Phosphodiesterase type 5 (PDE5) inhibitors were found to have statistical and clinical benefits for World Health Organization (WHO) Group 1 Pulmonary Arterial Hypertension (PAH) compared with placebo in terms of mortality, improvement in functional class, time to clinical worsening, hemodynamics, 6-minute walk distance (6MWD), and quality of life, including dyspnea, according to data published in the Cochrane Database of Systematic Reviews.
In this review, researchers analyzed 36 single randomized controlled trials, including 2999 patients in which PDE5 inhibitors were compared with placebo or any other treatment. Three formulations of PDE5 inhibitors were used, including sildenafil, tadalafil, and vardenafil. Studies lasted an average of 12 weeks.
Two review authors independently extracted data from included studies up to September 26, 2018, from The Cochrane Airways Group Register of Trials, Cochrane Central Register of Controlled Trials through the Cochrane Register of Studies Online, MEDLINE®, Embase®, US National Institutes of Health Ongoing Trials, and the WHO International Clinical Trials Registry Platform.
Included studies compared any type of PDE5 inhibitors by any route of administration with placebo or any other treatment used for pulmonary hypertension as well as any studies with co-interventions that were not part of the randomized treatment.
Nineteen of the 36 randomized control trials analyzed included findings for participants with group 1 PAH. Notable findings for these participants included significant improvement in WHO functional class favoring PDE5 inhibitors when compared with placebo (odds ratio [OR], 8.59; 95% CI, 3.95-18.72; P <.001; 4 trials, n=282); significant reduction in the mean pulmonary artery pressure (95% CI, −8.13 to −4.74; P <.001; 6 trials, n=453); and significant improvement in 6MWD using PDE5 inhibitors compared with placebo (95% CI, 40-56; P <.001; 8 trials, n=880).
There was an increased risk for adverse events with use of PDE5 inhibitors compared with placebo, including headache (OR, 1.97; 95% CI, 1.33-2.92; 5 trials, n=848), gastrointestinal upset (OR, 1.63; 95% CI, 1.07-2.48; 5 trials, n=848), flushing (OR, 4.12; 95% CI ,1.83-9.26; 3 trials, n=748), and muscle aches and joint pains (OR, 2.52; 95% CI, 1.59-3.99; 4 trials, n=792).
Researchers acknowledged potential limitations by publication bias and that failure to identify unpublished negative trials could have led to an overestimation of effect. The quality of evidence was high across all outcomes for trials including group 1 participants with PAH that compared PDE5 inhibitors with placebo, except with regard to 6MWD and cardiac index, which were downgraded to moderate because of high heterogeneity in the studies analyzed.
The researchers of this study suggested a benefit for the use of PDE5 inhibitors in group 1 PAH. Clinicians and patients should be aware of possible adverse effects, especially headache, flushing, gastrointestinal upset, and muscle and joint pain.
Disclosures: Multiple authors declare affiliations with the pharmaceutical industry. Please refer to reference for a complete list of authors’ disclosures.
Barnes H, Brown Z, Burns A, Williams T. Phosphodiesterase 5 inhibitors for pulmonary hypertension. Cochrane Database Syst Rev. 2019;1:CD012621.