The Long-Term Benefits of Long-Term Follow-up in Clinical Trials

Several high-impact heart rhythm papers have been published recently that made an impact primarily because of the long length of follow-up of the patients enrolled in the study. These papers have involved ablation, device, and stroke prevention trials.

One of the best examples of a high-impact, long-term ablation study is the 2011 publication by the Bordeaux group in which they shared their “sobering” 5-year data related to ablation for atrial fibrillation (AF) and demonstrated a steady decline in arrhythmia-free survival as far out as 5 years.¹ This forced the electrophysiology community to acknowledge that even patients with idiopathic, paroxysmal AF who often have great short-term outcomes remain at risk for late recurrences, and challenged the notion of ablation as a cure for AF. Without this type of long-term information from a trustworthy institution, the outcomes of catheter ablation would not have been fully understood.

Long-term data from device trials have also been presented in the past few years. The MADIT-II investigators published their 8-year data in 2010.² They presented outcome data associated with a median follow-up of 7.6 years, compared to the mean follow-up of the primary MADIT-II trial of 1.5 years, and were able to demonstrate that the survival benefit of defibrillator therapy for primary prevention is sustained at 8 years. One could not assume that an implantable defibrillator would lead to a survival advantage that long after the device was implanted. This is critical information and has an impact on both decision making by patients and cost-effectiveness analyses of device therapy. 

The data from two long-term studies related to stroke prevention for patients with AF have also recently become available. One study is the long-term data from the WATCHMAN left atrial appendage occlusion device trial, PROTECT AF, which was presented at the 2013 Scientific Sessions of the Heart Rhythm Society.³ It showed that after four years, patients who received the WATCHMAN device not only had fewer adverse events, but also lived longer. The all-cause mortality in the WATCHMAN group was actually superior to the control group (3.2% for WATCHMAN and 4.8% for control), with a 34% relative risk reduction in all-cause mortality in the WATCHMAN group (HR = 0.66, p=0.0379). These findings suggest that the long-term benefits of the device eventually overcome the short-term procedural risks. This type of data could have a huge impact on regulatory approval and potentially on patient selection. In the June issue of Circulation, the RE-LY investigators presented the RELY-ABLE study results.⁴ They found that during 2.3 years of continued treatment with dabigatran after RE-LY, there was a higher rate of major bleeding with dabigatran 150 mg twice daily in comparison with 110 mg, and similar rates of stroke and death. This data suggests that perhaps the lower dose, which was not approved by the FDA after RE-LY was completed, should now be available for prescription in the United States in light of this long-term data. This is a significant contribution.

In many randomized trials, it is clear at the end of the study that one of the treatment options is superior. When one treatment option is the clear preference, and is or becomes commercially available, most patients are advised to receive the superior treatment. However, there are times when there is no clear winner, or when the better therapy is not available, and patients are able to continue to receive the treatment to which they were initially assigned. When patients have the option to continue to receive the initial therapy, efforts should be made whenever possible to continue to follow these patients for the long term. Long-term patient outcomes data can reinforce the conclusions made from the initial main trial or can provide completely new information.

References

1. Weerasooriya R, Khairy P, Litalien J, et al. Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up? J Am Coll Cardiol. 2011;57:160-166.
2. Goldenberg I, Gillespie J, Moss AJ, et al. Long-term benefit of primary prevention with an implantable cardioverter-defibrillator: an extended 8-year follow-up study of the Multicenter Automatic Defibrillator Implantation Trial II. Circulation. 2010;122:1265-1271.
3. Reddy V, Doshi S, Sievert H, et al. Long term results of PROTECT AF: The mortality effects of left atrial appendage closure versus warfarin for stroke prophylaxis in AF. Heart Rhythm Society 2013 Scientific Sessions; May 9, 2013; Denver, CO.
4. Connolly SJ, Wallentin L, Ezekowitz MD. The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study. Circulation. 2013;128:237-243.