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Latest nitroxyl prodrug boosts cardiac performance in advanced HF

Heart Failure 2016 Congress News

Veselin Mitrovic (Kerckhoff Clinic, Bad Nauheim, Germany)

Late Breaking Trials I: Focus on acute heart failure; 21 May, 14:15–15:45; London

Advanced heart failure patients treated with a second-generation intravenous nitroxyl (HNO) prodrug experience improvements in key parameters of cardiac function without increased heart rates or other adverse effects, the results of a randomised trial suggest.

HNO prodrugs are a new class of therapies being developed for acute heart failure syndromes. Data in preclinical models support inotropic and lusitropic effects on the myocardium and peripheral vasodilation, without increases in heart rate or myocardium oxygen demand.

The second-generation nitroxyl prodrugs are a step forward over the previous generation due to their better safety and tolerability profile, primarily because the first-generation drugs caused local irritation of the venous system.

Veselin Mitrovic (Kerckhoff Clinic, Bad Nauheim, Germany) and colleagues examined the safety and haemodynamic efficacy of CXL-1427 in 46 patients with advanced heart failure, randomising them in a 3:1 ratio to a 6-hour continuous infusion of CXL-1427 (at doses of 3, 5, 7 or 12 µg/kg/min) or placebo.

The patients had an average age of 60 years, a mean systolic blood pressure of 107–115 mmHg, a mean pulmonary capillary wedge pressure (PCWP) of 24–28 mmHg and an average cardiac index of 1.77–2.20 L/min/m2, comparable with previous studies in advanced heart failure.

Doses of CXL-1427 of 5 µg/kg/min or greater resulted in significant ~5 mmHg reductions in time-averaged PCWP. CXL-1427 reduced PCWPs by a maximum of 4.8–6.9 mmHg across the treatment groups, versus 2.0 mmHg in the placebo group. There were also consistent reductions in pulmonary artery and right atrial pressure with the study drug.

Cardiac index also increased by 18%–62% across the four CXL-1427 dose groups, compared with just 2% with placebo. The study drug also increased stroke volume, at a significant maximum increase of 84% with the 12 µg/kg/min dose versus 4% in the placebo group.

The calculated mean arterial pressure was reduced in the CXL-1427 groups by 4.8 mmHg to 7.2 mmHg, compared with a reduction of 1.1 mmHg with placebo.

Transient, sporadic and asymptomatic reductions in systolic blood pressure ≥20 mmHg were seen in 21% and 18% of CXL-1427 and placebo patients, respectively. These resolved without the need for intervention.

There were no increases in heart rate with CXL-1427 versus placebo, and there were no cases of arrhythmia during infusion. No changes in circulating B-type natriuretic peptide levels or renal function markers were observed, and there were no CXL-1427-related toxicities, aside from potentially occasional headaches during infusion.

Discussing the findings, Prof. Mitrovic told Heart Failure Congress News that this new drug has an interesting profile with potential inotropic, lusitropic and vasodilator effects. In this phase 2a trial, there appeared to be a dose–response relationship with the study drug for stroke volume and cardiac index.

It remains to be seen whether future trials of CXL-1427 would focus on the higher doses or continue with all four. While Prof. Mitrovic feels that is “an important question”, for him the next step will be to examine the drug’s effect over a longer time period, more than 24 hours, “because here we have experience only in patients with advanced heart failure for a 6-hour infusion period.”

View the session programme and access the resources on SP&P