigators also evaluated the outcome of patients enrolled in SCD-HeFT who met MADIT II enrollment criteria -- those with LVEF ≤ 30%, ischemic heart failure, history of myocardial infarction -- which constituted approximately 80% of the ischemic patients enrolled in SCD-HeFT. Within the MADIT II-type subgroup of patients, the results of the overall study remained consistent: amiodarone was not associated with a survival benefit compared with placebo, and ICDs were associated with a 22% reduction in the relative risk for all-cause mortality compared with placebo.

When stratifying MADIT II-like patients treated with ICD therapy by QRS width, investigators found that ICD therapy was associated with a mortality benefit compared with placebo regardless of baseline QRS duration. Compared with placebo, ICD therapy in MADIT II-like patients with a wide QRS (≥ 120 ms; N = 366) interval did appear to have a greater benefit compared with the benefit over placebo observed in narrow QRS patients (N = 245) (HR 0.65 vs 0.92, respectively).

Slightly altering the cut-off point for QRS width in the MADIT II-like patients yielded similar interchangeable HRs to those seen after modifying the QRS intervals at baseline in the overall SCD-HeFT patient population, whereby the greatest benefit was noted in patients with an exact QRS width of 120 ms (Table 4).

Table 4. MADIT II-like Patients in SCD-HeFT: QRS Subanalysis
Patient Group N HR 97.5% CI
< 120 ms 526 0.98 0.67, 1.43
≥ 120 ms 358 0.61 0.42, 0.91
≤ 120 ms 583 0.78 0.55, 1.12
> 120 ms 301 0.81 0.53, 1.23
< 120 ms 526 0.98 0.67, 1.43
= 120 ms 57 0.1 .08, 0.59
> 120 ms 301 0.81 0.53, 1.23
CI = confidence interval; HR = hazard ratio
Conclusions

On the basis of the findings from the ECG analysis of the SCD-HeFT data, investigators concluded that for the overall SCD-HeFT patient population:

  • No ECG measure is specific enough to provide subgroup risk categorization for either excluding or selecting patients for ICD therapy.

  • Similarly, ECG measures cannot be used to select patients for amiodarone therapy.

  • The interpretation of ICD benefit, based upon QRS duration, is dependent on how the data are cut (> 120, = 120, or ≤ 120).

  • ICDs are beneficial in patients with narrow, as well as those with wide, QRS intervals.

Discussion

Following the conclusion of her presentation, Dr. Poole was asked whether she could speculate on the reaction that CMS would have to these findings with respect to their initial decision to reimburse only the MADIT II-like patients. Dr. Poole responded that "to exclude patients based on subgroup analysis is hazardous," and that results of a clinical trial should be applied to the entire group of patients. When she was asked finally: "Is it fair to say that your data would call into question the CMS decision on MADIT II?" Dr. Poole responded simply: "I hope so."

Reference
  1. Moss AJ, Zareba W, Hall WJ, et al, for the Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation on a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877-883.

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