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(MADIT-RIT) trial showed a significant reduction in inappropriate implantable cardioverter defibrillator (ICD) therapy in patients programmed to high-rate cut-off (Arm B) or delayed ventricular tachycardia therapy (Arm C), compared with conventional programming (Arm A). There is limited data on the effect of cardiac resynchronization therapy with a cardioverter defibrillator (CRT-D) on the effect of ICD programming. We aimed to elucidate the effect of CRT-D on ICD programming to reduce inappropriate ICD therapy in patients implanted with CRT-D or an ICD, enrolled in MADIT-RIT. METHODS AND RESULTS: The primary end point of this study was the first inappropriate ICD therapy. Secondary end points were inappropriate anti-tachycardia pacing and inappropriate ICD shock. The study enrolled 742 (49%) patients with an ICD and 757 (51%) patients with a CRT-D. Patients implanted with a CRT-D had 62% lower risk of inappropriate ICD therapy than those with an ICD only (hazard ratio [HR] =0.38, 95% confidence interval: 0.25-0.57; P<0.001). High-rate cut-off or delayed ventricular tachycardia therapy programming significantly reduced the risk of inappropriate ICD therapy compared with conventional ICD programming in ICD (HR=0.14 [B versus A]; HR=0.21 [C versus A]) and CRT-D patients (HR=0.15 [B versus A]; HR=0.23 [C versus A]; P<0.001 for all). There was a significant reduction in inappropriate anti-tachycardia pacings in both group and a significant reduction in inappropriate ICD shock in CRT-D patients. CONCLUSIONS: Patients implanted with a CRT-D have lower risk of inappropriate ICD therapy than those with an ICD. Innovative ICD programming significantly reduces the risk of inappropriate ICD therapy in both ICD and CRT-D patients. 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