Phosphodiesterase 5 inhibitors for pulmonary hypertension.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials
PubMed 30701543 · doi:10.1002/14651858.CD012621.pub2
What was done
A Cochrane systematic review searched CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science up to September 2018 for randomized controlled trials lasting at least 12 weeks comparing phosphodiesterase-5 (PDE5) inhibitors against placebo or other PAH-specific therapies across all WHO pulmonary hypertension (PH) groups. Primary outcomes were change in WHO functional class, six-minute walk distance (6MWD), and mortality, evaluated using GRADE criteria.
What was found
The review included 36 trials with 2,999 participants (mean trial duration 14 weeks). In Group 1 PAH (19 trials), PDE5 inhibitors improved WHO functional class (OR 8.59, 95% CI 3.95 to 18.72; 4 trials, n=282), increased 6MWD by 48 meters (95% CI 40 to 56; 8 trials, n=880), and reduced mortality (reported CI 0.07 to 0.68; 8 trials, n=1119; NNT = 32; high-certainty evidence). PDE5 inhibitors increased adverse events, including flushing (OR 4.12), myalgia/arthralgia (OR 2.52), headache (OR 1.97), and gastrointestinal upset (OR 1.63). In Group 1 combination therapy, adding a PDE5 inhibitor increased 6MWD by 19.66 meters (95% CI 9 to 30; 4 trials, n=509; moderate certainty). In Group 2 (left-heart disease, 5 trials), 6MWD improved by 34 meters (95% CI 23 to 46; 3 trials, n=284), but odds of functional class improvement were reduced (OR 0.53, 95% CI 0.32 to 0.87; 3 trials, n=285) with no mortality difference (low certainty). In Group 3 (lung disease, 5 trials), 6MWD increased by 27 meters (low certainty). In Group 4 (chronic thromboembolic disease, 3 trials), no significant differences were observed (low certainty).
Why it matters
This review establishes high-certainty evidence that PDE5 inhibitors improve survival and functional capacity in Group 1 PAH. It indicates that evidence remains weak, inconsistent, or potentially unfavorable for routine use in secondary pulmonary hypertension due to left-heart, lung, or thromboembolic diseases.
Limits
Mean trial duration was short (14 weeks), limiting conclusions about long-term efficacy and safety. Data for non-Group 1 PH were low quality due to imprecision, small sample sizes, and heterogeneity. Only two trials included pediatric participants, and direct head-to-head comparisons against other PAH-specific therapies like endothelin receptor antagonists were limited (2 trials, n=36).