The effect of the cardiac myosin activator, omecamtiv mecarbil, on right ventricular structure and function in chronic systolic heart failure ( COSMIC ‐ HF ) (2021)

Right ventricular (RV) dysfunction due to post-capillary pulmonary hypertension is a common sequela of elevated left ventricular (LV) filling pressures in patients with heart failure (HF) which has been demonstrated to be associated with poor clinical outcomes.1-3 Measures of RV–pulmonary artery (RV-PA) coupling that evaluate indices of RV function and pulmonary hypertension severity have been shown to be associated with clinical outcomes.4, 5 A phase 2 trial, COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure, NCT01786512) demonstrated that treatment with omecamtiv mecarbil (OM), a selective cardiac myosin activator, known as a myotrope, was related to an improved LV systolic function, beneficial reverse remodelling, sympathetic withdrawal and a reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients with HF with reduced ejection fraction (HFrEF).6 In this research letter, we report the treatment effect of OM on RV structure and function together with RV-PA coupling in patients with HFrEF. COSMIC-HF was a, multicentre, randomized, double-blind, placebo-controlled trial which assessed the tolerability of pharmacokinetic (PK)-guided dose of OM for 20 weeks and its effects on LV systolic function and remodelling in HFrEF patients. Detailed design and main results have been published.6 Eligible patients had chronic HFrEF (New York Heart Association functional class II or III) treated with stable, optimal pharmacologic therapy for at least 4 weeks, NT-proBNP ≥200 pg/mL (≥1200 pg/mL if the patient presented with atrial fibrillation), and LV ejection fraction ≤40%. Patients were randomized in a 1:1:1 fashion to receive oral placebo, 25 mg OM twice daily [fixed-dose (FD) group], or 25 mg OM twice daily titrated up to 50 mg twice daily based on the plasma concentration after 2 weeks at 25 mg (PK-titration group). The study protocol was approved by the institutional review board or ethics committee at each site. Written informed consent was obtained from all participants before enrolment. Echocardiograms were analysed in a core laboratory blinded to randomized treatment (Brigham and Women's Hospital, Boston, MA). Measures of RV structure and function included RV fractional area change (RV-FAC), measured using cavity area at end-diastole (EDA) and end-systole (ESA), tricuspid annular plane systolic excursion (TAPSE), RV outflow tract velocity time integral (RVOT-VTI), RV systolic ejection time (RV-SET), and pulmonary artery systolic pressure (PASP) which was estimated as: 4 × (peak tricuspid regurgitation velocity)2 + 5. RV-PA coupling was assessed as the TAPSE/PASP ratio and RVOT-VTI/PASP ratio. All measures of RV structure and function were obtained at baseline and after 20 weeks and were analysed using linear regression models, which included change from baseline as an outcome variable with corresponding baseline value as a continuous covariate. Predictors included in the statistical models were randomized treatment, the baseline value of the outcome of interest, and the stratification factor of presence or absence of atrial fibrillation or flutter at randomization. For significant parameters, additional adjustments for baseline and change in LV end-diastolic diameter, LV fractional shortening, and log (NT-proBNP) were performed. The primary comparison was the difference in the least-squares mean among the three groups from baseline and 20 weeks. A two-sided P-value <0.05 was considered statistically significant. Analyses were performed using STATA version 14.1 (Stata Corp., College Station, TX). Of the 448 patients enrolled in the trial, 149 were assigned to the placebo group, 150 to the FD group, and 149 to the PK-titration group. At baseline (mean age 63 ± 10 years; male 83%; LV ejection fraction 29 ± 7%), treatment groups were generally balanced with respect to echocardiographic parameters. At baseline patients had impaired measures of RV structure and function as determined by a high RV-EDA, low FAC, low TAPSE and increased PASP (Table 1). At 20 weeks of OM treatment, there were no significant differences in RV-FAC, RV-EDA nor TAPSE among the three groups. OM was significantly associated with an improvement in RVOT-VTI and RV-SET in both the FD and the PK-titration groups (Table 1 and Figure 1). In addition, the RV-ESA and PASP together with parameters of RV-PA coupling (TAPSE/PASP ratio and RVOT-VTI/PASP ratio) improved significantly in the PK-titration group as compared to the placebo group (Table 1 and Figure 1). These associations remained significant after further adjustment for baseline and change in LV parameters and NT-proBNP (online supplementary Table S1). 25.3 ± 8.5 (n = 114) 24.6 ± 7.9 (n = 112) 25.9 ± 8.0 (n = 107) 26.2 ± 8.8 (n = 97) 24.5 ± 8.0 (n = 97) 26.0 ± 7.0 (n = 87) −1.3 (−3.0, 0.5) P = 0.15 −1.4 (−3.3, 0.5) P = 0.15 14.5 ± 5.6 (n = 114) 14.5 ± 6.6 (n = 112) 15.4 ± 6.4 (n = 107) 15.2 ± 6.3 (n = 97) 14.2 ± 6.3 (n = 97) 14.7 ± 5.9 (n = 87) −1.1 (−2.2, 0.1) P = 0.07 −1.5 (−2.7, −0.2) P = 0.02 43.4 ± 9.0 (n = 114) 42.8 ± 10.0 (n = 112) 41.9 ± 9.9 (n = 107) 43.0 ± 8.9 (n = 97) 43.5 ± 9.9 (n = 97) 44.7 ± 11.2 (n = 87) 0.9 (−1.6, 3.3) P = 0.48 1.6 (−1.1, 1.1) P = 0.23 16.7 ± 5.2 (n = 123) 17.2 ± 4.8 (n = 129) 16.3 ± 4.7 (n = 134) 16.9 ± 4.2 (n = 116) 16.8 ± 4.3 (n = 121) 17.3 ± 4.2 (n = 113) −0.5 (−1.4, 0.4) P = 0.29 0.3 (−0.6, 1.2) P = 0.56 12.7 ± 3.3 (n = 136) 12.8 ± 3.7 (n = 140) 12.9 ± 3.8 (n = 138) 12.3 ± 3.6 (n = 118) 13.4 ± 3.4 (n = 123) 13.6 ± 3.3 (n = 111) 1.0 (0.3, 1.7) P = 0.006 1.1 (0.4, 1.8) P = 0.003 314.5 ± 29.3 (n = 134) 316.3 ± 34.1 (n = 141) 312.8 ± 26.2 (n = 137) 313.6 ± 24.3 (n = 126) 322.7 ± 27.4 (n = 126) 328.7 ± 30.1 (n = 115) 8.1 (3.3, 12.8) P = 0.001 16.1 (11.2, 21.0) P < 0.001 35.1 ± 12.5 (n = 63) 34.5 ± 10.0 (n = 71) 34.4 ± 10.1 (n = 64) 33.4 ± 8.4 (n = 60) 34.8 ± 8.7 (n = 42) 30.8 ± 8.0 (n = 51) 0.4 (−2.6, 3.3) P = 0.80 −3.8 (−6.7, −1.0) P = 0.009 0.51 ± 0.19 (n = 57) 0.54 ± 0.21 (n = 66) 0.49 ± 0.20 (n = 59) 0.51 ± 0.14 (n = 58) 0.48 ± 0.16 (n = 40) 0.57 ± 0.20 (n = 47) −0.03 (−0.09, 0.04) P = 0.39 0.08 (0.02, 0.14) P = 0.01 0.39 ± 0.17 (n = 59) 0.40 ± 0.19 (n = 67) 0.40 ± 0.16 (n = 58) 0.39 ± 0.18 (n = 56) 0.36 ± 0.11 (n = 38) 0.47 ± 0.19 (n = 47) 0.008 (−0.05, 0.06) P = 0.76 0.08 (0.02, 0.13) P = 0.005 The observed improvements in some RV metrics may be partially attributed to direct effects of OM on the right ventricle. This is supported by our finding that OM significantly improved RV-SET, since the main mechanism of action of OM is to increase the number of force-producing interactions between actin and myosin during cardiac systole, which increases the contractility and particularly the ejection time.6 In addition, the favourable effect of OM on LV systolic ejection time, together with beneficial LV reverse remodelling and a reduction in NT-proBNP levels may also contribute to the improvements in RV-ESA and RV-PA coupling observed in this study. Although the extent to which RV dysfunction reflects pulmonary hypertension due to LV dysfunction or intrinsic RV dysfunction is uncertain, our findings suggested that the improvement in LV function may lead to a decrease in pulmonary artery pressure, thereby resulting in reduced RV afterload, and at least in part, in the improvement of RV performance.7, 8 This is supported by our observation that statistically significant improvement in PASP and RV-ESA together with parameters of RV-PA coupling were observed despite only in the PK-titration group, where LV cardiac reverse remodelling (decrease in LV end-systolic and end-diastolic diameters) was also statistically significant.6 Although the number of subjects with complete data on RV measures at baseline and week 20 did not constitute the whole population, our exploratory analyses suggested that OM did not result in any adverse effects on RV function within the range of exposures achieved in COSMIC-HF. Our analyses demonstrated that 20 weeks of OM treatment in patients with HFrEF improved RV-SET, RV-VTI in both OM groups, and improved RV-ESA, RV afterload and RV-PA coupling only in the PK-titration group, whereas OM did not significantly improve TAPSE or RV-FAC. The effect of OM on clinical outcomes in HFrEF has been recently displayed in the GALACTIC-HF trial (NCT02929329). Our findings suggest a favourable effect of OM on RV-SET, RV-VTI, RV-ESA, RV afterload and RV-PA coupling, which should be considered hypothesis generating and need to be assessed and confirmed in larger studies. The authors thank all the participants (patients, caregivers, and staff) of the COSMIC-HF trial for providing their invaluable contributions. This study was funded by Amgen in collaboration with Cytokinetics. Conflict of interest: T.B.S. has received research grants from GE Healthcare and Sanofi Pasteur; and has consulted for Amgen, Sanofi Pasteur and Novartis. M.M. has received supports from the Japanese Circulation Society, the Japanese Society of Echocardiography, and the Uehara Memorial Foundation Overseas Research Fellowship. A.I.P. has received research grants from Bayer Lifescience. J.R.T. has received research contracts from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cytokinetics, Medtronic, St. Jude; and has consulted for Abbott, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, St. Jude. G.M.F. has received research grants from NHLBI, American Heart Association, Amgen, Bayer Merck, Cytokinetics, Myokardia, Bayer; he has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, V-Wave, Myokardia, Innolife, Boehringer Ingelheim, EBR Systems, Arena, Abbott, LivaNova, Eidos Therapeutics, Rocket Pharma, Reprieve, Sequana. N.H., C.E.K. and J.C.L. are employees and shareholders of Amgen Inc. S.D.S. has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has consulted for Akros, Alnylam, Amgen, AstraZeneca, Bayer, BMS, Cardior, Corvia, Cytokinetics, Gilead, GSK, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. F.I.M. is an employee and shareholder in Cytokinetics, Inc. Table S1. Right ventricular structure and function at baseline and week 20 after randomization. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.