What is the management of Pulmonary Arterial Hypertension (PAH) associated with Sickle Cell Disease (SCD)?

From the Guidelines

Management of sickle cell disease associated PAH requires a multidisciplinary approach, focusing on optimizing SCD management and PAH-specific therapy, with endothelin receptor antagonists like bosentan or ambrisentan as first-line treatments, as recommended by the American Society of Hematology 2019 guidelines 1. The cornerstone of treatment involves optimizing SCD management through regular blood transfusions or exchange transfusions to maintain hemoglobin S levels below 30%, and hydroxyurea therapy (starting at 15-20 mg/kg/day) to reduce hemolysis and vaso-occlusive crises.

• Key considerations for PAH-specific therapy include:
  • Endothelin receptor antagonists like bosentan (62.5 mg twice daily for 4 weeks, then 125 mg twice daily) or ambrisentan (5-10 mg daily) as first-line treatments
  • Phosphodiesterase-5 inhibitors such as sildenafil (20 mg three times daily) or tadalafil (40 mg once daily) may be added, though caution is warranted as they can potentially increase vaso-occlusive crises in some patients
  • Prostacyclin analogs like epoprostenol (initiated at 2 ng/kg/min and titrated upward) are reserved for severe cases
• Additional recommendations include:
  • Oxygen supplementation to maintain oxygen saturation above 90%
  • Regular echocardiographic monitoring every 6-12 months to assess treatment response, with right heart catheterization performed to confirm diagnosis and evaluate hemodynamics
  • Anticoagulation is generally avoided due to increased bleeding risk in SCD patients
  • A multidisciplinary approach, including hematology, PH specialist, pulmonary medicine, or cardiology, is essential when considering PAH-specific therapies for SCD patients who have PAH confirmed by right-heart catheterization 1. The American Thoracic Society clinical practice guideline also supports the use of targeted PAH therapy, including prostacyclin agonists, endothelin receptor antagonists, soluble guanylate cyclase stimulators, or phosphodiesterase-5 inhibitors, which has been shown to improve exercise capacity and hemodynamics in patients with SCD-related PH 1.

From the FDA Drug Label

The effectiveness and safety of sildenafil citrate in the treatment of PAH secondary to sickle cell anemia has not been established. In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil citrate than by those randomized to placebo

The management of sickle cell disease associated PAH with sildenafil is not established due to lack of sufficient clinical data.

• Key points:
  • Sildenafil may increase the risk of vaso-occlusive crises in patients with sickle cell disease.
  • The safety and efficacy of sildenafil in this patient population has not been established 2.
• Clinical decision: Use of sildenafil for PAH secondary to sickle cell anemia cannot be recommended due to insufficient evidence and potential increased risk of vaso-occlusive crises.

From the Research

Management of Sickle Cell Disease Associated PAH

• The management of sickle cell disease associated pulmonary arterial hypertension (PAH) involves the use of endothelin receptor antagonists, which have shown efficacy in improving exercise capacity and reducing pulmonary artery pressure 3, 4.
• Endothelin receptor antagonists, such as bosentan and ambrisentan, have been used in the treatment of PAH in adult patients with sickle cell disease, with significant improvements in 6-minute walk distance and reductions in amino-terminal brain natriuretic peptide and tricuspid regurgitant velocity 3.
• The use of endothelin receptor antagonists in PAH has been extensively studied, with moderate-certainty evidence suggesting that they improve exercise capacity, WHO functional class, and cardiopulmonary hemodynamics, and may reduce mortality 4.
• However, the use of endothelin receptor antagonists is not without risks, with potential adverse events including hepatic toxicity, peripheral edema, and headache 3, 4.
• The choice of endothelin receptor antagonist may depend on individual patient characteristics, such as the presence of liver disease or other comorbidities, and the potential for pharmacokinetic interactions with other medications 5, 6.

Endothelin Receptor Antagonists in Sickle Cell Disease

• Sickle cell disease is characterized by elevated levels of endothelin-1, which contributes to the development of PAH and other complications 7.
• Endothelin receptor antagonists have been shown to reduce endothelin-1 levels and improve PAH symptoms in patients with sickle cell disease 3.
• The use of endothelin receptor antagonists in sickle cell disease may also have benefits beyond the treatment of PAH, including reducing the risk of renal events and improving exercise capacity 7, 6.

Future Perspectives

• Further research is needed to fully realize the potential benefits of endothelin receptor antagonists in the treatment of sickle cell disease associated PAH and other complications 6.
• The development of new endothelin receptor antagonists with improved safety and efficacy profiles may also be an important area of research 6.