Trial stopped early due to increase in sickle cell crises associated with sildenafil

In July, the National Heart, Lung, and Blood Institute of the NIH halted a randomized trial examining the safety and efficacy of sildenafil in patients with sickle cell disease and pulmonary hypertension. According to data from a press release, 38% of patients assigned to sildenafil had serious adverse effects compared to 8% of patients assigned to placebo.

“The increase in sickle cell medical problems is concern enough for us to stop this clinical trial to protect the safety of our participants,” Elizabeth G. Nabel, MD, director of the NHLBI, said in a press release.

The study, walk test for Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (walk-PHaSST), was the first multicenter, randomized trial to examine the safety and efficacy of sildenafil (Revatio, Pfizer) in patients with sickle cell disease.

The purpose of the study was to determine whether sildenafil would reduce symptoms of pulmonary hypertension, including shortness of breath, by improving heart rate and lung function. The result of a six-minute walk test indicated participants’ heart and lung function; it was the primary outcome measure. Reports of adverse effects and laboratory tests were also used to evaluate the safety of sildenafil in this patient population.

Seventy-four patients with sickle cell disease and mild to severe pulmonary hypertension were enrolled. Patients were randomly assigned sildenafil or placebo for 16 weeks; other therapies used to manage sickle cell disease were allowed as needed. After 16 weeks patients had the choice of whether or not to participate in an open-label follow-up phase where they would be assessed for up to one year.

The interim review included safety data for 33 patients who completed 16 weeks of treatment. The review revealed that patients assigned to sildenafil were more likely to have sickle cell crises resulting in hospitalization compared with patients assigned to placebo (38% vs. 8%). The drug has not been associated with any deaths in the clinical trial.

Based on these findings, the Pulmonary Complications of Sickle Cell Disease Data and Safety Monitoring Board unanimously recommended the study be stopped; on July 7, 2009 the NHLBI complied. The advisory group had been monitoring the study since its inception.

The preliminary findings of the study were discussed with participants; they have been instructed to taper treatment over a period of three to seven days to minimize problems associated with immediate withdrawal from the drug, according to the press release. Potential problems include worsening symptoms of pulmonary hypertension. Researchers continue to observe participants and will perform further analyses to evaluate the findings.

“We will continue to look into the possible causes of these preliminary results,” Nabel said in the press release. “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 of this medication and how to best manage both sickle cell disease and pulmonary hypertension.”

According to Nabel, the findings from walk-PHaSST should not be applied to other groups of patients with pulmonary hypertension in which sildenafil was found to be safe and effective, due to the fact that the complications observed are specific to sickle cell disease.