LITTLE FALLS, N.J., July 29 -- The National Heart, Lung, and Blood Institute has halted a trial of sildenafil (Revatio) in sickle cell patients with pulmonary hypertension because of increased hospitalizations for sickle cell crises, or severe pain, the agency said.
Some 38% of sickle-cell patients in the Walk-PHaSST trial taking sildenafil to treat pulmonary hypertension had serious adverse events -- primarily sickle cell pain crises -- compared with 8% of placebo patients (P=0.006).
"Unexpectedly, the drug was inducing this sickle cell complication," said Mark Gladwin, MD, lead investigator of the trial and director of the Vascular Medicine Institute at the University of Pittsburgh.
Dr. Gladwin said the complication is "very serious, but common" among sickle-cell patients, with most having about two related hospitalizations per year.
But he said that the interim data show "a really big imbalance [between treatment and placebo groups]. It's hard to imagine that it's not real."
The study was halted nearly a year early, after an interim review of safety data from 33 patients over 16 weeks of treatment.
Dr. Gladwin said the researchers will now analyze the data gathered thus far for efficacy in treating pulmonary hypertension in these patients.
As far as an explanation for the pain findings, Dr. Gladwin said the drug may have an effect on nitric oxide signaling, which can increase the sensation of pain.
A previous pilot study of 12 patients did not yield similar results regarding sickle cell crises, Dr. Gladwin said. Patients in that trial, however, were treated with hydroxyurea, which is used to manage painful attacks associated with sickle cell disease.
"It may be that sildenafil is safe for patients on hydroxyurea therapy, but we don't know," he said.
The Walk-PHaSST study began recruiting patients in July 2007 and enrolled 74 who were randomly assigned to either sildenafil or placebo for 16 weeks. After that, patients could enroll in a yearlong open-label follow-up.
A total of 33 participants had completed the trial when it was halted on July 7, 2009.
NHLBI director Elizabeth Nabel, MD, noted that because the medical problems in the trial were complications specific to sickle cell disease, the findings don't apply to other patients with pulmonary hypertension for whom the drug "has been found to be safe and effective."
Dr. Nabel said sickle cell patients taking sildenafil for pulmonary hypertension should talk with their physicians about potentially tapering off the medication.