VARC-2 and MVRC definitions Ioannis Iakovou, MD, PhD

Transcription

1 VARC-2 and MVRC definitions Ioannis Iakovou, MD, PhD Interventional Cardiology Onassis Cardiac Surgery Center Athens, Greece

2 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

3 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. JACC 2012

4 Why do we need standardized definitions?

5 Definition of major vascular complications in multicentre registries

6 Incidence of major vascular complications according to different definitions 345 consecutive patients underwent transfemoral TAVR

7 VARC-2 Definitions Major Vascular Complications 1. Any aortic dissection, rupture, left ventricular perforation, or new apical aneurysm/pseudoaneurysm 2. Access site or access-site related vascular injury (dissection, perforation, stenosis, hematoma, etc.) leading to death, lifethreatening 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 Minor Vascular Complications 1. Access site or access-site related vascular injury (dissection, perforation, stenosis, hematoma, etc.) NOT leading to death, lifethreatening 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 5. Any new ipsilateral lower extremity ischemia 6. Surgery for access site-related nerve injury 7. Permanent access site-related nerve injury Source: Kappetein, et al. JACC 2012

8 The clinical impact of vascular complications as defined by VARC-1 vs. VARC-2 in patients following TAVI 376 patients undergoing TAVI by the transfemoral or transapical 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: , p=0.006)

9 Risk factors not captured by traditional risk scores

10 Risk factors not captured by traditional risk scores

11 Risk factors not captured by traditional risk scores

12 Risk factors not captured by traditional risk scores

13 Mortality

14 Myocardial infarction

15 Stroke and TIA

16 Bleeding

17 AKIN (acute kidney injury)

18 Conduction disturbances and arrhythmias

19 Other TAVI related complications

20 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.

21 Composite endpoints

22 VARC endpoint definition compliance rates in contemporary transcatheter aortic valve implantation studies EuroIntervention 2016;12:

23 VARC endpoint definition compliance rates in contemporary transcatheter aortic valve implantation studies EuroIntervention 2016;12:

24 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.

25 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

26 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

27 Echo grading of primary MR

28 Echo grading of secondary MR

29 How to identify pts unsuitable for SMVR and suitable for Mitraclip

30 Inclusion /exclusion criteria

31 Risk assessment

32 MVARC Highlights: Primary and Secondary Endpoints

33 Stroke and TIA

34 Access site and vascular complications

35 Bleeding complcations

36 AKIN

37 Conduction disturbances and arrhythmias

38 Technical, device, procedural and pt success

39 Specific device-related technical failure issues and complications

40 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).

41 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.