Multicenter Automatic Defibrillator Implantation Trial Research Articles

A Symmetric Kernel Smoothing Estimation of the Time-Varying Coefficient for Medical Costs

In longitudinal studies, subjects are repeatedly observed at a set of distinct time points until the terminal event time. The time-varying coefficient model extends the parametric method and captures the dynamic trajectories of time-dependent covariate effects, thus enabling it to describe the potential relationship between the longitudinal variable and the observed time points. In this study, we propose a novel approach to the estimation of medical costs using a symmetric kernel smoothing method in the time-varying coefficient joint model. A smooth function of medical costs is derived by weighting the values of longitudinal data at all distinct observed time points via the combination of the kernel method and the inverse probability weighting method. For the simulation study, we first set up the true functions of time-varying coefficients; we then generated random samples for covariates and censored survival times. Subsequently, the longitudinal data of response variables could be produced. Further, numerical simulation experiments were conducted by using the proposed method and applying R code to the generated data. The estimated results for the parameters and non-parametric functions were compared with different settings. The numerical results illustrate that as the sample size increases, the bias and model-based standard errors decrease, and the performance improves with larger sample sizes. The estimates of functions in the model almost coincide with the true functions, as shown in the figures of the simulation study. Furthermore, the consistency of the obtained estimator is demonstrated via theoretical analysis, and a numerical simulation is performed to illustrate the performance of the proposed estimators. The proposed model is applied to a real-world data set acquired from a multicenter automatic defibrillator implantation trial (MADIT).

Joint Model for Estimating the Asymmetric Distribution of Medical Costs Based on a History Process

In this paper, we modify a semi-parameter estimation of the joint model for the mean medical cost function with time-dependent covariates to enable it to describe the nonlinear relationship between the longitudinal variable and time points by using polynomial approximation. The observation time points are discrete and not exactly the same for all subjects; in order to use all of the information, we first estimate the mean medical cost at the same observed time points for all subjects, and then we weigh these values using the kernel method. Therefore, a smooth mean function of medical costs can be obtained. The proposed estimating method can be used for asymmetric distribution statistics. The consistency of the estimator is demonstrated by theoretical analysis. For the simulation study, we first set up the values of parameters and non-parametric functions, and then we generated random samples for covariates and censored survival times. Finally, the longitudinal data of response variables could be produced based on the covariates and survival times. Then, numerical simulation experiments were conducted by using the proposed method and applying the JM package in R to the generated data. The estimated results for parameters and non-parametric functions were compared with different settings. Numerical results illustrate that the standard deviations of the parametric estimators decrease as the sample sizes increases and are much smaller than preassigned threshold value. The estimates of non-parametric functions in the model almost coincide with the true functions as shown in the figures of simulation study. We apply the proposed model to a real data set from a multicenter automatic defibrillator implantation trial.

Abstract 13917: Predictors of Ventricular Arrhythmias in Patients With Left Ventricular Ejection Fraction Improvement to >35% Following Cardiac Resynchronization Therapy

Introduction: Patients undergoing cardiac resynchronization therapy with a defibrillator (CRT-D) show significant improvement in LVEF. We designed this study to identify predictors of ventricular arrhythmic (VA) events among patient with LVEF improvement > 35% after one year of treatment with CRT-D. Hypothesis: We hypothesized that LVEF improvement > 35% is associated with a decreased risk of VA events. Methods: Patients randomized to CRT-defibrillator from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) trial with LVEF > 35% at 12 months were included in this analysis (N=651). Predictors of an appropriate ICD therapy for VA subsequent to one year were evaluated by cox regression model. Cumulative probability of first event was analyzed by Kaplan Meier Method with time for follow-up beginning at 1 year after device implantation. Results: The average follow-up was 2.04 ± 0.83 years. We identified 3 independent predictors of VA among patients treated with CRT-D subsequent to LVEF improvement to > 35%: (1) baseline non-LBBB morphology (HR=1.93; 95% CI,1.23-3.04; p= 0.004); (2) the occurrence of VA during first year post CRT-D implant (HR=4.91 [95% CI, 2.99-8.07]; p<0.001); and (3) lower range improvement in LVEF (36-40% vs. >40%; HR =1.97 [95% CI 1.21-3.20]; p= 0.006). When compared with patients with 0 risk factors, having one and 2 or more risk factors had significantly higher risk of VTA (2-year rate of VT/VF = 4%, 11% and 32% respectively; HRs = 2.9 [p=0.002]and 7.9 [p=<0.001], respectively [Figure]). Conclusions: We identify a sub-group of patients who remain at high risk of VTA despite improvement in LVEF > 35% with CRT-D. Having a baseline non-LBBB morphology, experiencing VA during the first year post CRT-D, and lower-range LVEF improvement are associated with high risk of future arrhythmias, with a cumulative effect.

Primary prevention implantable cardioverter defibrillator in cardiac resynchronization therapy recipients with advanced chronic kidney disease.

The implantable cardioverter defibrillator (ICD) is effective for the prevention of sudden cardiac death (SCD) in patients with heart failure and a reduced ejection fraction (HFrEF). The benefit of the ICD in patients with advanced CKD, remains elusive. Moreover, the benefit of the ICD in patients with advanced chronic kidney disease (CKD) and HFrEF who are cardiac resynchronization therapy (CRT) recipients may be attenuated. We hypothesized that patients with CKD who are CRT recipients may derive less benefit from the ICD due to the competing risk of dying prior to experiencing an arrhythmia. The study population included 1,015 patients receiving CRT with defibrillator (CRT-D) device for primary prevention of SCD who were enrolled in either (Multicenter Automated Defibrillator Implantation Trial) MADIT-CRT trial or the Ranolazine in High-Risk Patients with Implanted Cardioverter Defibrillator (RAID) trial. The cohort was divided into two groups based on the stage of CKD: those with Stage 1 to 3a KD, labeled as (S1-S3a)KD. The second group included patients with Stage 3b to stage 5 kidney disease, labeled as (S3b-S5)KD. The primary endpoint was any ventricular tachycardia (VT) or ventricular fibrillation (VF) (Any VT/VF). The cumulative incidence of Any VT/VF was 23.5% in patients with (S1-S3a)KD and 12.6% in those with (S3b-S5)KD (p < 0.001) The incidence of Death without Any VT/VF was 6.6% in patients with (S1-S3a)KD and 21.6% in patients with (S3b-S5)KD (p < 0.001). A Fine and Gray multivariate competing risk regression model showed that Patients with (S3b-S5)KD had a 43% less risk of experiencing Any VT/VF when compared to those with (S1-S3a)KD (HR = 0.56, 95% CI [0.33-0.94] p = 0.03. After two years of follow up, there was almost a 5-fold increased risk of Death without Any VT/VF among patients with (S3b-S5)KD when compared to those with (S1-S3a)KD [HR = 4.63, 95% CI (2.46-8.72), p for interaction with time = 0.012]. Due to their lower incidence of arrhythmias and higher risk of dying prior to experiencing an arrhythmia, the benefit of the ICD may be attenuated in CRT recipients with advanced CKD. Future prospective trials should evaluate whether CRT without a defibrillator may be more appropriate for these patients.

Left-to-right atrioventricular activation delay, a novel measure of AV-conduction, predicts clinical outcomes in non-LBBB patients

Abstract Funding Acknowledgements Type of funding sources: None. Background The PR-interval reflects atrial and atrioventricular activation. A prolonged PR has been linked to heart failure (HF), atrial fibrillation and mortality. This might at least in part be the consequence of compromised cardiac performance (e.g. left ventricular filling). On the other hand, very long PR may just be a marker of advanced heart disease. Alternative measures that account for atrial and ventricular activation might better predict adverse hemodynamic consequences of delayed atrioventricular conduction. The DEEPER-PR mechanistic pilot study suggested that various novel measures of AV conduction are associated with Doppler-derived cardiac performance. However, the clinical significance of these novel parameters is unknown. Study objective: To examine the association of novel measures of AV conduction with clinical outcomes in a HFrEF population with non-LBBB and a wide QRS (non-LBBB ICD-only MADIT-CRT subset). Methods Time intervals from anonymized scanned baseline 12-lead ECGs from the Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy (MADIT-CRT), non-LBBB patients (n=537) were assessed in detail using ImageJ (public domain software provided by NIH). The primary endpoint of the study was the combined endpoint of heart failure (HF) or death events. The earliest onset of atrial activation (P wave onset), zero crossing of the P wave in lead V1, earliest onset of the QRS complex, time interval to the first peak of the R wave in V1 and V6, and QRS width were determined. The PR interval and 8 novel parameters (see figure 1) were measured and calculated accordingly. Bivariate non-parametric correlations were calculated to ascertain the associations between these covariates. In addition, Kaplan-Meier analyses by quintiles of all AV delay measures, and multivariable Cox regression analyses were performed among ICD-only patients (n=209) to determine the associated risk regarding of the combined MADIT-CRT clinical outcome of HF events or death. Results Weak correlations were found between the AV delay variables (figure 2). Four of the variables (P0PV1, P0R, PePV6, PR) were significantly associated to the risk of HF or death with the upper quintile defining a high-risk HF population, as compared to quintiles 1 to 4 (see figure 3). This indicated a threshold behavior of the associations. P0PV1 was the most powerful risk predictor (Chi-square=16.31, HR for Q5 vs. Q1-4=3.12, CI=1.80-5.41, p&amp;lt;0.001), followed by PRmax (Chi-square=13.19, HR for Q5 vs. Q1-4=2.81, CI=1.61-4.92, p&amp;lt;0.001), P0R (Chi-square=10.42, HR=2.54, CI=1.44-4.48, p=0.001), and PePV6 (Chi-square=7.96, HR for Q5 vs. Q1-4=2.2, CI=1.29-4.07, p=0.005). Conclusion This post-hoc ECG-based study identified in MADIT-CRT non-LBBB patients the left-to-right atrioventricular activation delay (P0PV1) as the most powerful risk predictor of HF or death. Prospective evaluation of this measure is warranted.

Age and the Risk of Ventricular Tachyarrhythmia in Patients With an Implantable Cardioverter-Defibrillator

BackgroundThe benefit of implantable cardioverter-defibrillators (ICDs) in elderly patients is controversial. ObjectivesThe aims of this study were to evaluate the risk for ventricular tachyarrhythmia (VTA) and ICD shocks by age groups and to assess the competing risk for VTA and death without prior VTA. MethodsThe study included 5,170 primary prevention ICD recipients enrolled in 5 landmark ICD trials (MADIT [Multicenter Automatic Defibrillator Implantation Trial] II, MADIT-Risk, MADIT-CRT [MADIT Cardiac Resynchronization Therapy], MADIT-RIT [MADIT Reduce Inappropriate Therapy], and RAID [Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillator]). Fine and Gray regression analysis was used to evaluate the risk for fast VTA (ventricular tachycardia ≥200 beats/min or ventricular fibrillation) vs death without prior fast VTA in 3 prespecified age groups: <65, 65 to <75, and ≥75 years. ResultsThe cumulative incidence of fast VTA at 3 years was similar for patients <65 years of age and those 65 to <75 years of age (17% vs 15%) and was lowest among patients ≥75 years of age (10%) (P < 0.001). Multivariate Fine and Gray analysis showed a 40% lower risk for fast VTA in patients ≥75 years of age (HR: 0.60; 95% CI: 0.46-0.78; P < 0.001) compared with patients <65 years of age. In patients ≥75 years of age, a risk reversal was observed whereby the risk for death without prior fast VTA exceeded the risk for developing fast VTA. A history of nonsustained ventricular tachycardia, male sex, and the presence of nonischemic cardiomyopathy were identified as predictors of fast VTA in patients ≥75 years of age. ConclusionsPatients ≥75 years of age have a significantly lower risk for VTA and ICD shocks compared with younger patients. Aging is associated with a higher risk for death compared with the risk for fast VTA, the reverse of what is seen in younger patients.

Effect of Novel Programming on Inappropriate Implantable Cardioverter-Defibrillator Therapy in Patients With Very Low Ejection Fraction (from A MADIT-RIT)

The Multicenter Automatic Defibrillator Implantation Trial - Reduce Inappropriate Therapy showed a significant reduction in the risk of inappropriate therapy in patients with a programmed high-rate cutoff ≥200 beats per minute or delayed therapy for events ≥170 beats per minute compared with conventional programming. We aimed to characterize outcomes by left ventricular ejection fraction (LVEF) ranges for patients with high-rate, delayed, or conventional implantable cardioverter-defibrillator programming. We assessed the effect of LVEF (LVEF &lt;15%, LVEF 15% to 25%, LVEF &gt;25%) on the risk of inappropriate conventional implantable cardioverter-defibrillator therapy and death in Multicenter Automatic Defibrillator Implantation Trial - Reduce Inappropriate Therapy. Inappropriate therapies and death were independently evaluated by the adjudication committee. Statistical methods involved Kaplan-Meier time-to-event graphs and Cox proportional hazards regression analyses. The study involved 140 patients (9%) with LVEF 15%, 585 with LVEF 15% to 25% (39%), and 774 with LVEF &gt;25% (52%). High-rate or delayed programming significantly reduced the risk of inappropriate therapy compared with conventional programming in patients with all LVEFs (p &lt;0.001 for all LVEF). Patients with LVEF &lt;15% had an exceptional 97% lower risk of inappropriate therapy, with high-rate programming than conventional programming (hazard ratio 0.028, p=0.001), without an increase in mortality. High-rate and delayed programming is superior to conventional programming in all LVEF ranges, without adverse effects.

Differences in mode of death between men and women receiving implantable cardioverter-defibrillators or cardiac resynchronization therapy in the MADIT trials

Studies have reported sex differences in outcomes following implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy-defibrillator (CRT-D) implantation. However, little is known about sex differences with regard to mode of death or device efficacy following ICD or CRT-D implantation. The purpose of this study was to investigate whether sex influenced mode of death or device efficacy in ICD and CRT-D subjects enrolled in the MADIT (Multicenter Automatic Defibrillator Implantation Trial) studies (MADIT-II, MADIT-CRT, and MADIT-RIT). The combined MADIT cohort consisted of 3038 men and 1000 women with ischemic cardiomyopathy (ICM) or nonischemic cardiomyopathy (NICM), left ventricular ejection fraction ≤30%; New York Heart Association functional class I-III heart failure who received ICD or CRT-D. Mode of death was divided into cardiac and noncardiac causes, reviewed by independent adjudication committees. A total of 295 men and 66 women died (9.7% vs 6.6%; P =.003) during 26 months. The most common cause of death was nonarrhythmic cardiac death in men (n = 121 [41%]) and noncardiac death in women (n = 22 [33%]). All-cause mortality and cardiac deaths were 1.5- to 2.0-fold higher in men vs women with ICM but similar for those with NICM after adjustment for covariates. ICD efficacy was similar in men and women, resulting in a 50% reduction in all-cause mortality. CRT-D was more effective at reducing all-cause and cardiac death in women than men. Mode of death differs between sex and is dependent on the underlying cardiac substrate. Compared to women, cardiac death is higher in men with ICM but similar in those with NICM. ICDs are equally effective at reducing mortality in both men and women. However, CRT-D may be more effective at reducing mortality in women.

PO-628-03 ASSOCIATION OF MINERALOCORTICOID RECEPTOR ANTAGONIST USE WITH MORTALITY AND VENTRICULAR ARRHYTHMIA RISK IN PATIENTS WITH IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS

Heart failure (HF) patients with implantable devices have improved outcomes on optimal Guideline-Directed Medical Therapy (GDMT), yet few studies have evaluated the impact of mineralocorticoid receptor antagonists (MRA) on mortality and arrythmia risk in patients who may be unable to tolerate optimal GDMT. To assess the impact of MRA use on the risk of all-cause mortality and ventricular tachyarrhythmia (VTA) in HF patients with an ICD or CRT-D who were not concomitantly treated with both beta blockers (BB) and ACE-inhibitors/angiotensin receptor blockers (ACE/ARB) in 4 MADIT (Multicenter Automatic Defibrillator Implantation Trial; MADIT-II, MADIT-CRT, MADIT-RIT, MADIT-RISK) and Ranolazine in High-Risk Patients with ICD (RAID) clinical trials. We included 5504 patients enrolled in 5 landmark ICD clinical trials. Patients were categorized by MRA use in addition to baseline BB and/or ACE/ARB use into subgroups of those who were prescribed both BB and ACE/ARB (2-drug GDMT) and those who were prescribed only one of the two drugs (1-drug GDMT) at enrollment. Cox proportional hazards regression models and Fine and Gray regression models, stratified by studies, were performed to assess the association between time-dependent MRA use and risks of all-cause mortality and VTA. VTA was defined as any treated or monitored sustained ventricular tachycardia (≥170 bpm) or ventricular fibrillation. Among 5504 study patients, 4392 (80%) were prescribed 2-drug GDMT and 1016 (18%) were prescribed 1-drug GDMT. MRA was prescribed to 1656 (30%) patients. Multivariate analysis demonstrated that MRA use was associated with a 52% reduction in mortality risk when prescribed in patients on 1-drug GDMT (HR=0.48 [95% CI: 0.27-0.86], p=0.014). The mortality benefit of MRA therapy was attenuated among patients on 2-drug GDMT (HR=1.05 [95% CI: 0.82-1.34], p=0.7) (Figure 1). Further, MRA use was associated with a 36% reduction in VTA risk in patients on 1-drug GDMT (HR=0.64 [95% CI: 0.40-1.01], p = 0.05), while among patients on 2-drug GDMT the association of MRA use with VTA risk was also attenuated (HR=1.09 [95% CI: 0.93-1.29], p=0.28) (Figure 2). In HF patients with an ICD or CRT-D who are unable to tolerate 2-drug GDMT, MRA use is associated with a reduction in the risk of mortality and VTA.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Hospitalization for HeartFailure and Subsequent Ventricular Tachyarrhythmias in Patients With LeftVentricular Dysfunction.

This study aimed to evaluate the risk of sustained life-threatening ventricular tachyarrhythmias (VTAs) after hospitalization for heart failure (HHF). HHF is common among patients with an implantable cardioverter-defibrillator (ICD). We analyzed all 5,511 ICD patients enrolled in the landmark MADIT (Multicenter Automatic Defibrillator Implantation Trial) and RAID (Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillator) trials. Multivariate Cox regression was used to evaluate the association of in-trial HHF occurrence with the risk of subsequent VTA and the composite end point of VTA or cardiac death. Mean age was 64 ± 11 years, 23% were women, 62% were ischemic, and 40% had cardiac resynchronization therapy with defibrillators. The 3-year cumulative rate of VTA subsequent to HHF was significantly higher than the corresponding rate without HHF (44% vs. 24%, respectively; p<0.001). After multivariable adjustment, time-dependent HHF was shown to be associated with a 79% increased risk for VTA and a 2.9-fold increased risk for VTA/cardiac death (p<0.001 for both). In-trial development of atrial tachyarrhythmia (ATA) was also identified as an independent risk factor for the VTA and VTA/cardiac death end points (hazard ratio [HR]: 1.59 and 1.43, respectively; p≤ 0.001 for both) but did not affect the association of HHF with VTA. Subgroup analysis demonstrated that the association of HHF with the risk of subsequent VTA was maintained among risk subsets categorized by age, sex, history of ATA, and implantation indication, but was significantly more pronounced among patients with nonischemic versus ischemic cardiomyopathy (HR: 2.54 and 1.43, respectively; p for interaction = 0.017). HHF is a powerful risk factor for subsequent VTA in patients implanted with an ICD. These data may be used for improved risk stratification in this population.

Systolic Blood Pressure and Risk for Ventricular Arrhythmia in Patients With an Implantable Cardioverter Defibrillator

Low systolic blood pressure (SBP) was previously suggested to be a marker for heart failure and mortality in patients with low left ventricular ejection fraction. We aimed to explore the association of SBP on risk of ventricular tachyarrhythmias (VTA) and atrial arrhythmias as well as appropriate and inappropriate Implantable Cardioverter Defibrillator (ICD) therapy. The study population comprised 1,481 of 1,500 (99%) patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial - Reduce Inappropriate Therapy trial. Multivariate Cox proportional hazards regression modeling was used to identify the association of baseline SBP (recorded prior to ICD implantation) with the risk of VTA > 170 beats/min during follow-up (primary end point) and atrial arrhythmia, appropriate and inappropriate ICD therapy, hospitalization and death (secondary end points). SBP was dichotomized at 120 mm Hg (approximate mean and median) and was also assessed as a continuous measure. Multivariate analysis showed that each 10 mm Hg decrement in SBP was associated with corresponding 11% increased risk for VTA (p = 0.008). Low SBP (≤120 mm Hg) was associated with a significant 58% (p = 0.002) increased risk for VTA ≥170 beats/min; 53% (p = 0.019) increased risk for VTA ≥200 beats/min; and 65% (p = 0.001) increased risk for appropriate ICD therapy, as compared with SBP >120 mm Hg. Low SBP was not associated with increased risk of atrial arrhythmias, and inappropriate ICD therapy. In conclusion, in MADIT-RIT, SBP (≤120 mm Hg) predicted higher rates of VTA. These findings suggest that SBP may be utilized for VTA risk stratification in candidates for primary ICD therapy.

Primary Prevention of Fatal Ventricular Arrhythmias With Implantable Cardioverter- Defibrillator Therapy – An Analysis of Implications Based on MADIT II Criteria

The primary aim of this retrospective study was to determine the proportion of patients with myocardial infarction (MI) who fulfil the criteria of the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II and the implications of MADIT II criteria in practice. We performed a retrospective analysis of three hundred and ninety four admissions to the Coronary Care Unit (CCU) of the Royal Infirmary of Edinburgh. We selected those with myocardial infarction (MI) and attempted to retrieve electronic copies of their echocardiogram reports. When available, these were used to assess requirement for primary-prevention Implantable Cardioverter Defibrillator (ICD) therapy based on reported left ventricular function. One hundred and ninety patients were admitted to the CCU with a diagnosis of MI. Of these, 100 patients (51.5%) had an echocardiogram. Requirement for ICD therapy was unlikely in 87 (87%), probable in 6 (6%) and necessary in 7 (7%). Since a significant number of patients in the probable category were also likely to meet MADIT II criteria, we concluded that the proportion of patients requiring primary-prevention ICD therapy would be no less than 7% and more likely to be 13%. In the context of a busy teaching hospital, a figure of 13% for the requirement of ICD therapy in MI patients represents annual implantation activity of at least 100 per million. This is likely to have very significant resource implications.

Reassessing the role of antitachycardia pacing in fast ventricular arrhythmias in primary prevention implantable cardioverter-defibrillator recipients: Results from MADIT-RIT

In Multicenter Automatic Defibrillator Implantation Trial - Reduce Inappropriate Therapy (MADIT-RIT), high-rate cutoff (arm B) and delayed therapy (arm C) reduced the risk of inappropriate implantable cardioverter-defibrillator (ICD) interventions when compared with conventional programming (arm A); however, appropriate but unnecessary therapies were not evaluated. The purpose of this study was to assess the value of antitachycardia pacing (ATP) for fast ventricular arrhythmias (VAs) ≥ 200 beats/min in patients with primary prevention ICD. We compared ATP only, ATP and shock, and shock only rates in patients in MADIT-RIT treated for VAs ≥ 200 beats/min. The only difference between these randomized groups was the time delay between ventricular tachycardia detection and therapy (3.4 seconds vs 4.9 seconds vs 14.4 seconds). In arm A, 11.5% patients had events, the initial therapy was ATP in 10.5% and shock in 1%, and the final therapy was ATP in 8% and shock in 3.5%. In arm B, 6.6% had events, 4.2% were initially treated with ATP and 2.4% with shock, and the final therapy was ATP in 2.8% and shock in 3.8%. In arm C, 4.7% had events, 2.5% were initially treated with ATP and 2.3% with shock, and the final therapy was ATP in 1.4% and shock in 3.3%. The final shock rate was similar in arm A vs arm B (3.5% vs 3.8%; P = .800) and in arm A vs arm C (3.5% vs 3.3%; P = .855) despite the marked discrepancy in initial ATP therapy utilization. In MADIT-RIT, there was a significant reduction in ATP interventions with therapy delays due to spontaneous termination, with no difference in shock therapies, suggesting that earlier interventions for VAs ≥ 200 beats/min are likely unnecessary, leading to an overestimation of the value of ATP in primary prevention ICD recipients.

Competing risk analysis of ventricular arrhythmia events in heart failure patients with moderately compromised renal dysfunction.

Patients with impaired renal function were shown to have an attenuated benefit from implantable cardioverter-defibrillator. However, there are limited data on the competing risk of ventricular arrhythmia events and death by renal function in patients without severe disease. Therefore, we aimed to assess the competing risk of ventricular arrhythmia events and death by renal function. We analysed 1782 patients (99%) enrolled in Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) with glomerular filtration rate (GFR) data available. Cumulative incidence function curves were used to display the rate of ventricular tachycardia (VT), ventricular fibrillation (VF), and the competing risk of death without experiencing VT/VF. Multivariable Fine and Gray regression models and recurrent event analysis were performed. There were 355 (20%) patients with GFR < 52 and 1427 with GFR ≥ 52 (lowest quintile). The incidence of non-fatal VT/VF at 4 years was higher in patients with high GFR (26%) as compared to low GFR (16%), whereas rates of death without non-fatal VT/VF were 5% and 20% (P < 0.001). In Fine and Gray models, the low GFR group was 35% less likely to experience VT/VF compared to the high GFR [95% confidence interval (CI) 0.48-0.88, P = 0.005]. In contrast,death without experiencing VT/VF was 3.5-fold higher in the low GFR group (95% CI 2.38-5.12, P-value < 0.001). Recurrent event analysis consistently showed a lower risk of recurrent VT/VF, recurrent anti-tachycardia pacing only, and shock in the low GFR group. We show, in a competing risk model, a lower risk of VT/VF events and a higher risk of mortality without an arrhythmic event in patients with moderate renal dysfunction in MADIT-CRT. These findings can be used for improved selection of patients for defibrillator therapy among CRT candidates. https://clinicaltrials.gov/ct2/show/NCT00180271.

Utility of 6-Minute Walk Test to Predict Response to Cardiac Resynchronization Therapy in Patients With Mild Heart Failure

Clinical studies of heart failure (HF) generally utilize the 6-minute walk test (6MWT) for functional capacity (FC) assessment. However, data on the impact of cardiac resynchronization therapy (CRT) on 6MWT and its role to predict long-term outcomes in mild HF patients with CRT are lacking. We studied 1,381 subjects with mild HF enrolled in Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy with 6MWT data at baseline and 1 year. We assessed the effects of CRT-D on percent change in 6MWT at 1 year by left bundle branch block (LBBB) status, identified independent predictors of 6MWT at 1 year, and evaluated the association between changes in 6MWT and risk for HF or death. Treatment with CRT-D versus implantable cardiac defibrillator (ICD) was not associated with a significant improvement in 6MWT at 1-year in LBBB subjects (2.2 % vs 0.0%, p = 0.428, but it was associated with a deterioration in 6MWT in non-LBBB subjects (4.1% vs 0.0%, p = 0.308). Multivariate analysis showed that each 5% reduction in 6MWT was independently associated with a corresponding 3% increase in the risk of subsequent HF or death (p = 0.014). In conclusion, our findings suggest that 6MWT has limited utility to identify CRT response in mild HF subjects with LBBB. However, 6MWT showed a signal toward deterioration in mild HF subjects with non-LBBB, and this was predictive of subsequent increased risk of HF or death.

Implantable cardioverter-defibrillator programming after first occurrence of ventricular tachycardia in the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT).

BackgroundImplantable cardioverter-defibrillator (ICD) programming to novel settings can reduce the risk of inappropriate therapies.ObjectiveThe purpose of this study was to evaluate the impact of novel ICD programming after the first occurrence of ventricular tachycardia (VT).MethodsIn MADIT-RIT (Multicenter Automatic Defibrillator Implantation Trial–Reduce Inappropriate Therapy) patients who experienced a first occurrence of VT, the risk of subsequent inappropriate and appropriate ICD therapies and adverse cardiovascular events by ICD programming to Arm A (conventional: VT ≥170 bpm), Arm B (high rate: VT ≥200 bpm), or Arm C (duration delay: ≥60-second delay before therapy ≥170 bpm) was determined.ResultsAmong 205 patients, ICD programming changes were made in 30 patients (15%) after they experienced a VT episode; 117 patients (57%) were programmed to Arm A settings and 88 patients (43%) to Arm B/C settings. At 15-month follow-up, the cumulative probability of inappropriate ICD therapy was significantly lower in Arm B/C compared to Arm A (9% vs 20%; log-rank P = .029 for overall difference). The rate of appropriate ICD therapy also was significantly lower in Arm B/C compared to Arm A (32% vs 64%; log-rank P = .001 for overall difference). Multivariate analysis showed that patients programmed to Arm B/C after the occurrence of VT had a 71% reduction (P = .02) in the risk of inappropriate ICD therapies and a 43% reduction (P = .02) in the risk of appropriate ICD therapies compared to Arm A.ConclusionThe benefit of high-rate cutoff or duration delay settings in patients with an ICD is maintained after the first occurrence of VT.

Prospective evaluation of outcome of Indian patients who meet MADIT II (Multicenter Automatic Defibrillator Implantation Trial) criteria for implantable cardioverter defibrillator implantation: is it appropriate for Indian patients?

BackgroundThe MADIT II investigators had concluded that prophylactic use of an ICD improved survival in patients with prior myocardial infarction reduced left ventricular ejection fraction. Whether MADIT II criteria for ICD implantation are appropriate for Indian patients also is unclear and not studied. MethodsA total of 144 patients, Mean age 56.23 ± 10.9 years who met MADIT II criteria were prospectively followed for 20.78 + 5.9 months. ResultsDuring the follow-up period, 26 (18.1%) patients died. 18 were sudden cardiac deaths and 8 were non SCD deaths. Total mortality did not correlate with Age, NYHA class, NSVT on Holter, PVC >10/hours, QRS width, or use of statins. Multivariate logistic regression model identified the following variables associated with increase all-cause mortality: No use of beta blocker (odd ratio:13.068, p = 0.021), No past revascularization (odd ratio:11.613,p = 0.007) and Increase serum creatinine level (odd ratio: 4.066, p = 0.035). The mortality rate in the present series was comparable with that in the MADIT II conventional therapy group though patient in present study are younger, less diabetic, hypertensive, smokers and better treated with beta-blockers, ACE/ARB and statin. ConclusionIndian patients with prior MI (more than one month back) and left ventricular ejection fraction of 30% or less had a cardiac mortality similar to western population who are not treated with prophylactic ICD. Patients of Indian origin should derive a similar benefit with prophylactic implantation of ICD as per MADIT II criteria as would a western population.

Need for pacing in patients who qualify for an implantable cardioverter‐defibrillator: Clinical implications for the subcutaneous ICD

BackgroundImplantation of the subcutaneous implantable cardioverter‐defibrillator (S‐ICD) is spreading and has been shown to be safe and effective; however, it does not provide brady‐pacing. Currently, data on the need for brady‐pacing and cardiac resynchronization therapy (CRT) implantation in patients with ICD indication are limited.MethodsThe Multicenter Automatic Defibrillator Implantation Trial (MADIT)‐II enrolled post‐MI patients with reduced ejection fraction (EF ≤ 35%), randomized to either an implantable cardioverter‐defibrillator (ICD) or conventional medical therapy. Kaplan–Meier analyses and multivariate Cox models were performed to assess the incidence and predictors of pacemaker (PM), or CRT implantation in the conventional arm of MADIT‐II, after excluding 32 patients (6.5%) with a previously implanted PM.ResultsDuring the median follow‐up of 20 months, 24 of 458 patients (5.2%) were implanted with a PM or a CRT (19 PM, 5 CRT). Symptomatic sinus bradycardia was the primary indication for PM implantation (n = 9, 37%), followed by AV block (n = 5, 21%), tachy‐brady syndrome (n = 4, 17%), and carotid sinus hypersensitivity (n = 1, 4%). Baseline PR interval >200 ms (HR = 3.07, 95% CI: 1.24–7.57, p = .02), and CABG before enrollment (HR = 6.88, 95% CI: 1.58–29.84, p = .01) predicted subsequent PM/CRT implantation. Patients with PM/CRT implantation had a significantly higher risk for heart failure (HR = 2.67, 95% CI = 1.38–5.14, p = .003), but no increased mortality risk (HR = 1.06, 95% CI = 0.46–2.46, p = .89).ConclusionThe short‐term need for ventricular pacing or CRT implantation in patients with MADIT‐II ICD indication was low, especially in those with a normal baseline PR interval, and such patients are appropriate candidates for the subcutaneous ICD.

CHA2DS2-VASc Score and the Risk of Ventricular Tachyarrhythmic Events and Mortality in MADIT-CRT.

BackgroundWe hypothesized that multiple cardiovascular comorbidities, incorporated in the CHA 2 DS 2‐VASc score, may be useful in the assessment of ventricular tachyarrhythmias (VTAs) and mortality risk in heart failure (HF) patients.Methods and ResultsWe evaluated the association between the CHA 2 DS 2‐VASc score (dichotomized as high at the upper quartile [≥5] and further assessed as a continuous measure) and the risk of VTA and death among 1804 patients enrolled in MADIT‐CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). A high CHA 2 DS 2‐VASc score (n=464; 26%) was inversely associated with the risk of any VTA (hazard ratio [HR]: 0.64; P=0.001), fast VTA >200 beats/min (HR; 0.51; P<0.001), and appropriate implantable cardioverter‐defibrillator shocks (HR: 0.60; P<0.001). In contrast, a high score was directly correlated with mortality risk (HR: 1.92; P<0.001) and the risk of HF or death (HR: 1.60; P<0.001). Consistently, each 1‐U increment in CHA 2 DS 2‐VASc was associated with a significant 13% (P=0.003) reduction in VTA risk but a corresponding 33% (P<0.001) increase in mortality risk. Patients with a high CHA 2 DS 2‐VASc score and left bundle‐branch block derived a pronounced 53% (P<0.001) reduction in the risk of HF or death with cardiac resynchronization therapy with defibrillator versus implantable cardioverter‐defibrillator–only therapy.ConclusionsOur findings suggest that a high CHA 2 DS 2‐VASc score can be used to identify patients with mild HF who have low VTA risk and high morbidity or mortality risk and may derive a pronounced clinical benefit from cardiac resynchronization therapy without a defibrillator. These data suggest a possible role for the CHA 2 DS 2‐VASc score in device selection among candidates for biventricular pacing.

Death with an implantable cardioverter-defibrillator: a MADIT-II substudy.

There are limited data regarding factors that identify implantable cardioverter-defibrillator (ICD) patients who will experience either ventricular tachyarrhythmic (VTA) or non-arrhythmic (NA) mortality, and the commonly used clinical classification of sudden cardiac death (SCD) vs. non-sudden cardiac death (NSCD) may not be accurate enough. We aimed to correlate clinical adjudication of mortality events to device interrogation data and to identify risk factors for VTA mortality in Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II). Of the 746 patients who received an ICD in MADIT-II, 44 died from cardiac causes and had available interrogation data at the time of death. Sudden cardiac death vs. NSCD was defined by an adjudication committee. Ventricular tachyarrhythmic and NA arrhythmic deaths were categorized by the presence or absence of ventricular tachycardia or fibrillation (VT/VF) during the terminal event. Mode of death was found to be inaccurate when validated by device interrogation for VTA events: 50% patients adjudicated as SCD did not have a VTA event at the time of death; and 25% of adjudicated NSCD were found to have VT/VF during the mortality event. Multivariate analysis showed that factors independently associated with VTA mortality included: VT/VF >72 h prior to the mortality event [hazard ratio (HR) 8.0; P < 0.001], hospitalization for heart failure (HR 6.7; P = 0.001), and a history of hypertension (HR 4; P = 0.04). Current classification of SCD vs. NSCD fails to identify VTA events at the time of death in a significant proportion of patients, and simple clinical parameters can be used to identify ICD recipients with increased risk for VTA mortality.