Long-Term Follow-Up of Implantable Cardioverter-Defibrillator for Secondary Prevention in Chagas Heart Disease

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1 Long-Term Follow-Up of Implantable Cardioverter-Defibrillator for Secondary Prevention in Chagas Heart Disease Martino Martinelli, MD, PhD a, *, Sérgio Freitas de Siqueira, MSc Eng a, Eduardo Back Sternick, MD, PhD, FHRS b, Anis Rassi, Jr., MD, PhD c, Roberto Costa, MD, PhD d, José Antônio Franchini Ramires, MD, PhD e, and Roberto Kalil Filho e Assessing the efficacy of implantable cardioverter-defibrillators (ICD) in patients with Chagas heart disease (ChHD) and identifying the clinical predictors of mortality and ICD shock during long-term follow-up. ChHD is associated with ventricular tachyarrhythmias and an increased risk of sudden cardiac death. Although ChHD is a common form of cardiomyopathy in Latin American ICD users, little is known about its efficacy in the treatment of this population. The study cohort included 116 consecutive patients with ChHD and an ICD implanted for secondary prevention. Of the 116 patients, 83 (72%) were men; the mean age was years. Several clinical variables were tested in a multivariate Cox model for predicting long-term mortality. The average follow-up was months. New York Heart Association class I-II developed in 83% of patients. The mean left ventricular ejection fraction was 42 16% at implantation. Of the 116 patients, 58 (50%) had appropriate shocks and 13 (11%) had inappropriate therapy. A total of 31 patients died (7.1% annual mortality rate). New York Heart Association class III (hazard ratio [HR] 3.09, 95% confidence interval 1.37 to 6.96, p ) was a predictor of a worse prognosis. The left ventricular ejection fraction (HR 0.972, 95% confidence interval 0.94 to 0.99, p ) and low cumulative right ventricular pacing (HR 0.23, 95% confidence interval 0.11 to 0.49, p ) were predictors of better survival. The left ventricular diastolic diameter was an independent predictor of appropriate shock (HR 1.032, 95% confidence interval to 1.060, p 0.025). In conclusion, in a long-term follow-up, ICD efficacy for secondary sudden cardiac death prevention in patients with ChHD was marked by a favorable annual rate of all-cause mortality (7.1%); 50% of the cohort received appropriate shock therapy. New York Heart Association class III and left ventricular ejection fraction were independent predictors of worse prognosis, and low cumulative right ventricular pacing defined better survival Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110: ) Data are conflicting regarding the efficacy of implantable cardioverter-defibrillator (ICD) in patients with Chagas heart disease (ChHD). The evidence is based on the results of 2 manufacturer-sponsored registries 1 3 and 1 retrospective cohort study. 4 The reported annual mortality rates in these 3 studies varied from 5.5% to 16.6%, with the upper value greater than the mortality rates reported in studies restricted to patients with sustained ventricular tachycardia (VT) who were treated with antiarrhythmic drugs. Thus, the aim of the present study was to assess, during long-term follow-up, the ICD efficacy of a ChHD cohort from a tertiary center, considering all-cause mortality and appropriate ICD shock therapy a Pacemaker Clinic, d Division of Cardiac Surgery, and e Division of Cardiology, Heart Institute (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil; b Arrhythmia and Electrophysiology Unit, Biocor Instituto, Nova Lima, MG, Brazil; and c Division of Cardiology, Anis Rassi Hospital, Goiânia, GO, Brazil. Manuscript received March 22, 2012; revised manuscript received and accepted May 23, *Corresponding author: Tel: ( 55) ; fax: ( 55) address: martino@incor.usp.br (M. Martinelli). rates and analyzing the predictive value of the clinical variables. Methods The inclusion criteria were ChHD, diagnosed by positive serologic tests, and an ICD implanted for secondary prevention of sudden cardiac death, according to the Brazilian guidelines. 5,6 The exclusion criteria were age 18 years old, advanced atrioventricular block, or previous pacemaker or cardiac resynchronization device at ICD implantation (n 76 patients). The study flow chart is shown in Figure 1. The present study was a retrospective cohort study of patients with ChHD and an ICD from the Heart Institute of the University of São Paulo Medical School (InCor) in Brazil. The ethics committee of our institution approved the study in January 2000 and the study was implemented in June The last inclusion occurred in June 2008, and follow-up was closed in March A database system was designed to include patient characteristics, medical history, ICD indication, and functional outcomes at implantation and during follow-up. The data were collected on several potential risk factors, including age, /12/$ see front matter 2012 Elsevier Inc. All rights reserved.

2 Cardiomyopathy/Implantable Cardioverter-Defibrillator in Chagas Heart Disease 1041 Figure 1. Flow-chart of patient selection. Criteria of patient selection for the study. CRT-D cardiac resynchronization therapy-defibrillator. gender, New York Heart Association functional class, syncope, left ventricular ejection fraction (LVEF), the use of drugs (amiodarone, blockers, angiotensin-converting enzyme inhibitors), echocardiographic parameters (LVEF, left ventricular diastolic diameter, left atrial diameter, and mitral regurgitation), the percentage of cumulative right ventricular pacing, and the occurrence of appropriate and inappropriate shock therapy. Radiofrequency catheter ablation was undertaken on a case-bycase basis. Before ICD implantation, all patients received optimal medical therapy. The ICD implants included 114 transvenous systems, manufactured by Medtronic (Minneapolis, Minnesota) (33%), Biotronik (Berlin, Germany) (25%), Guidant/CPI (St. Paul, Minnesota) (10%), and St. Jude Medical (Sylmar, California) (32%). The ICD programming included therapy for standard VT with antitachycardia pacing combined with low-energy shock therapy and for ventricular fibrillation (VF) shock therapy with a 300-ms cutoff cycle interval. It was considered standard VT in the presence of sustained tachycardia with a cycle interval ranging from 300 to 400 ms, not discriminated as supra-vt by specific algorithms. It was considered VF when the cycle interval was inferior to 300 ms. ICD therapy was classified as appropriate for VT/VF if the recorded intracardiac electrogram for the intervention was compatible with the clinical manifestation, on medical discretion. The shock therapy was considered inappropriate when the ICD therapy was applied to supra-vt, noise, myopotential oversensing, or R-wave double counting. Customized programs were performed according to individual needs. The decision regarding activation of pacing therapy for bradycardia was left to the discretion of each physician at the outpatient pacemaker clinic. The follow-up protocol included regular clinical and device evaluation performed 3 times annually. The primary outcome was death from all causes. The circumstances of the deaths were reviewed and categorized as from a cardiac or noncardiac cause, and the classification of Hinkle and Thaler 7 was used to evaluate the suspected mechanism of death. The primary data analysis examined the effect of the potential risk factors on appropriate shocks and long-term mortality. Cumulative survival was assessed using the Cox regression method adjusted for independent covariates, and the differences were compared using Cox proportional hazard models. Analyses, adjusted for potential confounders, were also performed using multivariate Cox proportional hazard models. The covariates were applied in a forward selection according to the unadjusted association of p 0.05 in the univariate models. The Cox model assumption of proportional hazards was found to be valid from the logminus-log curves and the Schoenfeld test. The software used was SPSS, version , for Windows (SPSS, Chicago, Illinois).

3 1042 The American Journal of Cardiology ( Table 1 Baseline clinical characteristics (n 116) Table 2 Causes of death during follow-up Characteristics at implantation Value Cause Patients (n) Men 73 (62%) Mean age (years) New York Heart Association functional class I 36 (31%) II 60 (52%) III 20 (17%) Syncope 73 (63%) Mean left ventricular ejection fraction (%) Left atrium (mm) Left ventricular end-diastolic diameter (mm) Amiodarone 90 (78%) Median daily dose (mg) 400 Blocker 38 (33%) Angiotensin-converting enzyme inhibitors 95 (82%) Electrophysiologic study 79 (68.1%) Not induced 3 (4%) Monomorphic ventricular tachycardia 1 (1%) Monomorphic sustained ventricular tachycardia 61 (77%) Polymorphic sustained ventricular tachycardia 11 (14%) Ventricular fibrillation 3 (4%) Mean QRS width (ms) Nonsustained ventricular tachycardia 59 (66%) Sustained ventricular tachycardia 3 (3%) Implantable cardioverter-defibrillator indication Aborted sudden cardiac death 21 (18%) Symptomatic sustained ventricular tachycardia 95 (82%) Type of implantable cardioverter-defibrillator Atrioventricular 67 (58%) Ventricular 49 (42%) Median percentage of cumulative right ventricular pacing 17% Results The study cohort consisted of 116 patients. Of the 116 patients, 73 were men. The patient age range was 18 to 79 years (mean years). New York Heart Association functional class I-II was present in 82.7%, and the mean LVEF was %. Of the 116 patients, 90 (77.6%) were taking a median daily dose of 400 mg (range 100 to 600) amiodarone, and 38 (32.8%) were using a blocker. The ICD indication was resuscitated VF or VT in 21 patients (18.1%) and symptomatic sustained VT in 95 (81.9%). Of these, 64 patients (55.2%) underwent an electrophysiologic study and had hemodynamic unstable VT or VF induced by 3 extra stimuli. ICD implantation was performed from June 1990 to June The baseline clinical characteristics of the cohort are listed in Table 1. During a mean follow-up of months, 31 deaths (26.7%) occurred (Table 2), corresponding to an annual mortality rate of 7.1%. The potential confounder variables applicable to the multivariate Cox proportional hazards models (those associated with death on univariate analysis, p 0.05) were New York Heart Association functional class, the use of amiodarone, LVEF, left ventricular enddiastolic diameter, left atrial diameter, nonsustained VT, rate of cumulative right ventricular pacing, and number of appropriate shocks. New York Heart Association functional class III (hazard ratio [HR] 3.09, 95% confidence interval [CI] 1.37 to 6.96, p ) was a predictor of a worse Unknown 3 (8%) Cardiac Heart failure 14 (45%) Sudden death 0 Non cardiac 14 (45%) Total 31 prognosis. The LVEF (HR 0.972, 95% CI 0.94 to 0.99, p ) and a low rate of cumulative right ventricular pacing (HR 0.23, 95% CI 0.11 to 0.49, p ) were predictors of better survival. The survival curves of the entire cohort, stratified according to New York Heart Association functional class and cumulative right ventricular pacing, are presented in Figures 2 and 3. Survival curves free of appropriate shock therapy, including the survival curve for the entire cohort, are presented in Figure 4. A total of 750 VT/VF episodes in 58 patients or 50% of the cohort. These patients received 339 appropriate shocks (5.8/patient, range 1 to 37), and 4 patients (3.4%) received only appropriate antitachycardia pacing therapy. Inappropriate shocks occurred in 18 patients (3.6/patient), corresponding to 15.5% of the cohort. The causes of inappropriate shocks were atrial fibrillation in 8 patients, noise in 8 patients, myopotential oversensing in 1 patient, and R-wave double counting in 1 patient. Seventeen patients with multiple appropriate ICD therapy events, including 11 patients with electrical storm, underwent radiofrequency catheter ablation. Mitral regurgitation and left ventricular end-diastolic diameter were the applicable potential confounder variables in the multivariate Cox regression models for appropriate shocks, with the left ventricular end-diastolic diameter the independent predictor of this outcome (HR 1.032, 95% CI to 1.060, p 0.025). Discussion In the present study, the all-cause annual mortality rate was 7.1%; 50% of the patients received appropriate ICD therapy. The mean age of the cohort was 54 years. Thus, they were, on average, 1 decade younger than patients with coronary heart disease (mean age 65 years) The mean LVEF of 42% differed notably from that in patients with ischemic heart disease, in whom the mean LVEF is lower, such as was seen in the Antiarrhythmics Versus Implantable Defibrillators (AVID) 8 study (32%) and Canadian Implantable Defibrillator Study (CIDS) 10 (34%). According to the functional findings in our patients, most had nonadvanced congestive heart failure (82.7%, functional class I or II). Mady et al, 11 in a 3-year follow-up study of 104 male patients with ChHD and congestive heart failure without sustained VT reported the excellent prognosis of the functional class II subgroup (97% survival during the follow-up period), suggesting the importance of ventricular arrhythmia as a cause of mortality. The mode of death in patients with ChHD is sudden in nearly 60% of patients,

4 Cardiomyopathy/Implantable Cardioverter-Defibrillator in Chagas Heart Disease 1043 Figure 2. Survival curves considering functional class. Adjusted probability survival curves of the ICD cohort with ChHD, according to functional class and entire cohort survival at mean values of independent covariates. Figure 3. Survival curves considering cumulative right ventricular pacing. Adjusted probability survival curves of ICD cohort with ChHD, according to cumulative right ventricular pacing and entire cohort survival at mean values of independent covariates. mostly from VT or VF. 12 A peculiar factor in these patients is the occurrence of sudden cardiac death in patients with normal or near-normal LVEF, without symptoms of congestive heart failure. 13 The annual all-cause mortality rate was low in the present study compared to the mortality in a similar series of patients with sustained VT receiving only antiarrhythmic medication. Scanavacca et al 14 studied 35 patients, with a short-term follow-up period (27 20 months) and observed an annual mortality rate of 5.1%, with sudden cardiac death

5 1044 The American Journal of Cardiology ( Figure 4. Appropriate shocks and survival curves. Kaplan-Meyer curves of probability of survival without appropriate shocks compared to all-cause mortality of cohort. rate of 40%. Only 46% recuperated from sudden cardiac death or syncopal-sustained VT (i.e., more than one half were not eligible for ICD implantation). Rassi et al 12 studied 34 patients with Chagas disease and found an annual mortality rate of 11.9%, with 71% reported as sudden death. Sarabanda and Marin-Neto 15 recently reported a similar mortality rate (10.7% annually) in a series of 28 patients after a mean follow-up of months; 78% of the deaths were sudden. In the present study, ICD efficacy seemed to have played an important role on the lower annual mortality rate (7.1%) and the nonoccurrence of sudden cardiac death cases. Most probably, amiodarone also had an effect on the survival of the cohort, although it was not an independent predictor. The ICD Latin America Chagas Registry, 1 which included 89 patients for primary and secondary sudden cardiac death prevention with a very short follow-up period, showed a 1-year mortality rate of 6.7%, similar to our findings. Toro et al 3 published the extended analyses of that cohort, identifying LVEF 30% and age 65 years as predictors of mortality. It is important to emphasize a critical point in these reports the mean follow-up period of 1 year with a minimal period of 1 month. Cardinalli-Neto et al 4 showed a much greater annual mortality rate (16.6%) in a recent report of a cohort with 90 patients with Chagas disease and an ICD. The main reason for the lower mortality rate observed in our cohort was radiofrequency catheter ablation. Our patients underwent catheter ablation for frequently recurrent VT before ICD implantation and in the setting of multiple appropriate therapies ( electrical storm ) after ICD implantation. We also believe that the high rate of patients in our study (81%) using angiotensin-converting enzyme inhibitors (not discussed by Cardinalli-Neto et al 4 ) seemed to have strongly influenced the differences in mortality rate. The occurrence of ICD shock in 50% of our cohort highlights the high risk of recurrent life-threatening tachyarrhythmia in patients with ChHD. At the end of 5 years of follow-up, the probability of nonoccurrence of appropriate shocks was 23.6%. It was not considered an independent mortality predictor; however, the high survival probability rate of 63.1% certainly reflected the efficacy of ICD therapy (Figure 4). This becomes evident if we consider that Sarabanda and Marin-Neto et al 15 showed a similar mortality rate after a shorter follow-up period (3 years) in patients without ICD. Our study also revealed 3 particular clinical or functional factors regarding the effect on survival outcomes. First, patients with an advanced New York Heart Association functional class (class III) had a worse prognosis (near 50% at 5 years). Mady et al 11 reported a 3-year survival rate of 58% in a class III subgroup versus 97% in the class II subgroup. Our data disagree with the data from Cardinalli- Neto, 4 in which almost all studied patients were in class I. Obviously, this variable did not have an effect on survival outcomes. Second, in addition to mild LV compromise, we observed during clinical follow-up that the lower the LVEF, the worse the patient s prognosis. The magnitude of this correlation was measured by multivariate statistical analysis. Each unit of LVEF reduction increased the risk of death by 2.8%. Mady et al 11 showed that patients with ChHD (receiving an only antiarrhythmic drug) with an LVEF of 0.31 to 0.50 had a 3-year survival probability of 70%, which decreased to 16% when the LVEF was lower than Third, our outcomes emulated the findings from the trial by Wilkoff et al 16 and have not been demonstrated before in

6 Cardiomyopathy/Implantable Cardioverter-Defibrillator in Chagas Heart Disease 1045 patients with ChHD. ICD programming without right ventricular pacing was a marker of a better prognosis than a pacing activated marker. This could have been related to the deleterious effect provided by a high cumulative right ventricular pacing on LV function or could be a consequence of the natural disease progression. The present study was retrospective and uncontrolled. The ICD recipients were not compared to patients with similarly high-risk features but without ICD, precluding the quantification of survival benefits. Just as in most studies assessing the predictors of ICD therapy, the clinical variables were considered at the moment of implantation without accounting for changes during follow-up. One could argue that the need for ventricular pacing could be a marker of more advanced disease and, consequently, an expression of patients with a worse clinical profile and prognosis. However, we must emphasize that patients with a previous pacemaker and patients with advanced atrioventricular block were excluded from the present study. The small size of the population precluded additional subgroup analysis. Acknowledgments: We are grateful to Julia Tizue Fukushima, MSc for her expert statistical analysis and to Rafael Greco, MD for the collection of data. 1. Muratore CA, Batista Sa LA, Chiale PA, Eloy R, Tentori MC, Escudero J, Lima AM, Medina LE, Garillo R, Maloney J. Implantable cardioverter defibrillators and Chagas disease: results of the ICD registry Latin America. Europace 2009;11: Dubner S, Valero E, Pesce R, Zuelgaray JG, Mateos JC, Filho SG, Reyes W, Garillo R. A Latin American registry of implantable cardioverter defibrillators: the ICD-LABOR study. Ann Noninvasive Electrocardiol 2005;10: Toro D, Muratore C, Aguinaga L, Batista L, Malan A, Greco O, Benchetrit C, Duque M, Baranchuk A, Maloney J. Predictors of allcause 1-year Mortality in implantable cardioverter defibrillator patients with chronic Chagas cardiomyopathy. Pacing Clin Electrophysiol 2011;34: Cardinalli-Neto A, Bestetti RB, Cordeiro JA, Rodrigues VC. Predictors of all-cause mortality for patients with chronic Chagas heart disease receiving implantable cardioverter defibrillator therapy. J Cardiovasc Electrophysiol 2007;18: Scanavacca MI, de Brito FS, Maia I, Hachul D, Gizzi J, Lorga A, Rassi A Jr, Filho MM, Mateos JC, D Avila A, Sosa E, Brasileira de Cardiologia S. Guidelines for the evaluation and treatment of patients with cardiac arrhythmias. [Portuguese]. Arq Bras Cardiol 2002;79(Suppl 5): Martinelli Filho M, Zimerman LI, Lorga AM, Vasconcelos JTM, Rassi A Jr. Guidelines for implantable electronic cardiac devices of the Brazilian Society of Cardiology. Arq Bras Cardiol 2007;89:e210 e Hinkle LE Jr, Thaler HT. Clinical classification of cardiac deaths. Circulation 1982;65: The Antiarrhythmics Versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal in ventricular arrhythmias. N Engl J Med 1997;337: Kuck KH, Cappato R, Siebels J, Rüppel R; CASH Investigators. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circulation 2000;102: Connolly SJ, Gent M, Roberts RS, Dorian P, Roy D, Sheldon RS, Mitchell LB, Green MS, Klein GJ, O Brien B; CIDS Investigators. Canadian Implantable Defibrillator Study (CIDS): a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation 2000;101: Mady C, Cardoso RH, Barretto AC, da Luz PL, Bellotti G, Pileggi F. Survival and predictors of survival in patients with congestive heart failure due to Chagas cardiomyopathy. Circulation. 1994;90: Rassi A Jr, Rassi SG, Rassi A. Sudden death in Chagas disease. Arq Bras Cardiol 2001;76: Sternick EB, Martinelli M, Sampaio R, Gerken LM, Teixeira RA, Scarpelli RA, Scanavacca M, Nishioka SD, Sosa E, Sosa E. Sudden cardiac death in patients with Chagas heart disease and preserved left ventricular function. J Cardiovasc Electrophysiol 2006;17: Scanavacca MI, Sosa EA, Lee JH, Bellotti G, Pileggi F. Empiric therapy with amiodarone in patients with chronic Chagas cardiomyopathy and sustained ventricular tachycardia. Arq Bras Cardiol 1990; 54: Sarabanda AV, Marin-Neto JA. Predictors of mortality in patients with Chagas cardiomyopathy and ventricular tachycardia not treated with implantable cardioverter-defibrillators. Pacing Clin Electrophysiol 2011;34: Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H, Kutalek SP, Sharma A; Dual Chamber and VVI Implantable Defibrillator Trial Investigators. 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: