Browsing by Author "Solomon, Scott D."

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    Haemodynamic effects of the nitroxyl donor cimlanod (BMS-986231) in chronic heart failure: a randomized trial
    (Wiley, 2021-07) Lang, Ninian N.; Ahmad, Faheem A.; Cleland, John G.; O'Connor, Christopher M.; Teerlink, John R.; Voors, Adriaan A.; Taubel, Jorg; Hodes, Anke R.; Anwar, Mohamed; Karra, Ravi; Sakata, Yasushi; Ishihara, Shiro; Senior, Roxy; Khemka, Abhishek; Prasad, Narayana G.; DeSouza, Mary M.; Seiffert, Dietmar; Ye, June Y.; Kessler, Paul D.; Borentain, Maria; Solomon, Scott D.; Felker, G. Michael; McMurray, John J. V.; Medicine, School of Medicine
    Aims Nitroxyl provokes vasodilatation and inotropic and lusitropic effects in animals via post-translational modification of thiols. We aimed to compare effects of the nitroxyl donor cimlanod (BMS-986231) with those of nitroglycerin (NTG) or placebo on cardiac function in patients with chronic heart failure with reduced ejection fraction (HFrEF). Methods and results In a randomized, multicentre, double-blind, crossover trial, 45 patients with stable HFrEF were given a 5 h intravenous infusion of cimlanod, NTG, or placebo on separate days. Echocardiograms were done at the start and end of each infusion period and read in a core laboratory. The primary endpoint was stroke volume index derived from the left ventricular outflow tract at the end of each infusion period. Stroke volume index with placebo was 30 ± 7 mL/m2 and was lower with cimlanod (29 ± 9 mL/m2; P = 0.03) and NTG (28 ± 8 mL/m2; P = 0.02). Transmitral E-wave Doppler velocity on cimlanod or NTG was lower than on placebo and, consequently, E/e′ (P = 0.006) and E/A ratio (P = 0.003) were also lower. NTG had similar effects to cimlanod on these measurements. Blood pressure reduction was similar with cimlanod and NTG and greater than with placebo. Conclusion In patients with chronic HFrEF, the haemodynamic effects of cimlanod and NTG are similar. The effects of cimlanod may be explained by venodilatation and preload reduction without additional inotropic or lusitropic effects. Ongoing trials of cimlanod will further define its potential role in the treatment of heart failure.
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    Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis
    (MMS, 2018-07) Benson, Merrill D.; Waddington-Cruz, Márcia; Berk, John L.; Polydefkis, Michael; Dyck, Peter J.; Wang, Annabel K.; Planté-Bordeneuve, Violaine; Barroso, Fabio A.; Merlini, Giampaolo; Obici, Laura; Scheinberg, Morton; Brannagan, Thomas H., III; Litchy, William J.; Whelan, Carol; Drachman, Brian M.; Adams, David; Heitner, Stephen B.; Conceição, Isabel; Schmidt, Hartmut H.; Vita, Giuseppe; Campistol, Josep M.; Gamez, Josep; Gorevic, Peter D.; Gane, Edward; Shah, Amil M.; Solomon, Scott D.; Monia, Brett P.; Hughes, Steven G.; Kwoh, Jesse; McEvoy, Bradley W.; Jung, Shiangtung W.; Baker, Brenda F.; Ackermann, Elizabeth J.; Gertz, Morie A.; Coelho, Teresa; Pathology and Laboratory Medicine, School of Medicine
    BACKGROUND Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin (TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2′-O-methoxyethyl–modified antisense oligonucleotide, inhibits hepatic production of transthyretin. METHODS We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, −22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life–Diabetic Neuropathy (QOL-DN) questionnaire (range, −4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement. RESULTS A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was −19.7 points (95% confidence interval [CI], −26.4 to −13.0; P<0.001) for the mNIS+7 and −11.7 points (95% CI, −18.3 to −5.1; P<0.001) for the Norfolk QOL-DN score. These improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were five deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring. CONCLUSIONS Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring.