Long-Term Phosphodiesterase 5 Inhibitor Use Improves Symptoms in Patients with Pre-Capillary Pulmonary Hypertension of Sickle Cell Disease

RATIONALE:

Pulmonary hypertension (PH) occurs in 6-10.5% of adults with sickle cell disease (SCD). Pre-capillary PH, or pulmonary arterial hypertension (PAH), occurs in approximately 40% of these patients and they may benefit from PAH-specific therapy. The use of phosphodiesterase-5 inhibitors (PDE5i) has been avoided due to evidence from prospective trials demonstrating an increased risk of vasoocclusive crises (VOCs). However, the physiologic understanding of the differences between patients who tolerate PDE5i therapy and those who do not remains poorly understood.

METHODS:

We performed a retrospective chart review of patients with SCD and pre-capillary PH diagnosed by right-heart catheterization (RHC) who were treated with PDE5i therapy for >4 months between 2008-2019 at two institutions. We collected demographics, medical history, medication use, and cardiopulmonary data on each patient before and after treatment with PDE5i. Data were analyzed using Stata 16.0.

RESULTS:

The 38 patients identified had a mean age of 44 ± 13.6 years; 60% were female and 82% had HbSS disease. Of these, 53% of patients had a history of acute chest syndrome, 42% had a history of venous thromboembolism and 26% had imaging consistent with chronic thromboembolic PH. In addition to PDE5i therapy, patients received the following treatments: hydroxyurea (61%), chronic transfusions (40%), epoprostenol (8%), bosentan (16%), riociguat (5%), and home oxygen therapy (43%). Patients were treated with PDE5i for a median of 25 months (25^th, 75^th percentile 13-60). At the time of data collection, 6/38 (16%) remain on this therapy. There was significant improvement in physical activity as reflected by NYHA Class associated with PDE5i use (p=0.002) but no improvement in six-minute walk distance or hemodynamics. Of 22 subjects with final RHC data, 2 subjects demonstrated complete normalization of hemodynamics following therapy. One subject (2.6%) reported discontinuing PDE5i therapy due to VOC.

CONCLUSION:

In SCD patients with pre-capillary PH defined by RHC, PDE5i therapy was tolerated long-term and may improve physical activity. This study supports the need for RHC evaluation of SCD patients with suspected PH and optimization of SCD-related treatments during long-term therapy. The use of these strategies in future PAH therapy clinical trials in patients with SCD is warranted.