Phosphodiesterase Type-5 Inhibitor Therapy in Sickle Cell People With Pulmonary Hypertension
Condition: Pulmonary Hypertension; Sickle Cell Disease
MeSH terms: Hypertension, Pulmonary; Hypertension; Anemia, Sickle Cell
Study type: Observational

Summary: 
      Background:

      Sickle cell disease (SCD) is a common inherited blood disorder. Many people with SCD are at
      risk to get pulmonary hypertension (PH). PH means that the blood pressure in the blood
      vessels to the lungs is high, and is a serious disease and. Very few studies have looked at
      the success of treatments for PH in people with SCD. Researchers want to learn more about
      treating PH with a type of drug called phosphodiesterase type 5 inhibitors (PDE5-I). They
      will look at the records of people who have already joined other studies.

      Objective:

      To identify people who already joined NIH SCD protocols whose medical records should be
      reviewed. The review will look at the description of SCD patients with PH who have already
      taken PDE5-I and the outcomes for these people.

      Eligibility:

      Adults ages 18 and older with SCD and PH. They must have joined certain NIH studies and taken
      PDE5-I therapy for at least 16 weeks.

      Design:

      This study is a review of medical records.

      Researchers will collect data from databases of existing studies. They will identify people
      in those studies who have SCD and PH and took the study drug for at least 16 weeks.

      Researchers will review the full medical records of those people.

      From that review, researchers will find participants who meet the inclusion criteria. They
      will extract data from those records.

      Researchers will analyze the data. This includes results from heart and lung tests, imaging,
      and walking tests. It will also include results of a procedure called right heart
      catheterization.

      Demographic data and lab data will also be collected.

      Researchers will remove identifying information from the data, then share it in a database.
    

Detailed description: 
      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.
    

Observational model: Cohort
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        Subjects aged 18 and older, participated in 001-H-0088 and 04-H-0161 and 1) a diagnosis of
        SCD 2) a diagnosis of PH 3) prescribed and/ or reported taking PDE5-I therapy for a
        duration of >16 weeks.
      
Keywords: Outcomes Assessment; Sickle Cell Disease