The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health has stopped a clinical trial testing a drug treatment for pulmonary hypertension in adults with sickle cell disease nearly one year early due to safety concerns.

According to an announcement from the NHLBI, an interim review of safety data from 33 participants who completed 16 weeks of treatment, showed that, compared to participants on placebo, participants taking sildenafil (Revatio) were significantly more likely to have serious medical problems. The most common problem was episodes of severe pain (called sickle cell crises), which resulted in hospitalization. No deaths have been associated with the drug in the clinical trial.

"The increase in sickle cell medical problems is concern enough for us to stop this clinical trial to protect the safety of our participants," said NHLBI director Elizabeth G. Nabel, MD, in the announcement. “We will continue to look into the possible causes of these preliminary results. In the meantime, we encourage patients with sickle cell disease who are taking sildenafil for pulmonary hypertension to talk with their physicians about the potential risks and benefits of the medication and what actions they should consider, including whether to taper off this medication and how to best manage both sickle cell disease and pulmonary hypertension."

The study, known as walk-PHaSST, was the first multicenter, randomized clinical trial to test the safety and effectiveness of sildenafil for pulmonary hypertension in patients with sickle cell disease. The NHLBI reports that approximately 30% of sickle cell disease patients develop pulmonary hypertension, and even mild levels of pulmonary hypertension have been associated with sudden death in people with sickle cell disease.

“The findings of the walk-PHaSST study should not be applied to other groups of patients with pulmonary hypertension where the drug has been found to be safe and effective,” said Nabel, because the medical problems experienced were complications specific to sickle cell diseas.

Researchers are conducting extensive analyses of the study results, which could contribute to recommendations for treating pulmonary hypertension in patients with sickle cell disease. They will prepare reports of their research for publication in peer-reviewed journals.

The study was stopped on July 7, 2009, based on the unanimous recommendations of the Pulmonary Complications of Sickle Cell Disease Data and Safety Monitoring Board (DSMB), an independent advisory group that has been monitoring the study since it began. This DSMB is composed of experts in sickle cell disease, lung disease, statistics, and bioethics.

According to the NHLBI, participants in walk-PHaSST discussed the preliminary findings of the study with their study clinicians and were instructed to taper sildenafil treatment over a period of three to seven days to minimize problems associated with immediate withdrawal from the drug. Researchers will continue to monitor participants and conduct further analyses to assess the findings.

"Although these preliminary results are disappointing, we expect that the study’s results, once fully analyzed, will provide important insights into the role of pulmonary hypertension in sickle cell disease," said lead investigator of walk-PHaSST Mark Gladwin, MD, director of the Vascular Medicine Institute at the University of Pittsburgh.