Michael J. Mack M.D.

Mack, M. J. and G. W. Stone (2019). “Response to Letters re: The COAPT Trial.” Cardiovasc Revasc Med 20(6): 531-532.

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The COAPT trial was a landmark study that demonstrated for the first time that correction of secondary or functional mitral regurgitation (MR) results in significant clinical benefits in patients with heart failure. The addition of the MitraClip to maximally tolerated guideline-directed medical therapy (GDMT) resulted in a 47% reduction in hospitalization for heart failure, the primary endpoint at two years. In addition, there were significant 2-year improvements in survival, quality-of-life and exercise performance. We appreciate the great interest generated by the COAPT outcomes as reflected by the letters to the editor in this issue. They raise some salient points that we would like to address. Khan et al. note that in COAPT, there was significant up-titration of both beta-blockers and mineralocorticoid receptor antagonists (MRA) during follow-up in the device arm. The protocol intent was to maintain GDMT in both arms, and as reported, there were few major increases or reductions in medical therapy in both groups. However, MR reduction by the MitraClip increases cardiac output and blood pressure, enabling up-titration of medical therapy in some patients. These medication changes, which might be expected in real-world practice, may have contributed in small part to the therapeutic benefit in the device arm. However, we do not agree with the authors that a double-blinded sham-controlled study is required to mitigate this potential “bias” (which is actually a response to improved hemodynamics, not bias). The beta-blocker increase was transient (1-year timepoint only), and the MRA difference was small and not significant. Nitrate use at 1 and 2 years was actually more common in the control arm. These modest changes in medications cannot explain the marked absolute benefits of MR reduction observed in COAPT (number needed-to-treat 3 and 6 patients, respectively, to prevent one hospitalization and save one life within 2 years). Given these outcomes, it would be both unfeasible and unethical to conduct a sham-controlled study in which a group of patients meeting COAPT-eligibility criteria were not offered active treatment. (Excerpt from text, p. 531; no abstract available.)

DeRose, J. J., Jr., D. M. Mancini, H. L. Chang, M. Argenziano, F. Dagenais, G. Ailawadi, L. P. Perrault, M. K. Parides, W. C. Taddei-Peters, M. J. Mack, D. D. Glower, B. A. Yerokun, P. Atluri, J. C. Mullen, J. D. Puskas, K. O’Sullivan, N. M. Sledz, H. Tremblay, E. Moquete, B. S. Ferket, A. J. Moskowitz, A. Iribarne, A. C. Gelijns, P. T. O’Gara, E. H. Blackstone and A. M. Gillinov (2019). “Pacemaker Implantation After Mitral Valve Surgery With Atrial Fibrillation Ablation.” J Am Coll Cardiol 73(19): 2427-2435.

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BACKGROUND: The incidence of permanent pacemaker (PPM) implantation is higher following mitral valve surgery (MVS) with ablation for atrial fibrillation (AF) compared with MVS alone. OBJECTIVES: This study identified risk factors and outcomes associated with PPM implantation in a randomized trial that evaluated ablation for AF in patients who underwent MVS. METHODS: A total of 243 patients with AF and without previous PPM placement were randomly assigned to MVS alone (n = 117) or MVS + ablation (n = 126). Patients in the ablation group were further randomized to pulmonary vein isolation (PVI) (n = 62) or the biatrial maze procedure (n = 64). Using competing risk models, this study examined the association among PPM and baseline and operative risk factors, and the effect of PPM on time to discharge, readmissions, and 1-year mortality. RESULTS: Thirty-five patients received a PPM within the first year (14.4%), 29 (83%) underwent implantation during the index hospitalization. The frequency of PPM implantation was 7.7% in patients randomized to MVS alone, 16.1% in MVS + PVI, and 25% in MVS + biatrial maze. The indications for PPM were similar among patients who underwent MVS with and without ablation. Ablation, multivalve surgery, and New York Heart Association functional (NYHA) functional class III/IV were independent risk factors for PPM implantation. Length of stay post-surgery was longer in patients who received PPMs, but it was not significant when adjusted for randomization assignment (MVS vs. ablation) and age (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.61 to 1.08; p = 0.14). PPM implantation did not increase 30-day readmission rate (HR: 1.43; 95% CI: 0.50 to 4.05; p = 0.50). The need for PPM was associated with a higher risk of 1-year mortality (HR: 3.21; 95% CI: 1.01 to 10.17; p = 0.05) after adjustment for randomization assignment, age, and NYHA functional class. CONCLUSIONS: AF ablation, multivalve surgery, and NYHA functional class III/IV were associated with an increased risk for permanent pacing. PPM implantation following MVS was associated with a significant increase in 1-year mortality. (Surgical Ablation Versus No Surgical Ablation for Patients With Atrial Fibrillation Undergoing Mitral Valve Surgery; NCT00903370).

Badhwar, V., M. Alkhouli, M. J. Mack, V. H. Thourani and G. Ailawadi (2019). “Surgical and transcatheter therapy for secondary mitral regurgitation.” J Thorac Cardiovasc Surg May 21. [Epub ahead of print].

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The importance of myocardial revascularization for viable myocardium is the cornerstone for the management of ischemia whenever appropriate targets exist. For patients with ischemic cardiomyopathy undergoing surgery for secondary MR, incomplete revascularization is a marker of mortality, but evidence that it influences residual MR in all patients remains lacking. For example, patients with chronic severe secondary MR often have papillary muscle fibrosis and the subsequently tethered MV apparatus is unlikely to improve regardless of the revascularization strategy. This is similar to the point that Nappi and colleagues make when discussing their approach to patients with nonviable myocardium. Although their experience with subvalvular papillary muscle repositioning or polytetrafluoroethylene tube reapproximation is compelling, widespread reproducibility of this technique remains limited. The nomenclature and assessment of MR is clear. Prolapse is defined in a patient with primary MR when leaflet motion extends above the annular plane in systole. There is no such entity in secondary MR, as the authors may suggest. In the case of a tethered posterior leaflet following myocardial infarction remodeling, a posteriorly directed jet of MR may be commonly misinterpreted as anterior leaflet prolapse and primary MR when it is in fact best defined as anterior leaflet override and secondary MR. Appropriate identification of pathology directs appropriate management. Nappi and colleagues are to be congratulated for their steadfast outcome reporting of adjunctive subvalvular papillary muscle repair and their institutional results are admirable, yet their recent identification of failures of this technique indicate that it may not actually be for everyone. They report failures of MV annuloplasty and subvalvular repair with MV tenting area ≥3.1 cm2 and left ventricle end-diastolic diameter ≥64 mm. In fact, their findings that patients with significant left ventricle remodeling and MV tenting have a higher incidence of recurrent MR aligns precisely with the recently proposed grading system. The cumulative evidence and surgical outcomes with MV repair and replacement in secondary MR do not amount to forfeiture of this complex disease state to transcatheter therapy. To the contrary, the proposed grading system suggests that MV repair still has a role in at least Grade I secondary MR in patients the heart team believes may benefit from surgical therapy. Perhaps MV annuloplasty and subvalvular repair may have a role in Grade II secondary MR, provided the patient does not have the predictors identified by Nappi and colleagues. (Excerpts from text, article in press, p. e1; refers to Nappi F., Santana O., and Mihos C.G.: Geometric distortion of the mitral valve apparatus in ischemic mitral regurgitation: should we really forfeit the opportunity for a complete repair? J Thorac Cardiovasc Surg 2019.)

Arnold, S. V., K. M. Chinnakondepalli, J. A. Spertus, E. A. Magnuson, S. J. Baron, S. Kar, D. S. Lim, J. M. Mishell, W. T. Abraham, J. A. Lindenfeld, M. J. Mack, G. W. Stone and D. J. Cohen (2019). “Health Status After Transcatheter Mitral-Valve Repair in Heart Failure and Secondary Mitral Regurgitation: COAPT Trial.” J Am Coll Cardiol 73(17): 2123-2132.

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BACKGROUND: In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial, transcatheter mitral valve repair (TMVr) led to reduced heart failure (HF) hospitalizations and improved survival in patients with symptomatic HF and 3+ to 4+ secondary mitral regurgitation (MR) on maximally-tolerated medical therapy. Given the advanced age and comorbidities of these patients, improvement in health status is also an important treatment goal. OBJECTIVES: The purpose of this study was to understand the health status outcomes of patients with HF and 3+ to 4+ secondary MR treated with TMVr versus standard care. METHODS: The COAPT trial randomized patients with HF and 3+ to 4+ secondary MR to TMVr (n = 302) or standard care (n = 312). Health status was assessed at baseline and at 1, 6, 12, and 24 months with the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the SF-36 health status survey. The primary health status endpoint was the KCCQ overall summary score (KCCQ-OS; range 0 to 100; higher = better; minimum clinically important difference = 5 points). RESULTS: At baseline, patients had substantially impaired health status (mean KCCQ-OS 52.4 +/- 23.0). While health status was unchanged over time in the standard care arm, patients randomized to TMVr demonstrated substantial improvement in the KCCQ-OS at 1 month (mean between-group difference 15.9 points; 95% confidence interval [CI]: 12.3 to 19.5 points), with only slight attenuation of this benefit through 24 months (mean between-group difference 12.8 points; 95% CI: 7.5 to 18.2 points). At 24 months, 36.4% of TMVr patients were alive with a moderately large (>/=10-point) improvement versus 16.6% of standard care patients (p < 0.001), for a number needed to treat of 5.1 patients (95% CI: 3.6 to 8.7 patients). TMVr patients also reported better generic health status at each timepoint (24-month mean difference in SF-36 summary scores: physical 3.6 points; 95% CI: 1.4 to 5.8 points; mental 3.6 points; 95% CI: 0.8 to 6.4 points). CONCLUSIONS: Among patients with symptomatic HF and 3+ to 4+ secondary MR receiving maximally-tolerated medical therapy, edge-to-edge TMVr resulted in substantial early and sustained health status improvement compared with medical therapy alone. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] [COAPT]; NCT01626079).

Mack, M. J., M. B. Leon, V. H. Thourani, R. Makkar, S. K. Kodali, M. Russo, S. R. Kapadia, S. C. Malaisrie, D. J. Cohen, P. Pibarot, J. Leipsic, R. T. Hahn, P. Blanke, M. R. Williams, J. M. McCabe, D. L. Brown, V. Babaliaros, S. Goldman, W. Y. Szeto, P. Genereux, A. Pershad, S. J. Pocock, M. C. Alu, J. G. Webb and C. R. Smith (2019). “Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in Low-Risk Patients.” New England Journal of Medicine 380(18): 1695-1705.

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BACKGROUND: Among patients with aortic stenosis who are at intermediate or high risk for death with surgery, major outcomes are similar with transcatheter aortic-valve replacement (TAVR) and surgical aortic-valve replacement. There is insufficient evidence regarding the comparison of the two procedures in patients who are at low risk. METHODS: We randomly assigned patients with severe aortic stenosis and low surgical risk to undergo either TAVR with transfemoral placement of a balloon-expandable valve or surgery. The primary end point was a composite of death, stroke, or rehospitalization at 1 year. Both noninferiority testing (with a prespecified margin of 6 percentage points) and superiority testing were performed in the as-treated population. RESULTS: At 71 centers, 1000 patients underwent randomization. The mean age of the patients was 73 years, and the mean Society of Thoracic Surgeons risk score was 1.9% (with scores ranging from 0 to 100% and higher scores indicating a greater risk of death within 30 days after the procedure). The Kaplan-Meier estimate of the rate of the primary composite end point at 1 year was significantly lower in the TAVR group than in the surgery group (8.5% vs. 15.1%; absolute difference, -6.6 percentage points; 95% confidence interval [CI], -10.8 to -2.5; P<0.001 for noninferiority; hazard ratio, 0.54; 95% CI, 0.37 to 0.79; P = 0.001 for superiority). At 30 days, TAVR resulted in a lower rate of stroke than surgery (P = 0.02) and in lower rates of death or stroke (P = 0.01) and new-onset atrial fibrillation (P<0.001). TAVR also resulted in a shorter index hospitalization than surgery (P<0.001) and in a lower risk of a poor treatment outcome (death or a low Kansas City Cardiomyopathy Questionnaire score) at 30 days (P<0.001). There were no significant between-group differences in major vascular complications, new permanent pacemaker insertions, or moderate or severe paravalvular regurgitation. CONCLUSIONS: Among patients with severe aortic stenosis who were at low surgical risk, the rate of the composite of death, stroke, or rehospitalization at 1 year was significantly lower with TAVR than with surgery. (Funded by Edwards Lifesciences; PARTNER 3 ClinicalTrials.gov number, NCT02675114.).