- Email: [email protected]
QRS duration and prediction of mortality in patients undergoing risk stratification for ventricular arrhythmias
QRS Duration and Prediction of Mortality in Patients Undergoing Risk Stratification for Ventricular Arrhythmias Vidyasagar Kalahasti, MD, Vijay Nambi, MD, David O. Martin, MD, MPH, Cathy T. Lam, MD, David Yamada, MD, Bruce L. Wilkoff, MD, Mark J. Niebauer, Fredrick J. Jaeger, DO, Patrick J. Tchou, MD, and Mina K. Chung, MD
MD,
This study tested the hypothesis that prolonged QRS duration independently predicts long-term mortality in patients who underwent risk stratification and treatment for ventricular arrhythmias. Patients who underwent risk stratification by electrophysiologic study were identified. Electrophysiologic study results were defined as positive if sustained monomorphic ventricular tachycardia was induced. Mortality was the primary end point. Of 915 patients studied, mean left ventricular (LV) ejection fraction (EF) was 35.3 ⴞ 15.7%, 608 (66.4%) had coronary artery disease, 233 (25.5%) had positive electrophysiologic study findings, 298 (32.6%) received implantable cardioverter-defibrillators, and 174 (19%) died (mean follow-up 35.0 ⴞ 15.0 months). Cox regression analysis identified older age, coronary artery disease, digoxin use, absence of  blockers, lower LVEF, and prolonged QRS duration to be independent predictors of mortality.
QRS duration >130 ms, present in 33.6% of patients, was associated with a twofold increase in mortality (hazard ratio 2.1, 95% confidence interval 1.5 to 2.8; p <0.0001). For every 10 ms increase in QRS duration, mortality rate increased 10%. In a subgroup of patients with coronary artery disease and LVEF <30%, prolonged QRS duration remained an independent predictor of mortality (hazard ratio 2.6, 95% confidence interval 1.6 to 4.2; p <0.0001). Thus, prolonged QRS duration is a strong independent marker of long-term mortality in patients who undergo risk stratification for ventricular arrhythmias. Whether QRS duration represents only a marker for mortality or if modification of this factor using resynchronization therapies will impact mortality merits further study. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;92:798 – 803)
espite current risk stratification strategies and implantable cardioverter-defibrillator (ICD) implanD tation directed toward reducing life-threatening ven-
and treatment for ventricular arrhythmias, including a high-risk subgroup identified for ICD implantation by MADIT II.2
tricular arrhythmias, patients remain at significant long-term risk for mortality. The Multicenter Unsustained Tachycardia Trial (MUSTT)1 reported overall mortality after 5 years reaching over 40% in patients with inducible ventricular arrhythmias, as well as in registry patients with negative electrophysiologic study findings. The Multicenter Automatic Defibrillator Implantation Trial (MADIT) II2 reported a 14.2% mortality at 20 months in patients with coronary artery disease and left ventricular (LV) ejection fraction (EF) ⱕ30% receiving ICDs. Hence, identification of tools for additional risk stratification is essential. QRS prolongation has been correlated with decreased LVEF3 and inducibility of sustained ventricular arrhythmias during electrophysiologic study.4 We sought to determine if QRS duration is an independent predictor of mortality in patients who underwent risk assessment From the Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio; Kwong Wah Hospital, Hong Kong, China; Heart Specialists of Sarasota, Sarasota, Florida; and the University of Nebraska Medical Center, Omaha, Nebraska. Manuscript received April 9, 2003; revised manuscript received and accepted June 16, 2003. Address for reprints: Mina K. Chung, MD, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F-15, Cleveland, Ohio 44195. E-mail: [email protected].
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©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 92 October 1, 2003
METHODS This study aimed to determine the independent predictors of long-term mortality in a population of patients who underwent electrophysiologic testing for risk stratification of ventricular arrhythmias. Specifically, we sought to assess whether QRS duration was a predictor of mortality independent of electrophysiologic testing outcome or ICD implantation in this population, as well as in a high-risk ischemic cardiomyopathy subgroup that may be targeted for prophylactic device implantation therapy. Patient population: All patients who underwent electrophysiologic testing for risk stratification of ventricular arrhythmias between August 1996 and December 1999 were retrospectively identified from a clinical database maintained in the electrophysiology laboratory of The Cleveland Clinic Foundation. A subgroup of patients with coronary artery disease and LVEF ⱕ30%, characteristics of patients identified by the MADIT II study as potentially benefiting from ICD implantation,2 was also identified for analysis of long-term mortality. Patients with permanent pacemakers at the time of electrophysiologic testing or who did not have Social Security numbers available were excluded from analysis. The study protocol was 0002-9149/03/$–see front matter doi:10.1016/S0002-9149(03)00886-5
trastimuli at 3 paced cycle lengths at 2 right ventricular sites; burst pacing; Patients With CAD and/or short-long-short coupling inTotal Cohort and LVEF ⱕ30% tervals. The stimulation protocols Variable (n ⫽ 915) (n ⫽ 309) that used burst pacing and up to 3 Age (yrs) mean ⫾ SD 63.0 ⫾ 13.1 65.4 ⫾ 10.1 extrastimuli were similar to those White 798 (87.2%) 268 (86.7%) used in MADIT5 and MUSTT.6 The Men 694 (76.1%) 262 (84.8%) protocol using 4 extrastimuli has Current cigarette smoker 113 (12.3%) 41 (13.3%) been reported to improve efficiency Structural heart disease Coronary artery disease 608 (66.4%) 309 (100%) and specificity without compromisPrior coronary bypass 373 (40.8%) 198 (64.1%) ing yield of monomorphic ventricuPrior coronary angioplasty 119 (13%) 60 (19.4%) lar tachycardia.7 The short-longValvular disease 119 (13%) 36 (11.7%) short stimulation protocol has been Hypertrophic cardiomyopathy 23 (2.5%) 1 (0.3%) reported to potentially add to the Primary cardiomyopathy 155 (17.0%) 3 (1%) No heart disease 73 (8.0%) 0 (0%) yield of ventricular tachycardia inLVEF (%) 35.3 ⫾ 15.7 22.0 ⫾ 5.9 duction in patients susceptible to Medications macroreentry in the His-Purkinje -adrenergic blockers 228 (29.4%) 78 (25.2%) system.8 A positive study result was Calcium antagonists 90 (11.6%) 29 (9.4%) Digoxin 292 (37.7%) 152 (49.2%) identified as inducible sustained Amiodarone 90 (11.6%) 42 (13.6%) monomorphic ventricular tachycarPR interval (ms) 181 ⫾ 45 188 ⫾ 49 dia, defined as monomorphic ventricQRS duration (ms) 121 ⫾ 33 127 ⫾ 32 ular tachycardia lasting ⬎30 seconds QT interval (ms) 415 ⫾ 57 419 ⫾ 62 or associated with syncope, hemodySinus cycle length (ms) 842 ⫾ 180 815 ⫾ 165 AH interval (ms) 98 ⫾ 37 103 ⫾ 39 namic compromise, or requiring inHV interval (ms) 55 ⫾ 22 59 ⫾ 27 tervention for termination. A negaInducible sustained monomorphic 233 (25.5%) 125 (40.5%) tive electrophysiologic study result ventricular tachycardia was defined as noninducibility of ICD implantation 298 (32.6%) 145 (46.9%) sustained monomorphic ventricular tachycardia. Data collection: Demographic, clinical, electrocardiographic, echocardiographic, and electrophysiTABLE 2 Univariate Predictors of Mortality in the Total Cohort of Patients Who ologic data, including age, type of Underwent Electrophysiologic Testing structural heart disease, use of antiMortality Status arrhythmic medications, LVEF, and surface and intracardiac electrocarVariable Alive (n ⫽ 741) Dead (n ⫽ 174) p Value diographic intervals (including sinus Age (yrs) 61.9 ⫾ 13.3 67.5 ⫾ 11.2 ⬍0.001 cycle length, PR interval, QRS duraCoronary artery disease 471 (63.6%) 137 (78.7%) ⬍0.001 tion, and HV interval) were colAmiodarone 63 (10.3%) 27 (16.5%) 0.029 -adrenergic blockers 200 (32.7%) 28 (17.1%) ⬍0.001 lected. Mortality data were obtained Digoxin 200 (32.7%) 92 (56.1%) ⬍0.001 using the Social Security Death LV end-systolic diameter (cm) 4.33 ⫾ 1.25 4.94 ⫾ 1.43 ⬍0.001 Index. LV end-diastolic diameter (cm) 5.67 ⫾ 1.01 6.18 ⫾ 1.21 ⬍0.001 Statistical analysis: Univariate preLVEF (%) 36.7 ⫾ 15.5 29.2 ⫾ 14.9 ⬍0.001 Sinus cycle length (ms) 848.0 ⫾ 184.7 816.7 ⫾ 155.5 0.048 dictors of mortality in the total coPR interval (ms) 178.3 ⫾ 43.5 193.7 ⫾ 47.0 ⬍0.001 hort were identified using indepenQRS duration (ms) 117.2 ⫾ 31.1 136.1 ⫾ 33.8 ⬍0.001 dent-sample t tests for continuous QT interval (ms) 413.5 ⫾ 54.5 423.2 ⫾ 65.4 0.044 variables and chi-square or Fisher’s AH interval (ms) 96.1 ⫾ 36.5 105.9 ⫾ 37.2 0.004 exact test for discrete variables. MulHV interval (ms) 53.7 ⫾ 22.5 61.2 ⫾ 17.1 ⬍0.001 Inducible sustained monomorphic 183 (24.7%) 50 (28.7%) 0.275 tivariate analysis was performed usventricular tachycardia ing Cox regression models. SPSS ICD implantation 238 (32.1%) 60 (34.5%) 0.549 version 9.0 (SPSS Inc., Chicago, Illinois) statistical software was used for analyses. Data are presented as reviewed and approved by the institutional review mean ⫾ SD unless otherwise stated. Results were considered statistically significant for p values ⬍0.05. board. Electrophysiologic testing: An electrophysiologic study was performed in the fasting state using pro- RESULTS grammed ventricular stimulation. The stimulation proOf 954 patients who underwent an electrophysitocols consisted of programmed ventricular stimula- ologic study for risk stratification, 915 patients met tion with up to 3 ventricular extrastimuli, following inclusion criteria for the study and formed the total 8-beat paced drive cycles at up to 2 paced cycle population of the study. Thirty-nine patients were lengths at 2 right ventricular endocardial sites; 4 ex- excluded due to unavailable Social Security numbers TABLE 1 Baseline Characteristics
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Univariate analysis: Significant univariate predictors of mortality in the total population (Table 2) included older age, coronary artery disease, use of amiodarone or digoxin, lack of -blocker use, larger LV size, lower LVEF, increased baseline heart rate at rest as measured by sinus cycle length during electrophysiologic study, and longer surface electrocardiographic and intracardiac conduction intervals. Inducibility of sustained monomorphic ventricular tachycardia and ICD implantation were not significantly predictive of mortality. Mortality increased as QRS duration became more prolonged (Figure 1). Multivariate analysis: Cox multiFIGURE 1. QRS duration and annual mortality rate in patients who underwent risk variate regression analysis identified stratification for ventricular arrhythmias. QRS duration, reported in milliseconds, was these variables as independent premeasured during the baseline electrophysiologic study. Values above the black bars dictors of mortality (Figure 2): older represent mortality (%). age (hazard ratio per decade 1.3, 95% confidence interval [CI] 1.1 to 1.6; p ⫽ 0.0003), coronary artery disease (hazard ratio 1.6, 95% CI 1.1 to 2.4; p ⫽ 0.016), LVEF (hazard ratio per 10% increase 0.84, 95% CI 0.73 to 0.98; p ⫽ 0.022), lack of -blocker use (-blocker use hazard ratio 0.60, 95% CI 0.40 to 0.90; p ⫽ 0.014), digoxin use (hazard ratio 2.0, 95% CI 1.4 to 2.8; p ⫽ 0.001), and QRS duration ⱖ130 ms (hazard ratio 2.1, 95% CI 1.5 to 2.8; p ⬍0.0001). QRS duration ⱖ130 ms, age, and digoxin use were the strongest independent predictors of mortality. Sustained monomorphic ventricular tachycardia inducibility and ICD implantation were not independent predictors of mortality. Adjusted Cox regression survival curves stratified by QRS duration ⬍130 ms versus FIGURE 2. Multivariate predictors of mortality in patients who underwent risk stratifiⱖ130 ms are depicted in Figure 3. cation. Hazard ratios and 95% CIs (error bars) reported for LVEF per 10%, coronary artery disease (CAD), -adrenergic blocker use at baseline, age per decade, digoxin Multivariate analysis using QRS duuse, and QRS duration >130 ms. ration as a continuous variable also showed QRS duration to be a significant independent risk factor (hazard and/or the presence of permanent pacemakers at the ratio per 10-ms increase 1.10, CI 1.05 to 1.15; p time of the electrophysiologic study. The subgroup of ⬍0.001). Thus, for every 10-ms increase in QRS patients with coronary artery disease and LVEF duration, mortality increased approximately 10%. ⱕ30% consisted of 309 patients. Patients with coronary artery disease and LVEF Baseline characteristics: Baseline characteristics of <30%: Baseline characteristics of this subgroup are the total group are listed in Table 1. Mean QRS duration listed in Table 1. Over a mean follow-up time of 31.1 was 120.8 ⫾ 32.5 ms (median 113) in the total popula- ⫾ 14.9 months (median 30.5) there were 84 deaths tion. Three hundred six patients (33.6%) had QRS dura- (27.2%). Mean QRS duration was 127.4 ⫾ 32.2 ms tion ⱖ130 ms. ICDs were implanted in 298 patients (211 (122 ms). Mortality increased as QRS duration prowith positive and 87 with negative electrophysiologic longed, particularly beyond 130 ms (Figure 4). One study findings). Mean follow-up time was 35.0 ⫾ 15.0 hundred thirty (42.1%) of these patients had QRS months (median 34.5); over that time there were 174 duration ⱖ130. deaths (19%) in the total population. Similar to the analysis of the total group, univariate 800 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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sus ⱖ130 ms are depicted in Figure 6. Multivariate analysis also showed QRS duration as a continuous variable to be a significant independent risk factor (hazard ratio per 10 ms 1.11, CI 1.03 to 1.17; p ⫽ 0.005) in this group. For every 10-ms increase in QRS duration, mortality rate increased approximately 11%.
DISCUSSION We sought to determine if QRS duration might be independently predictive of mortality in patients assessed and treated for a high risk of sudden arrhythmic death. Multivariate analysis identified QRS duration, age, LVEF, and digoxin use as independent predictors FIGURE 3. Cox regression survival curves for total mortality in of mortality both in the overall group and in a highpatients who underwent risk stratification, adjusted for age, risk subgroup with coronary artery disease and LVEF LVEF, coronary artery disease, -adrenergic blocker use, and digoxin use. Data are stratified by QRS duration <130 versus ⱕ30%. QRS duration was the strongest independent >130 ms. predictor of mortality even after adjustment for age and LVEF, particularly in the high-risk group with coronary artery disease and LVEF ⱕ30%. Overall and in the high-risk group, for every 10-ms increase in QRS duration, mortality rate increased approximately 10%. QRS duration ⱖ130 ms was associated with more than a twofold increase in mortality rate. Interestingly, inducibility for sustained monomorphic ventricular tachycardia was not a predictor of mortality in our analysis. This may have reflected the effectiveness of ICD implantation in reducing mortality in patients at high risk for sudden arrhythmic death or the limitations of electrophysiologic testing in risk stratification. Our results are concordant with recent trials highlighting the potential mortality impact of QRS duraFIGURE 4. QRS duration and annual mortality rate in patients with coronary artery tion in patients with heart disease. disease and LVEF <30%. QRS duration, reported in milliseconds, was measured durPrevious trials have established the ing the baseline electrophysiologic study. Values above the black bars represent morsignal-averaged electrocardiogram, tality (%). which includes assessment of QRS duration, as a test that can stratify risk for mortality.9 However, most analysis in this subgroup found older age, lack of trials excluded patients with bundle branch block, -blocker use, longer PR interval, and prolonged QRS who were included in the present study. Whereas duration to be associated with higher mortality (Table MADIT II showed a survival benefit in patients 3). Digoxin use was associated with increased mortal- with ICD implantation,2 a higher incidence of new ity. Again, inducibility of sustained monomorphic or worsened heart failure with a trend toward more ventricular tachycardia and ICD implantation were not hospitalizations with heart failure was seen in the predictive of mortality in this subgroup analysis. Cox defibrillator group. Preliminary results of a recent multivariate analysis identified independent predictors substudy of MADIT II reported that in patients of mortality to include older age (hazard ratio per randomized to receive conventional treatment, QRS decade 1.4, 95% CI 1.1 to 1.8; p ⫽ 0.017), digoxin use duration ⬎120 ms was an independent and signifi(hazard ratio 1.8, 95% CI 1.2 to 2.8; p ⫽ 0.01), cant predictor of mortality (Zareba et al, unpubprolonged QRS duration ⱖ130 ms (hazard ratio 2.6, lished data, May 2002). QRS prolongation was also 95% CI 1.6 to 4.2; p ⬍0.0001), and LVEF (hazard the only factor that predicted delivery of ventricular ratio per 10%-increase 0.56, 95% CI 0.39 to 0.81, p ⫽ tachycardia and ventricular fibrillation therapy in 0.0022; Figure 5). QRS duration was again the stron- the group randomized to ICD therapy. If progest predictor of mortality. Adjusted Cox regression grammed to deliver right ventricular pacing, imsurvival curves stratified by QRS duration ⬍130 ver- planted ICDs have the potential to prolong QRS ARRHYTHMIAS AND CONDUCTION DISTURBANCES/QRS DURATION AND MORTALITY
801
duration and precipitate development of heart failure due to dyssynchronous LV contraction. The Dual Mortality Status Chamber and VVI Implantable Defibrillator (DAVID) trial10 reported Variable Alive (n ⫽ 225) Dead (n ⫽ 84) p Value that in patients receiving ICDs with Age (yrs) 64.4 ⫾ 10.0 68.0 ⫾ 10.0 0.005 LVEF ⱕ40% and no pacing indica-adrenergic blockers 66 (29.3%) 12 (14.3%) 0.007 tions, dual chamber pacing was asCalcium antagonists 26 (11.6%) 3 (3.6%) 0.032 Digoxin 99 (44.0%) 53 (63.1%) 0.003 sociated with prolonged QRS duraLV end-systolic diameter (cm) 4.91 ⫾ 0.96 5.31 ⫾ 1.01 0.005 tion at follow-up, as well as higher LV end-diastolic diameter (cm) 6.06 ⫾ 0.87 6.47 ⫾ 0.90 0.001 mortality compared with single LVEF (%) 22.6 ⫾ 5.5 20.2 ⫾ 6.3 0.001 chamber back-up pacing. Our study PR interval (ms) 184.0 ⫾ 48.2 200.0 ⫾ 47.7 0.013 QRS duration (ms) 122.5 ⫾ 31.0 140.6 ⫾ 31.9 ⬍0.001 differs from MADIT II because it QT interval (ms) 414.5 ⫾ 59.2 430.4 ⫾ 67.8 0.046 included nonischemic patients, as Inducible sustained monomorphic 93 (41.3%) 32 (38.1%) 0.606 well as patients without the degree of ventricular tachycardia LV dysfunction required for enrollICD implantation 107 (47.6%) 38 (45.2%) 0.716 ment in MADIT II. The present study differs from DAVID in that it included patients with or without ICDs, as well as patients with normal LV function. However, our study is limited by its retrospective identification of the study population and inability to identify arrhythmic versus heart failure deaths from the Social Security Death Index. Currently, QRS duration, LVEF, and clinical severity of heart failure symptoms are factors used to select candidates who may benefit from ventricular resynchronization therapy with biventricular pacing,11–14 but our study may demonstrate a wider range of potential applicability to QRS duration as a risk stratifier. Although it is unlikely that any one of the currently available risk-stratifying tools will improve overall risk stratification, many cannot be easily FIGURE 5. Multivariate predictors of mortality in patients with coronary artery disease repeated over time. QRS width is and LVEF <30%. Hazard ratios and 95% CIs (error bars) reported for age per desimple to measure and can be meacade, digoxin use, LVEF per 10%, and QRS duration >130 ms. sured repeatedly over time. Whether dynamic changes in QRS duration can predict risk remains to be established. However, significant changes in QRS duration can occur with exacerbations of heart failure,15 and widening of QRS duration over time in patients with heart failure has been associated with higher occurrences of cardiac death or need for heart transplantation.16 Although QRS duration was the strongest predictor of mortality in the MADIT-II type patient, there is currently no prospectively collected evidence to support using QRS duration as a tool to identify patients who will benefit from ICD therapy. Interestingly, QRS duration and LVEF were both independent predictors of mortality in the present study, again supporting the primacy of ventricular conduction delay as a risk factor separate from its association with myocardial FIGURE 6. Cox regression survival curves for total mortality in dysfunction. However, the contribution of QRS durapatients who underwent risk stratification with coronary artery tion to stratifying benefit for ICD therapies remains to disease and LVEF <30% adjusted for age, LVEF, and digoxin be established in randomized studies. use. Data are stratified by QRS duration <130 versus >130 ms. TABLE 3 Univariate Predictors of Mortality in Patients With Coronary Artery Disease and Left Ventricular Ejection Fraction (LVEF) ⱕ30%
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1. Buxton AE, Lee KL, DiCarlo L, Gold MR, Greer GS, Prystowsky EN, O’Toole MF, Tang A, Fisher JD, Coromilas J, Talajic M, Hafley G. Electrophysiologic testing to identify patients with coronary artery disease who are at risk for sudden death. Multicenter Unsustained Tachycardia Trial Investigators. New Engl J Med 2000;342:1937–1945. 2. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–883. 3. Murkofsky RL, Dangas G, Diamond JA, Mehta D, Schaffer A, Ambrose JA. A prolonged QRS duration on surface electrocardiogram is a specific indicator of left ventricular dysfunction. J Am Coll Cardiol 1998;32:476 –482. 4. Brembilla-Perrot B. Correlation between inducibility of sustained ventricular tachycardia and QRS duration. Euro Heart J 1994;15:26 –31. 5. Multicenter Automatic Defibrillator Implantation Trial (MADIT): design and clinical protocol. MADIT Executive Committee. Pacing Clin Electrophysiol 1991;14:920 –927. 6. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999;341:1882–1890. 7. Hummel JD, Strickberger SA, Daoud E, Niebauer M, Bakr O, Man KC, Williamson BD, Morady F. Results and efficiency of programmed ventricular stimulation with four extrastimuli compared with one, two, and three extrastimuli. Circulation 1994;90:2827–2832. 8. Denker S, Lehmann M, Mahmud R, Gilbert C, Akhtar M. Facilitation of ventricular tachycardia induction with abrupt changes in ventricular cycle length. Am J Cardiol 1984;53:508 –515. 9. Gomes JA, Cain ME, Buxton AE, Josephson ME, Lee KL, Hafley GE. Prediction of long-term outcomes by signal-averaged electrocardiography in
patients with unsustained ventricular tachycardia, coronary artery disease, and left ventricular dysfunction. Circulation 2001;104:436 –441. 10. Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H, Kutalek SP, Sharma A. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial. JAMA 2002;288:3115–3123. 11. Bradley DJ, Bradley EA, Baughman KL, Berger RD, Calkins H, Goodman SN, Kass DA, Powe NR. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. JAMA 2003;289: 730 –740. 12. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 13. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C, Daubert JC. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873–880. 14. Bristow MR, Feldman AM, Saxon LA. Heart failure management using implantable devices for ventricular resynchronization: Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial. COMPANION Steering Committee and COMPANION Clinical Investigators. J Card Fail 2000;6:276 –285. 15. Aranda JM, Carlson ER, Pauly DF, Curtis AB, Conti CR, Ariet M, Hill JA. QRS duration variability in patients with heart failure. Am J Cardiol 2002;90: 335–337. 16. Grigioni F, Carinci V, Boriani G, Bracchetti G, Potena L, Magnani G, Bacchi-Reggiani L, Magelli C, Branzi A. Accelerated QRS widening as an independent predictor of cardiac death or of the need for heart transplantation in patients with congestive heart failure. J Heart Lung Transplant 2002;21:899 – 902.
ARRHYTHMIAS AND CONDUCTION DISTURBANCES/QRS DURATION AND MORTALITY
803
MD,
This study tested the hypothesis that prolonged QRS duration independently predicts long-term mortality in patients who underwent risk stratification and treatment for ventricular arrhythmias. Patients who underwent risk stratification by electrophysiologic study were identified. Electrophysiologic study results were defined as positive if sustained monomorphic ventricular tachycardia was induced. Mortality was the primary end point. Of 915 patients studied, mean left ventricular (LV) ejection fraction (EF) was 35.3 ⴞ 15.7%, 608 (66.4%) had coronary artery disease, 233 (25.5%) had positive electrophysiologic study findings, 298 (32.6%) received implantable cardioverter-defibrillators, and 174 (19%) died (mean follow-up 35.0 ⴞ 15.0 months). Cox regression analysis identified older age, coronary artery disease, digoxin use, absence of  blockers, lower LVEF, and prolonged QRS duration to be independent predictors of mortality.
QRS duration >130 ms, present in 33.6% of patients, was associated with a twofold increase in mortality (hazard ratio 2.1, 95% confidence interval 1.5 to 2.8; p <0.0001). For every 10 ms increase in QRS duration, mortality rate increased 10%. In a subgroup of patients with coronary artery disease and LVEF <30%, prolonged QRS duration remained an independent predictor of mortality (hazard ratio 2.6, 95% confidence interval 1.6 to 4.2; p <0.0001). Thus, prolonged QRS duration is a strong independent marker of long-term mortality in patients who undergo risk stratification for ventricular arrhythmias. Whether QRS duration represents only a marker for mortality or if modification of this factor using resynchronization therapies will impact mortality merits further study. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;92:798 – 803)
espite current risk stratification strategies and implantable cardioverter-defibrillator (ICD) implanD tation directed toward reducing life-threatening ven-
and treatment for ventricular arrhythmias, including a high-risk subgroup identified for ICD implantation by MADIT II.2
tricular arrhythmias, patients remain at significant long-term risk for mortality. The Multicenter Unsustained Tachycardia Trial (MUSTT)1 reported overall mortality after 5 years reaching over 40% in patients with inducible ventricular arrhythmias, as well as in registry patients with negative electrophysiologic study findings. The Multicenter Automatic Defibrillator Implantation Trial (MADIT) II2 reported a 14.2% mortality at 20 months in patients with coronary artery disease and left ventricular (LV) ejection fraction (EF) ⱕ30% receiving ICDs. Hence, identification of tools for additional risk stratification is essential. QRS prolongation has been correlated with decreased LVEF3 and inducibility of sustained ventricular arrhythmias during electrophysiologic study.4 We sought to determine if QRS duration is an independent predictor of mortality in patients who underwent risk assessment From the Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio; Kwong Wah Hospital, Hong Kong, China; Heart Specialists of Sarasota, Sarasota, Florida; and the University of Nebraska Medical Center, Omaha, Nebraska. Manuscript received April 9, 2003; revised manuscript received and accepted June 16, 2003. Address for reprints: Mina K. Chung, MD, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F-15, Cleveland, Ohio 44195. E-mail: [email protected].
798
©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 92 October 1, 2003
METHODS This study aimed to determine the independent predictors of long-term mortality in a population of patients who underwent electrophysiologic testing for risk stratification of ventricular arrhythmias. Specifically, we sought to assess whether QRS duration was a predictor of mortality independent of electrophysiologic testing outcome or ICD implantation in this population, as well as in a high-risk ischemic cardiomyopathy subgroup that may be targeted for prophylactic device implantation therapy. Patient population: All patients who underwent electrophysiologic testing for risk stratification of ventricular arrhythmias between August 1996 and December 1999 were retrospectively identified from a clinical database maintained in the electrophysiology laboratory of The Cleveland Clinic Foundation. A subgroup of patients with coronary artery disease and LVEF ⱕ30%, characteristics of patients identified by the MADIT II study as potentially benefiting from ICD implantation,2 was also identified for analysis of long-term mortality. Patients with permanent pacemakers at the time of electrophysiologic testing or who did not have Social Security numbers available were excluded from analysis. The study protocol was 0002-9149/03/$–see front matter doi:10.1016/S0002-9149(03)00886-5
trastimuli at 3 paced cycle lengths at 2 right ventricular sites; burst pacing; Patients With CAD and/or short-long-short coupling inTotal Cohort and LVEF ⱕ30% tervals. The stimulation protocols Variable (n ⫽ 915) (n ⫽ 309) that used burst pacing and up to 3 Age (yrs) mean ⫾ SD 63.0 ⫾ 13.1 65.4 ⫾ 10.1 extrastimuli were similar to those White 798 (87.2%) 268 (86.7%) used in MADIT5 and MUSTT.6 The Men 694 (76.1%) 262 (84.8%) protocol using 4 extrastimuli has Current cigarette smoker 113 (12.3%) 41 (13.3%) been reported to improve efficiency Structural heart disease Coronary artery disease 608 (66.4%) 309 (100%) and specificity without compromisPrior coronary bypass 373 (40.8%) 198 (64.1%) ing yield of monomorphic ventricuPrior coronary angioplasty 119 (13%) 60 (19.4%) lar tachycardia.7 The short-longValvular disease 119 (13%) 36 (11.7%) short stimulation protocol has been Hypertrophic cardiomyopathy 23 (2.5%) 1 (0.3%) reported to potentially add to the Primary cardiomyopathy 155 (17.0%) 3 (1%) No heart disease 73 (8.0%) 0 (0%) yield of ventricular tachycardia inLVEF (%) 35.3 ⫾ 15.7 22.0 ⫾ 5.9 duction in patients susceptible to Medications macroreentry in the His-Purkinje -adrenergic blockers 228 (29.4%) 78 (25.2%) system.8 A positive study result was Calcium antagonists 90 (11.6%) 29 (9.4%) Digoxin 292 (37.7%) 152 (49.2%) identified as inducible sustained Amiodarone 90 (11.6%) 42 (13.6%) monomorphic ventricular tachycarPR interval (ms) 181 ⫾ 45 188 ⫾ 49 dia, defined as monomorphic ventricQRS duration (ms) 121 ⫾ 33 127 ⫾ 32 ular tachycardia lasting ⬎30 seconds QT interval (ms) 415 ⫾ 57 419 ⫾ 62 or associated with syncope, hemodySinus cycle length (ms) 842 ⫾ 180 815 ⫾ 165 AH interval (ms) 98 ⫾ 37 103 ⫾ 39 namic compromise, or requiring inHV interval (ms) 55 ⫾ 22 59 ⫾ 27 tervention for termination. A negaInducible sustained monomorphic 233 (25.5%) 125 (40.5%) tive electrophysiologic study result ventricular tachycardia was defined as noninducibility of ICD implantation 298 (32.6%) 145 (46.9%) sustained monomorphic ventricular tachycardia. Data collection: Demographic, clinical, electrocardiographic, echocardiographic, and electrophysiTABLE 2 Univariate Predictors of Mortality in the Total Cohort of Patients Who ologic data, including age, type of Underwent Electrophysiologic Testing structural heart disease, use of antiMortality Status arrhythmic medications, LVEF, and surface and intracardiac electrocarVariable Alive (n ⫽ 741) Dead (n ⫽ 174) p Value diographic intervals (including sinus Age (yrs) 61.9 ⫾ 13.3 67.5 ⫾ 11.2 ⬍0.001 cycle length, PR interval, QRS duraCoronary artery disease 471 (63.6%) 137 (78.7%) ⬍0.001 tion, and HV interval) were colAmiodarone 63 (10.3%) 27 (16.5%) 0.029 -adrenergic blockers 200 (32.7%) 28 (17.1%) ⬍0.001 lected. Mortality data were obtained Digoxin 200 (32.7%) 92 (56.1%) ⬍0.001 using the Social Security Death LV end-systolic diameter (cm) 4.33 ⫾ 1.25 4.94 ⫾ 1.43 ⬍0.001 Index. LV end-diastolic diameter (cm) 5.67 ⫾ 1.01 6.18 ⫾ 1.21 ⬍0.001 Statistical analysis: Univariate preLVEF (%) 36.7 ⫾ 15.5 29.2 ⫾ 14.9 ⬍0.001 Sinus cycle length (ms) 848.0 ⫾ 184.7 816.7 ⫾ 155.5 0.048 dictors of mortality in the total coPR interval (ms) 178.3 ⫾ 43.5 193.7 ⫾ 47.0 ⬍0.001 hort were identified using indepenQRS duration (ms) 117.2 ⫾ 31.1 136.1 ⫾ 33.8 ⬍0.001 dent-sample t tests for continuous QT interval (ms) 413.5 ⫾ 54.5 423.2 ⫾ 65.4 0.044 variables and chi-square or Fisher’s AH interval (ms) 96.1 ⫾ 36.5 105.9 ⫾ 37.2 0.004 exact test for discrete variables. MulHV interval (ms) 53.7 ⫾ 22.5 61.2 ⫾ 17.1 ⬍0.001 Inducible sustained monomorphic 183 (24.7%) 50 (28.7%) 0.275 tivariate analysis was performed usventricular tachycardia ing Cox regression models. SPSS ICD implantation 238 (32.1%) 60 (34.5%) 0.549 version 9.0 (SPSS Inc., Chicago, Illinois) statistical software was used for analyses. Data are presented as reviewed and approved by the institutional review mean ⫾ SD unless otherwise stated. Results were considered statistically significant for p values ⬍0.05. board. Electrophysiologic testing: An electrophysiologic study was performed in the fasting state using pro- RESULTS grammed ventricular stimulation. The stimulation proOf 954 patients who underwent an electrophysitocols consisted of programmed ventricular stimula- ologic study for risk stratification, 915 patients met tion with up to 3 ventricular extrastimuli, following inclusion criteria for the study and formed the total 8-beat paced drive cycles at up to 2 paced cycle population of the study. Thirty-nine patients were lengths at 2 right ventricular endocardial sites; 4 ex- excluded due to unavailable Social Security numbers TABLE 1 Baseline Characteristics
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Univariate analysis: Significant univariate predictors of mortality in the total population (Table 2) included older age, coronary artery disease, use of amiodarone or digoxin, lack of -blocker use, larger LV size, lower LVEF, increased baseline heart rate at rest as measured by sinus cycle length during electrophysiologic study, and longer surface electrocardiographic and intracardiac conduction intervals. Inducibility of sustained monomorphic ventricular tachycardia and ICD implantation were not significantly predictive of mortality. Mortality increased as QRS duration became more prolonged (Figure 1). Multivariate analysis: Cox multiFIGURE 1. QRS duration and annual mortality rate in patients who underwent risk variate regression analysis identified stratification for ventricular arrhythmias. QRS duration, reported in milliseconds, was these variables as independent premeasured during the baseline electrophysiologic study. Values above the black bars dictors of mortality (Figure 2): older represent mortality (%). age (hazard ratio per decade 1.3, 95% confidence interval [CI] 1.1 to 1.6; p ⫽ 0.0003), coronary artery disease (hazard ratio 1.6, 95% CI 1.1 to 2.4; p ⫽ 0.016), LVEF (hazard ratio per 10% increase 0.84, 95% CI 0.73 to 0.98; p ⫽ 0.022), lack of -blocker use (-blocker use hazard ratio 0.60, 95% CI 0.40 to 0.90; p ⫽ 0.014), digoxin use (hazard ratio 2.0, 95% CI 1.4 to 2.8; p ⫽ 0.001), and QRS duration ⱖ130 ms (hazard ratio 2.1, 95% CI 1.5 to 2.8; p ⬍0.0001). QRS duration ⱖ130 ms, age, and digoxin use were the strongest independent predictors of mortality. Sustained monomorphic ventricular tachycardia inducibility and ICD implantation were not independent predictors of mortality. Adjusted Cox regression survival curves stratified by QRS duration ⬍130 ms versus FIGURE 2. Multivariate predictors of mortality in patients who underwent risk stratifiⱖ130 ms are depicted in Figure 3. cation. Hazard ratios and 95% CIs (error bars) reported for LVEF per 10%, coronary artery disease (CAD), -adrenergic blocker use at baseline, age per decade, digoxin Multivariate analysis using QRS duuse, and QRS duration >130 ms. ration as a continuous variable also showed QRS duration to be a significant independent risk factor (hazard and/or the presence of permanent pacemakers at the ratio per 10-ms increase 1.10, CI 1.05 to 1.15; p time of the electrophysiologic study. The subgroup of ⬍0.001). Thus, for every 10-ms increase in QRS patients with coronary artery disease and LVEF duration, mortality increased approximately 10%. ⱕ30% consisted of 309 patients. Patients with coronary artery disease and LVEF Baseline characteristics: Baseline characteristics of <30%: Baseline characteristics of this subgroup are the total group are listed in Table 1. Mean QRS duration listed in Table 1. Over a mean follow-up time of 31.1 was 120.8 ⫾ 32.5 ms (median 113) in the total popula- ⫾ 14.9 months (median 30.5) there were 84 deaths tion. Three hundred six patients (33.6%) had QRS dura- (27.2%). Mean QRS duration was 127.4 ⫾ 32.2 ms tion ⱖ130 ms. ICDs were implanted in 298 patients (211 (122 ms). Mortality increased as QRS duration prowith positive and 87 with negative electrophysiologic longed, particularly beyond 130 ms (Figure 4). One study findings). Mean follow-up time was 35.0 ⫾ 15.0 hundred thirty (42.1%) of these patients had QRS months (median 34.5); over that time there were 174 duration ⱖ130. deaths (19%) in the total population. Similar to the analysis of the total group, univariate 800 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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sus ⱖ130 ms are depicted in Figure 6. Multivariate analysis also showed QRS duration as a continuous variable to be a significant independent risk factor (hazard ratio per 10 ms 1.11, CI 1.03 to 1.17; p ⫽ 0.005) in this group. For every 10-ms increase in QRS duration, mortality rate increased approximately 11%.
DISCUSSION We sought to determine if QRS duration might be independently predictive of mortality in patients assessed and treated for a high risk of sudden arrhythmic death. Multivariate analysis identified QRS duration, age, LVEF, and digoxin use as independent predictors FIGURE 3. Cox regression survival curves for total mortality in of mortality both in the overall group and in a highpatients who underwent risk stratification, adjusted for age, risk subgroup with coronary artery disease and LVEF LVEF, coronary artery disease, -adrenergic blocker use, and digoxin use. Data are stratified by QRS duration <130 versus ⱕ30%. QRS duration was the strongest independent >130 ms. predictor of mortality even after adjustment for age and LVEF, particularly in the high-risk group with coronary artery disease and LVEF ⱕ30%. Overall and in the high-risk group, for every 10-ms increase in QRS duration, mortality rate increased approximately 10%. QRS duration ⱖ130 ms was associated with more than a twofold increase in mortality rate. Interestingly, inducibility for sustained monomorphic ventricular tachycardia was not a predictor of mortality in our analysis. This may have reflected the effectiveness of ICD implantation in reducing mortality in patients at high risk for sudden arrhythmic death or the limitations of electrophysiologic testing in risk stratification. Our results are concordant with recent trials highlighting the potential mortality impact of QRS duraFIGURE 4. QRS duration and annual mortality rate in patients with coronary artery tion in patients with heart disease. disease and LVEF <30%. QRS duration, reported in milliseconds, was measured durPrevious trials have established the ing the baseline electrophysiologic study. Values above the black bars represent morsignal-averaged electrocardiogram, tality (%). which includes assessment of QRS duration, as a test that can stratify risk for mortality.9 However, most analysis in this subgroup found older age, lack of trials excluded patients with bundle branch block, -blocker use, longer PR interval, and prolonged QRS who were included in the present study. Whereas duration to be associated with higher mortality (Table MADIT II showed a survival benefit in patients 3). Digoxin use was associated with increased mortal- with ICD implantation,2 a higher incidence of new ity. Again, inducibility of sustained monomorphic or worsened heart failure with a trend toward more ventricular tachycardia and ICD implantation were not hospitalizations with heart failure was seen in the predictive of mortality in this subgroup analysis. Cox defibrillator group. Preliminary results of a recent multivariate analysis identified independent predictors substudy of MADIT II reported that in patients of mortality to include older age (hazard ratio per randomized to receive conventional treatment, QRS decade 1.4, 95% CI 1.1 to 1.8; p ⫽ 0.017), digoxin use duration ⬎120 ms was an independent and signifi(hazard ratio 1.8, 95% CI 1.2 to 2.8; p ⫽ 0.01), cant predictor of mortality (Zareba et al, unpubprolonged QRS duration ⱖ130 ms (hazard ratio 2.6, lished data, May 2002). QRS prolongation was also 95% CI 1.6 to 4.2; p ⬍0.0001), and LVEF (hazard the only factor that predicted delivery of ventricular ratio per 10%-increase 0.56, 95% CI 0.39 to 0.81, p ⫽ tachycardia and ventricular fibrillation therapy in 0.0022; Figure 5). QRS duration was again the stron- the group randomized to ICD therapy. If progest predictor of mortality. Adjusted Cox regression grammed to deliver right ventricular pacing, imsurvival curves stratified by QRS duration ⬍130 ver- planted ICDs have the potential to prolong QRS ARRHYTHMIAS AND CONDUCTION DISTURBANCES/QRS DURATION AND MORTALITY
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duration and precipitate development of heart failure due to dyssynchronous LV contraction. The Dual Mortality Status Chamber and VVI Implantable Defibrillator (DAVID) trial10 reported Variable Alive (n ⫽ 225) Dead (n ⫽ 84) p Value that in patients receiving ICDs with Age (yrs) 64.4 ⫾ 10.0 68.0 ⫾ 10.0 0.005 LVEF ⱕ40% and no pacing indica-adrenergic blockers 66 (29.3%) 12 (14.3%) 0.007 tions, dual chamber pacing was asCalcium antagonists 26 (11.6%) 3 (3.6%) 0.032 Digoxin 99 (44.0%) 53 (63.1%) 0.003 sociated with prolonged QRS duraLV end-systolic diameter (cm) 4.91 ⫾ 0.96 5.31 ⫾ 1.01 0.005 tion at follow-up, as well as higher LV end-diastolic diameter (cm) 6.06 ⫾ 0.87 6.47 ⫾ 0.90 0.001 mortality compared with single LVEF (%) 22.6 ⫾ 5.5 20.2 ⫾ 6.3 0.001 chamber back-up pacing. Our study PR interval (ms) 184.0 ⫾ 48.2 200.0 ⫾ 47.7 0.013 QRS duration (ms) 122.5 ⫾ 31.0 140.6 ⫾ 31.9 ⬍0.001 differs from MADIT II because it QT interval (ms) 414.5 ⫾ 59.2 430.4 ⫾ 67.8 0.046 included nonischemic patients, as Inducible sustained monomorphic 93 (41.3%) 32 (38.1%) 0.606 well as patients without the degree of ventricular tachycardia LV dysfunction required for enrollICD implantation 107 (47.6%) 38 (45.2%) 0.716 ment in MADIT II. The present study differs from DAVID in that it included patients with or without ICDs, as well as patients with normal LV function. However, our study is limited by its retrospective identification of the study population and inability to identify arrhythmic versus heart failure deaths from the Social Security Death Index. Currently, QRS duration, LVEF, and clinical severity of heart failure symptoms are factors used to select candidates who may benefit from ventricular resynchronization therapy with biventricular pacing,11–14 but our study may demonstrate a wider range of potential applicability to QRS duration as a risk stratifier. Although it is unlikely that any one of the currently available risk-stratifying tools will improve overall risk stratification, many cannot be easily FIGURE 5. Multivariate predictors of mortality in patients with coronary artery disease repeated over time. QRS width is and LVEF <30%. Hazard ratios and 95% CIs (error bars) reported for age per desimple to measure and can be meacade, digoxin use, LVEF per 10%, and QRS duration >130 ms. sured repeatedly over time. Whether dynamic changes in QRS duration can predict risk remains to be established. However, significant changes in QRS duration can occur with exacerbations of heart failure,15 and widening of QRS duration over time in patients with heart failure has been associated with higher occurrences of cardiac death or need for heart transplantation.16 Although QRS duration was the strongest predictor of mortality in the MADIT-II type patient, there is currently no prospectively collected evidence to support using QRS duration as a tool to identify patients who will benefit from ICD therapy. Interestingly, QRS duration and LVEF were both independent predictors of mortality in the present study, again supporting the primacy of ventricular conduction delay as a risk factor separate from its association with myocardial FIGURE 6. Cox regression survival curves for total mortality in dysfunction. However, the contribution of QRS durapatients who underwent risk stratification with coronary artery tion to stratifying benefit for ICD therapies remains to disease and LVEF <30% adjusted for age, LVEF, and digoxin be established in randomized studies. use. Data are stratified by QRS duration <130 versus >130 ms. TABLE 3 Univariate Predictors of Mortality in Patients With Coronary Artery Disease and Left Ventricular Ejection Fraction (LVEF) ⱕ30%
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