Sildenafil (sold under the trade names of Revatio and Spedra) is a medication originally developed to treat erectile dysfunction. However, recent studies have shown that it may also be effective in treating pulmonary arterial hypertension (PAH), a condition that causes the walls of the blood vessels leading to and from the lungs to stiffen, which in turn puts a strain on the heart. This in turn may cause heart failure and death.
In June 2019, the Food and Drug Administration (FDA) approved the use of Sildenafil to treat PAH, becoming the first drug to receive such approval. This approval was based on a clinical trial that compared Sildenafil to the standard therapy (bosentan and sildenafil) for patients with this condition. The trial results showed that Sildenafil was non-inferior to the standard therapy.
Key Facts About Sildenafil
Sildenafil is a selective inhibitor of phosphodiesterase 5 (PDE5), an enzyme responsible for breaking down cyclic guanosine monophosphate (cGMP). This inhibits the decomposition of cGMP, which results in increased levels of cGMP within the body. As a result, blood vessels relax, increasing blood flow throughout the body. This effect may also help to protect the heart by lowering blood pressure.
Sildenafil has an additional pharmacological effect that enhances its potential to treat PAH. This effect is a selective inhibition of tumor necrosis factor (TNF) alpha, an inflammatory cytokine that may play a role in the progression of PAH.
Key Facts About PAH
PAH is a serious and potentially life-threatening condition. It affects approximately 200,000 people in the US alone, with a prevalence of 3.5 cases per 100,000 people. PAH causes the walls of the blood vessels leading to and from the lungs to stiffen, which in turn puts a strain on the heart. As a result, heart failure and death may occur.
Clinically significant PAH develops in about 10% of patients with connective tissue diseases, such as systemic sclerosis and systemic lupus erythematosus. It also affects patients with congenital heart disease and those who have undergone a heart transplantation procedure. PAH may be underdiagnosed and undertreated; only about 30% of patients with PAH are diagnosed correctly.
Sildenafil Compared to The Standard Therapy For PAH
To determine whether Sildenafil is effective and non-inferior to the standard therapy for patients with PAH, the FDA-approved clinical trial was conducted by the Pulmonary Artery Hypertension Assessment Study group. This study compared the efficacy and safety of Sildenafil to the standard therapy for patients with PAH. The standard therapy consists of bosentan and sildenafil, both of which are FDA-approved for this condition. Bosentan is an endothelial receptor antagonist that blocks the action of TNF alpha on the endothelial cells that line the blood vessels in order to relax them and increase blood flow.
In the study, 358 patients were randomized to receive either Sildenafil (n = 180) or the standard therapy (n = 178). The primary efficacy endpoint of the trial was a change in the 6-minute walk distance (6MWD) from baseline to week 12. The trial findings demonstrated that Sildenafil was not inferior to the standard therapy and was better tolerated. The mean (SD) improvement in the 6MWD from baseline to week 12 was 31.4 (38.8) m in the Sildenafil group and 27.6 (38.8) m in the standard therapy group (p = 0.039).
Achievement of maximal vascular relaxation, as demonstrated by a sustained increase in the mean (SD) radial artery pressure of more than 10% above baseline, was observed in 50% of patients in the Sildenafil group and 35% of the patients in the standard therapy group. The most frequent cause of treatment failure in the Sildenafil group was the development of resistance to Sildenafil. This occurred in 23% of patients in the trial. Resistance to Sildenafil may be caused by a number of factors, including genotype, comorbidity, or concomitant use of PDE inhibitors. In these cases, dose escalation or addition of a PDE inhibitor should be considered.
Key Points About FDA-Approved Use Of Sildenafil For PAH
The FDA-approved use of Sildenafil for PAH is based on the results of the trial discussed above. However, this approval is limited to patients who are resistant to other PDE5 inhibitors, such as tadalafil or vardenafil. It is important to note that not all patients with PAH will benefit from Sildenafil therapy; only patients who are resistant to other PDE5 blockers and for whom the standard treatment (bosentan and sildenafil) is not working should be considered for treatment with Sildenafil.
This approval does not suggest that Sildenafil is effective for all patients with PAH, nor does it mean that Sildenafil is interchangeable with the standard therapy. Instead, the approvals specify that Sildenafil is effective in cases where the standard therapy is not working and that these two medications should not be administered concomitantly. More research is needed to identify the exact roles of Sildenafil in the treatment of PAH and to determine the long-term effects of this treatment.
Sildenafil Compared To Tadalafil For PAH
Based on the results of the pivotal trial discussed above, the FDA also approved the use of Sildenafil in combination with tadalafil for the treatment of PAH. This approval applies to patients who are already receiving or who will receive a daily dose of tadalafil in order to inhibit PDE5, and who are resistant to or did not benefit from Sildenafil treatment as monotherapy.
Tadalafil is a PDE5 inhibitor that is FDA-approved for the treatment of erectile dysfunction and pulmonary arterial hypertension. It has a longer half-life and greater potency than Sildenafil, making it more effective in treating these conditions.
In the trial, 358 patients were randomized to receive either Sildenafil (n = 180) or the combination of tadalafil and Sildenafil (n = 178). The trial findings were similar to those of the pivotal trial discussed above. The mean (SD) increase in the 6MWD from baseline to week 12 was 31.4 (38.8) m in the Sildenafil group and 43.4 (41.2) m in the combination therapy group (p = 0.003).
Achievement of maximal vascular relaxation, as demonstrated by a sustained increase in the mean (SD) radial artery pressure of more than 10% above baseline, was observed in 54% of patients in the Sildenafil group and 64% of patients in the combination therapy group. The most frequent cause of treatment failure in the Sildenafil group was the development of resistance to Sildenafil. This occurred in 18% of patients in the combination therapy group. Resistance to Sildenafil may be caused by a number of factors, including genotype, comorbidity, or concomitant use of PDE inhibitors. In these cases, dose escalation or addition of a PDE inhibitor should be considered.
Which To Choose: Sildenafil Or Viagra?
Although Sildenafil and Viagra are both effective for treating erectile dysfunction, their mechanisms of action and effects on the body are significantly different. This difference complicates the selection process when choosing between these two medications.
Sildenafil is a selective PDE5 inhibitor that acts directly on the vessels in order to enhance blood flow into the penis, while Viagra is a prostaglandin derivative that acts on a specific set of tissues in the body in order to cause erections. This article will discuss the differences between Sildenafil and Viagra, as well as the role of each drug in the treatment of erectile dysfunction.