Phosphodiesterase Type-5 Inhibitor Therapy in Sickle Cell People With Pulmonary Hypertension

There is a lack of evidence-based treatment for patients with sickle cell disease (SCD) with pulmonary hypertension (PH). PH is a leading cause of mortality in SCD and is an independent risk factor for mortality in this population. SCD is a major health problem worldwide, primarily affecting people of African descent. In the United States approximately 100,000 individuals have SCD and 0.2% of African Americans have homozygous SS sickle cell disease, while 8% of African Americans carry one allele and have sickle cell trait. In developed countries, even in the current era of hydroxyurea, SCD patients have relatively shortened lifespans with a median life expectancy of approximately 48 years for females and 42 years for males.

PH affects up to 1/3 of adults screened by echocardiography and pre-capillary PH is diagnosed in 6% by right heart catheterization (RHC). Data suggest that either precapillary or post-capillary PH in SCD are associated with a 5-fold risk of early mortality, and SCD subjects with echocardiographic signs of both have a 13-fold risk of early mortality. Though a cause and effect relationship between the presence of PH and early mortality in adult subjects with SCD has not been conclusively established, data regarding the causes of death in a prospective observational study of adult SCD patients suggest that cardiopulmonary cause of death was present in at least 35% of patients.

The World Health Organization (WHO) reclassified SCD-related PH as Group 5 in 2013. Therefore, SCD-related PH is not eligible for vasodilator therapies currently available for WHO Group 1 pulmonary arterial hypertension (PAH). There have only been three prospective clinical trials of vasodilator therapies in sickle cell patients with RHC-defined PH. After the findings of the Walk-PHaSST study were reported, a strong recommendation against sildenafil in sickle cell patients with PH was made in guidelines published by the American Thoracic Society in 2014. However, a major limitation of the trial was that, in order to improve trial feasibility, subjects were eligible for enrollment based on an elevated TRV, as well as RHC-defined PH, leading to incomplete hemodynamic characterization of study patients. The physiologic understanding of the differences between subjects who developed SAEs and those who tolerated sildenafil remains poorly understood. In individual circumstances, some patients may have chosen to continue sildenafil. If some patients with SCD-related PH have continued to benefit from sildenafil therapy in the time since this clinical trial was reported, it would raise the question of whether a subgroup of SCD-related PH patients may still benefit from PDE5-Is and how these patients could be clinically characterized.

Given the difficulty of enrolling SCD-related PH patients into prospective, multi-center trials, for example as demonstrated by the ASSET trials being closed due to low enrollment, we plan to utilize existing clinical data available on patients who were documented to have RHC- defined PH prior to initiation of PDEI-5 therapy, in order to better characterize the use of this medication in patients with SCD-related PH.

• INCLUSION CRITERIA:
• Subjects aged 18 and older, participated in 001-H-0088 and 04-H-0161
• a diagnosis of SCD
• a diagnosis of PH by right heart catheterization
• prescribed and/ or reported taking PDE5-I therapy for a duration of greater than or equal to 16 weeks. (We will not be able to use medication dispensation records alone to verify whether subjects were compliant as not all medications were dispensed directly from the NIH pharmacy.)