Scott McNitt

Mortality Reduction in Relation to Implantable Cardioverter Defibrillator Programming in the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT)

Background —The benefit of novel ICD programming in reducing inappropriate ICD therapy and mortality was demonstrated in MADIT-RIT. However, the cause of the mortality reduction remains incompletely evaluated. We aimed to identify factors associated with mortality, with focus on ICD therapy and programming in the MADIT-RIT population. Methods and Results —In MADIT-RIT, 1500 patients with a primary prophylactic indication for ICD or CRT-D were randomized to one of three different ICD programming arms: conventional programming (VT-zone ≥170 bpm); high-rate programming (VT-zone ≥200 bpm); and delayed programming (60 sec. delay before therapy≥170 bpm). Multivariate Cox models were used to assess the influence of time-dependent appropriate and inappropriate ICD therapy (shock and/or antitachycardia pacing [ATP]) and randomized programming arm on all-cause mortality. During an average follow-up of 1.4±0.6 years, 71 of 1500 (5%) patients died: cardiac in 40 patients (56.3 %), non-cardiac in 23 patients (32.4%), and unknown in 8 patients (11.3%). Appropriate shocks (Hazard Ratio [HR] = 6.32 [95% CI: 3.13-12.75], p<0.001) and inappropriate therapy (HR=2.61 [1.28-5.31], p=0.01) were significantly associated with an increased mortality risk. There was no evidence of increased mortality risk in patients who experienced appropriate ATP only (HR=1.02 [0.36-2.88], p=0.98). Randomization to conventional programming was identified as an independent predictor of death when compared to patients randomized to high-rate programming (HR=2.0 [1.06-3.71], p=0.03). Conclusions —In the MADIT-RIT trial, appropriate shocks, inappropriate ICD therapy, and randomization to conventional ICD programming were independently associated with an increased mortality risk. Appropriate ATP was not related to an adverse outcome. Clinical Trial Registration —clinicaltrials.gov; Unique Identifier: [NCT00947310][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00947310&atom=%2Fcircae%2Fearly%2F2014%2F08%2F17%2FCIRCEP.114.001623.atomBackground—The benefit of novel implantable cardioverter defibrillator (ICD) programming in reducing inappropriate ICD therapy and mortality was demonstrated in Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT). However, the cause of mortality reduction remains incompletely evaluated. We aimed to identify factors associated with mortality, with focus on ICD therapy and programming in the MADIT-RIT population. Methods and Results—In MADIT-RIT, 1500 patients with a primary prophylactic indication for ICD or cardiac resynchronization therapy with defibrillator were randomized to 1 of 3 different ICD programming arms: conventional programming (ventricular tachycardia zone ≥170 beats per minute), high-rate programming (ventricular tachycardia zone ≥200 beats per minute), and delayed programming (60-second delay before therapy ≥170 beats per minute). Multivariate Cox models were used to assess the influence of time-dependent appropriate and inappropriate ICD therapy (shock and antitachycardia pacing) and randomized programming arm on all-cause mortality. During an average follow-up of 1.4±0.6 years, 71 of 1500 (5%) patients died: cardiac in 40 patients (56.3%), noncardiac in 23 patients (32.4%), and unknown in 8 patients (11.3%). Appropriate shocks (hazard ratio, 6.32; 95% confidence interval, 3.13–12.75; P<0.001) and inappropriate therapy (hazard ratio, 2.61; 95% confidence interval, 1.28–5.31; P=0.01) were significantly associated with an increased mortality risk. There was no evidence of increased mortality risk in patients who experienced appropriate antitachycardia pacing only (hazard ratio, 1.02; 95% confidence interval, 0.36–2.88; P=0.98). Randomization to conventional programming was identified as an independent predictor of death when compared with patients randomized to high-rate programming (hazard ratio, 2.0; 95% confidence interval, 1.06–3.71; P=0.03). Conclusions—In MADIT-RIT, appropriate shocks, inappropriate ICD therapy, and randomization to conventional ICD programming were independently associated with an increased mortality risk. Appropriate antitachycardia pacing was not related to an adverse outcome. Clinical Trial Registration—URL: clinicaltrials.gov Unique identifier: NCT00947310.

Dyssynchrony, Contractile Function, and Response to Cardiac Resynchronization Therapy

Background—Despite benefits of cardiac resynchronization therapy (CRT) in patients with severe but less symptomatic heart failure, approximately 30% of patients do not fully respond to treatment. We hypothesized that a combined assessment of left ventricular (LV) dyssynchrony and contractile function by strain-based imaging would identify patients who would most benefit from CRT. Methods and Results—We studied 1077 patients with New York Heart Association class I/II, LV ejection fraction ⩽30% and QRS width ≥130 ms enrolled in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy trial with sufficient echocardiographic image quality for cardiac deformation analysis (implantable cardioverter-defibrillator [ICD], n=416; CRT, n=661). Patients were assigned to CRT plus an ICD or to ICD alone in 3:2 random assignment. We assessed the degree to which baseline echocardiographic assessments of dyssynchrony, measured as the standard deviation of time-to-peak transverse strain over 12 segments, contractile function, measured as global longitudinal strain, or both predicted the effect of treatment on the primary outcome of death or heart failure. With 213 primary events occurring over a mean of 2.4 years, the benefit of CRT plus an ICD relative to ICD alone was greatest in patients with mild to moderate dyssynchrony (time-to-peak transverse strain standard deviation, 142 to 230 ms) and greater baseline contractile function (global longitudinal strain ⩽−8.7%). Overall, those patients with mild to moderate dyssynchrony and those with best contractile function at baseline demonstrated the greatest benefit from CRT (adjusted hazards ratio, 0.20; 95% confidence interval, 0.09 to 0.44). Dyssynchrony and global longitudinal strain predicted response to CRT independent of each other, QRS width, LV ejection fraction, and presence versus absence of left bundle-branch block, although the observed benefit remained greatest in patients with left bundle-branch block. Conclusions—Both mechanical dyssynchrony and contractile function are important independent correlates of benefit from CRT. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.