BACKGROUND Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in chronic systolic heart failure with a wide QRS complex. Mechanical dyssynchrony also occurs in patients with a narrow QRS complex, which suggests the potential usefulness of CRT in such patients. METHODS We conducted a randomized trial involving 115 centers to evaluate the effect of CRT in patients with New York Heart Association class III or IV heart failure, a left ventricular ejection fraction of 35% or less, a QRS duration of less than 130 msec, and echocardiographic evidence of left ventricular dyssynchrony. All patients underwent device implantation and were randomly assigned to have CRT capability turned on or off. The primary efficacy outcome was the composite of death from any cause or first hospitalization for worsening heart failure. RESULTS On March 13, 2013, the study was stopped for futility on the recommendation of the data and safety monitoring board. At study closure, the 809 patients who had undergone randomization had been followed for a mean of 19.4 months. The primary outcome occurred in 116 of 404 patients in the CRT group, as compared with 102 of 405 in the control group (28.7% vs. 25.2%; hazard ratio, 1.20; 95% confidence interval [CI], 0.92 to 1.57; P = 0.15). There were 45 deaths in the CRT group and 26 in the control group (11.1% vs. 6.4%; hazard ratio, 1.81; 95% CI, 1.11 to 2.93; P = 0.02). CONCLUSIONS In patients with systolic heart failure and a QRS duration of less than 130 msec, CRT does not reduce the rate of death or hospitalization for heart failure and may increase mortality. (Funded by Biotronik and GE Healthcare; EchoCRT ClinicalTrials.gov number, NCT00683696.)

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Cardiac-Resynchronization Therapy in Heart Failure with a Narrow QRS Complex

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 …

Cardiac resynchronization therapy: state-of-the-art of current applications, guidelines, ongoing trials, and areas of controversy.

Background—Although the benefits of cardiac resynchronization therapy are well established in selected patients with heart failure and a prolonged QRS duration, salutary effects in patients with narrow QRS complexes remain to be demonstrated. Methods and Results—The Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) trial is a randomized, double-blind, 12-center study that was designed to compare the effects of active and inactive cardiac resynchronization therapy in patients with severe left ventricular dysfunction and a QRS duration <120 milliseconds. The trial was interrupted prematurely by the Data Safety and Monitoring Board because of futility and safety concerns after 85 patients were randomized. Changes in exercise duration after 12 months were no different in patients with and without active cardiac resynchronization therapy (−0.7 minutes [95% confidence interval (CI), −2.9 to 1.5] versus 0.8 minutes [95% CI, −1.2 to 2.9]; P=0.31]. Similarly, no significant differences were ...

Cardiac Resynchronization Therapy in Patients With Heart Failure and a QRS Complex <120 Milliseconds The Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) Trial

Background— 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.

Methods and Results— 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.

Conclusions— 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.

Clinical Trial Registration— ; Unique Identifier: [NCT00180271][1].

 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00180271&atom=%2Fcircae%2F7%2F4%2F645.atom

PR Interval Identifies Clinical Response in Patients With Non–Left Bundle Branch Block A Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy Substudy

Effect of QRS Morphology on Clinical Event Reduction With Cardiac Resynchronization Therapy: Meta-Analysis of Randomized Controlled Trials

Previous studies suggest that CRT may benefit narrow QRS patients with mechanical dyssynchrony (MD). We conducted an acute and chronic study, evaluating the response of heart failure patients with a narrow QRS to cardiac resynchronization therapy (CRT). ESTEEM-CRT was a multi-center, single-arm, feasibility study that evaluated ICD-indicated, medically-optimized patients with EF ≤ 35%, NYHA class III heart failure, QRS duration <120 ms, and MD as defined by the standard deviation of time to peak systolic velocity of 12 segments (Ts-SD). Sixty-eight patients received a CRT defibrillator, exercise testing, and echo exams, and 47 of these patients underwent invasive hemodynamic testing at implant. Follow-up was at 6 and 12 months. The average maximal improvement in LV dP/dtmax was minor (2 ± 2%). NYHA and quality of life scores were substantially improved at 6 and 12 months (P < 0.001), while exercise capacity and LV volumes were unchanged. The echo indices of MD were difficult to collect, discordant, and failed to predict clinical outcomes. ESTEEM-CRT patients with a narrow QRS and MD as defined in this study did not improve as measured by acute hemodynamics, chronic exercise performance, or reverse remodeling. These multi-center results support the notion that dyssynchrony indices are ineffective or at least require greater refinement for the selection of narrow QRS patients for CRT.

Tim Donahue

Papers

Acute and Chronic Response to CRT in Narrow QRS Patients

Acute Change in Dyssynchrony Indices before and after CRT in Heart Failure Patients with Narrow QRS from a Multi-Center Study: ESTEEM-CRT