By Anthony J. Brown, MD
NEW YORK (Reuters Health) Dec 07 - A study to see whether sildenafil would improve walk distance in patients with sickle cell anemia and pulmonary hypertension had to be stopped when it turned out the drug increased the risk of vaso-occlusive crises.
The trial results were presented this week at the 51st annual meeting of the American Society of Hematology in New Orleans.
"The increase in vaso-occlusive pain episodes was unexpected," senior researcher Dr. Mark Gladwin told Reuters Health. "The results suggest that increasing NO-cGMP signaling can increase pain. We expected the effects of NO-cGMP to increase blood flow and reduce vaso-occlusion, but other effects on pain signaling may have been greater."
The findings stem from the Walk-PHaSST (Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) study -- "the first placebo-controlled trial of a drug to treat pulmonary hypertension in sickle cell disease," noted Dr. Gladwin, who is with the University of Pittsburgh Medical Center.
The researchers had enrolled 150 adolescents and adults with Doppler-defined pulmonary hypertension and a 6-minute walk distance of 150 to 500 meters. However, only 74 patients received the assigned treatment (either sildenafil or placebo) and only 33 completed the final 16-week assessment, as the study was terminated early due to a significant increase in adverse events in the sildenafil arm.
Overall, 46% of sildenafil-treated subjects had a serious adverse event compared with 22% of controls (p = 0.048). Further analysis revealed that the difference was due to a higher rate of hospitalization for sickle cell anemia with crisis in the sildenafil group: 35% vs. 11% (p = 0.025). No adverse events were classified as life threatening.
In terms of efficacy, testing in 22 subjects showed that a single 60-mg test dose of sildenafil significantly reduced mean pulmonary arterial pressure and mean systemic arterial pressure, but did not affect pulmonary vascular resistance. No side effects were noted with this one-time dose.
Despite the acute changes seen with a single dose of sildenafil, no significant improvements in Doppler-defined pulmonary hypertension or 6-minute walk distance were seen after 16 weeks of therapy.
At 6- and 10-week assessments, the sildenafil-treated subjects reported worsening pain during walking and less enjoyment of life compared with the controls.
"Pulmonary hypertension remains the most common risk for death in adults with sickle cell disease, but sildenafil or phosphodiesterase-5 inhibitors cannot be used safely in this population unless their sickle cell disease is well controlled," Dr. Gladwin emphasized. "New studies are needed to find new treatments" and to investigate "why increasing NO-cGMP signaling increases pain."
Reuters Health Information © 2009
Cite this: Sildenafil for Pulmonary Hypertension Increases Pain Crises in Sickle Cell Patients - Medscape - Dec 07, 2009.