THV May 13, 2017
VARC-2 and MVRC definitions
Ioannis Iakovou, MD, PhD
Interventional Cardiology
Onassis Cardiac Surgery Center
Athens, Greece
THV May 13, 2017
Aims of Valve Academic Research
Consortium (VARC)
(i) selecting appropriate clinical endpoints reflecting device, procedure
and patient related effectiveness and safety, and
(ii) standardizing definitions for single and composite clinical endpoints,
for transcatheter aortic valve implantation (TAVI) clinical trials
EHJ 2011, JACC 2012
THV May 13, 2017JACC 2012
The aim of VARC-2 initiative was to
(1) revisit the selection and definitions of TAVI clinical endpoints to make
them more suitable to the present and future needs of clinical trials and
(2) intended to expand the understanding of patient risk stratification and
case selection.
THV May 13, 2017
Incidence of major vascular complications
according to different definitions
345 consecutive patients underwent transfemoral TAVR
VARC-2 Definitions
Major Vascular Complications
1. Any aortic dissection, rupture, left ventricular
perforation, or new apical aneurysm/pseudo-
aneurysm
2. Access site or access-site related vascular
injury (dissection, perforation, stenosis,
hematoma, etc.) leading to death, life-
threatening or major bleeding, visceral
ischemia, or neurological impairment
3. Distal embolization requiring vascular surgery,
amputation, or irreversible end organ damage
4. Unplanned endovascular or surgical
intervention associated with death, major
bleeding, visceral ischemia, or neurological
impairment
5. Any new ipsilateral lower extremity ischemia
6. Surgery for access site-related nerve injury
7. Permanent access site-related nerve injury
Minor Vascular Complications
1. Access site or access-site related vascular
injury (dissection, perforation, stenosis,
hematoma, etc.) NOT leading to death, life-
threatening or major bleeding, visceral
ischemia, or neurological impairment
2. Distal embolization treated with embolectomy
and/or thrombectomy and NOT resulting in
amputation or end organ damage
3. Unplanned endovascular stenting or
unplanned surgical intervention not meeting
the criteria for a major vascular complication
4. Vascular repair or the need for vascular repair
(via surgery, ultrasound-guided compression,
transcatheter embolization, or stent-graft
Source: Kappetein, et al. JACC 2012
THV May 13, 2017
The clinical impact of vascular complications as defined
by VARC-1 vs. VARC-2 in patients following TAVI
Cox regression analysis showed major VC with
VARC-2 definition to be an independent
predictor of mortality (hazard ratio of 3.0, 95%
confidence interval: 1.4-6.6, p=0.006)
376 patients undergoing TAVI by the transfemoral or transapical
THV May 13, 2017
Prosthetic valve dysfunction
The EOA should generally be calculated with the use of the LVOT diameter and the velocity
measured just underneath the apical margin of the valve stent.
In cases where the landing zone of the stent is low in the LVOT, the diameter and velocity may
both be measured in the proximal portion of the stent.
Unlike the surgically implanted valve, the transcatheter prosthetic valve EOA is defined not only
by the size of the valve but also by the patient’s aortic valve/annular anatomy and procedural
variables.
Thus, well-established normal transcatheter valve gradients and EOAs based on preimplant aortic annular dimensions do not currently exist.
THV May 13, 2017
EuroIntervention 2016;12:375-380
VARC endpoint definition compliance rates in contemporary
transcatheter aortic valve implantation studies
THV May 13, 2017 EuroIntervention 2016;12:375-380
VARC endpoint definition compliance rates in contemporary
transcatheter aortic valve implantation studies
THV May 13, 2017
Mitral Valve Academic Research
Consortium (MVARC)
• to develop endpoint definitions for clinical studies of MR
therapies.
• given the complexity of issues that must be considered for MV
trials, MVARC to develop design principles for clinical trials and
registries investigating transcatheter device therapies to treat MR,
which may also be applied to surgical and other approaches.
THV May 13, 2017
Clinical Trial Design for Transcatheter
Mitral Valve Therapy: Major issues
• How should the disease be classified?
• How should “severe” MR be defined and measured, and
what constitutes a meaningful reduction in MR?
• What is the appropriate control arm therapy?
• How should high risk be defined?
• Is a sham control necessary?
• What are appropriate inclusion and exclusion criteria?
• What are appropriate primary and secondary endpoints –
imaging/anatomic, functional, QOL, clinical?
• What are the roles of the heart team, eligibility committee,
and central core laboratories?
• What is optimal analysis group and statistical methodology?G.Stone 2015
• How should the disease be classified?
• How should “severe” MR be defined and measured, and
what constitutes a meaningful reduction in MR?
• What is the appropriate control arm therapy?
• How should high risk be defined?
• Is a sham control necessary?
• What are appropriate inclusion and exclusion criteria?
• What are appropriate primary and secondary endpoints –
imaging/anatomic, functional, QOL, clinical?
• What are the roles of the heart team, eligibility committee,
and central core laboratories?
• What is optimal analysis group and statistical methodology?G.Stone 2015
Clinical Trial Design for Transcatheter
Mitral Valve Therapy: Major issues
THV May 13, 2017
VARC highlights: Conclusions
• The VARC-2 document has provided further standardization of endpoint
definitions for studies evaluating the use of TAVR.
• To have comparability and interpretability of the study results, supplying
an increasingly growing body of evidence with respect to TAVR and/or
surgical aortic valve replacement.
• This initiative and document can furthermore be used as a model during
current endeavors of applying definitions to other transcatheter valve
therapies (for example, mitral valve repair).
THV May 13, 2017
MVARC Highlights: Conclusions
• In contrast to calcific aortic stenosis, a relatively simple disease with limited
etiologies and a straight-forward pathophysiology, MR is a more complicated entity,
owing to the greater complexity of the MV structure and the numerous lesions and
mechanisms that may lead to its failure.
• Continuing the analogy, developing effective therapies (and surgical approaches) for
MR, and demonstrating their safety and effectiveness in clinical trials is much more
challenging than for aortic stenosis, and requires the intimate collaboration between
physician-scientists across numerous disciplines, clinical trialists, statisticians, industry
and regulatory authorities.
• Although each device trial will entail its own nuanced considerations, adopting
MVARC principles as a template for clinical investigation should allow sponsors and
investigators to avoid the most common errors that can render interpretation of their
findings problematic.
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