Eugene S. Chung

Results of the Predictors of Response to CRT (PROSPECT) Trial

Background— Data from single-center studies suggest that echocardiographic parameters of mechanical dyssynchrony may improve patient selection for cardiac resynchronization therapy (CRT). In a prospective, multicenter setting, the Predictors of Response to CRT (PROSPECT) study tested the performance of these parameters to predict CRT response. Methods and Results— Fifty-three centers in Europe, Hong Kong, and the United States enrolled 498 patients with standard CRT indications (New York Heart Association class III or IV heart failure, left ventricular ejection fraction ≤35%, QRS ≥130 ms, stable medical regimen). Twelve echocardiographic parameters of dyssynchrony, based on both conventional and tissue Doppler–based methods, were evaluated after site training in acquisition methods and blinded core laboratory analysis. Indicators of positive CRT response were improved clinical composite score and ≥15% reduction in left ventricular end-systolic volume at 6 months. Clinical composite score was improved in 69% of 426 patients, whereas left ventricular end-systolic volume decreased ≥15% in 56% of 286 patients with paired data. The ability of the 12 echocardiographic parameters to predict clinical composite score response varied widely, with sensitivity ranging from 6% to 74% and specificity ranging from 35% to 91%; for predicting left ventricular end-systolic volume response, sensitivity ranged from 9% to 77% and specificity from 31% to 93%. For all the parameters, the area under the receiver-operating characteristics curve for positive clinical or volume response to CRT was ≤0.62. There was large variability in the analysis of the dyssynchrony parameters. Conclusion— Given the modest sensitivity and specificity in this multicenter setting despite training and central analysis, no single echocardiographic measure of dyssynchrony may be recommended to improve patient selection for CRT beyond current guidelines. Efforts aimed at reducing variability arising from technical and interpretative factors may improve the predictive power of these echocardiographic parameters in a broad clinical setting.

Characteristics of heart failure patients associated with good and poor response to cardiac resynchronization therapy: a PROSPECT (Predictors of Response to CRT) sub-analysis

AIMS Predictors of Response to Cardiac Resynchronization Therapy (CRT) (PROSPECT) was the first large-scale, multicentre clinical trial that evaluated the ability of several echocardiographic measures of mechanical dyssynchrony to predict response to CRT. Since response to CRT may be defined as a spectrum and likely influenced by many factors, this sub-analysis aimed to investigate the relationship between baseline characteristics and measures of response to CRT. METHODS AND RESULTS A total of 286 patients were grouped according to relative reduction in left ventricular end-systolic volume (LVESV) after 6 months of CRT: super-responders (reduction in LVESV > or =30%), responders (reduction in LVESV 15-29%), non-responders (reduction in LVESV 0-14%), and negative responders (increase in LVESV). In addition, three subgroups were formed according to clinical and/or echocardiographic response: +/+ responders (clinical improvement and a reduction in LVESV > or =15%), +/- responders (clinical improvement or a reduction in LVESV > or =15%), and -/- responders (no clinical improvement and no reduction in LVESV > or =15%). Differences in clinical and echocardiographic baseline characteristics between these subgroups were analysed. Super-responders were more frequently females, had non-ischaemic heart failure (HF), and had a wider QRS complex and more extensive mechanical dyssynchrony at baseline. Conversely, negative responders were more frequently in New York Heart Association class IV and had a history of ventricular tachycardia (VT). Combined positive responders after CRT (+/+ responders) had more non-ischaemic aetiology, more extensive mechanical dyssynchrony at baseline, and no history of VT. CONCLUSION Sub-analysis of data from PROSPECT showed that gender, aetiology of HF, QRS duration, severity of HF, a history of VT, and the presence of baseline mechanical dyssynchrony influence clinical and/or LV reverse remodelling after CRT. Although integration of information about these characteristics would improve patient selection and counselling for CRT, further randomized controlled trials are necessary prior to changing the current guidelines regarding patient selection for CRT.

Cardiac resynchronization therapy may benefit patients with left ventricular ejection fraction >35%: a PROSPECT trial substudy.

Cardiac resynchronization therapy (CRT) is currently limited to those with left ventricular ejection fraction (LVEF) ≤35%. To evaluate whether patients with LVEF >35% might benefit from CRT, we performed a retrospective analysis of the predictors of response to CRT (PROSPECT) database.

Effects of cardiac resynchronisation therapy in patients with heart failure having a narrow QRS Complex enrolled in PROSPECT

Introduction Current guidelines recommend cardiac resynchronisation therapy (CRT) in patients with severe symptomatic heart failure, depressed left ventricular (LV) systolic function and a wide QRS complex (≥120 ms). However, patients with heart failure having a narrow QRS complex might also benefit from CRT. Design setting patients interventions During the Predictors of Response to Cardiac Resynchronisation Therapy (PROSPECT) trial, 41 patients were enrolled in a ‘narrow’ QRS sub-study. These patients had a QRS complex <130 ms, but documented evidence of mechanical dyssynchrony by any of seven pre-defined echocardiographic measures. Results After 6 months of CRT, 26 (63.4%) patients showed improvement according to the Clinical Composite Score, 4 (9.8%) remained unchanged and 11 (26.8%) worsened. In patients with paired data, the 6-min walking distance increased from 334±118 m to 382±128 m, (p=0.003) and quality-of-life score improved from 44.2±19.7 to 26.8±20.2 (p<0.0001). Furthermore, there was a significant decrease in LV end-systolic diameter (from 59±9 to 55±12 mm, p=0.002) and in LV end-diastolic diameter (from 67±9 to 63±11 mm, p=0.007). Conclusion The results suggest that CRT may have a beneficial effect in heart failure patients with a narrow QRS complex and mechanical dyssynchrony as assessed by echocardiography. The majority of patients improved on clinical symptoms, and there was an evident reduction in LV diameters. Larger studies are needed to clearly define selection criteria for CRT in patients with a narrow QRS complex.

Clinical response with adaptive CRT algorithm compared with CRT with echocardiography- optimized atrioventricular delay: a retrospective analysis of multicentre trials

AIMS Adaptive cardiac resynchronization therapy (aCRT) is a novel algorithm for CRT pacing that provides automatic ambulatory selection between synchronized left ventricular (LV) or bi-ventricular (BiV) pacing and optimization of atrioventricular (AV) and inter-ventricular (VV) delays based on periodic measurement of intrinsic conduction. We aimed to compare the clinical response between aCRT and standard CRT in historical trials. METHODS AND RESULTS The treatment arm of the aCRT trial was compared with a pooled historical control (HC) derived from the CRT arms of four clinical trials (MIRACLE, MIRACLE ICD, PROSPECT, and InSync III Marquis) with respect to the proportion of patients who had an improved clinical composite score (CCS) at the 6-month follow-up. Patients in the HC underwent echocardiography-guided AV optimization after the implant. A propensity score model was used to adjust for 22 potential baseline confounders of the effect of CRT. Patients were stratified into quintiles according to the propensity score and the adjusted absolute treatment effect was obtained by averaging estimates across these quintiles. The propensity score model included 751 patients (aCRT: 266, historical trials: 485). The adjusted absolute difference in percent improved in CCS between the aCRT and HC arms was 11.9% [95% confidence interval (CI): 2.7-19.2%] favouring aCRT. The patients in the aCRT group were significantly more likely to have an improved CCS than the patients in the HC (odds ratio = 1.65, 95% CI: 1.1-2.5). CONCLUSION The aCRT algorithm may be associated with additional improvement in clinical response compared with historical CRT with echocardiographic AV optimization.

Peri-infarct zone pacing to prevent adverse left ventricular remodelling in patients with large myocardial infarction

AIMS We sought to determine whether peri-infarct pacing prevents left ventricular (LV) remodelling and improves functional and clinical outcomes in patients with large first myocardial infarction (MI). METHODS AND RESULTS A total of 126 patients at 27 international sites within 10 days of onset of anterior or non-anterior MI with creatine phosphokinase >3000 U/L and QRS duration ≤120 ms were randomized 1:1:1 to dual-site biventricular pacing vs. single-site LV only pacing vs. non-implanted control. The primary endpoint was the echocardiographic core laboratory-assessed change in LV end-diastolic volume (ΔLVEDV) from baseline to 18 months between the pooled pacing therapy groups and the control group. ΔLVEDV increased by 15.3 ± 28.6 mL in the control group and by 16.7 ± 30.5 mL in the pooled pacing groups during follow-up (adjusted mean difference (95% CI) = 0.6 (-12.3, 13.5) mL, P = 0.92). There were also no significant between-group differences in the change in LV end-systolic volume or ejection fraction over time. Quality of life, as assessed by the Minnesota Living with Heart Failure (HF) and European Quality of Life-5 Dimension questionnaires and New York Heart Association class, was also similar between groups during 18-month follow-up. Six-minute walk distance improved during follow-up to an equal degree between groups, and there were no significant differences in the 18-month rates of death or HF hospitalization between the pooled pacing therapy vs. control groups (17.4 vs. 21.7% respectively, P = 0.59). CONCLUSIONS In the present multicentre, randomized trial, peri-infarct pacing did not prevent LV remodelling or improve functional or clinical outcomes during 18-month follow-up in patients with large first MI. CLINICALTRIALSGOV IDENTIFIER NCT01213251.

The Post–Myocardial Infarction Pacing Remodeling Prevention Therapy (PRomPT) Trial: Design and Rationale

BACKGROUND Despite considerable improvements in the medical management of patients with myocardial infarction (MI), patients with large MI still have substantial risk of developing heart failure. In the early post-MI setting, implantable cardioverter defibrillators have reduced arrhythmic deaths but have no impact on overall mortality. Therefore, additional interventions are required to further reduce the overall morbidity and mortality of patients with large MI. METHODS The Pacing Remodeling Prevention Therapy (PRomPT) trial is designed to study the effects of peri-infarct pacing in preventing adverse post-MI remodeling. Up to 120 subjects with peak creatine phosphokinase >3,000 U/L (or troponin T >10 μg/L) at time of MI will be randomized to either dual-site or single-site biventricular pacing with the left ventricular lead implanted in a peri-infarct region or to a nonimplanted control group. Those randomized to a device will be blinded to the pacing mode, but randomization to a device or control cannot be blinded. Subjects randomized to pacing will have the device implanted within 10 days of MI. The primary objective is to assess the change in left ventricular end-diastolic volume from baseline to 18 months. Secondary objectives are to assess changes in clinical and mechanistic parameters between the groups, including rates of hospitalization for heart failure and cardiovascular events, the incidence of sudden cardiac death and all-cause mortality, New York Heart Association functional class, 6-minute walking distance, and quality of life. CONCLUSIONS The PRomPT trial will provide important evidence regarding the potential of peri-infarct pacing to interrupt adverse remodeling in patients with large MI.

Predictors of Left Ventricular Remodeling After Myocardial Infarction in Patients With a Patent Infarct Related Coronary Artery After Percutaneous Coronary Intervention (from the Post-Myocardial Infarction Remodeling Prevention Therapy [PRomPT] Trial)

Left ventricular (LV) remodeling after myocardial infarction (MI) is a strong predictor of heart failure and mortality. The predictors of long-term remodeling after MI have been incompletely studied. We therefore examined the correlates of LV remodeling in patients with large ST-segment elevation myocardial infarction and a patent infarct artery after percutaneous 2coronary intervention (PCI) from the randomized Post-Myocardial Infarction Remodeling Prevention Therapy trial. Peri-infarct pacing had a neutral effect on long-term remodeling in patients with large first MI. The present analysis includes 109 patients in whom an open artery was restored after PCI, and in whom LV end-diastolic volume (LVEDV) at baseline and 18 months was assessed by transthoracic echocardiography. Multivariable models were fit to identify the independent predictors of LVEDV at baseline and 18 months. By multivariable analysis, male sex (p = 0.004) and anterior MI location (p = 0.03) were independently associated with baseline LVEDV. The following variables were independent predictors of increased LVEDV at 18 months: younger age (p = 0.01), male sex (p = 0.03), peak creatine phosphokinase (p = 0.03), shorter time from MI to baseline transthoracic echocardiography (p = 0.04), baseline LVEDV (p < 0.0001), and lack of statin use (p = 0.03). In conclusion, patients with large MI and an open infarct artery after PCI, anterior MI location, and male sex were associated with greater baseline LVEDV, but MI location was not associated with 18-month LVEDV. In contrast, younger age, peak creatine phosphokinase, male sex, baseline LVEDV, and lack of statin use were associated with long-term LV remodeling.