Translational Pathway for Catheter Ablation
Marco Cannella, PhD
Douglas L. Packer, MD
Douglas L. Packer, MD
Marco Cannella, PhD
Clinical study endpoints are measures intended to reflect the effectiveness and/or safety of a given treatment. Study endpoints should be clinically meaningful and relevant to the study objectives. Whenever possible, the endpoints should be objective and be measurable with minimal bias.
The following factors may play a role in selecting endpoints for catheter ablation device studies:
- Indications for use (desired intended use and targeted population)
- The mechanism of action of a technology (i.e., radiofrequency, cryo, laser, other ablating energy source)
- Clinical evidence collected in feasibility studies (for new technology) or in previous clinical trials (for known similar technology)
- Relevant U.S. Food and Drug Administration (FDA) guidance documents and professional society consensus documents.
The indications for use to be sought (e.g., typical atrial flutter [AFL], symptomatic drug refractory paroxysmal atrial fibrillation [AF], drug/device refractory ischemic ventricular tachycardia [VT]) should be taken into account because they have a significant impact on what endpoints are considered clinically meaningful and relevant.
The mechanism of action of a technology is typically considered when assessing the possible risks associated with the study device. Same or similar technologies already implemented in a medical device with a different indication for use may help develop a preliminary list of major complications that could be used to inform a safety endpoint.
Scientific evidence collected in relevant previous clinical and preclinical studies (e.g., animal studies, feasibility studies with the study device, pivotal studies with similar devices for the same indication for use) can facilitate the assessment of the possible risks and benefits of the study device and procedure, which may help inform the effectiveness and safety endpoint of a prospective pivotal study.
FDA issued guidance documents on catheter ablation device studies for the treatment of AFL, AF, and VT that represent the agency’s thinking on study design issues including study endpoints at the time of their publication. Professional society consensus documents on catheter ablation often provide contemporary and systemic review of the clinical indications, techniques, and outcomes of certain catheter ablation procedures. Some consensus documents also provide recommendations for designing clinical trials of catheter ablation of a specific arrhythmia. The expert consensus statement on catheter and surgical ablation of AF from the Heart Rhythm Society and other associations is, for example, a useful document for developing endpoints for clinical studies of AF ablation (1).
Based on the general principles above, the primary safety endpoint for many catheter ablation studies was evaluated by major complication rate and is typically constructed as a composite endpoint. The list of adverse events included in the composite safety endpoint is typically developed to capture device- and/or procedure-related major complications.
The primary effectiveness endpoint of a catheter ablation study is greatly affected by the indications for use to be sought. Primary effectiveness success or treatment success, which is often defined as freedom from arrhythmia recurrence, is typically evaluated during a prespecified follow-up period. For instance, a 12-month follow-up period is typically expected to determine the primary effectiveness endpoint for a catheter ablation study for an AF indication, while a minimum follow-up duration of 6 to 12 months is anticipated for assessing treatment success for a catheter ablation study for a VT indication. One exception to this general rule is a study of conventional radiofrequency ablation catheter for a typical AFL indication in which acute procedural success (defined as the creation of bidirectional cavo-tricuspid isthmus block) has been accepted as a surrogate effectiveness endpoint due to its excellent predictive value for chronic success.
It is worth noting that as our understanding of the underlying mechanisms of arrhythmias and their ablation therapies continues to improve, endpoints currently being used in catheter ablation studies are likely to evolve and novel endpoints may be developed to facilitate the evaluation of new catheter ablation devices and procedures.
- Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. 2017;14:e275-e444.