“Anagrelide-induced pulmonary arterial hypertension”: a rare case of drug-induced pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension can be associated with exposure to certain drugs or toxins. However, only a few cases of drug-induced pulmonary arterial hypertension have been previously reported. Anagrelide is an oral imidazoquinazoline agent that is prescribed for reducing elevated platelet counts in patients with myeloproliferative disorders. We report the case of a 70-year-old female patient who developed pulmonary arterial hypertension after taking anagrelide for the treatment of polycythemia vera. Pulmonary arterial hypertension promptly improved after the discontinuation of anagrelide. Anagrelide-induced pulmonary arterial hypertension is a very rare disease, and our case shows that it might be reversible.

Introduction

Pulmonary arterial hypertension (PAH) is a rare disease characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance due to pulmonary vascular remodeling, which results in right ventricular failure and sometimes becomes fatal if left untreated. Pulmonary endothelial cell injury and dysfunction as well as major endothelial dysfunction pathways are strongly suspected to be involved in the development of pulmonary vascular remodeling in patients with PAH.^1,2 PAH can be induced by exposure to some kinds of drugs or toxins. Drug-induced PAH is categorized into group 1 (PAH) and subgroup 1.3 (drug- and toxin-induced PAH) in the updated clinical classification of pulmonary hypertension (PH) proposed in the recent 2018 World Symposium on PH. ³

The pathological and clinical assessments of drug-induced PAH are similar to those of other forms of PAH including intimal fibromuscular proliferation or plexiform lesions. ³ Surveillance of suspicious drugs and investigation of the clinical course are crucial in diagnosing this type of PAH.^4,5

Anagrelide (Agrylin®) is an oral imidazoquinazoline agent that is prescribed for reducing elevated platelet counts and ameliorating thrombohemorrhagic events in patients with myeloproliferative disorders. ⁶

Here, we report the case of a 70-year-old female patient who developed PAH associated with anagrelide use for the treatment of polycythemia vera.

Case description

A 70-year-old female patient with polycythemia vera was referred and admitted to our hospital because of severe dyspnea and systemic edema. She had been treated previously for polycythemia vera with hydroxycarbamide. However, because of severe adverse effects such as nausea and diarrhea, hydroxycarbamide was switched to anagrelide about a month before hospitalization. After the switch to anagrelide, nausea and diarrhea quickly improved. However, about a week after the switch, she realized chest discomfort. Symptoms including shortness of breath and systemic edema gradually appeared over a month. These symptoms worsened, and the World Health Organization functional class of the patient on admission became III. Her serum brain natriuretic peptide (BNP) level was elevated (847 pg/mL), whereas the blood test was negative for D-dimer. Chest radiography showed dilatation of the pulmonary artery and cardiomegaly with a cardiothoracic ratio of 65.5%. Transthoracic echocardiography revealed right atrial and ventricular dilatation and severe tricuspid regurgitation with an elevated trans-tricuspid pressure gradient of 45 mmHg and compression of the left ventricle (D-shaped left ventricle), whereas the left ventricle ejection fraction was normal at 58% (Fig. 1). McConnell sign was observed on right ventricular wall motion. Pulmonary embolism was not detected on contrast computed tomography. Lung ventilation and perfusion scintigraphy revealed no evidence of ventilation perfusion mismatch. As anagrelide was considered a potential contributor to the development of PAH, it was discontinued and replaced with hydroxycarbamide. Within 20 days after discontinuing anagrelide, the clinical symptoms associated with PAH completely disappeared. The serum BNP level decreased to 40.53 pg/mL. Transthoracic echocardiography showed downsized right atrium and ventricle and trace tricuspid regurgitation with a normalized trans-tricuspid pressure gradient of 18 mmHg. The echocardiographic parameters also improved. The hemodynamic parameters of right heart catheterization were within the normal limits, with mean pulmonary arterial pressure of 16 mmHg and pulmonary vascular resistance of 2.36 Wood units.

Fig. 1.

Transthoracic echocardiography at the first visit. (a) Right atrial and ventricular dilatation. (b) Left ventricle is compressed by right ventricle. (c) Tricuspid regurgitation is severe. (d) Trans-tricuspid pressure gradient is 45 mmHg.

Discussion

The patient in this case report had polycythemia vera and developed severe PAH after about a month of treatment with anagrelide. Anagrelide was discontinued, and PAH promptly improved within 20 days. To our best knowledge, this is probably the first case report on anagrelide-induced PAH. In the aforementioned clinical classification of PH, PH due to hematological disorders is classified into group 5.1. Although the present patient had polycythemia vera, PAH was judged to be induced by anagrelide based on the clinical course. In a prospective long-term observational cohort (3649 patients) study evaluating the efficacy and safety of anagrelide, Birgegard et al. reported that 4 of 804 patients treated with anagrelide developed PAH (0.15%), whereas 5 of 2666 patients treated with cytoreductive therapy developed PAH (0.05%). There was a trend of a high incidence of PAH induced by anagrelide; however, no significant difference was observed (p = 0.226 by Fisher’s exact test). ⁷ The 2018 World Symposium task force proposed classifying PAH associated with drugs and toxins into two subgroups. “Definite association” refers to association with drugs having data based on epidemics, epidemiological case–control studies, large multicenter series, and pathophysiological mechanisms, including aminorex, fenfluramine, dexfenfluramine, methamphetamines, benfluorex, dasatinib, and toxic rapeseed oil. “Possible association” is suggested from isolated case reports, small series, or cases treated with drugs with similar mechanisms of action, including cocaine, amphetamines, phenylpropanolamine, L-tryptophan, St. John’s wort, interferon α and β, alkylating agents, bosutinib, direct-acting antiviral agents against hepatitis C virus, leflunomide, and indirubin (Chinese herb Qing-Dai). ³ Montani et al. reported that the incidence of PAH in patients exposed to dasatinib, which is one of the “Definite association” agents inducing PAH, was estimated to be 0.45%. ⁸ Guignabert et al. reported that dasatinib caused pulmonary vascular damage, induction of endoplasmic reticulum stress, and mitochondrial reactive oxygen species production, which led to increased susceptibility to PAH development, in their study using human blood samples and a rat model. ² The mechanism of anagrelide-induced PAH remains unclear. However, in the present case report, rapid clinical, functional, and hemodynamic improvements were observed within 20 days of anagrelide discontinuation. These observations support the hypothesis that anagrelide-induced PAH might be reversible.

Improved awareness and recognition of the possibility that anagrelide can induce the development of PAH will allow the early diagnosis and management of these patients. More studies investigating the mechanism of anagrelide-induced PAH are still needed.