Higher Revatio dose not linked to increased mortality in PAH: Trial

FDA allows dose titration up to 80 mg following study

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by Andrea Lobo |

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Treatment with Revatio (sildenafil) at a higher dose than the recommended and previously approved doses did not significantly increase mortality of adults with pulmonary arterial hypertension (PAH).

That’s according to results from the Phase 3b/4 AFFILIATE trial (NCT02060487), which compared three treatment doses, each given three times a day (5 mg, 20 mg, and 80 mg).

The 80 mg dose was superior to the lower, 5 mg regimen in improving exercise capacity and extending the time to clinical worsening.

“On the basis of these findings, the U.S. Food and Drug Administration [FDA] recently revoked the approval of 5 mg of sildenafil for adults with PAH, reinforced 20 mg TID [three times daily] as the recommended dose, and now allows dose titration up to 80 mg TID if needed,” the researchers wrote.

The study, “Randomized, Multicenter Study to Assess the Effects of Different Doses of Sildenafil on Mortality in Adults With Pulmonary Arterial Hypertension,” was published in the journal Circulation.

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FDA required study to evaluate risk

PAH is a form of pulmonary hypertension characterized by the narrowing of the pulmonary arteries, the blood vessels that transport blood through the lungs, leading to high blood pressure, or hypertension.

Revatio is marketed by Viatris for children and adults with PAH. It works by prompting blood vessels to relax and widen, reducing blood pressure. The treatment is approved at a dose of 20 mg, three times a day. Regulators had approved a lower, 5 mg dose, also three times daily, after a clinical trial showed similar benefits in exercise capacity compared with the 20 mg dose.

A long-term study including a parent clinical trial and its extension in children and adolescents showed therapeutic benefit, but also suggested an increased risk of death with higher-than-recommended doses of Revatio. Based on this, the FDA required a study to evaluate the risk of death in adults receiving at 5 mg, 20 mg, and 80 mg. The FDA recommended against chronic use of Revatio in children.

In the Phase 3b/4 trial, 385 adults with PAH were randomly assigned to receive one of the three doses of Revatio, given as oral tablets three times a day with or without food. Most participants were women (77.1%), mean age was 51.6 years, and idiopathic PAH, or of unknown cause, was the most common diagnosis (71.6%).

The main goal of the trial was to demonstrate that the 80 mg dose did not increase mortality compared with the 5 mg dose. Secondary goals included the time to clinical worsening and changes in exercise capacity, evaluated by the six-minute walk test.

During a mean observation period of 32 months, 78 patients (20%) died. The higher percentage was found in the 5 mg group (26.4%) and the lowest with 80 mg group (14.8%). The most common cause of death was PAH-related complications.

Further analysis revealed that patients treated with 80 mg three times daily had a statistically significant, 49% lower risk of death due to any cause than participants in the 5 mg group. Compared with the 20 mg dose, the risk was 26% lower.

The estimated five-year overall survival was significantly superior with 80 mg than with 5 mg (79.4% vs. 60.3%). Survival at three years already indicated superiority of the 80 mg regimen.

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Clinical outcomes evaluated

Treatment with 80 mg Revatio significantly reduced the time for the first event of clinical worsening compared with the 5 mg dose, defined as a reduction of at least 15% in the 6-minute walking distance and worsening of the patient’s functional class from baseline (before the treatment).

The mean improvement in six-minute walking distance after six months, compared with baseline, was higher with 80 mg (31.2 m), followed by 20 mg (27.3 m), and 5 mg (12.2 m). The benefit with 80 mg three times daily was significantly superior to the 5 mg dose group. Results at one year of treatment were similar.

As for safety, the number of patients with treatment-emergent adverse events (worsening with or occurring only with Revatio) was similar between the three groups, and they were mostly mild to moderate intensity. The incidence of serious side effects was higher in the 5 mg group, but few treatment-related serious adverse events were reported overall.

The proportion of patients who discontinued treatment due to adverse events was higher in the 80 mg group (15.6%) than in the 5 mg (11.6%) and the 20 mg (10.2%) groups.

The researchers noted that study limitations included the lack of a placebo group and a long study period (starting in 2012) that as a result included different PAH treatment strategies that changed with time.

The study was funded by Pfizer and Upjohn, a former division of Pfizer that merged with Mylan to form Viatris.

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