Study of Treatment for Pulmonary Hypertension In Sickle Cell Patients Stopped Due to Safety Concerns

 *NHLBI Stops Study of Treatment for Pulmonary Hypertension in Patients 
with Sickle Cell Disease Due to Safety Concerns *

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. In an interim review of 
safety data from 33 participants who completed 16 weeks of treatment, 
researchers found that, compared to participants on placebo (dummy 
pill), 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.

Known as walk-PHaSST, the study was the first multicenter, randomized 
clinical trial to test the safety and effectiveness of sildenafil for 
pulmonary hypertension in patients with sickle cell disease, one of the 
most common genetic blood disorders in the United States. Pulmonary 
hypertension is a debilitating condition of high blood pressure in the 
arteries that carry blood to the lungs, which can lead to heart failure 
and death. Approximately 30 percent 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 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, M.D. “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."

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,” Nabel added.

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 NHLBI stopped the study 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.

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 three to seven days to 
minimize 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 six-minute walk test, a standard indicator of a 
person's heart and lung function. Hence, the name walk-PHaSST reflects 
the primary test used to assess effectiveness of the treatment ("walk" 
test) for _P_ulmonary _H_ypertension _a_nd _S_ickle Cell Disease with 
_S_ildenafil _T_herapy. Researchers also evaluated the safety of the 
drug for sickle cell disease patients through reports of adverse effects 
and laboratory tests.

Sildenafil is approved by the Food and Drug Administration for use in 
patients with pulmonary hypertension. In general, the drug treats 
pulmonary hypertension by relaxing the blood vessels in the lungs to 
allow blood to flow more easily. Since sildenafil is not FDA-approved to 
treat pulmonary hypertension in patients with sickle cell disease, the 
walk-PHaSST study was conducted under an investigational new drug 
application. The FDA was notified of the termination of the study on 
July 14.

Walk-PHaSST began recruiting participants in July 2007 and enrolled 74 
patients over the age of 19 (average age 45). 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 one 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.

Researchers found that 38 percent of participants taking sildenafil had 
serious adverse effects -- primarily sickle cell pain crises -- compared 
to 8 percent of participants in the placebo group.

"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 Mark Gladwin, M.D., lead investigator of walk-PHaSST and 
director of the Vascular Medicine Institute at the University of 
Pittsburgh. Gladwin is also a special volunteer for the NHLBI and was 
formerly a senior investigator with the Critical Care Medicine 
Department at the NIH Clinical Center and chief of the NHLBI Pulmonary 
and Vascular Medicine Branch.

The design of the walk-PHaSST study was based on extensive evidence that 
sildenafil improves pulmonary hypertension regardless of its cause and 
on results of a small, open-label, nonrandomized pilot study led by 
Gladwin while he was at the NIH. The pilot study evaluated 12 sickle 
cell patients with mild or moderate pulmonary hypertension who were 
being treated with sildenafil and with hydroxyurea, a drug known to help 
reduce the numbers of episodes of sickle cell pain crises and acute 
chest syndrome, as well as hospitalizations and blood transfusions 
needed. In 2005, Gladwin and his colleagues reported that after about 6 
months, sildenafil was well tolerated, decreased pulmonary blood 
pressure, and increased exercise capacity.

"Walk-PHaSST emphasizes the importance of multi-site, blinded, 
randomized clinical trials to increase our understanding of both the 
benefits and the potential risks of specific treatments," noted Jonathan 
C. Goldsmith, M.D., NHLBI project officer of walk-PHaSST. "As with all 
clinical studies, patient safety is paramount."