Table 2.

Drugs that showed encouraging results in the early phase of clinical heart failure trials

Class	Molecules	Class/molecular mode of action	Postulated mechanism in HF	Clinical effects, safety/efficacy in HF
Endothelin receptor antagonists (ETRAs)	Bosentan, Darusentan, Tezosentan	Bosentan, Tezosentan: mixed endothelin‐1 (ET1) A/B receptor antagonists Darusentan: selective ET1A receptor antagonist	Antagonism of ET1‐A receptors to functionally antagonize the vasoconstrictor effects of ET Agonists of ET1‐B receptors leads to vasodilatation via release of NO and prostacyclin	Despite pharmacological differences between ET1A‐selective (Darusentan) and mixed ETRAs (Bosentan, Tezosentan), none of them could reduce morbidity or mortality rates in mid‐sized dose‐finding trials on HF35, 36, 37
Vasopressin receptor antagonist (VRAs, vaptans)	Tolvaptan, Conivaptan, Lixivaptan	VRAs block the vasoconstriction caused by VP and block renal water reabsorption. They are vasodilatory and aquaretic in nature	Decrease PCWP and RAP, increase water excretion	Tolvaptan: • EVEREST trial: neither positive nor negative effect on all‐cause mortality or combined endpoint of CV mortality or subsequent hospitalization for worsening HF38 • METEOR study: No effects on LVEF or volumes39 Conivaptan: Lowering of PCWP, RAP, and PAP after a single dose.40 No data on the long‐term use on HF patients available Lixivaptan: No trial on morbidity and mortality conducted
Soluble guanylyl‐cyclase modulators (sGC modulators)	Cinaciguat, Vericiguat	Activate sGC, increase levels of soluble cGMP and lead to vasodilatation	Reduce BP, PAP, PCWP, increase CO, preserve GFR41	Cinaciguat: • Reduced BP, PCWP, PVR, and increased CI. Reduction in BP led in part to severe hypotension42 • COMPOSE program (consisting of 3 independent RCTs): BP reductions without improvement in dyspnea or CI. Program was prematurely stopped43 Vericiguat: • SOCRATES‐REDUCED trial: Patients who received vericiguat did not meet the primary endpoint of lowering NT‐proBNP levels44
Prostacyclin analogs (prostanoids)	Epoprostenol	Prostanoids are direct vasodilators of pulmonary and systemic arterial vascular beds, inhibit platelet aggregation	Increase CI, decrease PAP, RAP, PVR	Epoprostenol: Reduced PCWP and SVR and increased CI. The trial was prematurely terminated owing to trend for lower survival rate with epoprostenol15
Calcium sensitizers	Levosimendan, Pimobendan	Inodilators, i.e., combination of calcium sensitization (positive inotrope without affecting calcium transient) and vasodilatation via PDE3 inhibition	Inodilators are positive inotropic agents, reduce preload/afterload, and increase coronary and organ blood flow	Levosimendan: Despite reductions in BNP levels and mortality benefits suggested by several meta‐analyses,45, 46 RCTs with levosimendan either indicated an increased risk of adverse cardiovascular events47 or were neutral48 Pimobendan: The PICO trial showed increased exercise capacity but increased mortality rate after treatment 49
Natriuretic peptides (BNP analogues)	Recombinant BNP, Nesiritide	BNP is the endogenous ligand for natriuretic peptide‐A receptors, stimulation of GC leads to increased cGMP	Body's physiological reaction to pressure or volume overload. Vasodilatation in venous and arterial beds	Nesiritide: • ASCEND‐HF and the FUSION II trial did not demonstrate a reduction of mortality rates. • No indication of increased CV risk, supporting its use in the treatment of patients with acute decompensated HF who have dyspnea at rest or with minimal activity50, 51
Phosphodiesterase 3‐ inhibitor (PDE3I)	Amrinone Milrinone	PDE3I prevents degradation of cAMP to AMP, cAMP stimulates PKA which provides vasodilatation, increases intracellular calcium (positive inotropic), and activates SERCA (positive lusitropic)	Amrinone: Reduction in cardiac afterload, increase in CO, reduction in left ventricular filling pressure, no changes in BP and HR Milrinone: Increases CI, reduces PCWP52	Amrinone: • Beneficial acute hemodynamic effects were not reproducible after 12‐weeks of administration. No change in NYHA class, LVEF, and mortality rates. Adverse events (nausea, vomiting, and diarrhea) with amrinone were frequent and led to need for treatment down‐titration or discontinuation53 Milrinone: • Despite beneficial hemodynamic effects, long‐term use was associated with increased frequency of ventricular arrhythmias and reduced survival duration.16, 54 Milrinone is approved for short‐term IV use in acute decompensated HF
Partial PDE3 inhibitor, an ion‐channel modifier	Vesnarinone	Complex mechanism of action with following components: ‐ Weak PDE3 inhibition ‐ Prolongation of action potential duration ‐ Increases intracellular sodium and calcium concentrations ‐Inhibition of cytokine production	Increases CI, reduced PCWP, increases exercise capacity	Vesnarinone was associated with a dose‐dependent increase in mortality in chronic HF patients55

AMP, adenosine monophosphate; BP, blood pressure; cAMP, cyclic adenosine monophosphate; BP, blood pressure; BNP, B‐type natriuretic peptide; cGMP, cyclic guanosine monophosphate; CHF, chronic heart failure; CI, cardiac index; CO, cardiac output; CV, cardiovascular; ET, endothelin; ETRA, endothelin receptor antagonist; EVEREST, Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan; FUSION, Follow‐Up Serial Infusions of Nesiritide; GC, guanylyl cyclase; GFR, glomerular filtration rate; HF, heart failure; HR, heart rate; IV, intravenous; LVEF, left ventricular ejection fraction; METEOR, Multicenter Evaluation of Tolvaptan Effect On Remodeling; NO, nitric oxide; NT‐proBNP, N‐terminal pro B‐type natriuretic peptide; NYHA, New York Heart Association; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PDE, phosphodiesterase; PDE3I, PDE3 inhibitor; PKA, protein kinase A; PICO, Pimobendan in Congestive Heart Failure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RCT, randomized controlled trial; REVIVE, Randomized EValuation of Intravenous LeVosimendan Efficacy; sGC, soluble guanylyl cyclase; SOCRATES‐REDUCED, The Soluble Guanylate Cyclase Stimulator in Heart Failure with Reduced Ejection Fraction Study; SURVIVE, The Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support; SVR, systemic vascular resistance; VRA, vasopressin receptor antagonist; VP, vasopressin; SERCA, sarco/endoplasmic reticulum Ca²⁺‐ATPase.