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Study of PAH Treatment in Patients With Sickle Cell Disease Halted Due to Safety Concerns

BETHESDA, Md -- July 28, 2009 -- 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 1 year early due to safety concerns.

In an interim review of safety data from 33 participants who completed 16 weeks of treatment, researchers found that 38% of participants taking sildenafil (Revatio) had serious adverse effects -- primarily sickle cell pain crises -- compared with 8% of participants in the placebo group. No deaths have been associated with the drug in the clinical trial.

The walk-Pulmonary Hypertension and Sickle Cell Disease With Sildenafil Therapy (walk-PHaSST) study was a multicentre, randomised trial testing the safety and effectiveness of sildenafil for pulmonary hypertension in patients with sickle cell disease

"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 Elizabeth G. Nabel, MD, NHLBI, Bethesda, Maryland. "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," she said.

Because the medical problems experienced in walk-PHaSST were complications specific to 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," Dr. Nabel added.

The NHLBI stopped the study on July 7, 2009, based on the unanimous recommendations of the Pulmonary Complications of Sickle Cell Disease Data and the Safety Monitoring Board (DSMB). This DSMB is composed of experts in sickle cell disease, lung disease, statistics, and bioethics.

Participants in walk-PHaSST have discussed the preliminary findings of the study with their study clinicians. They have been instructed to taper sildenafil treatment over a period of 3 to 7 days to minimise problems associated with immediate withdrawal from the drug, such as worsening of symptoms of pulmonary hypertension. Researchers will continue to monitor participants and conduct further analyses to assess the findings.

Walk-PHaSST was designed to determine whether sildenafil lessens the symptoms of pulmonary hypertension, such as shortness of breath, by improving heart and lung function, in individuals with sickle cell disease who develop pulmonary hypertension. The primary outcome measure was the results of a 6-minute walk test.

Researchers began recruiting participants in July 2007 and enrolled 74 patients aged over 19 years (mean age, 45 years). Participants had sickle cell disease and mild to severe pulmonary hypertension. They were randomly assigned to receive sildenafil or placebo for 16 weeks. Participants could also receive other therapies as needed to manage sickle cell and related complications.

After completing the study treatment (or placebo), participants could choose to be part of the open-label follow-up phase of the study and continue to be assessed for up to 1 year. In the open-label study, participants and clinicians knew that sildenafil was being taken. When the study was stopped, 33 participants had completed the clinical trial.

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

SOURCE: National Institutes of Health

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