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CLINICAL RESEARCH: HEART RHYTHM DISORDERS

Treatment Crossovers Did Not Affect Randomized Treatment Comparisons in the Mode Selection Trial (MOST)

Anne S. Hellkamp, MS^_*,_*, Kerry L. Lee, PhD^_*, Michael O. Sweeney, MD, FACC, Mark S. Link, MD, FACC, Gervasio A. Lamas, MD, FACC for the MOST Investigators

^_* Duke Clinical Research Institute, Durham, North Carolina
Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Tufts-New England Medical Center, Boston, Massachusetts
Mount Sinai Medical Center, Miami Beach, Florida

Manuscript received August 2, 2005; revised manuscript received January 3, 2006, accepted January 9, 2006.

^_* Reprint requests and correspondence: Anne S. Hellkamp, MS, 20177 105th Avenue NE, Bothell, Washington 98011 (Email: anne.hellkamp{at}duke.edu).

OBJECTIVES: We evaluated the impact of treatment crossovers on study results in the Mode Selection Trial (MOST).

BACKGROUND: The MOST study, a 2,010-patient, 6-year trial comparing dual-chamber pacing (DDDR) and ventricular pacing (VVIR) in sinus node dysfunction, demonstrated no difference in death or stroke and modest reductions in heart failure hospitalization (HFH) and atrial fibrillation (AF) with DDDR pacing. However, a moderate proportion of VVIR-randomized patients were temporarily or permanently crossed over to DDDR pacing.

METHODS: Intent-to-treat (ITT) analyses compared treatment arms by randomized pacing mode. On-treatment analyses used time-dependent covariates to account for all crossovers. All analyses used Cox proportional hazards models and included covariates prespecified in the study design: age, gender, Charlson index, and prior stroke, heart failure, myocardial infarction, supraventricular tachyarrhythmia, and ventricular tachycardia or fibrillation.

RESULTS: Of 996 VVIR-randomized patients, 375 (38%) were DDDR paced at some time, accounting for 27% of follow-up days among all VVIR-randomized patients. Of 1,014 DDDR-randomized patients, 53 (5%) were VVIR paced at some time, accounting for 1.5% of follow-up days among all DDDR-randomized patients. On-treatment analyses showed slightly lower hazard ratios favoring DDDR versus VVIR compared with ITT: death or stroke 0.88 (on-treatment) versus 0.91 (ITT); death 0.94 versus 0.95; stroke 0.74 versus 0.81; HFH 0.72 versus 0.73; and AF 0.72 versus 0.77. Interpretation of treatment effects was unchanged.

CONCLUSIONS: Although treatment crossovers accounted for >25% of follow-up time in the VVIR-randomized group, this did not affect study results. End point comparisons between randomized modes are accurate reflections of DDDR versus VVIR pacing in this study population.

Abbreviations and Acronyms   AF = atrial fibrillation   CTOPP = Canadian Trial Of Physiologic Pacing   DDDR = dual-chamber pacing   HFH = heart failure hospitalization   MOST = Mode Selection Trial   PASE = Pacemaker Selection in the Elderly   SND = sinus node dysfunction   UKPACE = UK Pacing and Cardiovascular Events   VVIR = ventricular pacing