Valve Academic Research Consortium 3 and 2 Recommendations
Aortic valve clinical research is in a rapidly evolving field. To make relevant comparisons between trials, standardized endpoint definitions are needed.
The first VARC definitions were published in 2011 and updated in 2012 (VARC-2). The writing committee consisted of a broad range of experts from academic medical centers, professional societies and the FDA.
Endpoints
VARC-3 recommends the use of clinically relevant, consistent definitions for a variety of single and composite endpoints in large randomized trials or rigorous registry studies. These should reflect device, procedure, and patient-related efficacy and safety.
VAR-3 endorses the inclusion of rehospitalization in both the clinical efficacy and safety composite endpoints, as well as heart failure hospitalizations (for more than 24 hours). It also places emphasis on reporting visits to emergency departments and urgent care facilities, especially if they involve substantial intensification of medical therapy.
Using troponin measurements, VARC-3 adopts a more ‘centrist’ approach to the definition of MI after TAVI and SAVR, recommending that any peri-procedural MI associated with documented or suspected myocardial necrosis be classified as an event of significant clinical importance. VARC-3 further defines coronary obstruction as any adverse clinical consequence possibly related to the access site, including stenosis resulting in haemodynamic compromise, unplanned surgery or percutaneous intervention and death.
Creatinine levels should be measured at a minimum, at baseline and within 48 h post-procedure, and ideally on a daily basis up to 48 h after discharge. The rate of permanent pacemaker implantation should be reported excluding patients with prior permanent pacemakers from the denominator to facilitate comparability across studies.
Definitions
The VARC-2 manuscript aims to standardize definitions for clinical endpoints used in aortic valve research and to facilitate relevant comparisons between studies. This is primarily achieved by clarifying and expanding classic definitions of specific complications, by establishing standardized threshold values for cardiac biomarker measurements (with focus on troponin) and by including an entirely new category of clinical events – peri-procedural myocardial injury defined as a significant increase in cardiac biomarkers in the absence of a documented and clinically significant ischaemic insult.
The definition of procedure-related vascular complications has been revised to reflect the increasing use of alternative access approaches for TAVI, particularly femoral and iliac (subclavian/axillary) catheterisation. In addition, the definition of a stroke has been shifted towards the modified Rankin scale and includes assessment of functional recovery (e.g. mRS).
The VARC-2 document also extends the concept of device failure to encompass impaired prosthetic valve performance and outlines a comprehensive definition that includes valve dysfunction, endocarditis and thrombotic complications of the aortic bioprosthesis. These categories are further harmonised with existing surgical valve disease guidelines and incorporated into a composite endpoint of time-related valve safety.
Recommendations
Valve Academic Research Consortium-2 recommends the use of a composite endpoint that incorporates prosthetic valve dysfunction, endocarditis and thrombotic complications of the prosthesis (Table 11). This endpoint is recommended for all clinical trials investigating BAV, TAVR and SAVR.
The VARC-2 document also recommends that the rate of new permanent pacemaker implantation be reported in all trials. This criterion excludes patients with a prior permanent pacemaker, and thereby maximizes the capture of events that have clinical significance. In addition, the mRS score should be recorded to assess the degree of disability resulting from stroke and assist in future analysis of this important outcome.
The VARC-2 document recommends that any coronary obstruction resulting in death, haemodynamic compromise, myocardial infarction or unplanned surgical or percutaneous coronary intervention should be classified as a major cardiac structural complication (Table 7). The timing of the event should also be captured, acknowledging the potential for delayed coronary obstruction. Additionally, any patient requiring renal replacement therapy should be recorded (stage 3 renal failure) given the well-documented adverse impact of contrast medium on kidney function.
References
A specialized heart team (including interventional cardiologists, cardiac surgeons, and imaging specialists) should be responsible for patient evaluation. This should also include a vascular neurologist experienced in assessing stroke and other neurological complications, particularly in trials with an endpoint involving stroke.
VARC-2 recommends using the modified Rankin Scale (mRS) to assess clinical disability following a stroke, rather than the more traditional stroke scales. This will enable appropriate differentiation of TIAs and stroke, provide a robust measure of the effect of a stroke on functional outcome, and avoid under-reporting or over-reporting of stroke events.
Given the common presence of coronary artery disease in patients with aortic valve disease, it is important to accurately capture and classify the incidence of coronary obstruction+ resulting in death, haemodynamic compromise, MI, or unplanned surgical or percutaneous coronary intervention. In addition, VARC-2 introduces a new category of complications referred to as “access-related non-vascular complications” to capture injury to structures surrounding the access site that are not vascular in nature.