Author: Michael A. Evans, MD; Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern Feinberg School of Medicine
A three-year-old female toddler with severe idiopathic pulmonary arterial hypertension presents to the emergency department with two months of worsening lethargy. Routine labs demonstrate a hemoglobin of 8.2 g/dL. Which of the following medications for the treatment of pulmonary hypertension is MOST LIKELY associated with the observed hemoglobin level?
Macitentan is an orally-active endothelin receptor antagonist (ERA) used in the treatment of pulmonary hypertension. Currently, three oral ERAs are prescribed in children for the treatment of pulmonary hypertension: macitentan, bosentan, and ambrisentan. Currently, the only FDA-approved oral ERA in children is bosentan. A fourth oral endothelin receptor antagonist, sitaxsentan, was withdrawn from the market in 2010 due to several reports of fatal liver injury.
A meta-analysis of 4894 patients taking macitentan, bosentan, or ambrisentan from 24 randomized trials found that the most common adverse effects of oral ERAs were abnormal liver function, peripheral edema, and anemia. Interestingly, the adverse effects stratified differently by drug type.
• Bosentan use poses a statistically significant risk of elevated hepatic enzymes when compared to placebo, whereas macitentan does not demonstrate an increased risk. Ambrisentan significantly decreases the risk of abnormal liver function.
• Bosentan and ambrisentan have a statistically significant risk of causing peripheral edema when compared to placebo, but there is no increased risk with macitentan.
• Bosentan and macitentan pose a significantly higher risk of anemia when compared to placebo, but there is no increased risk with ambrisentan.
Bosentan-induced anemia has generally been mild in clinical trials and has not been associated with a need for discontinuation of the drug. Regardless, the current recommendation for clinical surveillance of anemia in patients on bosentan includes monitoring a hemoglobin level every three months. Macitentan-induced anemia appears to be dose-dependent and may warrant discontinuation of the medication. The mechanism by which oral ERAs cause anemia is not known, but it is suspected that fluid retention yields at least some dilutional anemia.
Selexipag is an additional pulmonary hypertension medication that is used off-label in children. It is also associated with anemia. In fact, 8.6% of patients treated with selexipag will experience a decrease in hemoglobin concentration to less than 10 g/dL during treatment. Selexipag and its metabolite selectively bind the prostacyclin PGI2 receptor, which promotes pulmonary vasodilation, but also inhibits platelet aggregation. Fortunately, the largest trial to date, the GRIPHON trial, did not demonstrate an increased rate of bleeding in patients with PAH who were taking selexipag. Other side effects of selexipag include headache, jaw pain, and hyperthyroidism.
Sildenafil is a phosphodiesterase-5 inhibitor (PDE5-I) used in the treatment of pulmonary arterial hypertension in adults. It is often used off-label for the same indication in children. It induces smooth muscle relaxation in the pulmonary arterial bed. Side effects are relatively rare, but include headache, pyrexia, upper respiratory tract infection, vomiting, and diarrhea. Importantly, an increased risk of mortality was observed with increasing doses in children, especially after one to two years of chronic use. In 2012, the FDA revised the drug label for sildenafil to state that the “use of [sildenafil], particularly chronic use, is not recommended in children.” Later, the FDA clarified that “this recommendation was not intended to suggest that [sildenafil] should never be used in children." It remains a mainstay of therapy in pediatric pulmonary hypertension.
Epoprostenol is a prostanoid-type of pulmonary vasodilator used in the treatment of pulmonary arterial hypertension. Epoprostenol was the first and single drug that demonstrated a decrease in mortality with its use in patients with idiopathic or heritable pulmonary arterial hypertension. In children with higher risk of clinical deterioration, initiation of epoprostenol may be indicated. Epoprostenol acts as a synthetic analog of prostaglandin I2 in endothelial cells and has a vasodilatory effect. The drug also has anti-inflammatory, anti-aggregation, and antiproliferative effects as well. The drug is administered in an intravenous formulation, thus complications include catheter-associated infection or thrombosis. Other common side effects include jaw pain, headache, nausea, or diarrhea. Anemia is not associated with epoprostenol use.
Knowledge of the specific side effects of pulmonary hypertension medications is quite important, as it is common to treat pulmonary hypertension in children with a combination of medications. This practice may be referred to as “triple therapy,” when it includes a phosphodiesterase-5 inhibitor, an endothelin receptor antagonist, and a prostanoid. While efficacious, triple therapy poses an increased risk of anemia given adverse effect overlap of the three medication classes. The risk of anemia may be further compounded in the presence of therapy with antiplatelet agents, vitamin K antagonists, or factor Xa inhibitors due to an increased risk of bleeding.
Of the answer choices, macitentan is most likely to be associated with anemia.
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