Association of prolonged QRS duration with ventricular tachyarrhythmias and sudden cardiac death in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II)

doi:10.1016/j.hrthm.2008.02.013

Heart Rhythm

Volume 5, Issue 6, June 2008, Pages 807-813

https://doi.org/10.1016/j.hrthm.2008.02.013 Get rights and content

Background

There is conflicting literature on the relationship between prolonged QRS duration (QRSd) and arrhythmic events, including sudden cardiac death (SCD), in heart failure patients with or without implantable cardioverter-defibrillators (ICDs).

Objective

The purpose of this study was to evaluate the prognostic significance of prolonged QRSd relative to arrhythmic outcomes in medically and ICD-treated patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II.

Methods

Using a Cox proportional hazards model adjusting for ejection fraction, heart failure class, and blood urea nitrogen, we estimated the association of prolonged QRSd ≥140 ms with SCD in the medically treated arm and SCD or first appropriate ICD therapy for rapid ventricular tachycardia/fibrillation (VT/VF; cycle length ≤260 ms) in the ICD-treated arm.

Results

In the medically treated arm, prolonged QRSd was a significant independent predictor of SCD (hazard ratio 2.12; 95% confidence interval 1.20–3.76; P = .01). However, in the ICD-treated arm, prolonged QRSd did not predict SCD or rapid VT/VF (hazard ratio 0.77; 95% CI 0.47–1.24; P = .28). The difference in the prognostic effect of prolonged QRSd in these two groups was significant (P<.01). These results were not affected by varying the cycle length that defines rapid VT/VF or the duration that defines QRSd prolongation.

Conclusions

In patients with prior myocardial infarction and EF ≤30%, prolonged QRSd does not predict SCD/VT/VF in ICD-treated patients but does predict SCD in medically treated patients. This underscores the nonequivalence of VT/VF and SCD and the need for caution in inferring risk of SCD when using nonrandomized databases that include only patients with ICDs.

Introduction

Several studies have demonstrated that prolonged QRS duration (QRSd) is associated with increased mortality in medically treated patients with heart failure.¹ However, the association between prolonged QRSd and sudden cardiac death (SCD) is less certain.2, 3, 4 While the largest study to date examining the relationship of prolonged QRSd to SCD reported a significant independent association,⁴ other smaller studies have had inconsistent results.2, 3 Moreover, there is conflicting literature on the relationship of prolonged QRSd to arrhythmic events, including SCD, in patients treated with implantable cardioverter-defibrillators (ICDs), with the largest study to date showing that prolonged QRSd does not predict VT/VF in patients with ICDs⁵ and smaller studies reporting contradictory results.6, 7, 8, 9, 10, 11, 12

Defining the relationship between prolonged QRSd and SCD in patients with heart failure is crucial given the increased interest in risk stratification and assessing ICD efficacy in this population.¹³ Potential explanations for the conflicting literature on prolonged QRSd and arrhythmic outcomes in medically as well as in ICD-treated patients have included differences in study design, definition of prolonged QRSd, and risk profiles of the study populations. Furthermore, studies in ICD-treated populations have not included direct comparisons with comparable medically treated populations.

To overcome these limitations and address these apparently contradictory findings, we used the randomized Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) to compare the prognostic importance of prolonged QRSd in medically and ICD-treated patients drawn from the same population in the same study.

Section snippets

Patient population

The design, protocol, and results of MADIT-II have been described elsewhere.14, 15 MADIT-II was a randomized controlled trial conducted in 76 hospital centers that enrolled 1232 patients randomized to ICD implant plus conventional medical therapy versus conventional medical therapy alone in a 3:2 ratio. Patients 21 years or older with a left ventricular ejection fraction (LVEF) ≤30% were eligible if they had a myocardial infarction more than 1 month or coronary revascularization more than 3

Medically treated patients

SCD as determined by an independent endpoint review committee was used as the outcome for patients in the medically treated arm. SCD was ascertained using a modified Hinkle-Thaler classification system.¹⁶ SCD was defined when a patient died suddenly and unexpectedly within 1 hour of cardiac symptoms, during sleep, or within 24 hours after last being seen alive. For this analysis, patients with indeterminate or unknown causes of death were not included.

ICD-treated patients

In the ICD-treated patients, we endeavored

Statistical analysis

Baseline clinical characteristics of medically and ICD-treated patients were compared using the χ²-test for categorical variables and the Student's t-test for continuous variables.

Medically treated arm

Freedom from SCD was assessed using the Kaplan-Meier method with patients dichotomized by QRSd ≥140 ms. This threshold was arbitrarily chosen a priori. Recognizing that prior studies evaluating the prognostic value of prolonged QRSd used thresholds ranging from 120 to 150 ms,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 we assessed the effect of this arbitrary threshold on our findings in additional sensitivity analyses (see below).

ICD-treated arm

Freedom from rapid VT/VF or SCD was assessed in a similar fashion, with

Medically treated arm

Multivariate Cox proportional hazards regression analysis was used to assess the association of a prolonged QRSd (≥140 ms) with the risk for SCD, adjusting for New York Heart Association (NYHA) class (≤NYHA class II or >NYHA class II), LVEF (≤25% or >25%), and blood urea nitrogen (BUN) (≤25 mg/dL or >25 mg/dL). In a prior MADIT-II secondary analysis, all three variables were identified as risk factors for SCD.²⁰ Patients who died from non-SCD causes were censored.

ICD-treated arm

Multivariate Cox proportional

Significance of effect

The adjusted HRs for prolonged QRSd in each arm were compared by examining the statistical significance of the interaction term of treatment assignment by prolonged QRSd in a Cox proportional hazards model.

Sensitivity analyses

In sensitivity analyses, we tested the effects of using different definitions of the endpoint in the ICD arm. We varied the VT/VF threshold cycle length defining the endpoint from 240 to 320 ms. Sensitivity analyses were also done including and excluding SCD from the combined outcome in the ICD-treated arm. Additionally, we examined the effect of varying QRSd cutoffs at several values, from 120 to 150 ms.

For all analyses, a threshold two-sided P-value of .05 was used to determine statistical

Baseline characteristics

Twenty-four patients (10 in the ICD group and 14 in the medical treatment group) were eliminated from the analysis for indeterminate or unknown cause of death. Baseline patient characteristics and medication use for the two arms are shown in Table 1. Examined clinical and electrocardiographic characteristics did not differ significantly between the two groups, except for QRSd.

Outcomes

In the medically treated arm, the SCD rate was 10.3% (49/476). In the ICD-treated arm, the combined outcome of SCD or first appropriate ICD therapy for rapid VT/VF (cycle length ≤ 260 ms) was 10.5% (77/732).

Sensitivity analyses

To demonstrate the consistency of our findings over a range of VT/VF cycle length cutoffs, we performed sensitivity analyses varying the definition of the rapid VT/VF outcome in the ICD-treated arm. Details of the composition of various combined rapid VT/VF/SCD outcomes in the ICD-treated arm by varying VT/VF cycle length cutoffs are shown in Table 3. As longer cycle lengths (i.e., slower VT) were included in the outcome, the HR for VT/VF increased only marginally (Table 4). The overall ability

Discussion

To our knowledge, this is the first analysis to compare the association of prolonged QRSd to arrhythmic outcomes in medically treated patients versus a comparable ICD-treated population. It is also the largest study to date to examine the relationship between prolonged QRSd and appropriate ICD therapy in patients with Ischemic cardiomyopathy with ICDs. Using data from the MADIT-II study, we observed that prolonged QRSd is highly predictive for SCD in medically treated patients but not at all

Conclusions

This analysis of the MADIT II trial indicates that prolonged QRSd is associated with an approximately twofold increase in SCD in medically treated patients but not with any increase in ICD-treated VT/VF events or SCD in patients with an implanted defibrillator. If confirmed in other randomized databases, the finding suggests that ICD-treated VT/VF events may be a poor surrogate marker for SCD in patients with ischemic cardiomyopathy. Future work should examine possible mechanisms by which

Acknowledgments

The authors thank the MADIT-II investigators for use of the MADIT-II database.

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: Drs. Moss, Zareba, and Greenberg have received research grants from Boston Scientific; Dr. Zareba has also received a research grant from Medtronic. Dr. Moss has received honoraria for lectures from Boston Scientific. Dr. Daubert has ownership interest in Medtronic and Boston Scientific. Dr. Estes has spoken for Medtronic, Boston Scientific, and St. Jude Medical. Drs. Dhar, Alsheikh-Ali, Case, and Kent have nothing to disclose.

: Dr. Ritesh Dhar was funded by a T32 training grant awarded by the Agency for Healthcare Research and Quality. Dr. Alsheikh-Ali is a recipient of a faculty development award from Pfizer/Tufts Medical Center. The Multicenter Automatic Defibrillator Implantation Trial II was supported by a research grant from Guidant Corp., St. Paul, Minnesota, to the University of Rochester School of Medicine and Dentistry.

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Original-clinicalAssociation of prolonged QRS duration with ventricular tachyarrhythmias and sudden cardiac death in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II)

Background

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Patient population

Medically treated patients

ICD-treated patients

Statistical analysis

Medically treated arm

ICD-treated arm

Medically treated arm

ICD-treated arm

Significance of effect

Sensitivity analyses

Baseline characteristics

Outcomes

Sensitivity analyses

Discussion

Conclusions

Acknowledgments

J Am Coll Cardiol

Am Heart J

J Card Fail

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

Am J Cardiol

Electrocardiographic predictors of arrhythmic death and total mortality in the multicenter unsustained tachycardia trial

Circulation

Original-clinical
Association of prolonged QRS duration with ventricular tachyarrhythmias and sudden cardiac death in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II)