Research Spotlight

Saxon, J.T., Cohen, D.J., Chhatriwalla, A.K., Kotinkaduwa, L.N., Kar, S., Lim, D.S., Abraham, W.T., Lindenfeld, J., Mack, M.J., Arnold, S.V. and Stone, G.W. (2020). “Impact of COPD on Outcomes After MitraClip for Secondary Mitral Regurgitation: The COAPT Trial.” JACC Cardiovasc Interv 13(23): 2795-2803.

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OBJECTIVES: The aim of this study was to examine the relationship between chronic obstructive pulmonary disease (COPD) and outcomes after transcatheter mitral valve repair (TMVr) for severe secondary mitral regurgitation. BACKGROUND: TMVr with the MitraClip improves clinical and health-status outcomes in patients with heart failure and severe (3+ to 4+) secondary mitral regurgitation. Whether these benefits are modified by COPD is unknown. METHODS: COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) was an open-label, multicenter, randomized trial of TMVr plus guideline-directed medical therapy (GDMT) versus GDMT alone. Patients on corticosteroids or continuous oxygen were excluded. Multivariable models were used to examine the associations of COPD with mortality, heart failure hospitalization (HFH), and health status and to test whether COPD modified the benefit of TMVr compared with GDMT. RESULTS: Among 614 patients, 143 (23.2%) had COPD. Among patients treated with TMVr, unadjusted analyses demonstrated increased 2-year mortality in those with COPD (hazard ratio [HR]: 2.08; 95% confidence interval [CI]: 1.33 to 3.26), but this association was attenuated after risk adjustment (adjusted HR: 1.48; 95% CI: 0.87 to 2.52). Although TMVr led to reduced 2-year mortality among patients without COPD (adjusted HR: 0.47; 95% CI: 0.33 to 0.67), for patients with COPD, 2-year all-cause mortality was similar after TMVr versus GDMT alone (adjusted HR: 0.94; 95% CI: 0.54 to 1.65; p(int) = 0.04), findings that reflect offsetting effects on cardiovascular and noncardiovascular mortality. In contrast, TMVr reduced HFH (adjusted HR: 0.48 [95% CI: 0.28 to 0.83] vs. 0.46 [95% CI: 0.34 to 0.63]; p(int) = 0.89) and improved both generic and disease-specific health status to a similar extent compared with GDMT alone in patients with and without COPD (p(int) >0.30 for all scales). CONCLUSIONS: In the COAPT trial, COPD was associated with attenuation of the survival benefit of TMVr versus GDMT compared with patients without COPD. However, the benefits of TMVr on both HFH and health status were similar regardless of COPD. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] [COAPT]; NCT01626079).

Holmes, D.R., Jr., Farb, A.A., Chip Hance, R., Leon, M.B., Goldberg, P., Zuckerman, B.D., Kaplan, A.V., Rincon-Gonzalez, L., Hunt, J., Walkowiak, J. and Mack, M.J. (2020). “Early Feasibility Studies for Cardiovascular Devices in the United States: JACC State-of-the-Art Review.” J Am Coll Cardiol 76(23): 2786-2794.

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The development of technology to treat unmet clinical patient needs in the United States has been an important focus for the U.S. Food and Drug Administration and the 2016 Congressional 21st Century Cures Act. In response, a program of early feasibility studies (EFS) has been developed. One of the important issues has been the outmigration of the development and testing of medical devices from the United States. The EFS committee has developed and implemented processes to address issues to develop strategies for early treatment of these patient groups. Initial implementation of the U.S. Food and Drug Administration EFS program has been successful, but residual significant problems have hindered the opportunity to take full advantage of the program. These include delays in gaining Institutional Review Board approval, timeliness of budget and contractual negotiations, and lack of access to and enrollment of study subjects. This paper reviews improvements that have been made to the U.S. EFS ecosystem and outlines potential approaches to address remaining impediments to program success.

Sandau, K.E., Lee, C.S., Faulkner, K.M., Pozehl, B., Eckman, P., Garberich, R., Weaver, C.E., Joseph, S.M., Hall, S., Carey, S.A., Chaudhry, S.P., Schroeder, S.E., Hoffman, R.O., 3rd, Feldman, D., Birati, E.Y., Soni, M., Marble, J.F., Jurgens, C.Y., Hoglund, B. and Cowger, J.A. (2020). “Health-Related Quality of Life in Patients With a Left Ventricular Assist Device (QOLVAD) Questionnaire: Initial Psychometrics of a New Instrument.” J Cardiovasc Nurs Dec 9. [Epub ahead of print].

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BACKGROUND: Patients with a left ventricular assist device are a unique and growing population who deserve their own valid, reliable instrument for health-related quality of life. OBJECTIVE: We developed and tested the Health-Related Quality of Life with a Left Ventricular Assist Device (QOLVAD) questionnaire. METHODS: In a prospective, descriptive study, patients from 7 sites completed the QOLVAD and comparator questionnaires. Construct validity was tested using confirmatory factor analysis. Convergent validity was tested using correlations of QOLVAD scores to well-established measures of subjective health status, depression, anxiety, and meaning/faith. Reliability and test-retest reliability were quantified. RESULTS: Patients (n = 213) were 58.7 ± 13.9 years old; 81.0% were male, 73.7% were White, and 48.0% had bridge to transplant. Questionnaires were completed at a median time of 44 weeks post ventricular assist device. The 5 QOLVAD domains had acceptable construct validity (root mean square error of approximation = 0.064, comparative and Tucker-Lewis fit indices > 0.90, weighted root mean square residual = 0.95). The total score and domain-specific scores were significantly correlated with the instruments to which they were compared. Internal consistency reliability was acceptable for all subscales (α = .79-.83) except the cognitive domain (α = .66). Unidimensional reliability for the total score was acceptable (α = .93), as was factor determinacy for multidimensional reliability (0.95). Total test-retest reliability was 0.875 (P < .001). CONCLUSION: Our analysis provided initial support for validity and reliability of the QOLVAD for total score, physical, emotional, social, and meaning/spiritual domains. The QOLVAD has potential in research and clinical settings to guide decision making and referrals; further studies are needed.

Roger, S.D., Lavin, P.T., Lerma, E.V., McCullough, P.A., Butler, J., Spinowitz, B.S., von Haehling, S., Kosiborod, M., Zhao, J., Fishbane, S. and Packham, D.K. (2021). “Long-term safety and efficacy of sodium zirconium cyclosilicate for hyperkalaemia in patients with mild/moderate versus severe/end-stage chronic kidney disease: comparative results from an open-label, Phase 3 study.” Nephrol Dial Transplant 36(1): 137-150.

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BACKGROUND: Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for the treatment of adults with hyperkalaemia. This post hoc analysis of an open-label, single-arm trial (NCT02163499) compared SZC efficacy and safety >12 months among outpatients with hyperkalaemia and Stages 4 and 5 chronic kidney disease (CKD) versus those with Stages 1-3 CKD. METHODS: Adults with serum K+ ≥5.1 mmol/L (measured by point-of-care i-STAT device) received SZC 10 g three times daily for 24-72 h until normokalaemia (i-STAT K+ 3.5-5.0 mmol/L) was achieved [correction phase (CP)], followed by once daily SZC 5 g for ≤12 months [maintenance phase (MP)]. Here, patients were stratified by baseline estimated glomerular filtration rate (eGFR <30 or ≥30 mL/min/1.73 m2). Study endpoints included percent achieving normokalaemia during CP and MP, mean serum K+ and bicarbonate during MP, and adverse events (AEs). RESULTS: Of 751 patients enrolled, 289 (39%), 453 (60%) and 9 (1%) had baseline eGFR values of <30, ≥30 mL/min/1.73 m2 or missing, respectively. During the CP, 82% of patients achieved normokalaemia in both eGFR subgroups within 24 h, and 100 and 95% with baseline eGFR <30 and ≥30 mL/min/1.73 m2, respectively, within 72 h. Corresponding proportions with normokalaemia during the MP were 82 and 90% at Day 365, respectively. Mean serum K+ reduction from baseline during the CP was sustained throughout the MP and serum bicarbonate increased. AEs during the MP were more common in the eGFR <30 ≥30 mL/min/1.73 m2 subgroup. CONCLUSIONS: SZC corrects hyperkalaemia and maintains normokalaemia among outpatients regardless of the CKD stage.

Richardson, P.G., Oriol, A., Larocca, A., Bladé, J., Cavo, M., Rodriguez-Otero, P., Leleu, X., Nadeem, O., Hiemenz, J.W., Hassoun, H., Touzeau, C., Alegre, A., Paner, A., Maisel, C., Mazumder, A., Raptis, A., Moreb, J.S., Anderson, K.C., Laubach, J.P., Thuresson, S., Thuresson, M., Byrne, C., Harmenberg, J., Bakker, N.A. and Mateos, M.V. (2020). “Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma.” J Clin Oncol Dec 9;JCO2002259. [Epub ahead of print]. Jco2002259.

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PURPOSE: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS: Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS: Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION: Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease.