VARC-3 Updates Definitions of Clinical Endpoints for Transcatheter and Surgical Aortic Valve Clinical Trials
The VARC-3 writing committee updated standardized definitions of clinical endpoints for transcatheter and surgical aortic valve clinical trials. The update includes revised definitions of device success, periprocedural complications, structural complications and conduction disturbances.
Genereux rejected those who cast aspersions on the composition of the VARC-3 committee, saying that it included structural cardiologists, interventional cardiologists, surgeons, heart failure specialists and US Food and Drug Administration representatives.
As TAVR evolves with iterative improvements in medical device technologies and the expansion of clinical indications to lower surgical risk patients, attention is directed toward the selection of appropriate clinical endpoints to evaluate these changes. In particular, the emergence of novel vascular access approaches and the need to define vascular complications related to these emerging devices requires clarification and refinement of existing clinical endpoint definitions and refocusing on new ones.
For example, VARC-3 has clarified the definition of AKI by introducing a new metric (eGFR) as a measure of renal function and recommends that creatinine levels be measured at baseline, within 24 h, and daily up to 48 h after TAVR to identify the development of AKI. This will enable appropriate monitoring and early identification of AKI.
VARC-3 has also recommended that clinical event committees for large randomized trials or rigorous registry studies of TAVR include both a cardiologist and a cardiovascular surgeon, and when necessary, additional subspecialty physicians (eg, a neurologist for studies with stroke as an endpoint). This will allow the collection of accurate and consistent data and improve the quality of outcomes reporting.
Acute Kidney Injury
Several studies have shown that AKI is associated with adverse outcomes after TAVR, and it is believed that this is at least partially due to its independent association with baseline chronic kidney disease (CKD). The VARC-2 recommendations on the definition of AKI recommend adoption of the recently updated Kidney Disease: Improving Global Outcomes (KDIGO) criteria.
The VARC-2 writing committee included international societies, academic research organizations, the US Food and Drug Administration, and medical device manufacturers. This multidisciplinary process has resulted in important recommendations regarding clinical research methods and endpoint definitions, including a revised composite time-related valve safety endpoint that more appropriately directs attention to the potential long-term consequences and modes of failure of bioprosthetic valves.
A recent study evaluated the consistency of TEE and angiography in grading paravalvular regurgitation (PVR) using VARC-3 criteria, in 31 patients who underwent TAVR. The results showed high kappa coefficients and good agreement between the two techniques, with the highest kappa value observed in patients with moderate or severe PVR.
With the proliferation of alternative vascular access techniques for TAVR and new percutaneous closure device systems, future trials examining these emerging approaches should appropriately capture and classify vascular complications associated with the specific approach used. These may include periprocedural and late/spontaneous atrial fibrillation, new conduction disturbances or arrhythmias (particularly RBBB or LBBB), atrioventricular block, and coronary obstruction.
Coronary obstruction resulting in death, haemodynamic compromise, myocardial infarction, unplanned surgical or percutaneous coronary intervention, or non-fatal neurological event should be reported and classified as a major cardiac structural complication. The circumferential extent of PVR and the location, number and grading of its components (regurgitation volume, regurgitation fraction and effective regurgitant orifice area) should be assessed using TEE.
Studies should also report the rate of permanent pacemaker implantation, noting whether it is periprocedural or late/spontaneous. These endpoints have been shown to be important for assessing prognosis after aortic valve surgery (128-133). New, pre-existing or baseline conduction abnormalities and/or arrhythmias should be reported as they have been shown to impact post-procedure outcome (134). It is recommended that all studies use the same definitions and calculation methodology to facilitate comparison of results across studies.
Hospital clinicians are all too familiar with patients who return to their hospitals repeatedly, and it is important that a portion of those hospitalizations be considered avoidable. However, hospitalizations that represent progression of the natural course of a patient’s underlying disease or the consequence of nonadherence to portions of their discharge plan are often not captured by existing readmission definitions.
The increasing adoption of alternative access approaches and novel percutaneous vascular closure devices reinforces the need to adequately capture and classify vascular complications (84). Thus, VARC-3 expands the classic definitions of major and minor vascular complications to better accommodate these emerging techniques.
VARC-3 also updates the definition of thrombosis to include clinical sequelae of a thromboembolic event or imaging evidence of a prosthetic valve thrombus accompanied by either irreversible Stage 3 haemodynamic valve deterioration or signs of heart failure (105). Furthermore, VARC-3 recommends that coronary obstruction resulting in death, hemodynamic compromise, myocardial infarction, or unplanned surgical or percutaneous intervention should be classified as a cardiac structural complication, regardless of whether it occurs periprocedural or post-procedure.