Characterization and predictors of first and subsequent inappropriate ICD therapy by heart rate ranges: Result of the MADIT-RIT efficacy analysis.

BACKGROUND: Data on inappropriate implantable cardioverter-defibrillator (ICD) therapy and effects of programming by heart rate are lacking. OBJECTIVE: We aimed to characterize inappropriate ICD therapy and assess the effects of novel programming by heart rate. METHODS: Incidence and causes of inappropriate therapy by heart rate range (below or above 200 bpm) were assessed. Predictors of inappropriate therapy and effects of programming by heart rate were evaluated with multivariate Cox regression models. Crossovers were excluded. RESULTS: Inappropriate therapy occurred in 9.2% of the total patient population, with 19% of patients randomized to study arm A, 3.6% in arm B, and 4.7% in arm C. Inappropriate therapies <200 bpm were attributable to supraventricular tachycardia (SVT)/sinus tachycardia (78%) or atrial fibrillation/flutter (20%). Inappropriate therapy ≥200 bpm occurred because of SVT (47%), atrial fibrillation/flutter (41%), or electromagnetic interference (13%). Conventional ICD programming was associated with more inappropriate therapy <200 bpm than high-rate or delayed therapy, as were younger age, history of atrial arrhythmia, advanced New York Heart Association functional class, ICD versus cardiac resynchronization therapy with defibrillator, and absence of diabetes. High-rate and long-delay therapy significantly reduced the risk of inappropriate therapy in the <200 bpm range. Long delay was associated with further reduction of fast (≥200 bpm) inappropriate therapy (P = .032) and a reduction in subsequent inappropriate episodes (P = .006). CONCLUSION: In MADIT-RIT, inappropriate ICD therapy is most frequent at rates below 200 bpm and can be predicted, and effectively prevented, with high-rate cutoff programming. Long-delay therapy effectively reduces fast inappropriate therapy ≥200 bpm and subsequent events. [ CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT00947310].

Reduction in Inappropriate ICD Therapy in MADIT-RIT Patients Without History of Atrial Tachyarrhythmia.

BACKGROUND: There are limited data whether history of atrial tachyarrhythmia (AT) modifies the risk of inappropriate ICD therapy, or the efficacy of novel ICD programming to reduce inappropriate ICD therapy events. METHODS: In MADIT-RIT, we investigated the effects of novel ICD programming with high-rate cut-off VT zone ≥ 200 bpm (arm B), or 60-second delayed therapy in the VT zone 170-199 bpm (arm C), compared to conventional programming VT zone>170 bpm (arm A) on first inappropriate ICD therapy in those with or those without AT prior to enrollment. RESULTS: In patients with prior AT (n = 203, 14%) there was a higher risk of inappropriate ICD therapy (HR = 2.10, 95% CI: 1.38-3.20, P < 0.001), and inappropriate ICD shock (HR = 2.56, 95% CI: 1.38-4.74, P = 0.003) compared to those with no prior AT. The effects of innovative programming to reduce inappropriate ICD therapy with either high-rate cut-off or delayed VT therapy were similar in patients with prior AT (arm B vs. A HR = 0.11, P < 0.001, arm C vs. A HR = 0.17, P < 0.001), and also in patients without prior AT before enrollment (arm B vs. A HR = 0.15, P < 0.001, arm C vs. A HR = 0.24, P < 0.001, interaction P-values >0.10 for all). CONCLUSIONS: Novel ICD programming with a high-rate cut-off or delayed therapy is equally beneficial to reduce inappropriate ICD therapy in patients with or without prior AT, despite the lower risk of inappropriate ICD therapy in patients without prior AT.

Time-dependent risk reduction of ventricular tachyarrhythmias in cardiac resynchronization therapy patients: a MADIT-RIT sub-study.

AIMS: Data on the time-dependent benefit of cardiac resynchronization therapy with defibrillator (CRT-D) compared with a dual-chamber implantable cardioverter-defibrillator (ICD) to reduce death or ventricular tachycardia (VT) or ventricular fibrillation (VF) are limited. We aimed to evaluate the time-related risk of death or sustained VT or VF in patients receiving CRT-D vs. ICD in the MADIT-RIT trial. METHODS AND RESULTS: Kaplan-Meier survival analyses and multivariate Cox regression models were utilized to compare the incidence and the risk of death or sustained VT/VF in the CRT-D and ICD subgroups by the elapsed time after device implantation (6 months). Of the ICD (n = 742) and CRT-D (n = 757) patients enrolled, the risk of death was lower in CRT-D vs. in ICD early after device implantation [hazard ratio (HR) = 0.42, 95% confidence interval (CI): 0.17-1.03, P = 0.058] and beyond 6 months of follow-up (HR = 0.39, 95% CI: 0.21-0.73, P = 0.004), with the 6-month interaction P = 0.899. The overall risk of sustained VT/VF was reduced in CRT-D vs. ICD patients (HR = 0.73, 95% CI: 0.52-1.03, P = 0.07). However, the risk was similar in the first 6 months (HR = 1.00, 95% CI: 0.62-1.62, P = 0.988), and a lower risk emerged 6 months after CRT-D implantation (HR = 0.58, 95% CI: 0.38-0.88, P = 0.011), with the 6-month interaction P = 0.059. CONCLUSION: The reduced mortality risk of CRT-D compared with an ICD alone began early after device implantation and was sustained during long-term follow-up; the reduced risk for ventricular tachyarrhythmias did not emerge until 6 months after device implantation. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT00947310.

Smoking is associated with an increased risk of first and recurrent ventricular tachyarrhythmias in ischemic and nonischemic patients with mild heart failure: a MADIT-CRT substudy.

BACKGROUND: Limited data exist regarding the proarrhythmic effects of smoking. OBJECTIVE: To evaluate the relationship between smoking and the risk of first and recurrent ventricular tachyarrhythmias (VTAs) in patients with mild heart failure. METHODS: The risk of a first and recurrent appropriate implantable cardioverter-defibrillator therapy for VTAs or death was compared between nonsmokers (n = 465), past smokers (n = 780), and current smokers (n = 197) in patients with ischemic and nonischemic cardiomyopathy who were enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy study. RESULTS: The cumulative probability of a first VTA or death was significantly higher in current smokers than in past and nonsmokers (P < .001). Multivariate analysis showed that current smokers had a significantly higher risk of first ventricular tachycardia/ventricular fibrillation or death (hazard ratio [HR] 1.51; 95% confidence interval [CI] 1.14-2.01; P = .005) and a higher risk for first ventricular tachycardia/ventricular fibrillation episode (HR 1.54, 95% CI 1.12-2.13, P = .008) than did nonsmokers. Past smokers had a risk of first VTAs or death similar to that of nonsmokers (HR 1.01; 95% CI 0.80-1.27; P = .953). In comparison to nonsmokers, the risk of recurrent VTAs was significantly higher in the total cohort of patients (HR 1.54; 95% CI 1.21-1.95; P < .001) and in the subgroups of patients with ischemic and nonischemic cardiomyopathy (HR 1.48; 95% CI 1.03-2.13; P = .035). CONCLUSIONS: Current smokers with left ventricular dysfunction and mild heart failure are at a significantly higher risk of VTAs or death than are past smokers and nonsmokers. Smoking is associated with a significant increase in the risk of recurrent VTAs in both patients with ischemic and nonischemic cardiomyopathy.

Association between myocardial substrate, implantable cardioverter defibrillator shocks and mortality in MADIT-CRT.

OBJECTIVE: The aim of the present study was to assess a possible association between myocardial substrate, implantable cardioverter defibrillator (ICD) shocks, and subsequent mortality. METHODS: Within the multicentre automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) population (n = 1790), we investigated the association between myocardial substrate, ICD shocks and subsequent mortality using multivariate Cox regression analyses and landmark analyses at 1-year follow-up. RESULTS: The 4-year cumulative probability of ICD shocks was 13% for appropriate shock and 6% for inappropriate shock. Compared with patients who never received ICD therapy, patients who received appropriate shock had an increased risk of mortality [HR = 2.3 (1.47-3.54), P < 0.001], which remained increased after adjusting for echocardiographic remodelling at 1 year (HR = 2.8, P = 0.001). Appropriate anti-tachycardia pacing (ATP) only was not associated with increased mortality (P = 0.42). We were not able to show an association between inappropriate shocks (P = 0.53), or inappropriate ATP (P = 0.10) and increased mortality. Advanced myocardial structural disease, i.e. higher baseline echocardiographic volumes and lack of remodelling at 1 year, was present in patients who received appropriate shocks but not in patients who received inappropriate shocks or no shocks. CONCLUSION: In the MADIT-CRT study, receiving appropriate ICD shocks was associated with an increased risk of subsequent mortality. This association was not evident for appropriate ATP only. These findings, along with advanced cardiac structural disease in the patients who received appropriate shocks, suggest that the compromised myocardium is a contributing factor to the increased mortality associated with appropriate ICD shock therapy. Clinical trials.gov identifier: NCT00180271.

Syncope in high-risk cardiomyopathy patients with implantable defibrillators: frequency, risk factors, mechanisms, and association with mortality: results from the multicenter automatic defibrillator implantation trial-reduce inappropriate therapy (MADIT-RIT) study.

BACKGROUND: There is a relative paucity of studies investigating the mechanisms of syncope among heart failure patients with implantable cardioverter-defibrillators, and it is controversial whether nonarrhythmogenic syncope is associated with increased mortality. METHODS AND RESULTS: The Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) randomized 1500 patients to 3 different implantable cardioverter-defibrillator programming arms: (1) Conventional programming with therapy for ventricular tachycardia ≥170 bpm; (2) high-rate cutoff with therapy for ventricular tachycardia ≥200 bpm and a monitoring zone at 170 to 199 bpm, and (3) prolonged 60-second delay with a monitoring zone before therapy. Syncope was a prespecified safety end point that was adjudicated independently. Multivariable Cox models were used to identify risk factors associated with syncope and to analyze subsequent risk of mortality. During follow-up, 64 of 1500 patients (4.3%) had syncope. The incidence of syncope was similar across the 3 treatment arms. Prognostic factors for all-cause syncope included the presence of ischemic cardiomyopathy (hazard ratio [HR], 2.48; 95% confidence interval [CI], 1.42-4.34; P=0.002), previous ventricular arrhythmias (HR, 2.99; 95% CI, 1.18-7.59; P=0.021), left ventricular ejection fraction ≤25% (HR, 1.65; 95% CI, 0.98-2.77; P=0.059), and younger age (by 10 years; HR, 1.25; 95% CI, 1.00-1.52; P=0.046). Syncope was associated with increased risk of death regardless of its cause (arrhythmogenic syncope: HR, 4.51; 95% CI, 1.39-14.64, P=0.012; nonarrhythmogenic syncope: HR, 2.97; 95% CI, 1.07-8.28, P=0.038). CONCLUSIONS: Innovative programming of implantable cardioverter-defibrillators with therapy for ventricular tachycardia ≥200 bpm or a long delay is not associated with increased risk of arrhythmogenic or all-cause syncope, and syncope caused by slow ventricular tachycardias (<200 bpm) is a rare event. The clinical risk factors associated with syncope are related to increased cardiovascular risk profile, and syncope is associated with increased mortality irrespective of the cause. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00947310.

Influence of diabetes mellitus on inappropriate and appropriate implantable cardioverter-defibrillator therapy and mortality in the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) Trial.

BACKGROUND: The relationship between diabetes mellitus and risk of inappropriate or appropriate therapy in patients receiving an implantable cardioverter-defibrillator (ICD) and resynchronization therapy has not been investigated thoroughly. The effect of innovative ICD programming on therapy delivery in these patients is unknown. METHODS AND RESULTS: The Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) randomized patients with a primary prophylactic ICD indication to 3 different types of ICD programming: conventional programming with a ventricular tachycardia zone of 170 to 199 bpm (arm A), high-rate cutoff with a ventricular tachycardia zone ≥200 bpm (arm B), or 60-second-delayed therapy (arm C). The end points of inappropriate therapy, appropriate therapy, and death were assessed among 485 patients with and 998 without diabetes mellitus. Innovative ICD programming reduced the risk of inappropriate therapy regardless of diabetes mellitus, although a trend toward a more pronounced effect of high-rate cutoff programming was seen in patients without diabetes mellitus (P for interaction=0.06). Diabetes mellitus was associated with a decreased risk of inappropriate therapy (hazard ratio, 0.54; 95% confidence interval, 0.36-0.80; P=0.002) and increased risk of appropriate therapy (hazard ratio, 1.58; 95% confidence interval, 1.17-2.14; P=0.003). In diabetic patients, there was significantly increased risk of death in those who had inappropriate therapy (hazard ratio, 4.17; 95% confidence interval, 1.52-11.40; P=0.005) and appropriate therapy (hazard ratio, 2.49; 95% confidence interval, 1.06-5.87; P=0.037) compared with those who did not. CONCLUSIONS: Innovative high-rate cutoff or delayed ICD programming was associated with a reduction in inappropriate therapy in patients with and without diabetes mellitus. Diabetes mellitus was associated with lower risk of inappropriate therapy but higher risk of appropriate therapy. Appropriate and inappropriate ICD therapy was associated with increased mortality in diabetic patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT00947310.

Frequency of inappropriate therapy in patients implanted with dual- versus single-chamber ICD devices in the ICD arm of MADIT-CRT.

BACKGROUND: The majority of implantable cardioverter defibrillators (ICDs) are dual-chamber devices, but studies on the frequency of inappropriate therapy in dual- versus single-chamber devices have shown conflicting results. The aim of this study is to determine whether implantation of dual-chamber ICD devices decrease the incidence of inappropriate therapy without an unacceptable increase in complications. METHODS: In the ICD arm of the MADIT-CRT study (N = 704), comparisons of single- versus dual-chamber ICD devices were investigated on the endpoints of inappropriate therapy (antitachycardia pacing [ATP] and shocks) and device- and procedure-related complications by use of multivariate Cox proportional hazard regression analysis (hazard ratio dual:single chamber) adjusting for relevant covariates. RESULTS: The frequency of inappropriate therapies in single- and dual-chamber recipients was 41/294 (14%) and 50/410 (12%), respectively. There was no significant difference in overall inappropriate therapy (hazard ratio [HR] = 0.95 [CI: 0.63-1.45], P = 0.95) or inappropriate ATP (HR = 0.98 [CI: 0.61-1.58], P = 0.94), between single- and dual-chamber devices, using single-chamber as a reference (Dual:Single). However, there was a trend toward a decrease in inappropriate shocks (HR = 0.60 [CI: 0.34-1.08], P = 0.09) in the dual-chamber group. The same was evident when only analyzing inappropriate therapy for atrial tachyarrhythmias (HR = 0.88 [CI: 0.56-1.38], P = 0.58). There was no significant difference between the groups in device- or procedure-related complications (HR = 1.54 [CI: 0.82-2.90], P = 0.18). CONCLUSION: No significant difference was found in inappropriate therapy or complications in patients treated with single- versus dual-chamber ICD devices.

Effect of metoprolol versus carvedilol on outcomes in MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy).

OBJECTIVES: This study sought to compare the effects of metoprolol and carvedilol in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) study. BACKGROUND: The impact of beta-blockers in heart failure (HF) patients with devices is uninvestigated. METHODS: All patients receiving either metoprolol or carvedilol in the MADIT-CRT study were identified and compared. Time-dependent Cox proportional hazard regression analyses were performed to assess differences in hospitalization for HF or death and ventricular arrhythmias. RESULTS: Hospitalization for HF or death occurred in 30% of the patients on metoprolol and in 23% on carvedilol. Treatment with carvedilol was associated with a significantly decreased risk of hospitalization for HF or death when compared with metoprolol (hazard ratio [HR]: 0.70, [95% confidence interval (CI): 0.57 to 0.87], p = 0.001). This reduction in risk was further attenuated in the subgroup of cardiac resynchronization therapy with implantable cardioverter-defibrillator (CRT-D) patients (HR: 0.61 [95% CI: 0.46 to 0.82], p = 0.001) and CRT-D patients with left bundle branch block (LBBB) (HR: 0.51 [95% CI: 0.35 to 0.76], p < 0.001). Ventricular arrhythmias occurred in 26% and in 22%, respectively, of the patients receiving metoprolol or carvedilol (HR: 0.80 [95% CI: 0.63 to 1.00], p = 0.050). General use of beta-blockers and adherence in this study was high, and a clear dose-dependent relationship was found in carvedilol, but not in metoprolol. CONCLUSIONS: In HF patients in New York Heart Association functional class I and II and with wide QRS complexes, carvedilol was associated with a 30% reduction in hospitalizations for HF or death when compared with metoprolol. A novel beneficial and synergistic effect of carvedilol was seen in patients with CRT-D and LBBB. Furthermore, we found a pronounced dose-dependent relationship in carvedilol, but not in metoprolol.

Losartan versus atenolol-based antihypertensive treatment reduces cardiovascular events especially well in elderly patients: the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study.

BACKGROUND: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study has previously demonstrated a beneficial effect of losartan compared to atenolol-based antihypertensive treatment in patients with essential hypertension and left-ventricular hypertrophy (LVH). However, patient age often influences the choice of antihypertensive drugs. Therefore, we investigated the influence of age on the effects of losartan versus atenolol-based antihypertensive treatment. METHODS: A total of 9193 hypertensive patients with LVH aged 45-83 years were followed for a mean of 4.8 years. Blood pressure, high-density lipoprotein cholesterol (HDL-C), Sokolow-Lyon voltage, Cornell voltage-duration product and urine albumin-creatinine ratio (UACR) were measured yearly throughout the study. Patients were divided into two age groups according to the median age of 67 years and the effects of losartan versus atenolol-based antihypertensive treatment on the primary composite endpoint (CEP) consisting of cardiovascular death, nonfatal stroke or nonfatal myocardial infarction were investigated. RESULTS: The beneficial effect of losartan versus atenolol-based treatment was greater in the group of patients older than 67 years [hazard ratio 0.79 (0.69-0.91), P = 0.001] compared to the group of patients younger than 67 years [hazard ratio 1.03 (0.82-1.28), P = 0809], P = 0.045 for interaction. The beneficial effects of losartan versus atenolol-based antihypertensive treatment on pulse pressure, HDL-C, UACR, and Cornell and Sokolow-Lyon voltage were not more pronounced in patients older than 67 years compared to patients younger than 67 years. All five risk factors considered as time-varying covariates predicted CEP independently (P < 0.01) with the exception of pulse pressure (P = 0.37) and the interaction between age and treatment on outcome remained significant (P = 0.042). CONCLUSIONS: We showed a greater beneficial effect of losartan versus atenolol-based antihypertensive treatment in the group of patients older than 67 years compared to the group of patients younger than 67 years. This difference was not explained by a more pronounced effect of losartan-based treatment on any of the cardiovascular risk factors demonstrated to have independent prognostic importance.