bay-58-2667 and Acute-Disease

Vasoactive and inotropic drugs provide effective symptomatic and hemodynamic relief in the short term but can increase mortality in the long-term. Consequently, their use should be restricted to the indications described in clinical practice guidelines. The present article reviews the main drugs and the available evidence on their use.

Topics: Acute Disease; Benzoates; Cardiotonic Agents; Clinical Trials as Topic; Heart Failure; Hemodynamics; Humans; Mineralocorticoid Receptor Antagonists; Natriuretic Agents; Nitric Oxide Donors; Phosphodiesterase Inhibitors; Practice Guidelines as Topic; Recombinant Proteins; Relaxin; Renin-Angiotensin System; Sympathomimetics; Vasodilator Agents

Acute heart failure is a major cause of emergency hospital admission, with significant impact on health resources and patient outcomes. With no new treatments for over 20 years, the advent of new innovative therapies may facilitate a radical change in our approach to such patients. In this article, we examine the current evidence for the use of current intravenous vasodilators in AHF management, and review the potential of novel therapies currently in development.

Topics: Acute Disease; Administration, Intravenous; Atrial Natriuretic Factor; Benzoates; Heart Failure; Humans; Natriuretic Agents; Natriuretic Peptide, Brain; Natriuretic Peptides; Nitrates; Peptide Fragments; Recombinant Proteins; Relaxin; Snake Venoms; Vasodilator Agents

Although we have recently witnessed substantial progress in management and outcome of patients with chronic heart failure, acute heart failure (AHF) management and outcome have not changed over almost a generation. Vasodilators are one of the cornerstones of AHF management; however, to a large extent, none of those currently used has been examined by large, placebo-controlled, non-hemodynamic monitored, prospective randomized studies powered to assess the effects on outcomes, in addition to symptoms. In this article, we will discuss the role of vasodilators in AHF trying to point out which are the potentially best indications to their administration and which are the pitfalls which may be associated with their use. Unfortunately, most of this discussion is only partially evidence based due to lack of appropriate clinical trials. In general, we believe that vasodilators should be administered early to AHF patients with normal or high blood pressure (BP) at presentation. They should not be administered to patients with low BP since they may cause hypotension and hypoperfusion of vital organs, leading to renal and/or myocardial damage which may further worsen patients' outcome. It is not clear whether vasodilators have a role in either patients with borderline BP at presentation (i.e., low-normal) or beyond the first 1-2 days from presentation. Given the limitations of the currently available clinical trial data, we cannot recommend any specific agent as first line therapy, although nitrates in different formulations are still the most widely used in clinical practice.

Topics: Acute Disease; Atrial Natriuretic Factor; Benzoates; Elapid Venoms; Endothelin-1; Heart Failure; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nitrates; Peptide Fragments; Prognosis; Pyridines; Receptors, Endothelin; Relaxin; Tetrazoles; Vasoconstriction; Vasodilator Agents

Cinaciguat (BAY 58-2667) is a novel soluble guanylate cyclase activator. This study evaluated the haemodynamic effect and safety of cinaciguat added to standard therapy in patients with acute decompensated heart failure (ADHF).. In this placebo-controlled, phase IIb study (NCT00559650), 139 patients admitted with ADHF, pulmonary capillary wedge pressure (PCWP) ≥18 mmHg, left ventricular ejection fraction <40%, and a pre-existing need for invasive haemodynamic monitoring were randomized 2:1 to cinaciguat:placebo (continuous i.v. infusion). The dose was titrated for 8 h and maintained for 16-40 h (starting dose: 100 μg/h). At 8 h, mean PCWP changed from 25.7 ± 5.0 mmHg by -7.7 mmHg with cinaciguat and from 25.0 ± 5.3 mmHg by -3.7 mmHg with placebo (P < 0.0001). The mean right atrial pressure changed from 12.4 ± 5.3 mmHg by -2.7 mmHg with cinaciguat and from 11.8 ± 4.9 mmHg by -0.6 mmHg with placebo (P= 0.0019). Cinaciguat also decreased the pulmonary and systemic vascular resistance and the mean arterial pressure, and increased the cardiac index (all P < 0.0001 vs. placebo). Systolic blood pressure changed by -21.6 ± 17.0 mmHg with cinaciguat and -5.0 ± 14.5 mmHg with placebo. Adverse events were experienced by 71 and 45% of patients receiving cinaciguat and placebo, respectively. No adverse effects on the 30-day mortality were seen; however, the trial was stopped prematurely due to an increased occurrence of hypotension at cinaciguat doses ≥200 µg/h.. Cinaciguat unloaded the heart in patients with ADHF. However, high doses were associated with hypotension.

Topics: Acute Disease; Benzoates; Dose-Response Relationship, Drug; Double-Blind Method; Early Termination of Clinical Trials; Female; Glomerular Filtration Rate; Guanylate Cyclase-Activating Proteins; Heart Failure; Hemodynamics; Humans; Hypotension; Infusions, Intravenous; Male; Middle Aged; Tachycardia, Ventricular; Treatment Outcome

Cinaciguat (BAY 58-2667) is a soluble guanylate cyclase (sGC) activator that, in a previous study among patients with acute heart failure syndromes (AHFS), improved pulmonary capillary wedge pressure (PCWP) at the expense of significant hypotension at doses ≥200 µg/h. The aim of the COMPOSE programme was to investigate the safety and efficacy of fixed, low doses of intravenous cinaciguat (<200 µg/h for 24-48 h) as add-on to standard therapy in adults hospitalized with AHFS.. COMPOSE comprised three randomized, double-blind, placebo-controlled studies in patients with [COMPOSE 1 and 2 (NCT01065077 and NCT01067859)] or without [COMPOSE EARLY (NCT01064037)] a requirement for invasive haemodynamic monitoring. COMPOSE 1 and COMPOSE EARLY assessed the effects of cinaciguat (50, 100, and 150 µg/h) on haemodynamics and dyspnoea, respectively. COMPOSE 2 assessed the haemodynamic effects of 10 and 25 µg/h cinaciguat. COMPOSE was terminated early due to an excess of non-fatal hypotension and recruitment difficulties. In COMPOSE 1 (n = 12), cinaciguat reduced PCWP at 8 h compared with placebo, but there was no relevant change in cardiac index. In COMPOSE EARLY (n = 62), no meaningful difference in dyspnoea was shown between cinaciguat and placebo.. In this limited database, short-term use of intravenous cinaciguat decreased blood pressure without improving dyspnoea or cardiac index. Given the lack of effect on dyspnoea and cardiac index and the hypotensive effect seen even with low doses, it is doubtful that further studies with intravenous cinaciguat would prove beneficial in this patient population.

Topics: Acute Disease; Adjuvants, Pharmaceutic; Aged; Aged, 80 and over; Benzoates; Blood Pressure; Double-Blind Method; Dyspnea; Enzyme Activation; Female; Glomerular Filtration Rate; Guanylate Cyclase; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Syndrome

Cinaciguat (BAY 58-2667) is the first of a new class of soluble guanylate cyclase activators in clinical development for acute decompensated heart failure. We aimed to assess the hemodynamic effects, safety, and tolerability of intravenous cinaciguat in patients with acute decompensated heart failure (pulmonary capillary wedge pressure > or =18 mm Hg).. After initial dose finding (part A; n=27), cinaciguat was evaluated in the nonrandomized, uncontrolled proof-of-concept part of the study (part B; n=33) using a starting dose of 100 microg/h, which could be titrated depending on hemodynamic response. Patients were categorized as responders if their pulmonary capillary wedge pressure decreased by > or =4 mm Hg compared with baseline. Final doses of cinaciguat after 6 hours of infusion in part B were 50 microg/h (n=2), 200 microg/h (n=12), and 400 microg/h (n=16). Compared with baseline, a 6-hour infusion of cinaciguat led to significant reductions in pulmonary capillary wedge pressure (-7.9 mm Hg), mean right atrial pressure (-2.9 mm Hg), mean pulmonary artery pressure (-6.5 mm Hg), pulmonary vascular resistance (-43.4 dynes . s . cm(-5)), and systemic vascular resistance (-597 dynes . s . cm(-5)), while increasing heart rate by 4.4 bpm and cardiac output by 1.68 L/min. The responder rate was 53% after 2 hours, 83% after 4 hours, and 90% after 6 hours. Cinaciguat was well tolerated, with 13 of 60 patients reporting 14 drug-related treatment-emergent adverse events of mild to moderate intensity, most commonly hypotension.. Cinaciguat has potent preload- and afterload-reducing effects, increasing cardiac output. Further investigation of cinaciguat for acute decompensated heart failure is warranted.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Benzoates; Blood Pressure; Cardiac Output; Enzyme Activation; Female; Guanylate Cyclase; Heart Failure; Heart Rate; Hemodynamics; Humans; Hypotension; Infusions, Intravenous; Male; Middle Aged; Pulmonary Wedge Pressure; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Vascular Resistance; Vasodilator Agents

Cinaciguat (BAY 58-2667) is a novel soluble guanylate cyclase activator in clinical development for the treatment of acute decompensated heart failure (ADHF). In patients with ADHF, intravenously administered cinaciguat results in potent unloading of the heart with arterial vasodilation. The aims of this study were to define the structural pharmacokinetic and pharmacodynamic models of cinaciguat in patients with ADHF, to characterize interindividual variability and to explore the effects of potential covariates.. Modelling was performed using NONMEM version V software, based on data from 56 adult patients with ADHF (pulmonary capillary wedge pressure > or = 18 mmHg) participating in a phase II study.. Cinaciguat pharmacokinetics were well described using an open, two-compartment model with an 'effect compartment' and elimination from the central compartment. The population mean estimates for the clearance and volume of distribution at steady state were 26.4 L/h and 18.4 L, respectively. The pharmacokinetics were linear, with no dose-dependent or time-dependent effects on the clearance or volume of distribution, and with moderate interindividual variability. Covariate analyses showed that cardiac output significantly affected clearance, whereas patient age, bodyweight and renal function did not. Time delays between plasma concentrations and effect compartment concentrations, as described by the dissipation rate constant from the effect compartment, ranged from 0.32 h(-1) to 0.86 h(-1) for the different haemodynamic parameters of the final pharmacokinetic/pharmacodynamic model. A 50% recovery to pharmacodynamic baseline values was estimated to occur within 1 hour and a complete return to baseline was estimated to occur within 3-4 hours after the end of infusion.. Intravenously administered cinaciguat had predictable pharmacokinetic and haemodynamic effects in patients with ADHF.

Topics: Acute Disease; Aged; Benzoates; Dose-Response Relationship, Drug; Female; Guanylate Cyclase; Heart Failure; Hemodynamics; Humans; Male; Nonlinear Dynamics; Vasodilator Agents

The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine-3',5'-monophosphate (cGMP) pathway plays an important role in cardiovascular regulation by producing vasodilation and inhibiting platelet aggregation and vascular smooth muscle proliferation. The NO/SGC/cGMP pathway is disrupted in patients with heart failure as a result of a decrease in NO bioavailability and an increase in NO-insensitive forms of sGC, resulting in insufficient vasodilation. Drugs that activate sGC in a NO-independent manner may provide considerable therapeutic advantages in treating these patients. Cinaciguat (BAY-58-2667), currently in development by Bayer AG, preferentially activates sGC in its oxidized or heme-free state, when the enzyme is insensitive to both NO and nitrovasodilators. Cinaciguat exhibits potent vasodilator and antiplatelet activity, a long-lasting antihypertensive effect and a hemodynamic profile similar to that of nitrates. In clinical trials in patients with acute decompensated heart failure, cinaciguat potently unloaded the heart, increased cardiac output and renal blood flow, and preserved renal function and sodium and water excretion without further neurohumoral activation. The pharmacokinetics of cinaciguat demonstrated dose-proportionality with low individual variability and a low incidence of adverse events. The phase I and II clinical trials performed with cinaciguat so far, however, are insufficient to provide convincing evidence on the efficacy and safety of the drug. Thus, caution should be exerted before extrapolating the present preliminary data to the clinical practice.

Topics: Acute Disease; Animals; Benzoates; Cardiovascular System; Clinical Trials as Topic; Drug Evaluation, Preclinical; Enzyme Activators; Guanylate Cyclase; Heart Failure; Hemodynamics; Humans; Male; Vasodilator Agents