A Randomised, Double-Blinded, Placebo-Controlled Study of the Phosphodiesterase Type 5 Inhibitor Sildenafil for the Treatment of Preeclampsia

Abstract

Objective: To determine if the phosphodiesterase type 5 inhibitor sildenafil prolongs pregnancy in women with preeclampsia. Methods: Women with preeclampsia at gestational ages 24–34 weeks were recruited from nine hospitals in the UK, and randomly assigned to sildenafil citrate or placebo. Medication was increased every 3 days from 20 mg three times daily (tid), to 40 mg, and 80 mg tid. The primary endpoint was prolongation of pregnancy from randomisation to delivery (days). Secondary endpoints were markers of maternal disease and cord pH at delivery and infant weight. Details of all adverse events were also collected. Plasma samples were taken to establish pharmacokinetic information. Data analysed on a modified intention to treat analysis. The study had a power of >95% to detect a difference of 5 days. Results: Of 35 women, 17 were allocated to sildenafil and 18 to placebo. There was no difference in time from randomisation to delivery in the two treatment groups, with a median time of 4 days (range 1–15) in the sildenafil group and 4.5 days (range 1–30) in the placebo group. Sildenafil achieved maximum drug concentrations of 48 ng/ml, 88 ng/ml, and 271 ng/ml after 3 days of 20 mg, 40 mg and 80 mg tid, respectively. Conclusion: We have safely conducted a clinical trial of a drug not routinely used during pregnancy. Sildenafil in the escalating dose regimen 20–80 mg tid was well tolerated, with no increase in maternal or fetal morbidity or mortality but did not prolong pregnancy duration in women with preeclampsia. (ClinicalTrials.gov number, NCT 00141310).

Keywords:

• Phosphodiesterase type 5 inhibitors
• Preeclampsia
• Treatment
• Randomised controlled trial

Acknowledgements

Adjudication Committee: P. N. Baker, D. Howe

Data Monitoring Committee: J. Thornton (chairman), J. Rennie, T. Cole, and N. Brayshaw.

The authors thank Marianne Crombie, Jane Tracey, Rebekah Samangaya, Angeli Thallon and Bing Liu for recruiting patients. We thank the staff and principal investigators at the following centers: Ninewells Hospital, Dundee – G. Mires, Hope Hospital, Salford – T. Kelly, St Mary's Hospital, Manchester – P. Baker, Royal Bolton Hospital – J. Tomlinson, Forthpark Hospital – G. Tydeman, St Thomas Hospital, London – A. Shennan, C. Nelson-Piercy, Tameside General Hospital – A. Watson, T. Mahmood, Pembury Hospital – S. Flint, Chelsea & Westminster Hospital – D. Williams. Liverpool Womens Hospital – S. Quenby, Wythenshawe Hospital – T. Onon, Stepping Hill Hospital, Stockport – C. Candelier, West Middlesex Hospital – J. Girling, Stirling Royal Infirmary – F. Crichton

Declaration of Interests: The clinical trial was funded by Pfizer Ltd, Sandwich, UK. Each recruiting hospital received a sum of money for every woman they recruited. R.A. Samangaya was funded through a grant by Pfizer UK Ltd. G. Mires and A.H. Shennan have no conflict of interests. D. Howe and A. McLeod are current employees of Pfizer UK Ltd, and L. Skillern is a former employee of Pfizer UK Ltd. P.N. Baker was Primary Investigator on University of Manchester research grants funded by Pfizer UK Ltd.