Angel R. Leon

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.

Effect of Cardiac Resynchronization Therapy on Left Ventricular Size and Function in Chronic Heart Failure

Background—Cardiac resynchronization therapy (CRT) has recently emerged as an effective treatment for patients with moderate to severe systolic heart failure and ventricular dyssynchrony. The purpose of the present study was to determine whether improvements in left ventricular (LV) size and function were associated with CRT. Methods and Results—Doppler echocardiograms were obtained at baseline and at 3 and 6 months after therapy in 323 patients enrolled in the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial. Of these, 172 patients were randomized to CRT on and 151 patients to CRT off. Measurements were made of LV end-diastolic and end-systolic volumes, ejection fraction, LV mass, severity of mitral regurgitation (MR), peak transmitral velocities during early (E-wave) and late (A-wave) diastolic filling, and the myocardial performance index. At 6 months, CRT was associated with reduced end-diastolic and end-systolic volumes (both P <0.001), reduced LV mass (P <0.01), increased ejection fraction (P <0.001), reduced MR (P <0.001), and improved myocardial performance index (P <0.001) compared with control. &bgr;-Blocker treatment status did not influence the effect of CRT. Improvements with CRT were greater in patients with a nonischemic versus ischemic cause of heart failure. Conclusions—CRT in patients with moderate-to-severe heart failure who were treated with optimal medical therapy is associated with reverse LV remodeling, improved systolic and diastolic function, and decreased MR. LV remodeling likely contributes to the symptomatic benefits of CRT and may herald improved longer-term survival.

Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure

Background—The effects of cardiac resynchronization therapy (CRT) in patients with mildly symptomatic heart failure have not been fully elucidated. Methods and Results—The Multicenter InSync ICD Randomized Clinical Evaluation II (MIRACLE ICD II) was a randomized, double-blind, parallel-controlled clinical trial of CRT in NYHA class II heart failure patients on optimal medical therapy with a left ventricular (LV) ejection fraction ≤35%, a QRS ≥130 ms, and a class I indication for an ICD. One hundred eighty-six patients were randomized: 101 to the control group (ICD activated, CRT off) and 85 to the CRT group (ICD activated, CRT on). End points included peak &OV0312;o2, &OV0312;e/&OV0312;co2, NYHA class, quality of life, 6-minute walk distance, LV volumes and ejection fraction, and composite clinical response. Compared with the control group at 6 months, no significant improvement was noted in peak &OV0312;o2, yet there were significant improvements in ventricular remodeling indexes, specifically LV diastolic and systolic volumes (P=0.04 and P=0.01, respectively), and LV ejection fraction (P=0.02). CRT patients showed statistically significant improvement in &OV0312;e/&OV0312;co2 (P=0.01), NYHA class (P=0.05), and clinical composite response (P=0.01). No significant differences were noted in 6-minute walk distance or quality of life scores. Conclusions—In patients with mild heart failure symptoms on optimal medical therapy with a wide QRS complex and an ICD indication, CRT did not alter exercise capacity but did result in significant improvement in cardiac structure and function and composite clinical response over 6 months.

Safety and Efficacy of a Totally Subcutaneous Implantable-Cardioverter Defibrillator

Background— The most frequent complications associated with implantable cardioverter-defibrillators (ICDs) involve the transvenous leads. A subcutaneous implantable cardioverter-defibrillator (S-ICD) has been developed as an alternative system. This study evaluated the safety and effectiveness of the S-ICD System (Cameron Health/Boston Scientific) for the treatment of life-threatening ventricular arrhythmias (ventricular tachycardia/ventricular fibrillation). Methods and Results— This prospective, nonrandomized, multicenter trial included adult patients with a standard indication for an ICD, who neither required pacing nor had documented pace-terminable ventricular tachycardia. The primary safety end point was the 180-day S-ICD System complication-free rate compared with a prespecified performance goal of 79%. The primary effectiveness end point was the induced ventricular fibrillation conversion rate compared with a prespecified performance goal of 88%, with success defined as 2 consecutive ventricular fibrillation conversions of 4 attempts. Detection and conversion of spontaneous episodes were also evaluated. Device implantation was attempted in 321 of 330 enrolled patients, and 314 patients underwent successful implantation. The cohort was followed for a mean duration of 11 months. The study population was 74% male with a mean age of 52±16 years and mean left ventricular ejection fraction of 36±16%. A previous transvenous ICD had been implanted in 13%. Both primary end points were met: The 180-day system complication-free rate was 99%, and sensitivity analysis of the acute ventricular fibrillation conversion rate was >90% in the entire cohort. There were 38 discrete spontaneous episodes of ventricular tachycardia/ventricular fibrillation recorded in 21 patients (6.7%), all of which successfully converted. Forty-one patients (13.1%) received an inappropriate shock. Conclusions— The findings support the efficacy and safety of the S-ICD System for the treatment of life-threatening ventricular arrhythmias. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01064076.

Safety and Efficacy of the Totally Subcutaneous Implantable Defibrillator: 2-Year Results From a Pooled Analysis of the IDE Study and EFFORTLESS Registry

BACKGROUND The entirely subcutaneous implantable cardioverter-defibrillator (S-ICD) is the first implantable defibrillator that avoids placing electrodes in or around the heart. Two large prospective studies (IDE [S-ICD System IDE Clinical Investigation] and EFFORTLESS [Boston Scientific Post Market S-ICD Registry]) have reported 6-month to 1-year data on the S-ICD. OBJECTIVES The objective of this study was to evaluate the safety and efficacy of the S-ICD in a large diverse population. METHODS Data from the IDE and EFFORTLESS studies were pooled. Shocks were independently adjudicated, and complications were measured with a standardized classification scheme. Enrollment date quartiles were used to assess event rates over time. RESULTS Eight hundred eighty-two patients who underwent implantation were followed for 651±345 days. Spontaneous ventricular tachyarrhythmia (VT)/ventricular fibrillation (VF) events (n=111) were treated in 59 patients; 100 (90.1%) events were terminated with 1 shock, and 109 events (98.2%) were terminated within the 5 available shocks. The estimated 3-year inappropriate shock rate was 13.1%. Estimated 3-year, all-cause mortality was 4.7% (95% confidence interval: 0.9% to 8.5%), with 26 deaths (2.9%). Device-related complications occurred in 11.1% of patients at 3 years. There were no electrode failures, and no S-ICD-related endocarditis or bacteremia occurred. Three devices (0.3%) were replaced for right ventricular pacing. The 6-month complication rate decreased by quartile of enrollment (Q1: 8.9%; Q4: 5.5%), and there was a trend toward a reduction in inappropriate shocks (Q1: 6.9% Q4: 4.5%). CONCLUSIONS The S-ICD demonstrated high efficacy for VT/VF. Complications and inappropriate shock rates were reduced consistently with strategic programming and as operator experience increased. These data provide further evidence for the safety and efficacy of the S-ICD. (Boston Scientific Post Market S-ICD Registry [EFFORTLESS]; NCT01085435; S-ICD® System IDE Clinical Study; NCT01064076).

Agreement Is Poor Among Current Criteria Used to Define Response to Cardiac Resynchronization Therapy

Background— Numerous criteria believed to define a positive response to cardiac resynchronization therapy have been used in the literature. No study has investigated agreement among these response criteria. We hypothesized that the agreement among the various response criteria would be poor. Methods and Results— A literature search was conducted with the keywords “cardiac resynchronization” and “response.” The 50 publications with the most citations were reviewed. After the exclusion of editorials and reviews, 17 different primary response criteria were identified from 26 relevant articles. The agreement among 15 of these 17 response criteria was assessed in 426 patients from the Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) study with Cohens &kgr;-coefficient (2 response criteria were not calculable from PROSPECT data). The overall response rate ranged from 32% to 91% for the 15 response criteria. Ninety-nine percent of patients showed a positive response according to at least 1 of the 15 criteria, whereas 94% were classified as a nonresponder by at least 1 criterion. &kgr;-Values were calculated for all 105 possible comparisons among the 15 response criteria and classified into standard ranges: Poor agreement (&kgr;≤0.4), moderate agreement (0.4<&kgr;<0.75), and strong agreement (&kgr;≥0.75). Seventy-five percent of the comparisons showed poor agreement, 21% showed moderate agreement, and only 4% showed strong agreement. Conclusions— The 26 most-cited publications on predicting response to cardiac resynchronization therapy define response using 17 different criteria. Agreement between different methods to define response to cardiac resynchronization therapy is poor 75% of the time and strong only 4% of the time, which severely limits the ability to generalize results over multiple studies.

New-Onset Atrial Fibrillation Predicts Long-Term Mortality After Coronary Artery Bypass Graft

OBJECTIVES We sought to investigate the association between new-onset atrial fibrillation after coronary artery bypass graft (CABG) (post-operative atrial fibrillation [POAF]) and long-term mortality in patients with no history of atrial fibrillation. BACKGROUND POAF predicts longer hospital stay and greater post-operative mortality. METHODS A total of 16,169 consecutive patients with no history of AF who underwent isolated CABG at our institution between January 1, 1996, and December 31, 2007, were included in the study. All-cause mortality data were obtained from Social Security Administration death records. A multivariable Cox proportional hazards regression model was constructed to determine the independent impact of new-onset POAF on long-term survival after adjusting for several covariates. The covariates included age, sex, race, pre-operative risk factors (ejection fraction, New York Heart Association functional class, history of myocardial infarction, index myocardial infarction, stroke, chronic obstructive pulmonary disease, peripheral arterial disease, smoking, diabetes, renal failure, hypertension, dyslipidemia, creatinine level, dialysis, redo surgery, elective versus emergent CABG, any valvular disorder) and post-operative adverse events (stroke, myocardial infarction, acute respiratory distress syndrome, and renal failure), and discharge cardiac medications known to affect survival in patients with coronary disease. RESULTS New-onset AF occurred in 2,985 (18.5%) patients undergoing CABG. POAF independently predicted long-term mortality (hazard ratio: 1.21; 95% confidence interval: 1.12 to 1.32) during a mean follow-up of 6 years (range 0 to 12.5 years). This association remained true after excluding from the analysis those patients who died in-hospital after surgery (hazard ratio: 1.21; 95% confidence interval: 1.11 to 1.32). Patients with POAF discharged on warfarin experienced reduced mortality during follow-up. CONCLUSIONS In this large cohort of patients, POAF predicted long-term mortality. Warfarin anticoagulation may improve survival in POAF.

Renal insufficiency and the risk of infection from pacemaker or defibrillator surgery.

Background: Pacemakers and implanted cardioverter defibrillator (ICD) infection rates are rising. Renal insufficiency impairs immune function and is known to increase the risk of infection following implantation of orthopedic hardware. The purpose of the current study is to characterize the risk factors for pacemaker and ICD infection and to evaluate the role of renal insufficiency in this complication.

Differentiation of hypertrophic cardiomyopathy and cardiac amyloidosis from other causes of ventricular wall thickening by two-dimensional strain imaging echocardiography.

Hypertension is the most common cause of left ventricular (LV) hypertrophy. However, multiple causes can lead to LV hypertrophy, each of which has different histological and mechanical properties. To assess the value of a novel speckle-tracking echocardiographic measurement of myocardial strain and strain rate in defining the mechanical properties of LV hypertrophy, 20 patients with asymmetric hypertrophic cardiomyopathy, 24 patients with secondary LV hypertrophy, 12 patients with biopsy-proved confirmed cardiac amyloidosis, and 22 age-matched healthy asymptomatic volunteers were studied. Patients with amyloidosis had severe diastolic dysfunction, and myocardial deformation was significantly decreased. The new technique allowed cardiac amyloid to be easily differentiated from the other categories. In patients with hypertrophic cardiomyopathy, there was segmental myocardium dysfunction as assessed by strain imaging. LV global systolic velocity and radial displacement were higher, and abnormal relaxation was more frequent, in the group with secondary LV hypertrophy than in normal controls. In conclusion, the observations from strain parameters derived from speckle tracking were consistent with the known underlying pathology of each condition, which speaks to the value of strain imaging. Cardiac amyloid profoundly alters all strain parameters, and analysis of these parameters could aid in the diagnosis.

A Comparison of Ventricular Function During High Right Ventricular Septal and Apical Pacing after His-Bundle Ablation for Refractory Atrial Fibrillation

This study compares LV performance during high right ventricular septal (RVS) and apical (RVA) pacing in patients with LV dysfunction who underwent His‐bundle ablation for chronic AF. We inserted a passive fixation pacing electrode into the RVA and an active fixation electrode in the RVS. A dual chamber, rate responsive pulse generator stimulated the RVA through the ventricular port and the RVS via the atrial port. Patients were randomized to initial RVA (VVIR) or RVS (AAIR) pacing for 2 months. The pacing site was reversed during the next 2 months. At the 2 and 4 month follow‐up visit, each patient underwent a transthoracic echocardiographical study and a rest/exercise first pass radionuclide ventriculogram. We studied nine men and three women (mean age of 68 ± 7 years) with congestive heart failure functional Class (NYHA Classification): I (3 patients), II (7 patients), and III (2 patients). The QRS duration was shorter during RVS stimulation (158 ± 10vs 170 ± 11 ms, P < 0.001). Chronic capture threshold and lead impedance did not significantly differ. LV fractional shortening improved during RVS pacing (0.31 ± 0.05 vs 0.26 ± 0.07, P < 0.01). RVS activation increased the resting first pass LV ejection fraction (0.51 ± 0.14 vs 0.43 ± 0.10, P < 0.01). No significant difference was observed during RVS and RVA pacing in the exercise time (5.6 ± 3.2 vs 5.4 ± 3.1, P = 0.6) or the exercise first pass LV ejection fraction (0.58 ± 0.15 vs 0.55 ± 0.16, P = 0.2). The relative changes in QRS duration and LV ejection fraction at both pacing sites showed a significant correlation (P < 0.01). We conclude that RVS pacing produces shorter QRS duration and better chronic LV function than RVA pacing in patients with mild to moderate LV dysfunction and chronic AF after His‐bundle ablation.