National Institute for Health and Clinical Excellence

Results of Trials Presented at Heart Rhythm 2009

Compiled by D. Sakellariou, May 18, 2009

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ALTITUDE TRIAL

This was an observational study designed to address prospectively defined questions about the mortality outcomes and incidence of appropriate and inappropriate shock therapies in a large cohort of ICD and CRT-D recipients utilising de-identified data from the 100,000 patient Boston Scientific LATITUDE® remote monitoring system. Five-year survival in 47,032 patients after ICD placement and 38,967 CRT patients was 91.8% and 75.6%, respectively. Shock was associated with decreased survival for both ICD and CRT patients (HR 1.60, p<0.0001). The 5-year incidence of shock was 35.5% for ICD and 34.5% for CRT patients. As a conclusion, survival exceeds that reported within the confines of the pivotal clinical trials after ICD and CRT placement. However, inappropriate shocks remain a significant clinical issue and further effort needs to be made to decrease the incidence.

ATHENA TRIAL (SUBSTUDY)

ATHENA was a randomised placebo-controlled trial, which showed that dronedarone reduces important clinical outcomes including cardiovascular hospitalisation, cardiovascular death or stroke in pts with AF or atrial flutter. This post hoc study analysed in detail data from ATHENA with respect to CHF and outcomes. At randomisation 109 patients receiving placebo (P) and 91 patients receiving dronedarone (D) were in class III CHF. In these patients the primary endpoint occurred in 71 P pts compared to 40 pts in the D group (HR 0.56, p=0.003). Similar analyses were conducted in patients with a baseline LVEF <0.35. Of 87 such pts in the P group, 47 had a primary outcome compared to 39/92 such D pts (HR 0.68, p=0.07). The conclusion was that in the ATHENA study dronedarone had no adverse effect on mortality in AF pts with NYHA class III CHF and/or LVEF <0.35, as was shown in a previous study (ANDROMEDA trial).

MADIT II (long-term outcome)

The Multicenter Automatic Defibrillator Trial II (MADIT-II) showed a significant reduction in the risk of death with an implantable cardioverter defibrillator (ICD) during a mean follow-up period of 20 months. In the session the results of 8 years' follow up were announced. At the end of this period, the cumulative probability of all-cause mortality in the 1232 patients was 45% among patients treated with an ICD as compared with 61% among patients without an ICD (p<0.001), corresponding to 1.2 life-years saved with an ICD during the 8-year period. Post-trial ICD efficacy was shown to be influenced by heart failure (HF) status at trial closure: patients who did not experience symptomatic HF during the trial derived a pronounced survival benefit from the ICD after trial closure (HR 0.52, p=0.002). Moreover, patients who received dual-chamber devices during the trial (set to pacing rate at DDD-60 to 70) experienced an increase in mortality rate during the late phase of the extended follow up, whereas patients who received single-chamber devices (set to back-up pacing rate at VVI-40 to 50) derived enhanced benefit from the ICD during the post-trial period (HR 0.70, p=0.009). As shown by MADIT-II, the survival benefit from the ICD was sustained over 8 years of follow up. Long-term device efficacy was enhanced among patients who received a limited amount of right ventricular pacing from the ICD, and among those who did not develop HF progression during the study.

MRI Pacemaker

Worldwide Randomised Clinical Trial to Evaluate New Pacemaker System Designed for Use During Magnetic Resonance Imaging

This worldwide randomised clinical trial tested a new pacemaker and lead system (EnRhythm MRI system, Medtronic) that was designed to minimise lead tip heating and provide a programmable MRI pacing mode. A total of 464 patients received the device. At 9-12 weeks post-implant, MRI patients received 14 clinically relevant head and lumbar scan sequences performed on 1.5 Tesla machines and control patients waited 1 hour with no MRI. Two hundred and forty-four (244) MRI scan visits occurred and 444 patients were followed up 1 month after MRI scan/control visit. No MRI-related complications or MRI-attributed sustained ventricular arrhythmias, asystole episodes, or pacemaker malfunctions occurred. The system-related complication-free rate was 91.7% (p<0.001). There was no evidence of clinical (bradycardia or tachycardia), subclinical (pacemaker performance) or technical (pacemaker or lead damage) adverse events observed in patients receiving an MRI.

PASCAL trial

This study was conducted to investigate the safety and efficacy of budiodarone in patients with paroxysmal atrial fibrillation (PAF). Budiodarone is a chemical analogue of amiodarone that shares its mixed ion channel electrophysiological effects but has a different metabolic pathway. Patients with PAF and dual-chamber PM capable of recording and storing electrograms were eligible for the study. After discontinuation of all antiarrhythmic drugs for 5 half-lives patients were randomised to placebo, 200, 400 or 600 mg of budiodarone for 12 weeks, followed by 4 weeks of washout. The primary endpoint was percentage change from baseline in atrial fibrillation burden (AFB) at 12 weeks. At the end of the baseline period, 72 patients met the randomisation criteria: 61 completed the study. The primary efficacy endpoint achieved statistical significance in the 400 mg (p=0.015) and 600 mg (p=0.006) dose groups. The median reduction in AFB in these groups was 54.4% and 75.5%, respectively, compared to placebo. Safety was acceptable, with no drug-related SAEs. The investigators concluded that budiodarone seems to be a safe and effective alteranative to amiodarone at a dose of 600 mg in the prevention of AF recurrence.

PEGASUS CRT Trial

The purpose of this multi-centre trial was to evaluate the effect of atrial support pacing among heart failure patients receiving a CRT-defibrillator (CRT-D). A total of 1433 patients were randomised . For the first 6 weeks after implant, all devices were programmed DDD-40. At 6 weeks, patients were randomised 1:1:1 to DDD-40, DDD-70, or DDDR-40. The primary endpoint was the Clinical Composite Endpoint that included all-cause mortality, heart failure (HF) events, New York Heart Association (NYHA) functional class, and patient global self-assessment. No significant differences were found in the composite endpoint between either of the 2 atrial support treatment arms compared to the control arm. In addition, there was no difference among these patients in total mortality or heart failure events.