Defining endpoints in clinical trials on atrial fibrillation
1 St George's Hospital Medical School, Blackshaw Road, Tooting, London SW17 0QT, UK
2 Columbia University College of Physicians and Surgeons, New York, NY, USA
3 Columbia Presbyterian Medical Center, The New York Presbyterian Hospital, New York, NY, USA
* Corresponding author. Tel: +44 208 725 3554; fax: +44 208 767 7141. E-mail address: jcamm{at}sgul.ac.uk
The major factors influencing the choice of the primary endpoint in any clinical trial in patients with atrial fibrillation (AF) are the purpose of the trial, the specific characteristics of the study population in terms of the class and aetiology of AF concerned, co-morbidities, risk factors, symptom status, and whether the trial is designed for regulatory purposes. Clinically, symptom relief and improvement in quality of life are major therapeutic goals, but they are difficult to measure objectively and an effect of treatment on these parameters is currently insufficient to support drug registration. Hard endpoints such as mortality, stroke, and hospitalization are most relevant to patients with persistent AF and other concomitant morbidities resulting in a high risk of these outcomes; however, their inclusion in an appropriately weighted composite primary endpoint may be necessary in trials including less severely ill patient populations to demonstrate treatment efficacy in a regulatory context. A therapy that reduced AF and improved quality of life but increased mortality, heart failure, or other major morbid events would not be approved in the current era. Time to first AF recurrence has practical advantages as a primary endpoint, but does not accurately reflect clinically important parameters such as the frequency, type, and duration of AF recurrence and the overall AF burden. The clinical relevance of asymptomatic recurrence of AF with regard to prognosis, quality of life, and patient care, including the need for anticoagulation, is increasingly recognized. Improvement in devices enabling more continuous monitoring of cardiac rhythm now permits more accurate assessment of the effect of treatment on asymptomatic AF, representing the majority of episodes recorded in studies employing intensive monitoring procedures. An intention-to-treat analysis is always preferred, but this may not always be possible in clinical trials in patients with AF. Irrespective of the efficacy endpoint chosen, this should ideally be assessed starting from the time steady state is achieved, for drug therapy, or maturation of the lesions in the case of ablation. These time-points may be days to months after randomization. Events occurring during the period from randomization to the pre-defined start of endpoint assessment, known as the blanking period, are not taken into account in the primary efficacy analysis. The longer the blanking period, the further on-therapy analysis departs from true intention-to-treat analysis. However, on-therapy analysis is as essential as intention-to-treat analysis, especially when comparing drug vs. non-drug therapies, as it also takes into account both the frequently high crossover rates and the poor compliance with drug therapy commonly encountered in antiarrhythmic drug (AAD) trials.
Key Words: Atrial fibrillation • Clinical trial endpoints • Sinus rhythm • AF recurrence • Mortality • Quality of life