What is the effect of Tadalafil on heart failure?

From the Guidelines

Tadalafil has no established benefit in the treatment of heart failure, particularly in patients with heart failure with preserved ejection fraction (HFpEF) 1. The RELAX trial, which randomized 216 patients with EF ≥50% on stable HF therapy and with reduced exercise tolerance to phosphodiesterase-5 inhibition with sildenafil or placebo, did not show improvement in oxygen consumption or exercise tolerance.

• Mechanism of action: Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor, which augments the nitric oxide system by upregulating cGMP activity.
• Clinical trials: The RELAX trial and the NEAT-HFpEF trial found no beneficial effects of PDE5 inhibitors or nitrates on activity levels, quality of life, exercise tolerance, or NT-proBNP levels in patients with HFpEF.
• Guideline recommendations: The 2017 ACC/AHA/HFSA focused update recommends against the routine use of nitrates or phosphodiesterase-5 inhibitors to increase activity or quality of life in patients with HFpEF (Class III: No Benefit) 1.
• Other uses of Tadalafil: Tadalafil is approved for the treatment of erectile dysfunction and has been studied in the treatment of pulmonary arterial hypertension (PAH), where it has shown favorable results on exercise capacity and clinical worsening 1.

From the FDA Drug Label

Tadalafil is not recommended for patients with New York Heart Association Class 2 or greater heart failure in the last 6 months. The drug label for tadalafil 2 states that patients with certain cardiovascular diseases, including heart failure, were not included in clinical safety and efficacy trials, and therefore, tadalafil is not recommended for these groups of patients.

• Specifically, the label mentions that tadalafil has mild systemic vasodilatory properties that may result in transient decreases in blood pressure, which could be a concern for patients with heart failure.
• Additionally, the label notes that patients with left ventricular outflow obstruction can be sensitive to the action of vasodilators, including PDE5 inhibitors like tadalafil.
• The label also advises physicians to carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by the vasodilatory effects of tadalafil 2.
• Another study 2 found that tadalafil did not affect cardiac function, hemodynamics, or exercise tolerance in a clinical pharmacology study, but this study was conducted in patients with stable coronary artery disease, not heart failure.

From the Research

Effect of Tadalafil on Heart Failure

• Tadalafil, a phosphodiesterase-5 (PDE-5) inhibitor, has been shown to have a cardiovascular-protective effect in patients with erectile dysfunction and cardiovascular disease, including heart failure 3.
• A study published in 2024 found that tadalafil did not improve outcomes in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension, and may have potential safety concerns 4.
• Another study published in 2016 found that saxagliptin and tadalafil differentially altered cyclic guanosine monophosphate (cGMP) signaling and left ventricular function in aortic-banded mini-swine, with saxagliptin appearing superior for treating heart failure with preserved ejection fraction 5.
• A study published in 2022 found that tadalafil treatment improved cardiac, renal, and lower urinary tract dysfunctions in rats with heart failure, suggesting its potential as a multi-therapeutic drug 6.
• A retrospective observational cohort study published in 2024 found that tadalafil exposure was associated with lower rates of major adverse cardiovascular events and mortality in a general population of men with erectile dysfunction 7.

Mechanism of Action

• Tadalafil works by inhibiting the enzyme phosphodiesterase-5 (PDE-5), which catalyzes the hydrolysis of cyclic guanosine monophosphate (cGMP), a potent vasodilator 3.
• The increase in cGMP levels leads to the activation of protein kinase A, upregulation of the intracellular Ca2+ concentration, and improvement of hemodynamic indexes 3.
• Tadalafil has also been shown to elevate the endothelial cell-derived nitric oxide (NO) level, which is a key player in the regulation of vascular tone and cardiac function 3.

Clinical Implications

• The use of tadalafil in patients with heart failure should be carefully considered, taking into account the potential benefits and risks, as well as the individual patient's characteristics and medical history 4.
• Further studies are needed to fully understand the effects of tadalafil on heart failure and to determine its potential as a therapeutic option for this condition 4, 5, 6, 7.