Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy Research Articles

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<0.001), followed by PRmax (Chi-square=13.19, HR for Q5 vs. Q1-4=2.81, CI=1.61-4.92, p<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.

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.

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.

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.

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.

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.

Cardiac Resynchronization Therapy

More than 2 decades of research has established the role of cardiac resynchronization therapy (CRT) in medically refractory, mild to severe systolic heart failure (HF) with abnormal QRS duration and morphology. CRT confers a mortality benefit, reduces HF hospitalizations, and improves functional outcome in this population, but not all patients consistently demonstrate a positive CRT response. The reported nonresponder rate ranges between 20% and 40%, depending on the response criteria used.1 Efforts to improve response to CRT have focused on methods to optimize the correction of electrical and mechanical dyssynchrony (the primary target of CRT) and on improving patient selection and optimizing postimplant care. The present article reviews the state-of-the-art of CRT and discusses developments on potential promises and areas of controversy. Although CRT became common clinical practice >10 years ago, the last 2–3 years have shown a series of large clinical trials that clearly outlined the categories of patients that benefit of CRT. First of all, 3 landmark studies—REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE),2 Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT)3 and Resynchronization for Ambulatory Heart Failure Trial (RAFT)4—have been performed to investigate the effectiveness of CRT in HF patients with a wide QRS complex and mild symptoms (New York Heart Association [NYHA] class I–II), in which patients have been randomized to CRT-ON and CRT-OFF. The main findings were that REVERSE showed significant reverse remodeling, MADIT-CRT showed less hospitalization, and RAFT also showed significant reduction in mortality in the CRT arm. The CRT benefit shown in these studies is consistent with those from older studies performed in patients with more severe HF symptoms. Figure 1 displays that the increase in left ventricular (LV) ejection fraction (EF) by CRT is independent of baseline EF. Figure 1. Change in left ventricular ejection fraction after …

Usefulness of Echocardiographically Guided Left Ventricular Lead Placement for Cardiac Resynchronization Therapy in Patients With Intermediate QRS Width and Non–Left Bundle Branch Block Morphology

The current guidelines most strongly support cardiac resynchronization therapy (CRT) for patients with heart failure with a QRS width of ≥150 ms and left bundle branch block (LBBB). Our objective was to assess the potential benefit of echocardiographically guided left ventricular (LV) lead positioning for patients with a QRS width <150 ms or non-LBBB as a substudy of the Speckle Tracking Assisted Resynchronization Therapy for Electrode Region (STARTER) prospective, randomized controlled trial. The STARTER trial randomized 187 patients with heart failure, a QRS of ≥120 ms, and ejection fraction of ≤35% to LV lead guided to the site of latest mechanical activation by speckle tracking radial strain versus routine implantation. The predefined primary end point was heart failure hospitalization or death within 2 years. This substudy included 151 CRT patients with matching echocardiographic and LV lead position data and complete follow-up data. Patients with a QRS width of 120 to 149 ms or non-LBBB and LV lead concordant or adjacent to the site of latest mechanical activation had favorable outcomes after CRT similar to those with LBBB or a QRS width of ≥150 ms. In contrast, patients with a QRS of 120 to 149 ms or non-LBBB and remote LV leads had unfavorable outcomes (hazard ratio 5.45, 95% confidence interval 2.36 to 12.6, p <0.001, and hazard ratio 4.92, 95% confidence interval 2.12 to 11.39, p <0.001, respectively, with significant interaction after adjusting for baseline variables, p = 0.038 and p = 0.008). In conclusion, LV lead positioning with respect to the echocardiographic site of latest activation was significantly associated with more favorable clinical outcomes in patients with a QRS duration <150 ms and/or non-LBBB. Additional prospective study is warranted.

VT begets VT—and other bad stuff—in patients treated with CRT-D

Clinical trials have helped clarify the role of cardiac resynchronization therapy (CRT) in patients with heart failure. Early trials demonstrated reduction in mortality and heart failure hospitalization in patients with electrical dyssynchrony and moderate to severe functional impairment, and more recent trials showed that these benefits extend to heart failure patients even with mild symptoms. Most patients with a class 1 or 2 indication for CRT also have an appropriate indication for an implantable cardioverterdefibrillator (ICD) on the basis of the presence of ischemic or nonischemic cardiomyopathy, so the vast majority of CRT is delivered via a CRT with defibrillator (CRT-D). In fact, the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) study randomized 1820 patients with cardiomyopathy of any etiology with left ventricular ejection fraction ≤30%, QRS duration ≥130 ms, and mild heart failure (New York Heart Association class I or II) to either standard ICD or CRT-D, and it showed that CRT-D leads to improved outcome compared with ICD alone in this population. The MADIT-CRT study design has enabled the investigators to also examine the effect of CRT on ventricular arrhythmic events. In a recent report, this group showed that CRT-D was associated with a 29% reduction in the risk of a first episode of ventricular tachyarrhythmic events compared with ICD alone. Importantly, this arrhythmia risk reduction was not homogeneous across the entire study population. Among patients with left bundle branch block (LBBB), CRT-D conferred a 42% reduction in the risk of first arrhythmic event compared with standard ICD, but in nonLBBB patients, CRT-D provided no such advantage, a finding that mirrors the general lack of clinical response to CRT seen in non-LBBB patients. Conversely, one might wonder what effect arrhythmic events have on subsequent outcome in CRT-D treated patients compared with that in standard ICD recipients. In this issue of HeartRhythm, Kutyifa et al addresses this very question, once again taking the advantage of the rich database provided by the MADIT-CRT trial. These investigators sought to evaluate the prognostic value of ventricular tachyarrhythmias, categorized as slow ventricular tachycardia

Dyssynchrony and the Risk of Ventricular Arrhythmias

The aim of our study was to evaluate the relationship between left ventricular (LV) dyssynchrony and the risk of ventricular tachycardia (VT) or ventricular fibrillation (VF) in patients enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy) trial. Intraventricular mechanical dyssynchrony might be an important factor in ventricular arrhythmogenesis by enhancing electrical heterogeneity in heart failure patients. The effects of dyssynchrony have not yet been evaluated in a large cohort of implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy with defibrillator (CRT-D) patients. LV dyssynchrony was measured at baseline and at 12-months by speckle-tracking echocardiography, defined as the standard deviation of time to peak systolic strain in 12 LV myocardial segments. The endpoint was the first VT/VF/death or VT/VF. LV dyssynchrony was evaluated in 764 left bundle branch block (LBBB) patients and in 312 non-LBBB patients. Baseline LV dyssynchrony was not predictive of VT/VF/death or VT/VF in LBBB or non-LBBB patients in either treatment arm. In CRT-D patients with LBBB, improvement in LV dyssynchrony over a year was associated with significantly lower incidence of VT/VF/death (p < 0.001) and VT/VF (p < 0.001) compared to ICD patients and to CRT-D patients with unchanged or worsening dyssynchrony. Among LBBB patients, 15% decrease in LV dyssynchrony was associated with lower risk of VT/VF/death (hazard ratio: 0.49, 95% confidence interval: 0.24 to 0.99, p = 0.049) and VT/VF (hazard ratio: 0.30, 95% confidence interval: 0.12 to 0.77, p = 0.009) as compared to ICD patients. Patients without LBBB receiving CRT-D did not show reduction in VT/VF/death or in VT/VF in relation to improving dyssynchrony when evaluating cumulative event rates or risk of events. Baseline LV dyssynchrony did not predict VT/VF/death or VT/VF in mild heart failure patients with or without LBBB. CRT-induced improvement of LV dyssynchrony was associated with significant reduction of ventricular arrhythmias in patients with LBBB.

Differing effects of cardiac resynchronization therapy on long-term mortality in patient subgroups of MADIT-CRT defined by baseline conduction and 1-year post-treatment left ventricular remodeling

Long-term mortality data after cardiac resynchronization therapy with implanted defibrillator (CRT-D) in minimally symptomatic patients are limited. To clarify influences on long-term mortality after CRT-D, we assessed MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy) patient outcomes by baseline conduction abnormality and 1-year posttreatment remodeling. MADIT-CRT followed 1820 patients assigned to CRT-D or implanted cardioverter-defibrillator (ICD) only. Using Cox proportional hazards regression analysis, treatment effects (CRT-D vs ICD only) on mortality were evaluated in patients with left bundle branch block (LBBB) and non-LBBB. Among 1196 patients with echocardiography repeated at 1 year, effect of CRT-D on later mortality (landmark analysis) was analyzed by baseline conduction and 1-year change in left ventricular end-systolic volume (LVESV). Overall mortality was not reduced by CRT-D (hazard ratio [HR] for CRT-D/ICD only 0.94; P = .72). Among 761 patients with LBBB and CRT-D, mortality trended lower (HR 0.71; P = .10) after adjustment for clinical covariates. The effect of CRT-D on mortality was further evaluated in patients who did (responders) and did not (hypo-responders) have reduction in LVESV by ≥ 30%. LBBB responders (n = 323) had significantly reduced mortality with CRT-D (HR 0.36; P = .027), and LBBB hypo-responders (n = 182) did not (HR 0.99). By contrast, non-LBBB responders (n = 89) trended toward more deaths with CRT-D (HR 2.11; P = .22). Non-LBBB hypo-responders (n = 118) had significantly worsened mortality (HR 3.72; P =.011). In MADIT-CRT, late mortality with CRT-D varied markedly with baseline conduction defect and remodeling response. Patients with both LBBB and substantially reduced LVESV had improved mortality. Those with non-LBBB or with LBBB and less-reduced LVESV had unchanged or worsened mortality after CRT-D.