Drug-induced Pulmonary Arterial Hypertension

Drug induced pulmonary arterial hypertension is pre-capillary pulmonary hypertension caused by exposure to a drug or toxin. It presents with exertional dyspnoea and right heart failure, with pre-capillary haemodynamics (mean pulmonary artery pressure over 20 mmHg, pulmonary artery wedge pressure 15 mmHg or under, pulmonary vascular resistance over 2 Wood units). Early recognition matters because stopping the agent can lead to improvement or resolution in some patients.

Agents with a definite association are aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib and toxic rapeseed oil. Agents with a possible association include other amphetamines, cocaine, phenylpropanolamine, L-tryptophan, St John's wort, interferon alfa and beta, alkylating agents (mitomycin C and cyclophosphamide, usually in veno occlusive disease), bosutinib, leflunomide and direct acting antivirals for hepatitis C.

Dasatinib associated disease occurs in under 1% of treated patients, after a median of about 3 years of treatment (range from months to over 8 years). Methamphetamine associated disease is more severe than IPAH and carries worse survival.

Appetite suppressant associated disease can appear years after exposure, and fenfluramine also causes valvular heart disease.

Pathophysiology.

Serotonergic drugs (fenfluramine, aminorex, amphetamines) act on 5-HT2B receptors and the serotonin transporter, driving smooth muscle proliferation and endothelial dysfunction in susceptible patients.

Dasatinib causes endothelial injury through Src family kinase inhibition, mitochondrial stress and oxidative injury, and the effect partly reverses on withdrawal. Other tyrosine kinase inhibitors have different effects.

Genetic susceptibility (BMPR2 and other variants) may modify risk, so genetic counselling can be needed.

Exertional dyspnoea, fatigue, syncope, chest pain and oedema, appearing months to years after exposure. Patients on dasatinib may have pleural effusion at the same time. Fenfluramine exposure may add aortic and mitral valve regurgitation. Look for signs of right ventricular failure and for signs of drug use.

• Detailed drug history: prescription, over-the-counter, herbal, recreational and appetite suppressants, with dates of exposure.
• Echocardiography and NT-proBNP, ventilation perfusion scan, pulmonary function tests with diffusing capacity, high resolution CT, and tests to exclude other causes (HIV, autoimmune screen, liver tests).
• Right heart catheterisation: mean pulmonary artery pressure over 20 mmHg, wedge pressure of 15 mmHg or less, pulmonary vascular resistance over 2 Wood units. Acute vasoreactivity testing with inhaled nitric oxide 10 to 20 ppm (positive when mean pressure falls by 10 mmHg or more to under 40 mmHg with cardiac output preserved).
• Dasatinib: baseline echocardiography before starting, repeat for new dyspnoea, and confirm with catheterisation before attributing disease to the drug.
• Fenfluramine for epilepsy: echocardiography at baseline, every 6 months during treatment, and 3 to 6 months after stopping.
• Risk stratum: low (functional class I or II, 6-minute walk over 440 m, NT-proBNP under 300 ng/L), intermediate (class III, 165 to 440 m, 300 to 1100 ng/L), high (class IV, under 165 m, over 1100 ng/L, syncope).

Differential diagnosis.

• Idiopathic and heritable pulmonary arterial hypertension.
• Pulmonary hypertension from left heart disease, lung disease or thromboembolism.
• Pulmonary veno occlusive disease from chemotherapy.
• Drug induced pleural effusion, interstitial lung disease or cardiomyopathy.

Stop the agent. Withdraw the suspected drug as soon as the diagnosis is made, in discussion with the prescriber.

• Dasatinib: stop and monitor. Clinical and haemodynamic improvement occurs in many patients within 3 to 4 months, though a minority have persistent disease. Choose an alternative kinase inhibitor with the haematology team, accepting that this may carry its own cardiovascular risk. Do not rechallenge.
• Methamphetamine and other stimulants: refer to addiction services for sustained abstinence. Continued use worsens outcome, and treatment response is poorer than in IPAH.
• Appetite suppressants and fenfluramine: stop, and assess valve disease with echocardiography.
• Interferon: stop and use an alternative antiviral.

Specific therapy for persistent disease follows IPAH, by risk stratum. All drugs are continued long term.

• Ambrisentan 5 mg orally once daily, increased to 10 mg after 4 weeks (maximum 10 mg), with tadalafil 40 mg once daily (start 20 mg in mild to moderate renal or hepatic impairment; avoid when creatinine clearance is under 30 mL/min). Alternative: macitentan 10 mg once daily with tadalafil. Haemoglobin and liver tests at baseline and when indicated; avoid endothelin receptor antagonists in moderate to severe hepatic impairment. Contraindicated with nitrates and riociguat for tadalafil.
• Bosentan 62.5 mg orally twice daily for 4 weeks, then 125 mg twice daily (maximum 250 mg daily), with monthly ALT and AST, is an alternative.
• Sildenafil 20 mg three times daily is an alternative to tadalafil.
• Add on and high risk therapy: selexipag 200 microgram twice daily titrated weekly to a maximum of 1600 microgram twice daily; riociguat 1 mg three times daily titrated every 2 weeks by 0.5 mg to a maximum of 2.5 mg three times daily (not with phosphodiesterase-5 inhibitors); epoprostenol intravenously from 2 ng/kg/min or treprostinil from 1.25 ng/kg/min; sotatercept 0.3 mg/kg then 0.7 mg/kg subcutaneously every 3 weeks with haemoglobin and platelet monitoring.
• A calcium channel blocker is used only after a positive acute vasoreactivity test (nifedipine modified release up to 240 mg daily, diltiazem up to 720 mg daily, or amlodipine up to 20 mg daily), and continued only when functional class I or II is reached.
• Endothelin receptor antagonists, riociguat and sotatercept are teratogenic: exclude pregnancy before starting and monthly.

General measures. Diuretics (furosemide 40 to 120 mg orally daily with spironolactone 25 to 100 mg daily; potassium under 5.0 mmol/L, eGFR over 30), oxygen for PaO2 under 8 kPa, vaccination, iron correction and avoidance of pregnancy. Routine anticoagulation is not used. Lung transplantation assessment for progressive disease.

Monitoring. Clinical review, NT-proBNP and 6-minute walk at 3 to 4 months after stopping the drug, with repeat echocardiography and, when abnormal, catheterisation. Then every 3 to 6 months while on specific therapy. For fenfluramine, echocardiography every 6 months.

Referral and escalation. Refer to a pulmonary hypertension centre. Urgent referral for syncope, high risk status, or progression after withdrawal. Report the reaction to the medicines safety service.

Special groups.

• Pregnancy: pregnancy is advised against in persistent disease. Stop the causative drug; avoid teratogenic pulmonary hypertension drugs.
• Children: fenfluramine for epilepsy and dasatinib for leukaemia are used in children, so monitor with echocardiography under paediatric specialists.
• Kidney or liver impairment: adjust tadalafil and avoid endothelin receptor antagonists in significant hepatic impairment.
• Region specific: herbal and unregulated products and illicit stimulants are important sources of exposure, so ask directly.