A recent study in Circulation explained what is behind those changes. “Safety concerns arose because of common off-label use of higher doses, particularly after pediatric data linked higher doses to increased mortality,” an international study team led by German researchers from Hannover Medical School wrote. “To assess this, the Food and Drug Administration mandated a study evaluating the effects of various sildenafil doses on mortality in adults with PAH.”
The randomized, double-blind study compared sildenafil at dosages of 5, 20, or 80 mg tid in adults with PAH. The primary objective was defined as noninferiority of 80 mg of sildenafil versus 5 mg for all-cause mortality. The researchers considered secondary endpoints to be time to clinical worsening and the change in 6-minute walk distance at 6 months.
Interim analyses were planned at 50% and 75% of the anticipated mortality events. Safety and tolerability were assessed in the intention-to-treat population.
The study was halted after the first interim analysis when noninferiority for 80 mg of sildenafil versus 5 mg was clearly demonstrated.
The researchers pointed out that of the 385 patients enrolled across all dosage groups, 78 had died. “The primary analysis showed a hazard ratio of 0.51 (99.7% CI, 0.22-1.21; P <.001 for noninferiority) for overall survival comparing 80 mg of sildenafil with 5 mg,” the researchers wrote. “Time to clinical worsening favored 80 mg of sildenafil compared with 5 mg (hazard ratio, 0.44 [99.7% CI, 0.22-0.89]; P <.001). Sildenafil at 80 mg improved 6-minute walk distance from baseline at 6 months compared with 5 mg (least square mean change, 18.9 m [95% CI, 2.99-34.86]; P = .0201).”
On the other hand, no significant differences were found between 80 mg of sildenafil and 20 mg in mortality, clinical worsening, and 6-minute walk distance, although adverse event–related drug discontinuations were numerically higher with 80 mg of sildenafil.
The authors concluded, “Sildenafil at 80 mg was noninferior to sildenafil at 5 mg when examining all-cause mortality in adults with PAH. Secondary efficacy end points favored 80 mg of sildenafil over 5 mg.”
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