Michael J. Mack M.D.

Takahashi, K., Serruys, P.W., Gao, C., Ono, M., Wang, R., Thuijs, D., Mack, M.J., Curzen, N., Mohr, F.W., Davierwala, P., Milojevic, M., Wykrzykowska, J.J., de Winter, R.J., Sharif, F., Onuma, Y., Head, S.J., Kappetein, A.P., Morice, M.C. and Holmes, D.R., Jr. (2021). “Ten-Year All-Cause Death According to Completeness of Revascularization in Patients with Three-Vessel Disease or Left Main Coronary Artery Disease: Insights from the SYNTAX Extended Survival Study.” Circulation May 20. [Epub ahead of print].

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Background: Ten-year all-cause death according to incomplete (IR) versus complete revascularization (CR) has not been fully investigated in patients with three-vessel disease (3VD) and/or left main coronary artery disease (LMCAD) undergoing percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG). Methods: The SYNTAX Extended Survival Study evaluated vital status up to 10 years in patients who were originally enrolled in the SYNTAX trial. In the present sub-study, outcomes of the CABG CR group were compared with the CABG IR, PCI CR, and PCI IR groups. In addition, in the PCI cohort, the residual SYNTAX score (rSS) was used to quantify the extent of IR and to assess its association with fatal late outcome. The rSS of 0 suggests CR, whereas a rSS>0 identifies degree of IR. Results: IR was more frequently observed in patients with PCI vs. CABG (56.6% vs. 36.8%) and more common in those with 3VD than LMCAD in both PCI (58.5% vs. 53.8%) and CABG arm (42.8% vs. 27.5%). Patients undergoing PCI with CR had no significant difference in 10-year all-cause death compared with those undergoing CABG (22.2% for PCI with CR vs. 24.3% for CABG with IR vs. 23.8% for CABG with CR). In contrast, those with PCI and IR had a significantly higher risk of all-cause death at 10 years compared with CABG and CR (33.5% vs. 23.7%; adjusted hazard ratio [aHR]:1.48; 95% confidence interval [CI]:1.15-1.91). When patients with PCI were stratified according to the rSS, those with a rSS≤8 had no significant difference in all-cause death at 10 years as the other terciles (22.2% for rSS=0 vs. 23.9% for rSS>0-4 vs. 28.9% for rSS>4-8), whereas a rSS> 8 had a significantly higher risk of 10-year all-cause death as compared with those undergoing PCI with CR (50.1% vs. 22.2%; aHR:3.40; 95% CI:2.13-5.43). Conclusions: IR is common after PCI, and the degree of incompleteness was associated with 10-year mortality. If it is unlikely that complete (or nearly complete; rSS<8) revascularization can be achieved with PCI in patients with 3VD, CABG should be considered. Clinical Trial Registration: SYNTAX: https://www.clinicaltrials.gov Unique Identifier: NCT00114972. SYNTAX Extended Survival: https://www.clinicaltrials.gov Unique Identifier: NCT03417050.

Ono, M., Kawashima, H., Hara, H., O’Leary, N., Gao, C., Wang, R., Takahashi, K., Wykrzykowska, J.J., Piek, J.J., Mack, M.J., Holmes, D.R., Morice, M.C., Head, S.J., Kappetein, A.P., Thuijs, D., Noack, T., Friedrich, M.W., Davierwala, P.M., McEvoy, J.W., Onuma, Y. and Serruys, P.W. (2021). “Impact of Body Composition Indices on Ten-year Mortality After Revascularization of Complex Coronary Artery Disease (From the Syntax Extended Survival Trial).” Am J Cardiol May 25;S0002-9149(21)00361-1. [Epub ahead of print].

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Numerous studies have demonstrated a paradoxical association between higher baseline body mass index (BMI) and lower long-term mortality risk after coronary revascularization, known as the “obesity paradox”, possibly relying on the single use of BMI. The current study is a post-hoc analysis of the SYNTAX Extended Survival (SYNTAXES) trial, which is the extended follow-up of the SYNTAX trial comparing percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) in patients with left-main coronary artery disease (LMCAD) or three-vessel disease (3VD). Patients were stratified according to baseline BMI and/or waist circumference (WC). Out of 1,800 patients, 1,799 (99.9%) and 1,587 (88.2%) had available baseline BMI and WC data, respectively. Of those, 1,327 (73.8%) patients had High BMI (≥25 kg/m(2)), whereas 705 (44.4%) patients had High WC (>102 cm for men or >88 cm for women). When stratified by both BMI and WC, 10-year mortality risk was significantly higher in patients with Low BMI/Low WC (adjusted hazard ratio [HR]: 1.65; 95% confidence interval [CI]: 1.09 to 2.51), Low BMI/ High WC (adjusted HR: 2.74; 95% CI: 1.12 to 6.69), or High BMI/High WC (adjusted HR: 1.59; 95% CI: 1.11 to 2.27) compared to those with High BMI/Low WC. In conclusion, the “obesity paradox” following coronary revascularization would be driven by low long-term mortality risk of the High BMI/Low WC group. Body composition should be assessed by the combination of BMI and WC in the appropriate evaluation of the long-term risk of obesity in patients with LMCAD or 3VD.

Mack, M.J., Fullerton, D.A. and Fann, J.I. (2021). “The Answers You Get Depend on the Questions You Ask: Insights From the Recent EXCEL Trial Controversy.” Ann Thorac Surg 111(6): 1743-1745.

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Scientific evidence to inform clinical practice can be generally categorized as coming from 2 sources—observational registry or database studies and randomized clinical trials (RCTs). Observational studies have the advantage of being more readily available, and the outcomes are for the most part reflective of the way patients are actually treated. They are, however, not ideal to assess comparative effectiveness of treatments, since they are subject to selection bias for the treatment received, which can only be partially corrected by various methods of post hoc statistical matching. RCTs are considered to be the highest level of evidence and provide the strongest evidentiary support for society clinical practice guidelines. With RCTs, a treatment is assigned randomly, therefore obviating any concerns regarding selection bias of enrolled patients. [No abstract; excerpt from Editorial].

Kar, S., Mack, M.J., Lindenfeld, J., Abraham, W.T., Asch, F.M., Weissman, N.J., Enriquez-Sarano, M., Lim, D.S., Mishell, J.M., Whisenant, B.K., Rogers, J.H., Arnold, S.V., Cohen, D.J., Grayburn, P.A. and Stone, G.W. (2021). “Relationship Between Residual Mitral Regurgitation and Clinical and Quality-of-Life Outcomes After Transcatheter and Medical Treatments in Heart Failure: The COAPT Trial.” Circulation May 27. [Epub ahead of print].

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Background: In the randomized COAPT trial, among 614 heart failure (HF) patients with 3+ or 4+ secondary mitral regurgitation (MR), transcatheter mitral valve repair (TMVr) with the MitraClip reduced MR, HF hospitalizations (HFH), and mortality and improved quality of life compared with guideline-directed medical therapy (GDMT) alone. We sought to examine the prognostic relationship between MR reduction and outcomes after TMVr and GDMT alone. Methods: Outcomes in COAPT between 30 days and 2 years were examined based on the severity of residual MR at 30 days. Results: TMVr-treated patients had less severe residual MR at 30 days than GDMT-treated patients (0/1+, 2+, and 3+/4+: 72.9%, 19.9%, and 7.2% versus 8.2%, 26.1%, and 65.8%, respectively, P<0.0001). The rate of composite death or HFH between 30 days and 2 years was lower in patients with 30-day residual MR of 0/1+ and 2+ compared with 3+/4+ (37.7% versus 49.5% versus 72.2%, respectively, P<0.0001). This relationship was consistent in the TMVr and GDMT arms (P(interaction)=0.92). The improvement in KCCQ score from baseline to 30 days was maintained between 30 days and 2 years in patients with 30-day MR ≤2+ but deteriorated in those with 30-day MR 3+/4+ (-0.3±1.7 versus -9.4±4.6, P=0.0008) consistently in both groups (P(interaction)=0.95). Conclusions: In the COAPT trial, reduced MR at 30 days was associated with greater freedom from death or HFH and improved quality of life through 2-year follow-up whether the MR reduction was achieved by TMVr or GDMT. Clinical Trial Registration: https://www.clinicaltrials.gov Unique Identifier: NCT01626079.

Généreux, P., Piazza, N., Alu, M.C., Nazif, T., Hahn, R.T., Pibarot, P., Bax, J.J., Leipsic, J.A., Blanke, P., Blackstone, E.H., Finn, M.T., Kapadia, S., Linke, A., Mack, M.J., Makkar, R., Mehran, R., Popma, J.J., Reardon, M., Rodes-Cabau, J., Van Mieghem, N.M., Webb, J.G., Cohen, D.J. and Leon, M.B. (2021). “Valve Academic Research Consortium 3: updated endpoint definitions for aortic valve clinical research.” Eur Heart J 42(19): 1825-1857.

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AIMS: The Valve Academic Research Consortium (VARC), founded in 2010, was intended to (i) identify appropriate clinical endpoints and (ii) standardize definitions of these endpoints for transcatheter and surgical aortic valve clinical trials. Rapid evolution of the field, including the emergence of new complications, expanding clinical indications, and novel therapy strategies have mandated further refinement and expansion of these definitions to ensure clinical relevance. This document provides an update of the most appropriate clinical endpoint definitions to be used in the conduct of transcatheter and surgical aortic valve clinical research. METHODS AND RESULTS: Several years after the publication of the VARC-2 manuscript, an in-person meeting was held involving over 50 independent clinical experts representing several professional societies, academic research organizations, the US Food and Drug Administration (FDA), and industry representatives to (i) evaluate utilization of VARC endpoint definitions in clinical research, (ii) discuss the scope of this focused update, and (iii) review and revise specific clinical endpoint definitions. A writing committee of independent experts was convened and subsequently met to further address outstanding issues. There were ongoing discussions with FDA and many experts to develop a new classification schema for bioprosthetic valve dysfunction and failure. Overall, this multi-disciplinary process has resulted in important recommendations for data reporting, clinical research methods, and updated endpoint definitions. New definitions or modifications of existing definitions are being proposed for repeat hospitalizations, access site-related complications, bleeding events, conduction disturbances, cardiac structural complications, and bioprosthetic valve dysfunction and failure (including valve leaflet thickening and thrombosis). A more granular 5-class grading scheme for paravalvular regurgitation (PVR) is being proposed to help refine the assessment of PVR. Finally, more specific recommendations on quality-of-life assessments have been included, which have been targeted to specific clinical study designs. CONCLUSIONS: Acknowledging the dynamic and evolving nature of less-invasive aortic valve therapies, further refinements of clinical research processes are required. The adoption of these updated and newly proposed VARC-3 endpoints and definitions will ensure homogenous event reporting, accurate adjudication, and appropriate comparisons of clinical research studies involving devices and new therapeutic strategies.