Phosphodiesterase 5 Inhibitors for Pulmonary Hypertension

A Cochrane review [Abstract] 1 included four studies on the clinical efficacy of the vasodilator sildenafil in patients with pulmonary hypertension (PH), with a total of 77 subjects. Two studies assessed the acute effects of sildenafil. Two small crossover study assessed the effects of long term administration. The 'acute effect' studies indicated that sildenafil has a pulmonary vasodilatory effect. The two crossover studies showed improvement in symptoms. One study showed improvement in fatigue domains from a validated health status questionnaire. Both crossover studies reported that the drug was well tolerated.

Another Cocrane review [Abstract] 2 included 36 studies with a total of 2 999 subjects (with PH from all causes). Nineteen studies included World Health Organisation (WHO) group 1 pulmonary arterial hypertension (PAH) participants. PDE5 inhibitors decreased mortality, improved WHO functional class, and 6-minute walk distance (6MWD) in PAH patients (table T1). There was an increased risk of adverse events (headache, gastrointestinal upset, flushing, muscle aches and joint pains) with PDE5 inhibitors. PDE5 inhibitors compared to placebo whilst on other PAH-specific therapy: PAH participants on PDE5 inhibitors plus combination therapy walked 19.66 metres further in 6 minutes (95% CI 9 to 30, statistical heterogeneity I² =62%; 4 studies, n=509) compared to placebo. Limited number of studies compared PDE5 inhibitors directly with other PAH-specific therapy (endothelin receptor antagonists, ERAs). Subjects on PDE5 inhibitors walked 49 metres further than on ERAs (95% CI 4 to 95; 2 studies, n=36).

PH secondary to left-heart disease (PH-LHD): Significantly fewer people receiving PDE5 inhibitors improved in WHO functional class compared to placebo (OR 0.53, 95% CI 0.32 to 0.87, statistical heterogeneity I² =67%; 3 studies, n=285). Those using PDE5 inhibitors walked 34 metres further compared to placebo (95% CI 23 to 46, statistical heterogeneity I² =79%; 3 studies, n=284). PH secondary to lung disease/hypoxia, mostly in COPD: There was a small improvement of 27 metres in 6MWD using PDE5 inhibitors compared to placebo (5 studies, n=350). There was no evidence of worsening hypoxia using PDE5 inhibitors, although data were limited. Chronic thromboembolic disease: There was no significant difference in any outcomes (3 studies), but data quality was low due to imprecision of effect and heterogeneity across studies.

The following decision support rules contain links to this evidence summary:

• Drug therapy for severe pulmonary hypertension http://www.ebmeds.org/ebmeds/ebmeds_home.asp?mode=scripts&submode=view&id=scr00577&country=UK

References

• Kanthapillai P, Lasserson T, Walters E. Sildenafil for pulmonary hypertension. Cochrane Database Syst Rev 2004;(4):CD003562. [PubMed]
• Barnes H, Brown Z, Burns A et al. Phosphodiesterase 5 inhibitors for pulmonary hypertension. Cochrane Database Syst Rev 2019;(1):CD012621. [PubMed]