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Pulmonary arterial hypertension therapy

Drug therapy for group 1 pulmonary arterial hypertension in adults: the four treated pathways, each drug class and its trials, initial and follow-up combination strategy by risk, drug safety and interactions, special populations, and the use of these drugs outside group 1.

Which patients receive PAH-specific drug therapy

PAH-specific drugs are approved for group 1 pulmonary hypertension: idiopathic, heritable, and drug- or toxin-associated PAH, and PAH associated with connective tissue disease, human immunodeficiency virus (HIV) infection, portal hypertension, congenital heart disease, and schistosomiasis. The diagnosis rests on right heart catheterization showing pre-capillary pulmonary hypertension. This requires a mean pulmonary artery pressure (mPAP) above 20 mm Hg, a pulmonary artery wedge pressure (PAWP) of 15 mm Hg or less, and a pulmonary vascular resistance (PVR) above 2 Wood units (WU). Definitions, clinical groups, the diagnostic pathway, and risk scores are covered on the pulmonary hypertension page, and the measurements themselves on the right heart catheterization page.

The approved drugs were studied in patients who met the older hemodynamic definition, with an mPAP of 25 mm Hg or more and a PVR above 3 WU. No drug is approved for an mPAP of 21 to 24 mm Hg or a PVR of 2 to 3 WU. In that range, the 7th World Symposium on Pulmonary Hypertension (WSPH) recommends trial enrollment and close follow-up, and monotherapy if treatment is started anyway. An echocardiographic estimate of pulmonary pressure is never sufficient to start PAH therapy, because pulmonary hypertension from left heart disease, lung disease, and chronic thromboembolism looks the same on echocardiography and is treated differently. In left heart disease, PAH drugs can raise left atrial pressure and cause pulmonary edema.

The 2022 European Society of Cardiology and European Respiratory Society (ESC/ERS) guideline, the 7th WSPH treatment algorithm (2024), and the 2019 CHEST guideline all place diagnosis and the decision to treat in, or in collaboration with, a pulmonary hypertension center. No American College of Cardiology/American Heart Association (ACC/AHA) pulmonary hypertension guideline is current, and US practice follows the WSPH algorithm, the CHEST guideline, and US labeling. Pediatric PAH has separate dosing and evidence; sildenafil, bosentan, and selexipag also carry US pediatric labeling.

The four signaling pathways treated by PAH drugs

PAH is a proliferative vasculopathy of the small pulmonary arteries. Endothelial dysfunction lowers production of the vasodilator and antiproliferative mediators nitric oxide and prostacyclin and raises production of endothelin-1, a vasoconstrictor and mitogen. In parallel, reduced bone morphogenetic protein receptor type 2 (BMPR2) signaling, the pathway affected in most heritable PAH, shifts the balance of transforming growth factor-β superfamily signaling toward proliferation driven by activins and growth differentiation factors. Medial hypertrophy, intimal fibrosis, and plexiform lesions follow, PVR rises, and the right ventricle fails.

Endothelin pathway. Endothelin-1 binds endothelin A receptors on smooth muscle, causing vasoconstriction and proliferation. Endothelin B receptors are mostly on endothelium, where they release nitric oxide and prostacyclin and clear endothelin-1. Selective endothelin A blockade (ambrisentan) and dual A and B blockade (bosentan, macitentan) have similar clinical efficacy.

Nitric oxide, soluble guanylate cyclase, and cyclic GMP. Nitric oxide activates soluble guanylate cyclase (sGC) in smooth muscle, which forms cyclic guanosine monophosphate (cGMP), the mediator of relaxation and growth inhibition. PDE5, abundant in the pulmonary vasculature, degrades cGMP. PDE5 inhibitors slow degradation and depend on endogenous nitric oxide; the sGC stimulator riociguat sensitizes sGC to nitric oxide and stimulates it directly, so it acts when nitric oxide is scarce. Because both raise cGMP, they are never combined with each other or with nitrates.

Prostacyclin pathway. Prostacyclin binds the IP (prostacyclin) receptor, raises cyclic adenosine monophosphate (cAMP), and causes vasodilation, inhibition of platelet aggregation, and antiproliferative effects. Prostacyclin synthase expression is reduced in PAH. Epoprostenol is synthetic prostacyclin; treprostinil, iloprost, and beraprost are analogs; selexipag and ralinepag are nonprostanoid IP receptor agonists.

Activin signaling. Sotatercept is a fusion protein of the extracellular domain of activin receptor type IIA and the Fc portion of human immunoglobulin G1. It binds and sequesters activins and growth differentiation factors and rebalances growth-promoting and growth-inhibiting signaling. It has no acute vasodilator effect; its hemodynamic benefit develops over weeks and reflects reverse remodeling.

The four pathways treated in PAH, after the 7th WSPH treatment algorithm. Branded inhaled iloprost was withdrawn from the US market in 2025 after its only approved nebulizer was discontinued; beraprost is not approved in the United States or Europe. cGMP, cyclic guanosine monophosphate; sGC, soluble guanylate cyclase; BMPR2, bone morphogenetic protein receptor type 2.

PAH drugs approved in the United States: dosing, monitoring, and adverse effects

Adult dosing from current US prescribing information and the ESC/ERS 2022 dosing table. REMS, Risk Evaluation and Mitigation Strategy; CYP, cytochrome P450.

Supportive therapy that accompanies PAH drugs

General measures are part of every PAH regimen and are summarized in both the ESC/ERS guideline and the 7th WSPH.

• Supervised exercise training. Recommended in stable patients on medical therapy (ESC/ERS Class 1). In a randomized trial at 11 centers in 10 European countries, a standardized program improved 6-minute walk distance by 34 m over usual care, with gains in quality of life, functional class, and peak oxygen consumption. Exertion to the point of presyncope and heavy isometric effort are avoided.
• Diuretics. Recommended for fluid retention and signs of right ventricular failure (Class 1), with loop diuretics, thiazides, and mineralocorticoid receptor antagonists used alone or together. Fluid retention may be a drug effect, particularly of endothelin receptor antagonists, and not a sign of worsening disease. Intravascular depletion lowers cardiac output in a preload-dependent right ventricle.
• Oxygen. Long-term oxygen when arterial oxygen tension is below 60 mm Hg on at least two occasions (Class 1); ambulatory and nocturnal oxygen when desaturation is correctable and symptomatic.
• Iron. Iron deficiency (ferritin below 100 µg/L, or 100 to 299 µg/L with transferrin saturation below 20%) is common and is associated with worse symptoms and survival. Iron deficiency anemia is corrected (Class 1), preferably intravenously because oral absorption is impaired; repletion without anemia may be considered (Class 2b).
• Vaccination. Influenza, pneumococcal, and SARS-CoV-2 vaccination (Class 1). The 7th WSPH recommends respiratory syncytial virus vaccination for patients older than 60 years and states that it can be considered in PAH in general.
• Anticoagulation. Not generally recommended and individualized (Class 2b). Registry data in idiopathic PAH conflict; in systemic sclerosis-associated PAH, they suggest no benefit and probable harm. Anticoagulation is used for another indication, such as atrial fibrillation. Epoprostenol labeling advises anticoagulation in patients with a central catheter to reduce thromboembolism, while the ESC/ERS guideline leaves this to center practice.
• Drugs for systemic hypertension and left heart failure. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, beta-blockers, and ivabradine are not recommended in PAH unless a comorbidity requires them (Class 3), because they can lower blood pressure, heart rate, or both.
• Psychosocial support and adherence. Depression and anxiety are common; psychosocial support is recommended (Class 1), and adherence is reviewed regularly because unplanned interruption of some PAH drugs is dangerous.
• Travel and altitude. In-flight oxygen is recommended for patients on oxygen or with an arterial oxygen tension below 60 mm Hg at sea level (Class 1). Altitudes above 1,500 m without supplemental oxygen are avoided. Patients travel with a medication list and extra doses.
• Surgery and anesthesia. Procedures requiring anesthesia are planned with the pulmonary hypertension center (Class 2a). PAH drugs, especially infused prostacyclin, continue without interruption; intravenous sildenafil replaces oral sildenafil when oral intake stops. Perioperative care is covered on the pulmonary hypertension page.

Calcium channel blockers in vasoreactive PAH

A small group of patients with idiopathic, heritable, or drug-associated PAH has vasoconstriction that responds to high-dose calcium channel blockers. They are identified by acute vasoreactivity testing at the diagnostic catheterization with inhaled nitric oxide or inhaled iloprost (intravenous epoprostenol if neither is available). A positive response is a fall in mPAP of at least 10 mm Hg to an absolute value below 40 mm Hg (7th WSPH; 40 mm Hg or less in the ESC/ERS guideline) with unchanged or increased cardiac output. Testing protocol and interpretation are on the pulmonary hypertension page.

In the largest series of 557 patients with idiopathic PAH, 70 (12.6%) were acute responders under an older definition, and only 38 (6.8%) remained in functional class I or II after at least 1 year on calcium channel blockers alone. Long-term responders had less severe disease and near-normal pressures during the acute test. The ESC/ERS guideline estimates that fewer than 10% of patients with idiopathic, heritable, or drug-associated PAH are responders.

Calcium channel blockers in vasoreactive PAH. Doses follow the ESC/ERS 2022 dosing table; the choice by baseline heart rate follows the 2015 ESC/ERS guideline. Amlodipine and felodipine may be given once daily or in two divided doses; some diltiazem formulations are given once or three times daily. Verapamil is not used because of its negative inotropic effect.

The ESC/ERS guideline recommends high-dose calcium channel blockers for acute responders (Class 1). Complete reassessment, including repeat catheterization, is recommended after 3 to 4 months (Class 1). Treatment is continued in patients in functional class I or II with marked hemodynamic improvement, defined as an mPAP below 30 mm Hg and a PVR below 4 WU (Class 1). PAH therapy is started in patients who remain in functional class III or IV or lack marked improvement (Class 1). In acute responders who need additional therapy, the calcium channel blocker is continued alongside it (Class 2a), because some deteriorate when it is withdrawn. Calcium channel blockers are not recommended without a vasoreactivity study or after a negative one, except at standard doses for another indication such as Raynaud phenomenon (Class 3), because empirical use causes hypotension, syncope, and right ventricular failure. The 7th WSPH adds that doses are titrated by overall response, including hemodynamics, and that the goals are a low-risk noninvasive profile and near-normal hemodynamics.

Endothelin receptor antagonists: ambrisentan, bosentan, and macitentan

Bosentan. The first oral PAH drug, a dual endothelin A and B receptor antagonist. In BREATHE-1, bosentan improved 6-minute walk distance by 44 m over placebo at 16 weeks and delayed clinical worsening. Its use has declined because of hepatotoxicity and induction of CYP3A and CYP2C9. Dose-related aminotransferase elevation occurs in about 10% of patients and is reversible after dose reduction or withdrawal. US labeling requires aminotransferases before treatment and monthly. Confirmed elevation above 3 to 5 times the upper limit of normal calls for reduction to 62.5 mg twice daily or interruption. Elevation above 5 to 8 times calls for discontinuation with possible reintroduction, and elevation above 8 times for permanent discontinuation. Symptoms of liver injury, or bilirubin of 2 times normal or more, call for discontinuation at any level. Bosentan is contraindicated with cyclosporine (markedly increased bosentan levels) and glyburide (more liver enzyme elevation). Combinations of a CYP2C9 inhibitor with a strong or moderate CYP3A inhibitor are not recommended. In patients on ritonavir for at least 10 days, bosentan starts at 62.5 mg once daily or every other day; ritonavir is started 36 hours after bosentan is stopped. Bosentan is the endothelin receptor antagonist with randomized evidence in Eisenmenger syndrome (BREATHE-5).

Ambrisentan. A selective endothelin A receptor antagonist given once daily. In ARIES-1 and ARIES-2, 6-minute walk distance improved by 31 m and 51 m with 5 mg and 10 mg (ARIES-1) and by 32 m and 59 m with 2.5 mg and 5 mg (ARIES-2), with delayed clinical worsening in ARIES-2. Ambrisentan does not cause clinically significant aminotransferase elevation, and its hepatic boxed warning and monthly liver testing were removed in 2011. Peripheral edema is its main adverse effect, more frequent in patients 65 years or older and with tadalafil. Ambrisentan is contraindicated in idiopathic pulmonary fibrosis, including patients with pulmonary hypertension: in ARTEMIS-IPF, it increased disease progression (27.4% versus 17.2%) and respiratory hospitalization. Ambrisentan was the endothelin receptor antagonist studied in AMBITION and is limited to 5 mg daily with cyclosporine.

Macitentan. A tissue-penetrating dual antagonist with an active metabolite; the half-lives of drug and metabolite are about 16 and 48 hours. SERAPHIN was the first event-driven PAH trial. In 742 patients, 64% on background therapy (mostly sildenafil), macitentan 10 mg reduced the composite of death, atrial septostomy, lung transplantation, initiation of parenteral prostanoid, or worsening PAH from 46.4% to 31.4% (hazard ratio 0.55) over a median of about 2 years. The benefit was driven by worsening PAH, and the hazard ratio was 0.62 in patients on background therapy. Macitentan lowers hemoglobin, to 8 g/dL or less in 4.3% of patients, and has not shown hepatotoxicity in trials, although labeling still advises baseline liver enzymes and testing when clinically indicated. Macitentan 10 mg with tadalafil 20 or 40 mg is available as a single tablet, supported by A DUE, in which the combination lowered PVR by 29% more than macitentan alone and 28% more than tadalafil alone at 16 weeks.

Class effects of endothelin receptor antagonists. All endothelin receptor antagonists cause peripheral edema, nasal congestion, and dose-related decreases in hemoglobin that occur in the first weeks and then stabilize. All are teratogenic and contraindicated in pregnancy. Severe fluid retention, particularly in older patients with risk factors for left heart disease, raises the question of an unrecognized group 2 component.

Risk Evaluation and Mitigation Strategy (REMS). In April 2025 the US Food and Drug Administration (FDA) eliminated the REMS programs for ambrisentan and for macitentan-containing products. Later in 2025 it removed the embryo-fetal toxicity requirements from the bosentan REMS, which continues for hepatotoxicity. Labeling still contraindicates all three drugs in pregnancy and directs prescribers to exclude pregnancy before treatment and to advise effective contraception during treatment and for 1 month after stopping. Bosentan reduces the reliability of oral, injectable, transdermal, and implanted hormonal contraceptives, so hormonal contraception is not relied on alone.

PDE5 inhibitors: sildenafil and tadalafil

Sildenafil. In SUPER-1, 278 patients randomized to 20, 40, or 80 mg three times daily improved 6-minute walk distance by 45, 46, and 50 m over placebo, with improved functional class and hemodynamics. The approved dose was 20 mg three times daily, and a 5 mg dose was also approved. After pediatric data linked higher doses to higher mortality, the FDA required a mortality study in adults (AFFILIATE, 385 patients randomized to 5, 20, or 80 mg three times daily). It was stopped at the first interim analysis after 80 mg met noninferiority to 5 mg for mortality (hazard ratio 0.51, 99.7% confidence interval 0.22 to 1.21). Mortality was 26.4%, 19.5%, and 14.8% in the 5, 20, and 80 mg groups, with better clinical worsening and walk distance at 80 mg. The FDA revoked approval of the 5 mg dose, kept 20 mg three times daily as the recommended dose, and now permits titration to 80 mg three times daily. Sildenafil is metabolized by CYP3A; strong CYP3A inhibitors are not recommended with it, and moderate to strong inducers such as bosentan lower its levels. Intravenous sildenafil 10 mg three times daily replaces oral therapy temporarily.

Tadalafil. In PHIRST, 405 patients (about half on background bosentan) were randomized to tadalafil 2.5 to 40 mg once daily; only 40 mg met the prespecified threshold, improving walk distance by 33 m and reducing clinical worsening. Its half-life in PAH is about 35 hours, which permits once-daily dosing and requires a 48-hour interval before nitrates. Tadalafil starts at 20 mg with creatinine clearance of 31 to 80 mL/min and in Child-Pugh A or B cirrhosis, and is avoided with creatinine clearance below 30 mL/min, on dialysis, or in Child-Pugh C. With ritonavir, tadalafil is stopped 24 hours before ritonavir starts and resumed at 20 mg after at least 1 week, when ritonavir's induction offsets its inhibition.

Choice of PDE5 inhibitor for initial combination. Tadalafil is the preferred PDE5 inhibitor for initial combination because both landmark initial-combination trials, AMBITION and TRITON, and the single-tablet A DUE trial used it with ambrisentan or macitentan. Combinations with bosentan or sildenafil rest on weaker evidence, and bosentan lowers the levels of both PDE5 inhibitors.

Adverse effects and contraindications of PDE5 inhibitors. Headache, flushing, dyspepsia, epistaxis, nasal congestion, and myalgia are common. Sudden decrease or loss of vision (including nonarteritic anterior ischemic optic neuropathy) and hearing are rare and lead to prompt evaluation. Organic nitrates in any form, regular or intermittent, are contraindicated because of hypotension; a patient on a PDE5 inhibitor with an acute coronary syndrome is treated without nitrates. Combination with riociguat is contraindicated. Alpha-blockers and other antihypertensives add to blood pressure lowering.

Riociguat, the soluble guanylate cyclase stimulator

Evidence for riociguat in PAH. PATENT-1 randomized 443 patients, treatment-naive or on an endothelin receptor antagonist or a nonintravenous prostanoid, to riociguat titrated to 2.5 mg three times daily or placebo. Walk distance improved by 36 m at 12 weeks, with improvement in PVR, N-terminal pro-B-type natriuretic peptide (NT-proBNP), functional class, and time to clinical worsening. Riociguat is also the approved drug for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and for persistent or recurrent pulmonary hypertension after endarterectomy, based on CHEST-1 (walk distance +46 m).

Why riociguat and PDE5 inhibitors are not combined. In PATENT PLUS, riociguat added to sildenafil produced no hemodynamic or exercise benefit, and the long-term extension had high rates of discontinuation for hypotension. Riociguat is contraindicated with specific PDE5 inhibitors and with nonspecific phosphodiesterase inhibitors such as dipyridamole and theophylline. It is not given within 24 hours after sildenafil or within 48 hours after tadalafil; a PDE5 inhibitor is started at least 24 hours after riociguat is stopped.

Switching from a PDE5 inhibitor. REPLACE randomized 226 patients in functional class III with a walk distance of 165 to 440 m on a PDE5 inhibitor-based regimen to switch to riociguat or continue the PDE5 inhibitor. Clinical improvement at 24 weeks (no clinical worsening and improvement in at least two of walk distance, functional class, and NT-proBNP) occurred in 41% versus 20% (odds ratio 2.78), and clinical worsening was less frequent with riociguat. The trial was open-label with a composite end point not previously validated, so the ESC/ERS guideline gives the switch a Class 2b recommendation in intermediate-low-risk patients.

Dosing and pharmacology of riociguat. Riociguat starts at 1 mg three times daily, or 0.5 mg in patients at risk of hypotension or on strong cytochrome P450 (CYP) and P-glycoprotein/breast cancer resistance protein (BCRP) inhibitors (azole antifungals, HIV protease inhibitors). It is increased by 0.5 mg no sooner than every 2 weeks while systolic pressure remains above 95 mm Hg without symptoms, to a maximum of 2.5 mg three times daily, and reduced by 0.5 mg for symptomatic hypotension. Treatment interrupted for 3 days or more is retitrated. Smoking lowers plasma levels by 50% to 60%; US labeling allows doses above 2.5 mg three times daily to be considered in smokers and a dose reduction after smoking stops. Antacids are separated by at least 1 hour. Riociguat is not recommended with creatinine clearance below 15 mL/min, on dialysis, or in Child-Pugh C.

Safety of riociguat. Hypotension, dizziness, dyspepsia, headache, and bleeding occur. Serious bleeding occurred in 2.4% of riociguat-treated patients in placebo-controlled trials, including serious hemoptysis in 1%. Riociguat is teratogenic in animals and contraindicated in pregnancy; current US labeling requires pregnancy to be excluded before treatment and contraception during and for 1 month after treatment. It is contraindicated in pulmonary hypertension with idiopathic interstitial pneumonia because RISE-IIP was stopped early for more deaths and serious adverse events with riociguat.

Prostacyclin pathway agents: epoprostenol, treprostinil, iloprost, and selexipag

Epoprostenol. Synthetic prostacyclin with a half-life of 3 to 5 minutes, given by continuous intravenous infusion through a tunneled central catheter with a portable pump. In the 1996 trial of 81 patients with severe idiopathic PAH in functional class III or IV, median walk distance rose from 315 m to 362 m with epoprostenol and fell from 270 m to 204 m with conventional therapy. All 8 deaths during the 12 weeks occurred in the conventional-therapy group. It remains the only PAH drug with a survival benefit in a randomized trial and is the agent of choice in the sickest patients. A 12-week trial in systemic sclerosis-associated PAH improved exercise capacity and hemodynamics. A thermostable formulation remains stable for up to 48 hours, which reduces the need for ice packs. Infusion starts at 2 ng/kg/min and increases by 1 to 2 ng/kg/min. The 7th WSPH describes an initial target of 15 to 20 ng/kg/min reached over weeks to months, with further increases guided by hemodynamic reassessment to avoid excessive doses and a high-output state.

Treprostinil. A stable prostacyclin analog with a half-life of about 4 hours, given subcutaneously, intravenously, by inhalation, or orally.

• Subcutaneous. In the pivotal 12-week trial of 470 patients, the median walk distance difference was 16 m, with greater benefit in sicker patients and at higher doses. Infusion-site pain occurred in 85% and led to discontinuation in 8%. Subcutaneous delivery avoids a central catheter, an advantage in patients with right-to-left shunts and in those with prior line infection.
• Intravenous. Used when site pain prevents subcutaneous delivery. Because treprostinil is chemically stable, it can be given through a fully implantable pump, which improves convenience and likely reduces line infections. Treprostinil is also indicated for transition from epoprostenol: the treprostinil infusion is started and increased while epoprostenol is reduced, in hospital.
• Inhaled. TRIUMPH added nebulized treprostinil to bosentan or sildenafil in 235 patients and improved peak walk distance by 20 m at 12 weeks, with better quality of life and NT-proBNP. Inhaled treprostinil is also approved for pulmonary hypertension with interstitial lung disease (INCREASE). Two dry-powder inhalers are approved in the United States in addition to the nebulizer. Cough and throat irritation are common, and bronchospasm occurs in patients with reactive airways.
• Oral (extended release). Studies in patients on oral background therapy missed their walk distance end points, but FREEDOM-EV, an event-driven trial of 690 patients on oral monotherapy, reduced clinical worsening from 36% to 26% (hazard ratio 0.74). It is taken with food, titrated every 3 to 4 days, and not stopped abruptly.

Iloprost. In the AIR trial, six to nine daily inhalations in patients with PAH or CTEPH met a combined end point of functional class improvement and walk distance gain without deterioration in 16.8% versus 4.9% with placebo. Its short duration of action requires frequent inhalations. The branded product was withdrawn from the US market in 2025 after its only approved nebulizer was discontinued; the ESC/ERS guideline still lists inhaled iloprost at 2.5 to 5 µg six to nine times daily.

Selexipag. An oral nonprostanoid IP receptor agonist whose active metabolite has a terminal half-life of 6.2 to 13.5 hours. GRIPHON, the largest PAH outcome trial, randomized 1,156 patients, 80% on an endothelin receptor antagonist, a PDE5 inhibitor, or both, to selexipag up to 1,600 µg twice daily or placebo. The composite of death or a PAH complication fell from 41.6% to 27.0% (hazard ratio 0.60), driven by fewer disease progression and hospitalization events, with no difference in mortality and a 12 m gain in walk distance. In the 376 patients on dual oral therapy, the hazard ratio was 0.63. Doses are increased weekly to the highest tolerated dose; a dose that cannot be tolerated is reduced to the previous tolerated dose, which becomes the maintenance dose. An intravenous form bridges patients who temporarily cannot take tablets. Initial triple oral therapy with selexipag did not improve PVR in TRITON (below).

Ralinepag. A once-daily oral IP receptor agonist. In ADVANCE OUTCOMES (687 analyzed patients, 80% on dual background therapy), first clinical worsening occurred in 18% with ralinepag versus 36% with placebo (hazard ratio 0.45), with more discontinuations for adverse events. It is not yet incorporated into guidelines.

Prostanoid adverse effects. Headache, flushing, jaw pain, nausea, vomiting, diarrhea, and extremity pain are expected with every prostacyclin pathway agent. They are most prominent during titration and often lessen over time, and moderate effects are tolerated while the dose is increased. Chronic epoprostenol is also associated with thrombocytopenia and, at excessive doses, a high-output state.

Parenteral prostacyclin: infusion safety, interruption, and transitions

Catheter infection and thrombosis. Intravenous therapy requires a permanent tunneled catheter, and pump malfunction, catheter obstruction, local infection, and sepsis are its serious complications. Intravenous treprostinil carries a labeled warning for catheter-related bloodstream infection. Infection prevention relies on sterile technique and patient training; subcutaneous delivery or an implantable pump avoids an external line.

Interruption of parenteral prostacyclin. Abrupt withdrawal or a sudden large dose reduction causes rebound pulmonary hypertension with right ventricular failure; with epoprostenol this can occur within minutes. Patients carry a backup pump and supplies, and a lost or blocked line is treated as an emergency: a peripheral intravenous line restores the infusion until central access is reestablished. Dose decreases for adverse effects are made gradually, in epoprostenol steps of 2 ng/kg/min no faster than every 15 minutes.

Overdose of parenteral prostacyclin. Pump programming or concentration errors cause flushing, headache, nausea, vomiting, diarrhea, hypotension, and tachycardia. Because the half-life of epoprostenol is minutes, reducing the infusion reverses the effect quickly; treprostinil's longer half-life prolongs effects.

Transitions between drugs and routes. Switching between epoprostenol and treprostinil, or between subcutaneous and intravenous treprostinil, is done with close monitoring. No validated conversion formula exists; treprostinil doses are generally higher than epoprostenol doses, and modest underdosing during transition is preferred to overdosing. Transition from parenteral to oral or inhaled prostacyclin is considered only in patients with an excellent response (PVR below 5 WU, normal cardiac index, low-risk findings). Case series show mostly favorable short-term results, but some patients deteriorate and respond poorly when the infusion is restarted. Centers therefore taper over weeks to months, with hemodynamic reassessment during the transition and 3 to 4 months after it.

Sotatercept and activin signaling inhibition

Sotatercept was approved by the FDA in 2024 for adults with PAH. In October 2025, after ZENITH, the indication was updated to improving exercise capacity and functional class and reducing the risk of clinical worsening events, including hospitalization for PAH, lung transplantation, and death. All trials studied sotatercept added to background therapy; it has not been tested as initial therapy.

Randomized and extension trials of add-on sotatercept in PAH. Rates are sotatercept versus placebo. PVR, pulmonary vascular resistance; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Hemodynamic effects of sotatercept. Sotatercept lowers right atrial pressure, mPAP, and PVR and raises mixed venous saturation, but cardiac index has not increased significantly in the trials. Rising hemoglobin and systemic vascular resistance may contribute, and many patients had a normal cardiac index at baseline. For patients who present critically ill with a low cardiac index, the 7th WSPH continues to regard parenteral prostacyclin as first-line, because of its rapid effect and the early mortality benefit in the sickest patients.

Position of sotatercept in the treatment algorithm. The 7th WSPH lists sotatercept as an add-on option for patients at intermediate-low risk on oral combination therapy and for intermediate-high-risk patients, and as a fourth drug for patients at high risk who already receive parenteral prostacyclin. It suggests sotatercept for patients with greater symptom burden or exercise impairment. An oral prostacyclin pathway agent is suggested for patients with higher bleeding risk, such as hereditary hemorrhagic telangiectasia, or a preference for an agent with longer safety data. The 2022 ESC/ERS guideline preceded the phase 3 results.

Sotatercept dosing, monitoring, and adverse effects

Sotatercept is self-injected subcutaneously into the abdomen or upper thigh every 3 weeks after training. The starting dose is 0.3 mg/kg; after hemoglobin and platelet count are confirmed acceptable, the dose increases to the target of 0.7 mg/kg. Hemoglobin and platelets are measured before each of the first 5 doses, longer if values are unstable, and periodically thereafter. Treatment is not started if the platelet count is below 50,000/µL. A missed dose is given as soon as possible, and if more than 3 days late the schedule is reset to 3-week intervals.

Dose = weight × 0.3 or 0.7 mg/kg; injection volume = dose ÷ 50 mg/mL, rounded to the nearest 0.1 mL (70 kg: 21 mg, 0.4 mL at 0.3 mg/kg; 49 mg, 1.0 mL at 0.7 mg/kg). Treatment is delayed for at least 3 weeks if any of the following applies: hemoglobin rises more than 2 g/dL from the previous dose and is above the upper limit of normal; hemoglobin rises more than 4 g/dL from baseline; hemoglobin is more than 2 g/dL above the upper limit of normal; or platelets fall below 50,000/µL. After a delay longer than 9 weeks, treatment restarts at 0.3 mg/kg. The 7th WSPH notes that a reduction to 0.3 mg/kg can be used for adverse effects, particularly raised hemoglobin.

Adverse effects of sotatercept. In STELLAR, over the controlled and long-term blinded periods, epistaxis occurred in 22.1% versus 1.9%, telangiectasia in 16.6% versus 4.4% (median onset about 36 weeks), rash in 20.2% versus 8.1%, dizziness in 14.7% versus 6.3%, and headache in 24.5% versus 17.5%. Hemoglobin rose from normal to above normal in 53% versus 14%, managed by dose delay or reduction, and more than 2 g/dL above the upper limit of normal in 15% across trials. Severe thrombocytopenia below 50,000/µL occurred in 3% to 6%, more often in patients receiving prostacyclin infusions, which also lower platelets. Mean blood pressure rose by 2.2/4.9 mm Hg at 24 weeks.

Bleeding with sotatercept. Bleeding events occurred in 22% versus 13% in STELLAR, usually mucosal (epistaxis, gingival bleeding). Serious bleeding, including gastrointestinal and intracranial hemorrhage, occurred in 4% versus 1% in STELLAR, 7% versus 5% in ZENITH, and 4% versus 2% in HYPERION. Postmarketing gastrointestinal bleeding from angiodysplasia has been reported, and endoscopy is considered for recurrent or unexplained gastrointestinal bleeding. Sotatercept is withheld during serious bleeding. Caution is advised in patients with systemic sclerosis, who are prone to gastrointestinal vascular lesions, and in patients on anticoagulants or with hereditary hemorrhagic telangiectasia.

Reproductive risks of sotatercept. Sotatercept may cause fetal harm and impair male and female fertility. Effective contraception is used during treatment and for at least 4 months after the last dose, and breastfeeding is not recommended for the same period. Serious hypersensitivity, including anaphylaxis and angioedema, is a contraindication.

Initial therapy by risk at diagnosis

Treatment starts from the risk assessment at diagnosis. The ESC/ERS guideline uses a three-strata model (low, intermediate, and high estimated 1-year mortality), and the 7th WSPH separates patients only into high risk and not high risk for the initial decision. At follow-up, both use a four-strata model based on functional class, 6-minute walk distance, and B-type natriuretic peptide (BNP) or NT-proBNP, with REVEAL 2.0 or REVEAL Lite 2 as US alternatives. The variables and a four-strata calculator are on the pulmonary hypertension page.

Initial treatment of PAH, after the ESC/ERS 2022 guideline and the 7th WSPH algorithm (2024). The algorithm applies to idiopathic, heritable, drug-associated, and connective tissue disease-associated PAH; other forms are covered in the section on specific forms of PAH.

AMBITION and the case for initial dual therapy. AMBITION randomized 500 treatment-naive patients in functional class II or III to ambrisentan plus tadalafil or to either drug alone. Clinical failure (death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term response) occurred in 18% with combination therapy versus 31% with pooled monotherapy (hazard ratio 0.50). The difference was driven mainly by fewer hospitalizations, with better walk distance and NT-proBNP. In a secondary analysis of all 605 randomized patients, 10% of the combination group and 14% of the monotherapy group had died by the end of the study (hazard ratio 0.67, 95% confidence interval 0.42 to 1.08). The ESC/ERS guideline rates the quality of evidence for initial dual oral therapy as low but recommends it on the strength of improvement in functional class, exercise capacity, natriuretic peptides, and hospitalization.

TRITON and initial triple oral therapy. TRITON randomized 247 newly diagnosed patients to macitentan, tadalafil, and selexipag or to macitentan, tadalafil, and placebo. PVR fell by 54% and 52% at 26 weeks (ratio of geometric means 0.96), and walk distance and NT-proBNP improved equally. An exploratory analysis suggested less disease progression with triple therapy (hazard ratio 0.59, confidence interval crossing 1), with 2 deaths in the triple group and 9 in the double group. The primary end point was not met, and initial triple oral therapy is not recommended. TRITON also showed that initial dual therapy alone lowers PVR by about half.

Initial triple therapy with parenteral prostacyclin. No randomized trial has tested this strategy. In the French registry of 1,611 patients, those started on triple therapy including parenteral prostacyclin had 5-year survival of 91%, against 61% with dual therapy or monotherapy, and triple therapy was independently associated with lower mortality (hazard ratio 0.29). Patients started on triple therapy were younger, with fewer comorbidities, so the comparison is observational. The ESC/ERS guideline and the 7th WSPH recommend this approach in high-risk patients, and the WSPH notes that some patients who are not high risk but have high-risk features may also benefit.

Other initial options. Inhaled prostacyclin and riociguat can be components of initial therapy, but the evidence is weaker than for an endothelin receptor antagonist with a PDE5 inhibitor. When sildenafil is used, it starts at 20 mg three times daily and may be increased to 80 mg at the cost of more adverse effects.

Treatment goals and escalation at follow-up

Achieving and maintaining a low-risk profile on optimized therapy is the treatment goal (ESC/ERS Class 1). The first reassessment occurs 3 to 4 months after starting or changing therapy, when most prognostic measures have plateaued; patients who deteriorate before then are escalated without waiting. Reassessment includes functional class, walk distance, and natriuretic peptide in every patient, and echocardiography, cardiac magnetic resonance, or catheterization when a major change is considered or when age and comorbidities confound the noninvasive measures.

Escalation of therapy at follow-up, after the 7th WSPH algorithm and the ESC/ERS 2022 guideline. Maximal medical therapy is four drugs acting on four pathways.

Residual events and symptoms in low-risk patients. In a pooled analysis of AMBITION, GRIPHON, and SERAPHIN, more than 20% of patients classified as low risk had a clinical worsening event within 3 years. Most low-risk patients still have symptoms and reduced exercise capacity. The 7th WSPH lists expanded goals that are proposed but not yet validated: PVR below 5 WU, a fall in PVR of more than 50% to 60%, improved stroke volume index, and normal or near-normal right heart size and function. In registry data, fewer than half of patients started on dual oral therapy reached and kept a low-risk profile.

Evidence for sequential add-on therapy. The ESC/ERS guideline grades sequential combinations by the trial end point that supported them.

Sequential combination therapy in PAH. Event-driven trials (SERAPHIN, GRIPHON, FREEDOM-EV, ZENITH, HYPERION) support reduction of clinical worsening; trials with walk distance as the end point support improvement in exercise capacity.

Choosing among add-on options. The 7th WSPH compares the options by evidence and burden. Sotatercept and selexipag were studied in many patients on combination background therapy; oral and inhaled treprostinil were studied only on monotherapy. Sotatercept produced larger improvements in walk distance and hemodynamics, while the oral prostacyclin pathway agents have longer, event-driven trials and a longer safety record. Inhaled prostacyclin causes fewer systemic prostanoid effects but is less convenient (four treprostinil or six to nine iloprost inhalations daily), and it is used mainly when other drugs are not tolerated. The riociguat switch replaces one cGMP drug with another and needs a washout from the PDE5 inhibitor. Parenteral prostacyclin remains the choice when risk is intermediate-high or high, cardiac index is low, or deterioration is rapid.

Mortality evidence for combination therapy. A 2016 meta-analysis cited by the ESC/ERS guideline found that combination therapy reduced clinical worsening (relative risk 0.65) without a significant effect on all-cause mortality (relative risk 0.86). The 7th WSPH notes a modest mortality reduction in later meta-analyses and improving survival in registries, while median survival remains under 10 years.

Comparison of ESC/ERS, World Symposium, and CHEST recommendations

The three documents that guide PAH therapy in the United States agree on the core strategy and differ mainly in the evidence available when each was written. The 2019 CHEST guideline, an update of its 2014 guideline with 78 recommendations and consensus statements, predates TRITON, the four-strata model, and sotatercept. Its central change was the suggestion of initial ambrisentan plus tadalafil for treatment-naive patients in functional class II or III, and it emphasizes evaluation at an expert center, collaborative care, supervised exercise, and palliative care. The 2022 ESC/ERS guideline introduced the three-strata model at diagnosis, the four-strata model at follow-up, and a separate pathway for patients with cardiopulmonary comorbidities. The 7th WSPH algorithm (2024) simplified the initial decision to high versus not high risk and added sotatercept.

Main differences between the ESC/ERS 2022 guideline and the 7th WSPH treatment algorithm. The ESC/ERS guideline has a published corrigendum (2023); recommendations are cited from the corrected publication.

Lung transplantation, interventional palliation, and end-of-life care

Lung transplantation remains the option for patients who do not respond to maximal medical therapy. The ESC/ERS guideline recommends referral for evaluation when response to oral combination therapy is inadequate, indicated by intermediate-high or high risk or a REVEAL score above 7 (Class 1). Listing is recommended when risk remains high or the REVEAL score is 10 or more despite optimized therapy that includes parenteral prostacyclin (Class 1). The 7th WSPH adds referral for progressive disease or hospitalization despite therapy, need for parenteral prostacyclin, known or suspected pulmonary veno-occlusive disease or capillary hemangiomatosis, and secondary liver or kidney dysfunction. Waiting-list mortality in PAH is higher than in parenchymal lung disease, so referral is early. Bilateral lung transplantation is the usual operation; heart-lung transplantation is reserved for additional noncorrectable cardiac disease. Venoarterial extracorporeal membrane oxygenation bridges selected patients.

Balloon atrial septostomy and the Potts shunt (left pulmonary artery to descending aorta) decompress the right heart and raise systemic flow at the cost of desaturation. They carry substantial procedural mortality and are performed only in experienced centers, most often where drug therapy is unavailable. Pulmonary artery denervation is experimental. Palliative care and advance care planning are integrated as disease advances, and PAH drugs that no longer help may be withdrawn at the end of life. Acute right ventricular failure management and transplantation are covered in more detail on the pulmonary hypertension page.

Drug safety: liver tests, hemoglobin, blood pressure, and teratogenicity

Safety monitoring of PAH drugs, from US prescribing information, the ESC/ERS 2022 guideline, and the 7th WSPH. Since 2025, ambrisentan and macitentan have no REMS, and the bosentan REMS covers hepatotoxicity only.

New or worsening hypoxemia is uncommon on PAH therapy. When it develops, echocardiography with a bubble study looks for a right-to-left shunt, and high-resolution computed tomography looks for septal lines, ground-glass opacities, and adenopathy that suggest unrecognized pulmonary veno-occlusive disease.

Drug interactions in PAH therapy

The ESC/ERS guideline lists three clinically relevant pharmacokinetic interactions among PAH treatments: bosentan lowers sildenafil levels, bosentan reduces the efficacy of hormonal contraceptives, and bosentan lowers the effect of vitamin K antagonists. Pharmacodynamic interactions are the more dangerous ones.

Clinically important drug interactions in PAH therapy, from US prescribing information and the ESC/ERS 2022 guideline. INR, international normalized ratio; BCRP, breast cancer resistance protein.

PAH therapy in patients with cardiopulmonary comorbidities

The typical patient with idiopathic PAH is now aged about 60 years or older. In a cluster analysis of 841 patients with newly diagnosed idiopathic PAH from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), 12.6% had the classic phenotype of young patients without comorbidity. Another 35.8% had a left heart phenotype (older, mostly women, with hypertension, obesity, diabetes, or coronary disease, and atrial fibrillation in about 30%), and 51.6% a cardiopulmonary phenotype (older, mostly men, smokers with a diffusing capacity below 45% of predicted and often hypoxemia). These patients respond less to PAH drugs, discontinue them more often for intolerance, reach low risk less often, and, in the cardiopulmonary phenotype, have high mortality.

Occult group 2 disease is suspected with a wedge pressure of 12 to 15 mm Hg, a PVR of 3 to 5 WU, left atrial enlargement, grade 2 or higher diastolic dysfunction, reduced ejection fraction, left-sided valve disease, or multiple cardiometabolic risk factors. Exercise or fluid challenge may uncover post-capillary pulmonary hypertension (ESC/ERS Class 2b), as described on the heart failure with preserved ejection fraction page. Patients with these features but a clear pre-capillary profile receive initial monotherapy, usually a PDE5 inhibitor. Endothelin receptor antagonists cause more fluid retention in the left heart phenotype, and PAH drugs can lower oxygen saturation in the cardiopulmonary phenotype. Additional drugs may be added individually (Class 2b). In AMBITION, 105 patients excluded from the primary analysis for a left heart phenotype improved less and discontinued drugs more often for safety and tolerability. Patients with comorbidities who met trial entry criteria, about half of GRIPHON participants, had relative reductions in clinical worsening similar to the overall results. If therapy reveals a non-group 1 diagnosis, PAH drugs are generally stopped and treatment is directed at the underlying condition.

Therapy in specific forms of PAH

Connective tissue disease. Systemic sclerosis is the leading underlying disorder in the United States and Europe, and 30% to 40% of trial participants had connective tissue disease. The same treatment algorithm applies (ESC/ERS Class 1), and post hoc AMBITION data showed similar benefit from initial dual therapy in connective tissue disease and idiopathic PAH. Responses are smaller, adverse events more frequent, and survival worse than in idiopathic PAH. Immunosuppression with glucocorticoids and cyclophosphamide may help PAH associated with systemic lupus erythematosus or mixed connective tissue disease but not systemic sclerosis. Anticoagulation is not used in systemic sclerosis except for another indication such as antiphospholipid syndrome. Digital contractures can make parenteral therapy difficult, and gastrointestinal vascular lesions raise bleeding risk with sotatercept.

HIV infection. Antiretroviral therapy is recommended for all patients regardless of viral load or CD4 count (Class 1). Patients are usually not vasoreactive and do not receive calcium channel blockers. Initial monotherapy, followed by sequential combination as needed, is advised (Class 2a) because of drug interactions. Protease inhibitor regimens raise PDE5 inhibitor levels: sildenafil labeling does not recommend use with strong CYP3A inhibitors, tadalafil labeling specifies a reduced-dose protocol with ritonavir, and reduced-dose sildenafil has been reported when no alternative exists. Bosentan improved function and hemodynamics in an open-label study (BREATHE-4) but interacts with antiretrovirals. Anticoagulation is not recommended.

Portopulmonary hypertension. PAH occurs in 2% to 6% of patients with portal hypertension and makes up about 5% to 15% of PAH in US, French, and Japanese registries. Volume overload and high-output states are distinguished from true portopulmonary hypertension first; PAH drugs are not recommended for portal hypertension with high cardiac output and normal PVR (Class 3). PORTICO, the only randomized trial, showed a 35% fall in PVR with macitentan at 12 weeks. Initial monotherapy is advised (Class 2a), with caution in advanced cirrhosis, where drug metabolism is impaired and bosentan is generally avoided in moderate or severe hepatic impairment. Liver transplantation may be considered when PVR is normal or near normal on therapy. Before listing, the International Liver Transplantation Society suggests an mPAP below 35 mm Hg with PVR below 5 WU, or 35 to 45 mm Hg with PVR below 3 WU.

Congenital heart disease and Eisenmenger syndrome. Patients with PAH after defect repair (more than 1 year earlier) were included in major trials and are treated like idiopathic PAH, with initial oral combination therapy at low or intermediate risk and parenteral prostacyclin at high risk (Class 2a). In Eisenmenger syndrome, bosentan is recommended for symptomatic patients (Class 1) on the basis of BREATHE-5, in which it lowered PVR without worsening systemic oxygen saturation. In MAESTRO, macitentan did not improve walk distance in Eisenmenger syndrome but lowered NT-proBNP and PVR. Other endothelin receptor antagonists, PDE5 inhibitors, riociguat, and prostacyclin pathway agents should be considered (Class 2a), with sequential symptom-guided escalation. Subcutaneous delivery may be preferred over a central catheter because of paradoxical embolism, and intravenous lines use air filters. Shunt closure after drug therapy ("treat and repair") lacks long-term evidence. The atrial septal defect and patent foramen ovale page covers shunt closure criteria.

Drug- and toxin-associated PAH. The causative agent is stopped immediately (Class 1). PAH from dasatinib or interferon may partly or fully reverse; in low-risk patients, reassessment 3 to 4 months after withdrawal precedes PAH therapy (Class 2b), and intermediate- or high-risk patients are treated at once (Class 2a). Stimulant-associated PAH, now the most common drug-associated form, rarely remits, carries a worse prognosis than idiopathic PAH, and is treated by the standard algorithm with referral for substance use treatment. Alkylating agents such as mitomycin C and cyclophosphamide can cause a veno-occlusive phenotype.

Pulmonary veno-occlusive disease and capillary hemangiomatosis. These group 1 variants are diagnosed by clinical and radiologic findings, arterial blood gases, pulmonary function, and genetic testing (biallelic EIF2AK4 variants confirm the heritable form). Vasodilators can precipitate pulmonary edema. PAH drugs may be used with careful monitoring of symptoms and gas exchange (Class 2b), and transplant referral is made at diagnosis (Class 1).

Schistosomiasis. A leading cause of PAH worldwide, present in about 5% of patients with hepatosplenic disease. PDE5 inhibitors and endothelin receptor antagonists, alone or combined, are associated with improved survival.

Heritable PAH and genetic testing. Patients with familial, idiopathic, or anorexigen-associated PAH or with veno-occlusive disease are informed about possible genetic disease and offered counseling before testing, and pre-conception genetic counseling is considered in heritable PAH. Drug therapy is the same as for idiopathic PAH.

Pregnancy, contraception, and PAH drugs

Maternal mortality in PAH has fallen but remains 11% to 25%, and the ESC/ERS guideline recommends counseling against pregnancy at diagnosis and clear contraceptive advice (Class 1). In a pregnancy that continues, endothelin receptor antagonists, riociguat, and selexipag are stopped because of known or unknown teratogenicity, and endothelin receptor antagonists and riociguat are not recommended in pregnancy (Class 3). Calcium channel blockers, PDE5 inhibitors, and inhaled, intravenous, or subcutaneous prostacyclin are considered safe despite limited evidence; parenteral prostacyclin is the basis of treatment in severe disease. Sotatercept may cause fetal harm and requires contraception for 4 months after the last dose.

Effective contraception is advised with every drug that carries embryo-fetal toxicity. Bosentan reduces the efficacy of hormonal contraceptives, so an additional nonhormonal method is used. Delivery planning and management of pregnancy are covered on the pulmonary hypertension page.

PAH drugs outside group 1

Left heart disease (group 2). PAH drugs are not recommended in pulmonary hypertension from left heart disease (ESC/ERS Class 3, Level A). In SIOVAC, sildenafil 40 mg three times daily in 200 patients with persistent pulmonary hypertension after successful valve surgery worsened the composite clinical score (odds ratio 0.39 for improvement). Endothelin receptor antagonists, prostacyclin, and riociguat in heart failure have been neutral or harmful. PDE5 inhibitors are not recommended in isolated post-capillary disease with heart failure with preserved ejection fraction, and the guideline makes no recommendation for or against them in combined post- and pre-capillary disease. Patients with a severe pre-capillary component (PVR above 5 WU) are managed individually at a pulmonary hypertension center. In the phase 2 CADENCE trial of 164 patients with combined post- and pre-capillary pulmonary hypertension and preserved ejection fraction (median PVR 5.2 WU), sotatercept lowered PVR relative to placebo by 1.02 WU (0.3 mg/kg) and 0.75 WU (0.7 mg/kg). It also lowered mPAP by about 9 mm Hg. It remains investigational in this setting. The pulmonary hypertension page covers group 2 disease.

Lung disease and hypoxia (group 3). Treatment of the lung disease and hypoxemia and transplant referral come first. Inhaled treprostinil may be considered in pulmonary hypertension with interstitial lung disease (Class 2b) and is FDA-approved for it: in INCREASE, 326 patients improved walk distance by 31 m over placebo at 16 weeks, with fewer clinical worsening events. Ambrisentan is not recommended in pulmonary fibrosis (Class 3), riociguat is contraindicated with idiopathic interstitial pneumonia (Class 3), and PAH drugs are not recommended for nonsevere pulmonary hypertension with lung disease (Class 3). PDE5 inhibitors may be considered in severe pulmonary hypertension with interstitial lung disease at a center (Class 2b). In chronic obstructive pulmonary disease (COPD), the PERFECT trial of inhaled treprostinil was stopped early for more serious adverse events and a possible increase in mortality, and no PAH drug is approved. Group 3 disease is covered on the pulmonary hypertension page.

Chronic thromboembolic pulmonary hypertension (group 4). Lifelong anticoagulation, pulmonary endarterectomy for accessible disease, and balloon pulmonary angioplasty for distal or residual disease are the core treatments. Riociguat is recommended for inoperable or persistent disease (Class 1); in CHEST-1, walk distance improved by 46 m. Subcutaneous treprostinil may be considered in functional class III or IV (Class 2b), and off-label PAH drugs, including macitentan, may be considered in inoperable disease (Class 2b). Details are on the pulmonary hypertension page.

Group 5 and other settings. Treatment targets the underlying condition. In pulmonary hypertension with sickle cell disease, PDE5 inhibitors caused harm in a randomized trial and are avoided.

Access, specialty pharmacy, and adherence

Most oral PAH drugs and all infused, inhaled, and injected therapies are dispensed through specialty pharmacies, which coordinate insurance authorization, home infusion supplies, pump training, and nursing support. Generic sildenafil, tadalafil, ambrisentan, bosentan, and macitentan and generic treprostinil injection are available in the United States; sotatercept and the oral and inhaled treprostinil products are available only as branded drugs. Prior authorization and cost shape the order in which drugs are added and can delay escalation, and the 7th WSPH calls for wider access to generics and atrial septostomy where resources are limited. Adherence is reviewed at each visit, and any change in therapy is made with the pulmonary hypertension center, because unplanned interruption of prostacyclin can be fatal and gaps in oral therapy lead to clinical worsening.

Sources of error in PAH drug therapy

• Starting PAH drugs from an echocardiogram. Left heart disease, lung disease, and chronic thromboembolism produce the same echocardiographic estimate, and in left heart disease PAH drugs can cause pulmonary edema. Right heart catheterization comes first.
• Empirical calcium channel blockers. Without a positive vasoreactivity test, high doses cause hypotension and right ventricular failure. Acute responders who do not reach near-normal hemodynamics at 3 to 4 months need PAH therapy.
• Combining riociguat with a PDE5 inhibitor. The combination is contraindicated; switching requires 24 hours after sildenafil and 48 hours after tadalafil.
• Nitrates in a patient on a PDE5 inhibitor or riociguat. Chest pain is treated without nitrates, and nitrates are avoided for 48 hours after tadalafil.
• Initial triple oral therapy. TRITON showed no benefit of adding selexipag at diagnosis. High-risk patients need parenteral prostacyclin, not a third oral drug.
• Waiting at intermediate risk. Patients not at low risk at 3 to 4 months are escalated; deterioration before the scheduled visit is escalated at once.
• Delaying parenteral prostacyclin and transplant referral. Intermediate-high or high risk at follow-up calls for parenteral therapy or sotatercept and transplant evaluation.
• Interrupting infused prostacyclin. A lost or blocked line is an emergency; dose reductions are gradual.
• Missing sotatercept laboratory checks. Hemoglobin and platelets are needed before each of the first 5 doses; serious bleeding and telangiectasia are monitored throughout.
• Overlooking bosentan interactions. Hormonal contraception becomes unreliable, warfarin and sildenafil levels fall, and cyclosporine and glyburide are contraindicated.
• Treating fluid retention as disease progression. Edema on an endothelin receptor antagonist may be a drug effect or a sign of unrecognized left heart disease.
• Full combination therapy in older patients with cardiopulmonary comorbidity. These patients start with monotherapy and are escalated individually.
• Using PAH drugs in group 2 or 3 disease. Sildenafil worsened outcomes after valve surgery, riociguat harmed patients with idiopathic interstitial pneumonia, ambrisentan harmed patients with pulmonary fibrosis, and inhaled treprostinil increased serious adverse events in COPD. Inhaled treprostinil in interstitial lung disease and riociguat in CTEPH are the exceptions.
• Pregnancy on teratogenic drugs. Pregnancy is excluded before endothelin receptor antagonists, riociguat, and sotatercept, and contraception continues after they are stopped.

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