Wojciech Zareba

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. nnMethods 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). nnConclusions —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. nnClinical Trial Registration —clinicaltrials.gov; Unique Identifier: [NCT00947310][1].nn [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.

QT Interval and Its Drug-Induced Prolongation

QT interval prolongation may result from an inherited channelopathy, the long QT syndrome (LQTS), or can be induced by drugs, abnormal electrolyte/metabolic disorders, or other conditions affecting myocardial repolarization (1–5). The LQTS is characterized by prolongation of the QT interval on the electrocardiogram and is associated with an increased propensity to ventricular tachyarrhythmias, that can lead to cardiac events such as syncope, cardiac arrest, or sudden death (1,2). Over the last few decades, clinical observations in LQTS patients as well as clinical and basic science research have led to a better understanding of the role of repolarization in cardiac arrhythmias and cardiac electrophysiology.

Long QT Syndrome: Therapeutic Considerations

The hereditary long QT syndrome (LQTS) was first reported in 1957 by Jervell and Lange-Nielsen in a family in which several deaf children experienced recurrent syncope and sudden death. The electrocardiograms of these children showed QT prolongation. A few years later, Romano and Ward separately described syncope and sudden death in families without deafness. These “events” were thought to reflect a seizure disorder, and anticonvulsants (phenobarbital and diphenylhydantoin) were initially used to treat this condition. During the 1960s, LQTS was reported in a few dozen patients, with several of the syncopal events and sudden deaths occurring in the setting of acute arousal. A few patients had Holter recordings obtained during the syncopal episodes, and polymorphic ventricular tachyarrhythmias were documented as the cause of the syncope. Antiadrenergic therapy with surgical sympathectomy and β-adrenergic blocking agents was introduced in the early 1970s with what appeared to be favorable results. Many of the patients with LQTS had inappropriate sinus bradycardia, and pacemaker therapy was introduced in the 1980s with the rationale that backup physiologic pacing would reduce the probability of ventricular tachyarrhythmias initiated by pause-dependent mechanisms in the setting of disordered ventricular repolarization. Implantable defibrillators began to be used in the mid-1980s in patients with high-risk LQTS who experienced recurrent cardiac events while receiving antiadrenergic therapy. The molecular-genetic basis of LQTS was uncovered in the 1990s with the identification of mutations in several ion channel genes. With the discovery of these gene mutations and the disordered ion channel mechanisms involved in LQTS, it was hoped that gene- or mutation-specific therapy could be developed.