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.

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Why do we need standardized

definitions?

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Definition of major vascular

complications in multicentre registries

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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

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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

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Risk factors not captured by traditional risk

scores

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Risk factors not captured by traditional risk

scores

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Risk factors not captured by traditional risk

scores

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Risk factors not captured by traditional risk

scores

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Mortality

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Myocardial infarction

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Stroke and TIA

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Bleeding

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AKIN (acute kidney injury)

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Conduction disturbances and

arrhythmias

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Other TAVI related complications

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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.

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Composite endpoints

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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

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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.

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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

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Echo grading of primary MR

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Echo grading of secondary MR

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How to identify pts unsuitable for

SMVR and suitable for Mitraclip

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Inclusion /exclusion criteria

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Risk assessment

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MVARC Highlights: Primary and

Secondary Endpoints

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Stroke and TIA

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Access site and vascular

complications

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Bleeding complcations

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AKIN

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Conduction disturbances and

arrhythmias

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Technical, device, procedural and pt success

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Specific device-related technical

failure issues and complications

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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).

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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.