Why do drugs for acute heart failure fail?

Over the last decades, pharmacological treatment of patients hospitalized for acute decompensated heart failure have remained unchanged. Virtually all patients are treated with a loop diuretic, and the use of additional drugs depends on the type of heart failure and mainly on blood pressure. Only in patients with a blood pressure . 110 mmHg is the addition of intravenous nitrates recommended. In rare patients with cardiogenic shock, inotropes are administered. Nevertheless, evidence for this approach is generally lacking. Also, the majority of patients remain symptomatic, and in-hospital mortality remains 4%. More importantly, outcome after discharge is very poor. Most deaths and re-hospitalizations occur early after discharge, and 1 year mortality or re-hospitalization occurs in 40% of the patients. Therefore, there is a great need for improvement. In the current issue of this journal, clinical results of the COMPOSE programme are presented. The COMPOSE programme studied the effects of cinaciguat, a novel vasodilator, in three randomized, double-blind, placebo-controlled studies in acute decompensated heart failure patients with (COMPOSE 1 and 2) or without (COMPOSE EARLY) a requirement for invasive haemodynamic monitoring. Cinaciguat activates soluble guanylate cyclase, leading to increased cyclic guanosine monophosphate (cGMP). cGMP causes relaxation of smooth muscle cells, and has antiproliferative, anti-inflammatory, and antiremodelling effects. Cinaciguat is therefore a potent vasodilator, with specific antiplatelet activity, a long-lasting antihypertensive effect, and a haemodynamic profile similar to that of nitrates. In an uncontrolled clinical study in patients (n 1⁄4 60) with acute decompensated heart failure, cinaciguat produced strong reductions in preload and afterload, with increased cardiac output and preservation of renal function. The drug was well tolerated, with hypotension reported only in 10% of patients. In the present paper in this journal, the authors also referred to another unpublished placebo-controlled study, in which cinaciguat produced rapid, sustained improvement in pulmonary capillary wedge pressure (PCWP) at 8 h compared with placebo. However, the majority (73%) of patients receiving cinaciguat developed hypotension, especially those who received cinaciguat doses ≥200 mg/h. The COMPOSE programme was therefore aimed to study the safety and efficacy of lower doses of intravenous cinaciguat (,200 mg/h) as add-on to standard therapy in patients hospitalized with acute decompensated heart failure and a left ventricular ejection fraction of ,40%. COMPOSE was terminated early due to an excess of non-fatal hypotension and recruitment difficulties. COMPOSE was composed of three parts. In COMPOSE 1, a reduction in wedge pressure was confirmed but, considering the low number of patients (n 1⁄4 12), no meaningful conclusion could be drawn. In COMPOSE 2, only four patients were included, and no results were reported. Both studies had problems with their inclusion, since there had to be a clinical indication requiring invasive haemodynamic monitoring, and recent data indicated that haemodynamic monitoring is no longer routinely recommended in acute decompensated heart failure patients. In the third part of this programme, COMPOSE EARLY (n 1⁄4 62), no meaningful difference in dyspnoea was shown between cinaciguat and placebo. The authors conclude that ‘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. ’ So, why did cinaciguat fail? A consistent strong reduction in PWCP was found with cinaciguat, which is considered as the main mechanism to improve symptoms and clinical outcome in acute heart failure. However, with the same dose that reduced wedge pressure by 6 mm in COMPOSE 1, no effect was found on improvement of dyspnoea in COMPOSE EARLY. This is remarkable, given the general consensus that reducing wedge pressure in acute heart failure is a major treatment goal. However, such a strong and fast reduction of the wedge pressure might also have deleterious effects, and a sudden drop in blood pressure can cause other organs, such as the kidney, to fail as well. Unfortunately, cinaciguat is not the first acute heart failure drug that fails to demonstrate meaningful beneficial effects in patients with acute heart failure. Other failures include phosphodiesterase inhibitors (e.g. milrinone), endothelin antagonists (e.g. tezosentan),