Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Research Articles

Cardiac resynchronization therapy and ventricular tachyarrhythmia burden

Cardiac resynchronization therapy-defibrillator (CRT-D) may reduce the incidence of first ventricular tachyarrhythmia (VTA) in patients with heart failure (HF) and left bundle branch block (LBBB). The purpose of this study was to assess the effect of CRT-D on VTA burden in LBBB patients. We included 1281 patients with LBBB from MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy). VTA was defined as any treated or monitored sustained ventricular tachycardia (VT ≥180 bpm) or ventricular fibrillation (VF). Life-threatening VTA was defined as VT ≥200 bpm or VF. VTA recurrence was assessed using the Andersen-Gill model. During a mean follow-up of 2.5 years, 964 VTA episodes occurred in 264 patients (21%). The VTA rate per 100 person-years was significantly lower in the CRT-D group compared with the implantable cardioverter-defibrillator (ICD) group (20 vs 34; P<.01). Multivariate analysis demonstrated that CRT-D treatment was associated with a 32% risk reduction for VTA recurrence (hazard ratio 0.68; 95% confidence interval 0.57-0.82; P <.001), 57% risk reduction for recurrent life-threatening VTA, 54% risk reduction for recurrent appropriate ICD shocks, and 25% risk reduction for the combined endpoint of VTA and death. The effect of CRT-D on VTA burden was consistent among all tested subgroups but was more pronounced among patients in New York Heart Association functional class I. Landmark analysis showed that at 2 years, the cumulative probability of death subsequent to year one was highest (16%) among patients who had ≥2 VTA events during their first year. In patients with LBBB and HF, early intervention with CRT-D reduces mortality, VTA burden, and frequency of multiple appropriate ICD shocks. VTA burden is a powerful predictor of subsequent mortality.

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.

Marital Status and Long-Term Outcomes in Mild Heart Failure Patients With an Implantable Cardioverter Defibrillator or Cardiac Resynchronization Therapy With Defibrillator

Married patients have been shown to have a lower risk for adverse cardiovascular outcomes. However, the risk of heart failure (HF) or death in married versus unmarried patients with left ventricular (LV) dysfunction and an implantable cardioverter defibrillator (ICD), and the effect of cardiac resynchronization therapy with defibrillator (CRT-D) are unknown. In Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT), in patients with left bundle branch block, we evaluated long-term clinical outcomes of all-cause mortality or HF events in married (including common law status) compared with unmarried (single/divorced/widowed) patients with CRT-D versus an ICD-only. There were 937 married patients and 344 unmarried patients with left bundle branch block. Multivariate analysis showed that married patients had a 54% lower risk of all-cause mortality (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.30 to 0.71, p <0.001) compared with the unmarried. However, the survival benefit associated with marital status was pronounced in ICD patients (HR 0.40, 95% CI 0.23 to 0.69, p <0.001) and attenuated in CRT-D patients (HR 0.74, 95% CI 0.51 to 1.06, p = 0.10), interaction (p = 0.07). Consistently, during the median follow-up of 5.6 years, in patients with ICD, married patients had a significantly lower incidence of death (24%) compared with unmarried patients (42%; p = 0.004), whereas the corresponding mortality rates in CRT-D patients were not significantly different (p = 0.814). In conclusion, during long-term follow-up of mild HF patients with LV dysfunction, married patients were at a significantly lower risk for death compared with those not married. The survival benefit associated with marital status was pronounced in patients implanted with an ICD and is attenuated in those implanted with a CRT-D device.

The prognostic benefit of cardiac resynchronization therapy is greater in concordant vs. discordant left bundle branch block in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT).

Discordant and concordant left bundle branch block (dLBBB/cLBBB) are characterized by negative or positive T waves, respectively, in lateral leads. We assessed if the two morphologies are associated with different clinical status and prognosis in patients with heart failure (HF) and current indication to Cardiac Resynchronization Therapy (CRT)/CRT-Defibrillator (CRT-D). Baseline electrocardiograms of 1270 patients with LBBB in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy cohort were analysed to identify dLBBB and cLBBB. The two groups were compared with respect to baseline clinical characteristics, primary endpoint (HF event or death), and secondary endpoint (ventricular tachycardia, ventricular fibrillation, or death) over a 3.5-year period, and benefit of CRT-D over implantable cardioverter defibrillator (ICD). dLBBB was identified in 909 (72%) patients, and cLBBB in 361 (28%). Patients with dLBBB were older, had more severe symptoms and systolic dysfunction, as well as higher brain natriuretic peptide. CRT-D was superior to ICD in patients with both LBBB morphologies. The occurrence of the primary outcome was significantly more frequent in patients with dLBBB than in those with cLBBB, both in the entire cohort (P = 0.005), and in the CRT-D arm (P = 0.002). There was a trend towards more frequent occurrence of the secondary endpoint in patients with dLBBB than in those with cLBBB, but statistical significance was not reached in the whole population or in the subgroup undergoing CRT-D. Among patients receiving CRT-D, dLBBB was an independent predictor of the primary endpoint. dLBBB morphology is associated with more severe HF clinical status and worse prognosis, even in patients receiving CRT-D, compared with cLBBB morphology.

Effect of Significant Weight Change on Inappropriate Implantable Cardioverter-Defibrillator Therapy.

Weight loss has been associated with adverse outcomes among heart failure (HF) patients, including those receiving cardiac resynchronization therapy with defibrillator (CRT-D). The effect of significant weight change on inappropriate implantable cardioverter-defibrillator (ICD) therapy among CRT-D patients is not well understood. We evaluated the impact of significant weight change at 1 year on subsequent inappropriate ICD therapy during follow-up among 993 CRT-D patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy. Patients were divided into three subgroups based on weight change at 1 year after enrollment: weight loss (weight loss ≥ 5%), weight gain (weight gain ≥ 5%), and stable weight (weight loss and weight gain < 5%). The primary end point was inappropriate ICD therapy. Secondary end point included inappropriate ICD therapy related to supraventricular arrhythmias (SVAs). There were 102 (10.3%) patients who experienced weight loss, 689 (69.4%) whose weight was stable, and 202 (20.3%) who gained weight at 1 year. Patients with weight loss had increased risk of subsequent inappropriate ICD therapy relative to patients with stable weight (hazard ratio [HR] = 2.35, 95% confidence interval [CI]: 1.39-3.98, P = 0.001) or weight gain (HR = 2.27, 95% CI: 1.18-4.38, P = 0.014). Furthermore, patients losing weight were at greater risk of subsequent inappropriate ICD therapy related to SVAs when compared to patients with stable weight (HR = 2.16, 95% CI: 1.18-3.95, P = 0.013) or weight gain (HR = 2.02, 95% CI: 0.95-4.29, P = 0.068). In mild HF patients receiving CRT-D, significant weight loss at 1 year is associated with increased risk of subsequent inappropriate ICD therapy, including risk related to SVAs.

Regional Longitudinal Deformation Improves Prediction of Ventricular Tachyarrhythmias in Patients With Heart Failure With Reduced Ejection Fraction

Background— Left ventricular dysfunction is a known predictor of ventricular arrhythmias. We hypothesized that measures of regional longitudinal deformation by speckle-tracking echocardiography predict ventricular tachyarrhythmias and provide incremental prognostic information over clinical and conventional echocardiographic characteristics. Methods and Results— We studied 1064 patients enrolled in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy) with speckle-tracking data available. Peak longitudinal strain was obtained for the septal, lateral, anterior, and inferior myocardial walls at baseline. The end point was the first event of ventricular tachycardia (VT) or fibrillation (VF). During the median follow-up of 2.9 years, 254 (24%) patients developed VT/VF. Patients with VT/VF had significantly lower left ventricular ejection fraction (28.3% versus 29.5%; P &lt;0.001) and longitudinal strain in all myocardial walls compared with patients without VT/VF (anterior-strain, −7.7% versus −8.8%; P &lt;0.001; lateral-strain, −7.3% versus −7.9%; P =0.022; inferior-strain, −8.3% versus −9.9%; P &lt;0.001; septal-strain, −9.1% versus −10.0%; P &lt;0.001). After multivariate adjustment, only anterior and inferior longitudinal strain remained independent predictors of VT/VF (anterior: hazard ratio, 1.08 [1.03–1.13]; P =0.001; inferior: hazard ratio, 1.08 [1.04–1.12]; P &lt;0.001; per 1% absolute decrease for both). When including B-type natriuretic peptide in the model, only a decreasing myocardial function in the inferior myocardial wall predicted VT/VF (hazard ratio, 1.05 [1.00–1.11]; P =0.039). Only strain obtained from the inferior myocardial wall provided incremental prognostic information for VT/VF over clinical and echocardiographic parameters (C statistic 0.71 versus 0.69; P =0.005). Conclusions— Assessment of regional longitudinal myocardial deformation in the inferior region provided incremental prognostic information over clinical and echocardiographic risk factors in predicting ventricular tachyarrhythmias. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00180271.

Effectiveness of cardiac resynchronization therapy by the frequency of revascularization procedures in ischemic cardiomyopathy patients

It is not known whether the number of revascularizations modifies clinical outcomes in patients with ischemic cardiomyopathy (ICM) implanted with cardiac resynchronization therapy defibrillator (CRT-D) vs. an implantable cardioverter-defibrillator (ICD)-only. In Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT), we evaluated the effect of CRT-D vs. ICD-only on heart failure (HF) or death, on ventricular tachycardia (VT), ventricular fibrillation (VF) or death, and on reverse remodeling in 592 ICM patients with left bundle branch block, by the number of pre-enrollment revascularizations (0, 1 or ≥ 2 revascularizations). There was a risk reduction of HF/death with CRT-D vs. ICD-only in all three sub-groups: ICM with no need for revascularization (HR 0.51 [0.26-1.02]; p = 0.055), ICM with 1 revascularization (HR 0.45 [0.30-0.70]; p < 0.001), and ICM with 2 or more revas-cularizations (HR 0.37 [0.20-0.66]; p < 0.001). Similarly, there was a risk reduction of VT/ /VF/death with CRT-D vs. ICD-only in patients with no need for revascularization (HR 0.55 [0.31-0.99]; p = 0.044); with 1 revascularization (HR 0.77 [0.51-1.18]; p = 0.23); or with ≥ 2 revascularizations (HR 0.63 [0.34-1.17]; p = 0.14). There was a similar degree of left ventricular reverse remodeling in all three subgroups (p > 0.05 for LVESV, LVEDV, and LAV percent change at 1-year follow-up). In ICM patients, CRT-D is associated with a reduction in HF or death and VT/VF or death - irrespective of the frequency of pre-enrollment revascularization procedures - and is accompanied by a similar degree of beneficial left ventricular reverse remodeling.

Time Dependence of VentricularTachyarrhythmias AfterMyocardial Infarction: A MADIT-CRT Substudy.

The purpose of this study was to assess the relationship between the time since a myocardial infarction (MI) and the risk of ventricular tachyarrhythmic events (VTEs) in patients with left ventricular dysfunction and mild symptoms of heart failure. Patients with left ventricular dysfunction after MI are at high risk for VTEs. Ventricular tachycardia (VT), ventricular fibrillation (VF), or death as a function of time since MI was assessed in 693 patients enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy). Patients were categorized as those with a period of<3 years since an MI (lowest quartile, n= 172) versus those with a period of≥3 years since an MI (n= 521). Risk of VT/VF or death was compared. Cumulative probability of VT/VF or death was significantly higher among patients in the highest quartile of time since an MI compared with those in the lowest quartile (41% vs. 22%, p= 0.015). Multivariate analysis showed that in patients with left bundle branch block (LBBB), those with a period of≥3 years since an MI had a significantly higher risk of VT/VF or death (hazard ratio: 2.33; 95% confidence interval: 1.43 to 3.80; p= 0.001) and a higher risk of VT/VF (hazard ratio: 3.18; 95% confidence interval: 1.71 to 5.90; p< 0.001) compared with patients with a period of<3 years since an MI. These findings were consistent when the time since an MI was analyzed in a continuous fashion. A significant relationship between the time since an MI and outcomes was not observed in patients with non-LBBB. Among post-MI patients with left ventricular dysfunction and LBBB, the risk of VTEs is directly relatedto the time since an MI occurred. (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271).

Scar burden assessed by Selvester QRS score predicts prognosis, not CRT clinical benefit in preventing heart failure event and death: A MADIT-CRT sub-study

BackgroundThere is a need for improved selection criteria for cardiac resynchronization therapy (CRT). High myocardial scar burden has been associated with worse outcome in CRT patients. However, it is unclear whether high scar burden prevents CRT clinical benefit or is merely predictive of prognosis in heart failure (HF) patients regardless of CRT implantation. We aimed to study the predictive value of scar burden estimated by electrocardiographic Selvester QRS scoring in determining CRT benefit in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) population. MethodsSelvester QRS scoring was performed on all 1820 ECGs of the MADIT-CRT population by a single observer. In both arms and in their respective LBBB subgroups, QRS score was analyzed in comparison to echocardiographic volumes and in relation to time to HF event or death using Cox proportional hazard ratios. To determine effect on CRT clinical benefit, we tested for interaction between the effects of CRT assignment and QRS score on time to HF event or death. ResultsIn the CRT-D arm, a significant correlation was found between higher continuous QRS score and less increase of left ventricular ejection fraction (LVEF) as well as less decrease of left ventricular end-systolic volume (LVESV) (multivariate -p-values: <0.001). QRS score was significantly correlated with HF event/death in the left bundle branch block (LBBB) subgroup (n=1037, multivariate HR 1.07 per point, p=0.046). Scar extent estimated by QRS scoring was neither predictive of CRT clinical benefit in the total study population (interaction -p-value=0.25) nor in the LBBB subgroup (interaction p-value=0.86). ConclusionHigh scar burden estimated by Selvester QRS score is predictive of adverse overall prognosis in LBBB patients regardless of CRT implantation. However, QRS score does not identify patients who benefit clinically from CRT-D compared to implantation of ICD only.

Long-Term Outcomes With Cardiac Resynchronization Therapy in Patients With Mild Heart Failure With Moderate Renal Dysfunction.

We aimed to determine the impact of renal function on long-term outcomes with cardiac resynchronization therapy with defibrillator among patients with mild heart failure (HF). We stratified 1820 Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy patients by QRS morphology into those with and without left bundle-branch block. Subgroups within each QRS morphology category were created based on glomerular filtration rate (GFR): GFR <60 and ≥60 mL/min per 1.73 m(2). Primary end point was death; secondary end points were HF/death and HF events alone during long-term follow-up. Among 1274 left bundle-branch block patients, 413 (32%) presented with GFR <60 (mean, 48.1±8.3) mL/min per 1.73 m(2). Relative to the 861 (68%) patients with GFR ≥60 (mean, 79.6±16.0) mL/min per 1.73 m(2), low-GFR patients experienced higher risk of death (hazard ratio [HR], 2.09; 95% confidence interval [CI], 1.53-2.86; P<0.01) and HF/death (HR, 1.46; 95% CI, 1.17-1.82; P<0.01). In both GFR groups, cardiac resynchronization therapy with defibrillator was associated with reduction in death (GFR <60: HR, 0.66; 95% CI, 0.44-1.00; P=0.05 and GFR ≥60: HR, 0.68; 95% CI, 0.44-1.05; P=0.08) and HF/death (GFR <60: HR, 0.49; 95% CI, 0.36-0.67; P<0.01 and GFR ≥60: HR, 0.50; 95% CI, 0.38-0.66; P<0.01). In the low-GFR group, there was greater absolute reduction in risk of death (GFR <60: 14% and GFR ≥60: 6%) and HF/death (GFR <60: 25 and GFR ≥60: 15%). Among non-left bundle-branch block patients, low GFR predicted outcomes; however, no benefit from cardiac resynchronization therapy with defibrillator was observed. In patients with mild HF, moderate renal dysfunction is associated with higher risk of death and HF during long-term follow-up. Patients with left bundle-branch block, regardless of baseline renal function, derive long-term benefit from cardiac resynchronization therapy with defibrillator, with greater absolute risk reduction in death and HF among those with moderate renal dysfunction. URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00180271, NCT01294449, and NCT02060110.

Opportunity to Increase Life Span in Narrow QRS Cardiac Resynchronization Therapy Recipients by Deactivating Ventricular Pacing: Evidence From Randomized Controlled Trials

ObjectivesThis study examined the time course of clinical events in cardiac resynchronization therapy (CRT) trials. BackgroundRecent randomized controlled trial results suggest that in heart failure with narrow QRS, biventricular pacing (CRT) may increase mortality. The authors proposed implant complications as the cause, rather than a progressive adverse physiological effect. MethodsThe study identified all trials comparing CRT with no CRT, which reported Kaplan-Meier curves in groups defined by QRS: narrow, non–left bundle branch block (LBBB) broad, and LBBB broad. For each trial, the change in life span every 3 months up to 3.5 years (the longest time for which data are available) was calculated and a power law was fitted, that is, ∝ timen. ResultsFour trials (MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure Trial], REVERSE [REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction], and EchoCRT [Echocardiography Guided Cardiac Resynchronization Therapy]), totaling 4,717 patients, reported curves for mortality or heart failure–related hospitalization, or for mortality. In patients with LBBB broad QRS (within MADIT-CRT), life span gain increased in proportion to time1.94. In contrast, in patients with non-LBBB broad QRS (within MADIT-CRT) and patients with narrow QRS (EchoCRT), life span was lost in proportion to time1.92 and time,1.96 respectively. Hospitalization-free survival showed similar patterns. ConclusionsThe nonlinear growth of life span gained when a CRT device is implanted in patients with LBBB broad QRS is unfortunately mirrored by a similarly progressive loss in life span in narrow QRS heart failure. This suggests the culprit is a progressive physiological effect of pacing rather than implant complications. If these data are not sufficient, a randomized controlled trial of deactivating CRT in patients with narrow QRS may now be needed, with a primary endpoint of increasing survival.

Prognostic Significance of Heart Rate Variability Among Patients Treated With Cardiac Resynchronization Therapy: MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy)

ObjectivesThis study sought to evaluate the prognostic value of heart rate variability (HRV) for death or heart failure in patients with mildly symptomatic heart failure undergoing cardiac resynchronization therapy with a defibrillator (CRT-D). BackgroundThere are limited data regarding the prognostic value of HRV as a means of identifying high-risk patients treated with CRT-D. MethodsWe analyzed the relationship between pre-implant time-domain (SD of all normal-to-normal RR intervals [SDNN], SDs of averaged 5-min normal-to-normal RR intervals, root mean square of successive differences, and mean of the SDs of all normal-to-normal RR intervals for all 5-min segments of the entire recording), and frequency-domain (low-frequency power, very-low-frequency power [VLF], high-frequency power, low-frequency power/low-frequency power ratio) HRV parameters, and the end point of death or heart failure and death alone. Study subjects include 719 patients in normal sinus rhythm enrolled in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy); outcomes of CRT-D patients with low HRV (lower tertile) were compared with CRT-D patients with preserved HRV (2 upper tertiles) and with patients receiving implantable cardioverter-defibrillators only. ResultsDuring a mean 3.4 ± 0.9 years of follow-up, 124 patients reached the primary end point of death or heart failure, and 47 died. In multivariate analysis, low SDNN (≤93 ms) was associated with significantly higher risk of death or heart failure (hazard ratio [HR] 1.63 [95% confidence interval (CI): 1.12 to 2.36]; p = 0.010) and mortality (HR 2.10 [95% CI: 1.14 to 3.87]; p = 0.017) compared with higher SDNN (>93 ms). Similarly, low VLF (≤179 ms2) was associated with an increased risk of death or heart failure (HR 2.14 [95% CI: 1.46 to 3.13]; p < 0.001) and death alone (HR 2.49 [95% CI: 1.35 to 4.57]; p = 0.003). There was no significant difference in outcome between low HRV patients treated with CRT-D and patients receiving an implantable cardioverter-defibrillator only. ConclusionsOur findings indicate that autonomic dysfunction (quantified by low SDNN and low VLF) identified patients with no benefit or limited benefit from cardiac resynchronization therapy. Pre-implant HRV analysis might help in optimizing qualifications for this treatment.

Temporal Influence of Heart Failure Hospitalizations Prior to Implantable Cardioverter Defibrillator or Cardiac Resynchronization Therapy With Defibrillator on Subsequent Outcome in Mild Heart Failure Patients (from MADIT-CRT)

The temporal effect of heart failure (HF) hospitalization occurring at different time periods before implantation has not yet been studied in detail. The aim of the present study was to investigate the potential association between time from last HF hospitalization to device implantation and effects on subsequent outcomes and benefit from cardiac resynchronization therapy with a defibrillator (CRT-D). Multivariate Cox models were used to determine the temporal influence of previous HF hospitalization on the end point of HF or death within all left bundle branch block implantable cardioverter-defibrillator (ICD) and CRT-D patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial (n = 1,250) and to evaluate the clinical benefit of CRT-D implantation, comparing CRT-D patients with ICD patients within each previous HF hospitalization group. The patients with previous HF hospitalization ≤12 months before device implantation had the greatest incidence of HF or death during 4-year follow-up (31%), while those with previous HF hospitalization >12 months and those with no previous HF hospitalization had similar lower rates of HF or death (22% and 24%, respectively). All patients treated with CRT-D derived significant clinical benefit compared with their ICD counterparts, regardless of time of previous hospitalization (hazard ratios 0.38 [no previous hospitalization], 0.49 (≤12 months), and 0.45 (>12 months); p for interaction = 0.67). In conclusion, in the present study of patients with mild HF with prolonged QRS intervals and LBBB, a previous HF hospitalization ≤12 months was associated with increased risk for HF or death compared with >12 months and no previous HF hospitalizations. The clinical benefit of CRT-D was evident in all patients regardless of time from last HF hospitalization to implantation compared with ICD only.

The Burden and Morphology of Premature Ventricular Contractions and their Impact on Clinical Outcomes in Patients Receiving Biventricular Pacing in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT).

Premature ventricular contractions (PVCs) frequently occur in patients with left ventricular dysfunction. However, there are limited data regarding the burden and morphologic characteristics of PVCs in patients receiving cardiac resynchronization therapy. Patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) with >5000 PVCs on a predevice implant 12-lead, 24-hour Holter were identified. The putative PVC site of origin for the most dominant PVC was characterized and their effects on clinical outcomes were evaluated. A total of 146 patients were identified to have >5000 PVCs on Holter of which 75 (51%) had PVCs originating from a non-outflow tract site. Other sites included the left ventricular outflow tract (LVOT), right ventricular outflow tract (RVOT), and the sinus of Valsalva. In multivariate analysis, the risk for HF/Deatd was similar in patients with Outflow tract PVCs when compared to patients with Non-outflow tract PVCs (HR 1.4, 95% CI 0.7-2.8, P = 0.3). The degree of echocardiographic reverse remodeling was similar in patients with outflow tract versus Non-outflow tract PVCs. One-third of patients with nonischemic cardiomyopathy were found to have PVCs originating from the RVOT. In patients with mild symptoms of heart failure, there is no difference in the risk of HF or death in patients with outflow versus non-outflow tract PVCs. One-third of patients with NICM have frequent PVCs originating from the RVOT.

WITHDRAWAL: Prognostic Significance of Heart Rate Variability Among Patients Treated With Cardiac Resynchronization Therapy in MADIT-CRT

This study sought to evaluate the prognostic value of heart rate variability (HRV) for death or heart failure in patients with mildly symptomatic heart failure undergoing cardiac resynchronization therapy with a defibrillator (CRT-D). There are limited data regarding the prognostic value of HRV as a means of identifying high-risk patients treated with CRT-D. We analyzed the relationship between pre-implant time-domain (SD of all normal-to-normal RR intervals [SDNN], SDs of averaged 5-min normal-to-normal RR intervals, root mean square of successive differences, and mean of the SDs of all normal-to-normal RR intervals for all 5-min segments of the entire recording), and frequency-domain (low-frequency power, very-low-frequency power [VLF], high-frequency power, low-frequency power/low-frequency power ratio) HRV parameters, and the end point of death or heart failure and death alone. Study subjects include 719 patients in normal sinus rhythm enrolled in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy); outcomes of CRT-D patients with low HRV (lower tertile) were compared with CRT-D patients with preserved HRV (2 upper tertiles) and with patients receiving implantable cardioverter-defibrillators only. During a mean 3.4 ± 0.9 years of follow-up, 124 patients reached the primary end point of death or heart failure, and 47 died. In multivariate analysis, low SDNN (≤93 ms) was associated with significantly higher risk of death or heart failure (hazard ratio [HR] 1.63 [95% confidence interval (CI): 1.12 to 2.36]; p = 0.010) and mortality (HR 2.10 [95% CI: 1.14 to 3.87]; p = 0.017) compared with higher SDNN (>93 ms). Similarly, low VLF (≤179 ms 2 ) was associated with an increased risk of death or heart failure (HR 2.14 [95% CI: 1.46 to 3.13]; p < 0.001) and death alone (HR 2.49 [95% CI: 1.35 to 4.57]; p = 0.003). There was no significant difference in outcome between low HRV patients treated with CRT-D and patients receiving an implantable cardioverter-defibrillator only. Our findings indicate that autonomic dysfunction (quantified by low SDNN and low VLF) identified patients with no benefit or limited benefit from cardiac resynchronization therapy. Pre-implant HRV analysis might help in optimizing qualifications for this treatment.

PR interval identifies clinical response in patients with non-left bundle branch block: a Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy substudy.

In Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT), patients with non-left bundle branch block (LBBB; including right bundle branch block, intraventricular conduction delay) did not have clinical benefit from cardiac resynchronization therapy with defibrillator (CRT-D). We hypothesized that baseline PR interval modulates clinical response to CRT-D therapy in patients with non-LBBB. Non-LBBB patients (n=537; 30%) were divided into 2 groups based on their baseline PR interval as normal (including minimally prolonged) PR (PR <230 ms) and prolonged PR (PR ≥230 ms). The primary end point was heart failure or death. Separate secondary end points included heart failure events and all-cause mortality. Cox proportional hazards regression models were used to compare risk of end point events by CRT-D to implantable cardioverter defibrillator therapy in the PR subgroups. There were 96 patients (22%) with a prolonged PR and 438 patients (78%) with a normal PR interval. In non-LBBB patients with a prolonged PR interval, CRT-D treatment was associated with a 73% reduction in the risk of heart failure/death (hazard ratio, 0.27; 95% confidence interval, 0.13-0.57; P<0.001) and 81% decrease in the risk of all-cause mortality (hazard ratio, 0.19; 95% confidence interval, 0.13-0.57; P<0.001) compared with implantable cardioverter defibrillator therapy. In non-LBBB patients with normal PR, CRT-D therapy was associated with a trend toward an increased risk of heart failure/death (hazard ratio, 1.45; 95% confidence interval, 0.96-2.19; P=0.078; interaction P<0.001) and a more than 2-fold higher mortality (hazard ratio, 2.14; 95% confidence interval, 1.12-4.09; P=0.022; interaction P<0.001) compared with implantable cardioverter defibrillator therapy. The data support the use of CRT-D in MADIT-CRT non-LBBB patients with a prolonged PR interval. In non-LBBB patients with a normal PR interval, implantation of a CRT-D may be deleterious. http://clinicaltrials.gov; Unique Identifier: NCT00180271.

The impact of nonsustained ventricular tachycardia on reverse remodeling, heart failure, and treated ventricular tachyarrhythmias in MADIT-CRT.

This study determined whether the presence of nonsustained ventricular tachycardia (NSVT) was predictive of clinical events in MADIT-CRT (multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy) patients treated with CRT-defibrillator. We analyzed 24-hour Holters for the presence of NSVT. Patients were then stratified by the etiology (ischemic or nonischemic) of cardiomyopathy. The impact of NSVT on heart failure events (HF), implantable cardioverter-defibrillator (ICD) therapy for rapid ventricular tachycardia (VT) or fibrillation (VF), and reverse remodeling was determined. At least a single episode of NSVT was recorded in 483 (49%) patients. These patients had a higher burden of premature ventricular contractions, lower percentage of biventricular (BiV) pacing, and significantly less reduction in left ventricular end-diastolic and end-systolic volumes. The risk of HF was significantly greater in patients with nonischemic cardiomyopathy and NSVT (hazard ratio [HR] 2.89; 95% confidence interval [CI]: 1.49-5.61; P = 0.002). The risk of rapid VT/VF was significantly greater (in both ischemic and nonischemic patients) when NSVT was observed (HR 2.06; 95% CI: 1.30-3.26; P = 0.002 in ischemic patients; HR 3.09; 95% CI: 1.80-5.28; P < 0.001 in nonischemic patients). MADIT-CRT patients with NSVT had a high burden of ventricular ectopy, lower percentage of BiV pacing, and less reverse remodeling. These patients had an increase in HF (in nonischemic cardiomyopathy patients) and rapid VT/VF ICD therapies (in ischemic and nonischemic patients). These findings may have implications for the management of nonsustained ventricular ectopy in CRT patients.

Predictors of spontaneous reverse remodeling in mild heart failure patients with left ventricular dysfunction.

There are limited data regarding factors associated with spontaneous left ventricular reverse remodeling (S-LVRR) among mildly symptomatic heart failure (HF) patients and its prognostic implications on clinical outcomes. Best subsets logistic regression analysis was used to identify factors associated with S-LVRR (defined as ≥15% reduction in left ventricular end-systolic volume at 1-year of follow-up) among 612 patients treated with internal cardioverter defibrillator-only therapy in Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) and to create a score for the prediction of S-LVRR. Cox proportional hazards regression modeling was used to assess the clinical outcome of all internal cardioverter defibrillator-only patients (n=714) with a high S-LVRR score. S-LVRR occurred in 25% of internal cardioverter defibrillator-only patients. Predictors of S-LVRR included systolic blood pressure≥140 mm Hg, serum creatinine<1.0 mg/dL, QRS 130 to 160 ms, and nonischemic cardiomyopathy. Multivariate analysis showed that each 1-point increment in S-LVRR score (range, 0-7) was associated with an 11% (P=0.019) reduction in the risk of HF or death. Treatment with cardiac resynchronization therapy was associated with a significant reduction in the risk of HF or death only among internal cardioverter defibrillator-treated patients with a low (Q1-3) S-LVRR score (hazard ratio=0.55; P<0.001), but not among those with a higher (Q4) score (hazard ratio=1.06; P=0.72). Our data suggest that approximately one quarter of mild HF patients eligible for biventricular pacing experience S-LVRR. Combined assessment of clinical factors associated with S-LVRR can be used to identify mild HF patients with a low risk for clinical events without cardiac resynchronization therapy intervention. http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

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

Limited data exist regarding the proarrhythmic effects of smoking. To evaluate the relationship between smoking and the risk of first and recurrent ventricular tachyarrhythmias (VTAs) in patients with mild heart failure. 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. 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). 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.

The Effect of Weight Loss on Clinical Outcomes in Patients Implanted With a Cardiac Resynchronization Therapy Device—A MADIT-CRT Substudy

BackgroundThere are no data regarding the effect of weight loss on clinical outcomes in patients undergoing cardiac resynchronization therapy. This study was designed to evaluate the effect of weight loss on clinical outcomes in patients implanted with a cardiac resynchronization therapy with defibrillator (CRT-D). Methods and ResultsThe risk of heart failure (HF) or death, and of death alone, was compared between patients with and without weight loss of ≥2 kg or more at 1 year in the CRT-D arm of the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT). Weight loss was observed in 170 of 994 patients (17%) implanted with a CRT-D. Multivariate analysis showed a significant increase in the risk of HF or death among patients with weight loss compared with those without weight loss (hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.26–2.63; P = .001). Weight loss was associated with a 79% increase in the risk of all-cause mortality (HR 1.79, 95% CI 1.16–3.34; P = .01). When analyzed in a continuous fashion, each kg of weight loss was associated with a 4% increase in the risk of HF or death (P = .03). In left bundle branch block (LBBB) patients with a CRT-D, weight loss was associated with an especially high risk of HF or death (HR 2.23, 95% CI 1.36–3.65; P = .002) and of death alone (HR 2.33, 95% CI 1.07–5.06; P = .03; interaction P = .26). ConclusionsIn patients with mild symptoms of HF receiving CRT-D, weight loss observed at 1 year is associated with adverse clinical outcomes, especially in those with a LBBB electrocardiographic pattern.