Pulmonary Hypertension

Clinically reviewed Aug 29, 2026 Updated Aug 30, 2026

Clinical Snapshot

Pulmonary hypertension (PH) is not a single disease but a hemodynamic state — persistently elevated pressure in the pulmonary arterial circulation — that arises from at least five mechanistically distinct groups of underlying disease, each with a fundamentally different treatment approach (see below). Confirming which group a patient's PH belongs to is the single most consequential step in their work-up, because the disease-modifying, PAH-specific vasodilator therapy detailed in this chapter is appropriate for only one of the five groups and can cause real harm in two of the others (see Choose Initial Treatment and Red Flags & Refer).

The diagnostic threshold — and a recent, genuinely important update

PH is defined hemodynamically by right heart catheterization (RHC), the diagnostic gold standard that cannot be replaced by echocardiography or any other noninvasive test.^[1] For decades the diagnostic threshold was a mean pulmonary arterial pressure (mPAP) of 25 mmHg or higher at rest. The 2022 ESC/ERS international guideline lowered this threshold to mPAP greater than 20 mmHg at rest — a change based on normative right heart catheterization data in healthy adults (in whom mPAP averages roughly 14 mmHg) and on prognostic data showing worse outcomes even in this lower range.^[2] Pulmonary arterial hypertension (PAH) specifically requires, in addition to mPAP >20 mmHg: a pulmonary arterial wedge pressure (PAWP) of 15 mmHg or less (confirming a precapillary process), and a pulmonary vascular resistance (PVR) greater than 2 Wood units — itself lowered from the historical >3 Wood unit threshold.^[2] This refinement better reflects the true upper limit of normal, but the guideline is explicit that it does not yet change who should be treated: the efficacy of PAH-specific therapy in patients who fall only in this newly captured, mildly elevated range (mPAP 21-24 mmHg and/or PVR 2-3 Wood units) remains unknown, and starting therapy on hemodynamics alone in that grey zone is not currently supported.^[2]

Epidemiology

PH overall is common — an estimated 1% of the global population, rising to roughly 10% of those aged 65 and older — and in the great majority of these patients it is due to left heart disease or lung disease (Groups 2 and 3 below), not PAH.^[1] PAH itself is comparatively rare, with an estimated incidence of up to 7.6 cases per million adults and a prevalence of up to 26-100 per million adults, but its morbidity and mortality are disproportionate to its rarity: a diagnosis of PH of any type confers roughly a sevenfold increase in age- and sex-standardized mortality.^[1]

The WHO five-group clinical classification

The current classification, summarized below, is the framework every subsequent section of this chapter refers back to.^[1]

Group	Includes	Core treatment principle
Group 1 — Pulmonary arterial hypertension (PAH)	Idiopathic; heritable (most often BMPR2); drug- and toxin-induced; associated with connective tissue disease, HIV, portal hypertension, congenital heart disease, or schistosomiasis; long-term calcium-channel-blocker responders; PAH with overt venous/capillary involvement (PVOD/PCH); persistent PH of the newborn	The focus of this chapter — PAH-specific vasodilator therapy targeting the endothelin, nitric oxide-cGMP, and prostacyclin pathways (see Choose Initial Treatment)
Group 2 — PH due to left heart disease	Heart failure with preserved or reduced ejection fraction; valvular heart disease; congenital/acquired conditions causing postcapillary PH	Treat the underlying cardiac disease and optimize filling pressures — PAH-specific vasodilators are not recommended and can cause harm (see Choose Initial Treatment)
Group 3 — PH due to lung disease and/or hypoxia	Obstructive lung disease, restrictive lung disease, mixed patterns, hypoxia without intrinsic lung disease, developmental lung disorders	Optimize the underlying lung disease and correct hypoxemia — PAH-specific vasodilators are not recommended outside a narrow, specialist-directed exception (see Choose Initial Treatment)
Group 4 — PH due to pulmonary artery obstruction	Chronic thromboembolic PH (CTEPH) and other pulmonary artery obstructions	A distinct, potentially curable pathway — pulmonary endarterectomy for operable disease, with riociguat and balloon pulmonary angioplasty for inoperable or residual disease (see Choose Initial Treatment)
Group 5 — PH with unclear or multifactorial mechanisms	Hematologic disorders, systemic and metabolic disorders, complex congenital heart disease, and others	Individualized to the underlying cause; PAH-specific therapy is not routinely supported

Recognize the Condition

Symptoms — nonspecific and easy to miss early

The hallmark early symptom of PH, across every group, is exertional dyspnea — breathlessness disproportionate to exertion that progresses gradually and is easy to misattribute to deconditioning, aging, obesity, or a more common cardiopulmonary diagnosis. Fatigue is similarly common and similarly nonspecific. Because right ventricular reserve can compensate for rising afterload for a long time before symptoms clearly localize to the heart, the interval between symptom onset and a confirmed diagnosis is often measured in months rather than days — which is exactly why unexplained, progressive exertional dyspnea without an obvious alternative explanation deserves a deliberate diagnostic pathway (see Assessment & Diagnosis) rather than a reflexive trial of an inhaler or a reassurance visit.

Symptoms that signal more advanced disease

Exertional syncope or presyncope — reflects an inability to augment cardiac output during exertion and is a genuinely worrying symptom that should prompt urgent evaluation (see Red Flags & Refer), not reassurance.
Exertional chest pain/angina — right ventricular ischemia from a mismatch between oxygen demand and a compromised right coronary supply as RV pressure rises.
Peripheral edema, abdominal distension, and early satiety — signs of right heart failure and hepatic/gut venous congestion as disease advances.
Palpitations, and in advanced disease, cyanosis.

Examination findings

A loud, sometimes palpable P2 (pulmonary component of the second heart sound) — the most specific bedside sign of elevated pulmonary artery pressure.
A right ventricular heave along the left sternal border.
A holosystolic tricuspid regurgitation murmur at the left lower sternal border that characteristically increases with inspiration.
Elevated jugular venous pressure with a prominent "a" wave (reflecting a stiff, hypertrophied right ventricle), progressing to signs of overt right heart failure — peripheral edema, ascites, hepatomegaly, a pulsatile liver — as disease advances.

Assessment & Diagnosis

Step 1 — Echocardiography establishes the initial probability of PH

Transthoracic echocardiography (TTE) is recommended as the initial test in every patient with clinically suspected PH or otherwise-unexplained dyspnea.^[1] A complete assessment estimates systolic pulmonary artery pressure from the tricuspid regurgitation jet velocity and estimated right atrial pressure, and evaluates "secondary" signs of PH — right atrial and right ventricular enlargement, right ventricular hypertrophy, interventricular septal flattening, and right ventricular dysfunction.^[1] TTE is also central to distinguishing a precapillary from a postcapillary process: left ventricular hypertrophy, systolic or diastolic dysfunction, significant aortic or mitral valve disease, and an enlarged left atrium all point toward Group 2 (left heart disease) PH, while a severely dilated, remodelled right ventricle without left-sided pathology points toward a precapillary cause.^[1] A normal echocardiogram does not reliably exclude postcapillary PH related to left heart disease, which is one of several reasons TTE alone can never substitute for right heart catheterization.^[1]

Step 2 — Excluding the more common causes before landing on PAH

PAH is, in practice, a diagnosis reached by systematically excluding the far more common causes of PH: pulmonary function testing and HRCT chest to evaluate for significant lung disease (Group 3), the echocardiographic and clinical assessment above for left heart disease (Group 2), and ventilation/perfusion (V/Q) scanning to screen for CTEPH (Group 4) — the single most sensitive test for this purpose, where a normal perfusion scan effectively rules out CTEPH but a negative CT pulmonary angiogram does not.^[1] Serologic screening for connective tissue disease and a directed history for HIV risk, portal hypertension, congenital heart disease, drug/toxin exposure, and family history complete the initial work-up.

Step 3 — Right heart catheterization confirms the diagnosis

RHC is required in every patient with suspected PAH or CTEPH to confirm the hemodynamic diagnosis of precapillary PH and to establish its severity, and should be performed only in centres with the technical expertise to avoid measurement error that can alter both PH classification and treatment choice.^[1] Rigorous technique matters: the pressure transducer should be positioned at mid-thoracic height, and pressures — including wedge pressure — should be read at end-expiration from several respiratory cycles rather than relying on a device's automated digital estimate, since this alone can change PH classification in 25-30% of patients.^[1] Thermodilution is the preferred method for cardiac output because it correlates best with right ventricular function and outcomes.^[1] See Clinical Snapshot for the current mPAP >20 mmHg, PAWP ≤15 mmHg, PVR >2 Wood unit hemodynamic definition of PAH.

Acute vasodilator testing

Acute vasodilator testing at the time of RHC — using inhaled nitric oxide, intravenous epoprostenol, or adenosine — is essential in patients with suspected idiopathic, heritable, or drug/toxin-induced PAH, since it identifies the roughly 10-15% of these patients with marked short-term hemodynamic responsiveness (a fall in mPAP of at least 10 mmHg to below 40 mmHg with a stable or increased cardiac output) who are candidates for high-dose calcium channel blocker therapy instead of standard PAH-targeted therapy (see Choose Initial Treatment).^[1]

Targeted screening in high-risk groups

Annual echocardiography and DLCO measurement is recommended to screen for PH in every patient with systemic sclerosis, given the disproportionate PAH prevalence in this group; the DETECT algorithm — a validated two-step decision tree incorporating clinical, serologic, and pulmonary-function variables — improves the sensitivity of identifying PAH in scleroderma from roughly 71% to 96% compared with unstructured screening.^[1] Echocardiography is also recommended in every patient with portal hypertension being assessed for liver transplantation, since moderate-to-severe portopulmonary hypertension is a contraindication to transplant (see Special Populations).^[1]

Choose Initial Treatment

Confirm the diagnosis and involve a PH centre before starting any PAH-specific therapy

Every patient with confirmed or strongly suspected PAH should be assessed in a recognized PH centre to confirm the diagnosis, direct the choice of PH-targeted therapy, and evaluate the response to treatment.^[1] These medications are expensive, carry real toxicity, and — as detailed below — can cause serious harm if started in the wrong patient (the wrong PH group, or a non-vasoresponder given high-dose calcium channel blockers). This is not a drug class to initiate empirically outside specialist care.

Calcium channel blockers — only for a confirmed acute vasodilator responder

High-dose calcium channel blockers (amlodipine or diltiazem) are appropriate only for the roughly 10-15% of idiopathic, heritable, or drug/toxin-induced PAH patients who demonstrate a marked acute vasodilator response on RHC — a fall in mPAP of at least 10 mmHg to below 40 mmHg with a stable or increased cardiac output.^[1] Initiation, uptitration, and confirmation of a sustained low-risk clinical and hemodynamic response all require a PH expert centre; the same high-dose therapy is dangerous and contraindicated in a non-responder, where it can precipitate hypotension and right ventricular failure.^[1] Do not start a calcium channel blocker for "pulmonary hypertension" without a documented positive vasodilator response — this is one of the most consequential and avoidable errors in PAH management (see Common Errors to Avoid).

Multiparametric risk stratification drives how aggressively to start therapy

For patients who are not acute vasodilator responders, a multiparametric risk assessment at diagnosis — combining functional class, exercise capacity, natriuretic peptides, and hemodynamic/imaging measures of right heart function — stratifies patients into low, intermediate, and high risk, and is the single most important determinant of how intensively to start treatment.^[1] Parameters used include WHO/NYHA functional class, presence of clinical right heart failure, syncope, rate of symptom progression, 6-minute walk distance, BNP/NT-proBNP, right atrial pressure, cardiac index, mixed venous oxygen saturation, echocardiographic/CMR right atrial area, pericardial effusion, and cardiopulmonary exercise testing parameters where available.^[1] The 2022 ESC/ERS international guideline formalizes this into a comprehensive 3-strata model at diagnosis (up to 18 parameters, mapping to estimated 1-year mortality of under 5%, 5-20%, and over 20% for low, intermediate, and high risk respectively) and a simplified 4-strata model — low, intermediate-low, intermediate-high, and high risk, based on functional class, 6-minute walk distance, and BNP/NT-proBNP — for use at follow-up visits.^[2] The REVEAL 2.0 risk score and its abridged version, REVEAL Lite 2, are validated alternative numeric calculators developed from North American PAH registry data and are increasingly used alongside the ESC/ERS-based approach.^[3]^[4]

Initial therapy by risk category — combination therapy is now the standard for most patients

Low risk, treatment-naive: initial oral monotherapy with an endothelin receptor antagonist (ERA), a PDE5 inhibitor, or the soluble guanylate cyclase (sGC) stimulator riociguat is an acceptable, guideline-supported starting point.^[1]

Intermediate risk, treatment-naive: initial dual oral combination therapy — an ERA plus a PDE5 inhibitor — is now recommended rather than starting with a single agent.^[1] This is a genuine, evidence-driven shift from the historical monotherapy-first approach: the randomized AMBITION trial found that initial combination therapy with ambrisentan and tadalafil reduced the risk of a composite clinical-failure endpoint (death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term response) by roughly 50% compared with pooled monotherapy.^[5] No head-to-head trials define one combination as superior to another, and other ERA/PDE5-inhibitor pairings are reasonable, though less directly supported by trial evidence than ambrisentan plus tadalafil specifically.^[1]

High risk, including WHO/NYHA functional class IV: initial combination therapy that includes a parenteral prostacyclin is recommended — intravenous epoprostenol carries the stronger recommendation, with subcutaneous or intravenous treprostinil as an alternative.^[1] This population should not be started on oral therapy alone.

At every risk level: reassess within 3-4 months of starting or changing therapy, and regularly thereafter (every 6-12 months once low-risk status is achieved and maintained, depending on access to a PH centre).^[1] If low-risk status is not achieved, escalate rather than waiting (see Treatment Failure/Next Step).

Endothelin receptor antagonists (ERAs)

Mechanism: PAH is associated with elevated endothelin-1, a potent vasoconstrictor and smooth-muscle mitogen; ERAs block its receptor-mediated effects.^[1] Three oral agents are available in Canada.

Bosentan: 62.5 mg PO twice daily for 4 weeks, then increase to the 125 mg PO twice daily maintenance dose.^[6] Bosentan is the one ERA that requires mandatory monthly liver aminotransferase monitoring for the full duration of treatment, reflecting a dose-dependent hepatotoxicity risk (ALT/AST rising to at least 3 times the upper limit of normal in roughly 11% of trial patients).^[6] It is contraindicated with cyclosporine (co-administration increased bosentan trough levels roughly 30-fold in a formal interaction study) and with glyburide (increased risk of liver enzyme elevation with both agents together) — confirm the full medication list before starting.^[6]

Ambrisentan: 5 mg PO once daily, may be increased to 10 mg PO once daily. Peripheral edema/fluid retention is more prominent with ambrisentan than with the other ERAs.

Macitentan: 10 mg PO once daily, a single fixed dose with no titration required.^[7] Macitentan is the one ERA with randomized-trial evidence of a reduction in a composite morbidity/mortality endpoint (the SERAPHIN trial, comparing macitentan against placebo in an event-driven design).^[8]

Class effects: all three ERAs are teratogenic and contraindicated in pregnancy — confirm a negative pregnancy test before starting in anyone of reproductive potential, repeat monthly during treatment, and ensure effective, non-hormonal-inclusive contraception is in place and reviewed at every visit (see Non-Pharmacologic Treatment and Special Populations). Anemia is a recognized class effect and hemoglobin should be checked periodically.

PDE5 inhibitors and the sGC stimulator riociguat — never combine these two classes

Mechanism: both act on the nitric oxide-cGMP pathway, which is deficient in PAH. Phosphodiesterase type-5 (PDE5) inhibitors — sildenafil (20 mg PO three times daily) and tadalafil (40 mg PO once daily) — block the breakdown of cGMP generated downstream of endogenous nitric oxide.^[1] Riociguat works differently and more directly: it is a soluble guanylate cyclase (sGC) stimulator that both sensitizes sGC to low levels of endogenous nitric oxide and stimulates it directly, independent of nitric oxide availability — part of why it also has a distinct, dedicated indication in CTEPH (see below).^[1] Riociguat requires a careful, individualized uptitration: starting at 1 mg PO three times daily, increased by 0.5 mg three times daily no more often than every 2 weeks based on systolic blood pressure and tolerability, up to a maximum of 2.5 mg three times daily (maximum total daily dose 7.5 mg), typically over about 8 weeks.^[9]^[1]

The critical interaction: a PDE5 inhibitor and riociguat must never be used together — both converge on the same NO-cGMP pathway, and the combination is contraindicated because of a real risk of clinically significant, symptomatic systemic hypotension.^[1]^[9] If switching a patient from a PDE5 inhibitor to riociguat, discontinue sildenafil at least 24 hours, or tadalafil at least 48 hours, before the first riociguat dose.^[9] Both classes are separately contraindicated with organic nitrates and with recreational nitrate use ("poppers") for the same additive-hypotension reason — ask directly, since patients may not volunteer recreational drug use unprompted.^[9]

Prostacyclin pathway agents — for higher-risk disease, with genuinely serious delivery-related considerations

Mechanism: patients with PAH have deficient endogenous prostacyclin; these agents replace that pathway, producing vasodilation along with antiplatelet and antiproliferative effects.^[1]

Intravenous epoprostenol is the preferred agent for high-risk, including WHO/NYHA functional class IV, patients, and remains the only PAH-targeted agent with randomized-trial evidence of an overall survival benefit as monotherapy in this sickest population.^[1] Its extremely short half-life (roughly 6 minutes) is a double-edged feature: it allows rapid, careful dose titration, but also means the drug must be delivered by continuous infusion through a permanent central venous catheter, and any unplanned interruption — a pump failure, a delayed line change, a missed prescription refill — is a genuine medical emergency, since abrupt cessation can cause rapid, severe rebound PH and death.^[1] Dosing starts low (approximately 2 ng/kg/min) and is titrated upward based on symptom control and tolerability (flushing, headache, jaw/bone pain, nausea, diarrhea, and catheter-related complications), with no fixed ceiling — many patients are eventually maintained well above 20-40 ng/kg/min after months to years of uptitration.^[1]

Treprostinil offers more flexibility across the severity spectrum: continuous subcutaneous infusion avoids the infection risk of an indwelling central catheter (though infusion-site pain is common and can itself limit tolerability), continuous intravenous infusion is available where subcutaneous delivery is not feasible, and inhaled and oral extended-release formulations extend the prostacyclin pathway to patients who are not candidates for continuous parenteral therapy.^[1] Subcutaneous/intravenous dosing typically starts around 1.25 ng/kg/min and is titrated by symptoms and tolerability, the same way as epoprostenol.

Selexipag is an oral, non-prostanoid prostacyclin (IP) receptor agonist — mechanistically in the same pathway, but chemically distinct and taken as a tablet, meaningfully lowering the delivery burden compared with the parenteral and inhaled options.^[1] Start at 200 mcg PO twice daily, increasing in 200 mcg twice-daily increments approximately weekly, as tolerated, to the individualized highest tolerated maintenance dose, up to a maximum of 1600 mcg twice daily.^[10] The randomized GRIPHON trial demonstrated a reduction in a composite morbidity/mortality endpoint with selexipag; adverse effects (headache, jaw/bone pain, flushing, diarrhea, nausea) are dose-related, prostacyclin-class-typical, and generally most prominent during uptitration.^[11]

Inhaled iloprost is a further option in this pathway, though its short duration of action requires 6-9 nebulized doses daily — a genuinely significant adherence burden compared with the other agents in this class.

PAH-specific vasodilator therapy is not indicated — and can cause real harm — in Group 2 or Group 3 PH

Group 2 (left heart disease): there is no evidence to support PAH-targeted therapy in PH due to left heart disease, and PAH-specific agents have instead been associated with systemic hypotension, fluid retention, pulmonary edema, and increased mortality when used in this population.^[1] Management should instead focus on optimizing ventricular filling pressures and treating the underlying cardiac disease — valvular intervention, cardiac resynchronization therapy, guideline-directed heart failure therapy, and volume management, as applicable.^[1]

Group 3 (lung disease/hypoxia): published experience with PAH-targeted drugs in this group is scarce, and there is no evidence of improved clinical outcomes; because these agents are not selective for the pulmonary vasculature supplying well-ventilated lung units, a real potential risk is worsening ventilation-perfusion matching and therefore worsening hypoxemia.^[1] This is not merely a theoretical concern — the randomized RISE-IIP trial of riociguat in patients with PH associated with idiopathic interstitial pneumonia (a common Group 3 substrate) was stopped early because of an increased risk of serious adverse events and death in the riociguat arm, a genuine demonstration of harm rather than simple lack of benefit.^[12] Routine RHC and PAH-targeted therapy are not recommended in mild-to-moderate Group 3 PH without right ventricular failure; refer moderate-to-severe Group 3 PH, or Group 3 PH with RV failure, to a PH centre for individualized assessment rather than either ignoring it or empirically starting PAH therapy.^[1] The 2022 ESC/ERS guideline carves out one narrow, evolving exception — a PDE5 inhibitor may be considered specifically in severe PH associated with interstitial lung disease, with individualized decision-making at a PH centre — but this is a specialist-directed exception, not a default approach.^[2]

CTEPH (Group 4) is a distinct pathway, with its own dedicated therapy — and, for eligible patients, a realistic prospect of cure

Chronic thromboembolic PH is common, under-recognized when a prior pulmonary embolism history is absent (as it is in 30-50% of CTEPH patients), and — unlike Groups 2 and 3 — treatable and potentially curable, which is why it must always be actively excluded (with V/Q scanning) rather than assumed away.^[1] Pulmonary endarterectomy (PEA), performed by a multidisciplinary team including an experienced PEA surgeon, is the treatment of choice for operable disease and now carries a mortality of only 1-2% at experienced centres.^[1] For patients with inoperable disease, or with residual/recurrent PH after PEA, riociguat monotherapy is recommended — riociguat's other, distinct Health Canada indication, and an important nuance: this is the one situation outside Group 1 PAH where a PAH-class drug is guideline-recommended, precisely because CTEPH has its own dedicated trial evidence that Groups 2 and 3 do not.^[1] Balloon pulmonary angioplasty is a reasonable option for patients ineligible for, or declining, PEA. Lifelong anticoagulation is required in every CTEPH patient regardless of which of these treatments is used.^[1]

Anticoagulation, diuretics, and oxygen — supportive therapy, individualized by PAH subtype

Anticoagulation: warfarin (INR target 2-3) is a reasonable, guideline-supported option in selected idiopathic, heritable, or drug/toxin-induced PAH patients without an elevated bleeding risk, reflecting evidence of in-situ pulmonary arterial thrombosis in this population — though no randomized trial has confirmed benefit, and registry data have raised questions about the practice.^[1] Anticoagulation is specifically not recommended in PAH associated with connective tissue disease, congenital heart disease, portal hypertension, or HIV, given an unfavourable bleeding-risk balance in these subgroups.^[1] There are no studies supporting a direct oral anticoagulant for PAH-specific anticoagulation — warfarin remains the guideline-supported choice where anticoagulation is indicated for PAH itself (see Common Errors to Avoid).^[1]

Diuretics: carefully titrated diuretic therapy — furosemide is typical — reduces fluid overload from right heart failure; individualize to volume status and renal function rather than a fixed dose.^[1]

Oxygen: long-term oxygen therapy is recommended for resting hypoxemia, and should be reassessed for exertional hypoxemia as well; treat this the same as any other chronic hypoxemic lung/cardiac condition rather than a PAH-specific consideration.^[1]

Non-Pharmacologic Treatment

General supportive measures and education

Every PAH patient should receive disease-specific education, psychosocial support, and structured, supervised exercise rehabilitation, which improves functional capacity and health-related quality of life.^[1]

Contraception and pregnancy planning — a genuinely high-stakes counseling point

Pregnancy in PAH carries a well-documented, high maternal mortality risk and is generally strongly discouraged; reliable contraception should be discussed proactively with every patient of reproductive potential, not deferred until pregnancy is raised by the patient.^[1] This is inseparable from the pharmacotherapy in Choose Initial Treatment: ERAs, riociguat, and selexipag are all teratogenic, and women of childbearing age taking any of them should stop the medication before attempting conception and use effective, non-hormonal-inclusive contraception in the meantime.^[2]

Vaccination and infection prevention

Keep routine immunization current, with particular attention to annual influenza and age-appropriate pneumococcal vaccination — a respiratory infection is a recognized precipitant of acute right heart decompensation in a patient with limited RV reserve.

Activity, altitude, and travel

Encourage regular, moderate activity within symptom limits (formal rehabilitation above is preferred where available) while counseling against strenuous isometric exertion; discuss oxygen planning for air travel and avoidance of unpressurized high-altitude exposure given the added hypoxic stress on an already-compromised pulmonary circulation.

Genetic counseling

Offer genetic counseling, and discuss cascade testing of first-degree relatives, once heritable PAH (most often a BMPR2 mutation) is identified.

Advance care planning

Despite genuine treatment advances, prognosis remains guarded for many patients, particularly those who do not achieve a sustained low-risk profile; integrate goals-of-care conversations and palliative care alongside disease-directed therapy as risk status and functional class decline, rather than reserving these conversations for the final stages of disease.

Pharmacologic Treatment Options

Drug / intervention	Role	Dose / use	Important adverse effects	Teaching points
Bosentan ERA — combination therapy	Endothelin receptor antagonist — combination therapy for intermediate-risk PAH	62.5 mg PO twice daily x4 weeks, then 125 mg PO twice daily maintenance	Hepatotoxicity (mandatory monthly LFTs), peripheral edema, anemia, teratogenicity	Monthly LFTs for the full duration of treatment; contraindicated with cyclosporine and glyburide; confirm reliable contraception
Ambrisentan ERA — AMBITION regimen	Endothelin receptor antagonist — the ERA studied together with tadalafil in the AMBITION upfront-combination trial	5 mg PO once daily, may increase to 10 mg once daily	Peripheral edema/fluid retention (more prominent than other ERAs), anemia, teratogenicity	Best-evidenced initial dual-combination partner alongside tadalafil; monthly pregnancy testing if applicable
Macitentan ERA — combination therapy	Endothelin receptor antagonist with RCT morbidity/mortality outcome data (SERAPHIN)	10 mg PO once daily — single fixed dose, no titration	Anemia, headache, nasopharyngitis, teratogenicity	No mandatory monthly LFT monitoring unlike bosentan; still confirm reliable contraception and check hemoglobin periodically
Sildenafil PDE5 inhibitor — combination therapy	PDE5 inhibitor — combination-therapy backbone for intermediate-risk PAH	20 mg PO three times daily	Headache, flushing, dyspepsia, epistaxis	Never combine with riociguat or any nitrate — risk of severe hypotension
Tadalafil PDE5 inhibitor — AMBITION regimen	PDE5 inhibitor — the agent studied together with ambrisentan in the AMBITION trial	40 mg PO once daily	Headache, flushing, myalgia, dyspepsia	Once-daily dosing may support adherence; never combine with riociguat or any nitrate
Riociguat sGC stimulator — monotherapy or CTEPH	Soluble guanylate cyclase stimulator — PAH monotherapy option, or CTEPH-specific therapy	Start 1 mg PO three times daily; titrate by 0.5 mg three times daily every 2+ weeks by BP/tolerability to a maximum of 2.5 mg three times daily	Hypotension, headache, dyspepsia, peripheral edema, hemoptysis	Contraindicated with any PDE5 inhibitor and with nitrates; switching from a PDE5 inhibitor requires a washout (24h sildenafil, 48h tadalafil)
Epoprostenol Preferred — high risk/FC IV	IV prostacyclin — preferred initial parenteral agent for high-risk/functional class IV PAH	Continuous IV infusion via a permanent central venous catheter; start ~2 ng/kg/min, titrate by symptoms/tolerability	Flushing, headache, jaw/bone pain, nausea, diarrhea, catheter-related infection	Never interrupt the infusion — ~6-minute half-life means abrupt cessation risks rapid, fatal rebound PH; confirm a backup pump/plan
Treprostinil High risk — alternative delivery	Prostacyclin analogue — SC/IV, inhaled, or oral formulations for high-risk PAH or when parenteral epoprostenol is not feasible	SC/IV: start ~1.25 ng/kg/min, titrate by symptoms; inhaled/oral dosing per specific formulation	Infusion-site pain (SC, often treatment-limiting), flushing, headache, jaw pain, diarrhea	SC delivery avoids central-catheter infection risk but infusion-site pain is common — proactive site-pain management improves adherence
Selexipag Add-on oral prostacyclin pathway	Oral, non-prostanoid IP-receptor agonist — extends the prostacyclin pathway without parenteral/inhaled delivery	Start 200 mcg PO twice daily; increase by 200 mcg twice-daily increments weekly as tolerated to a maximum of 1600 mcg twice daily	Headache, jaw/bone pain, flushing, diarrhea, nausea — dose-related, most prominent during uptitration	Individualize the maintenance dose; do not abandon therapy for expected, manageable titration-phase adverse effects
Diltiazem Vasoresponders only	High-dose calcium channel blocker — for confirmed acute vasodilator responders only (IPAH/HPAH/DPAH)	High-dose, individualized and uptitrated in a PH expert centre	Hypotension, peripheral edema, bradycardia — dangerous in a non-responder	Never start without a documented positive acute vasodilator response on RHC; confirm sustained low-risk status at follow-up
Warfarin Selected IPAH/HPAH/DPAH only	Anticoagulation — selected idiopathic, heritable, or drug/toxin-induced PAH without elevated bleeding risk	Individualized to target INR 2-3	Bleeding	Not recommended in CTD-, HIV-, portal-hypertension-, or CHD-associated PAH; no evidence supports a DOAC for PAH-specific anticoagulation
Furosemide Supportive — volume overload	Loop diuretic — supportive therapy for right heart failure/volume overload	Individualized to volume status and renal function	Electrolyte disturbance, renal function changes, hypotension	Titrate carefully — both under- and over-diuresis can worsen right ventricular filling and cardiac output

Special Populations

Pregnancy

PAH carries a well-documented, high maternal mortality risk, and pregnancy is generally strongly discouraged; when pregnancy does occur, management requires a specialized, multidisciplinary high-risk obstetric/PH-centre team.^[1] ERAs, riociguat, and selexipag are teratogenic and should be stopped, with any switch to a therapy with more reassuring (though still limited) safety data — chiefly the PDE5 inhibitors — made under specialist direction rather than as a default choice.^[2]

Connective-tissue-disease-associated PAH (especially systemic sclerosis)

The highest-prevalence PAH subgroup, and the only one with a dedicated, validated screening algorithm (DETECT; see Assessment & Diagnosis).^[1] Anticoagulation is specifically not recommended in this group, in contrast to idiopathic/heritable/drug-toxin PAH (see Choose Initial Treatment).^[1]

Portopulmonary hypertension

Associated with poor prognosis if untreated, with 5-year survival reported as low as 14% in some series in the absence of medical therapy.^[1] Moderate-to-severe portopulmonary hypertension is a contraindication to liver transplantation — a genuinely high-stakes, easy-to-miss fact — which is why echocardiographic screening is recommended in every portal hypertension patient being assessed for transplant.^[1] Anticoagulation is not recommended in this group given bleeding risk from portal-hypertension-related varices.^[1]

HIV-associated and congenital-heart-disease-associated PAH

HIV-associated PAH has a prevalence of roughly 0.5%, still meaningfully above the general population, and echocardiography is reasonable in patients with unexplained dyspnea or multiple HIV-PAH risk factors.^[1] Nearly 10% of adult congenital heart disease patients may have PAH, and screening should be performed at centres with adult CHD expertise.^[1] Anticoagulation is not recommended in either subgroup (see Choose Initial Treatment).^[1]

Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (PVOD/PCH)

A PAH subtype that can closely mimic idiopathic PAH clinically but carries a distinct, dangerous risk: standard PAH vasodilator and calcium-channel-blocker therapy can precipitate life-threatening pulmonary edema in these patients. New or worsening pulmonary edema shortly after starting either class of therapy should prompt urgent reassessment for PVOD/PCH rather than dose escalation (see Red Flags & Refer).

Lung and heart-lung transplantation

Refer PAH or CTEPH patients with persistent severe PH (WHO/NYHA functional class III-IV and/or right ventricular failure) despite maximal medical therapy for lung transplant assessment, and consider extracorporeal life support as a bridge in patients with refractory RV failure or hemodynamic instability.^[1] Unlike some other progressive cardiopulmonary diseases, PAH-directed pharmacotherapy is not itself curative for most patients outside the calcium-channel-blocker-responder subgroup, so transplant referral timing should not be deferred while additional medical options are still being tried indefinitely.

Common Errors to Avoid

Combining a PDE5 inhibitor with riociguat — this is contraindicated and can cause serious symptomatic hypotension (see Choose Initial Treatment).^[9]
Prescribing a PDE5 inhibitor or riociguat without asking directly about nitrate use, including recreational nitrate ("poppers") use — the interaction is the same additive-hypotension mechanism, and patients may not volunteer this history unprompted.^[9]
Starting a high-dose calcium channel blocker for "pulmonary hypertension" without a documented positive acute vasodilator response on RHC — this can be dangerous, even fatal, in a non-responder (see Choose Initial Treatment).^[1]
Starting any PAH-specific vasodilator in a patient whose PH is actually due to left heart disease (Group 2) or lung disease/hypoxia (Group 3) without RV failure — there is no evidence of benefit and real evidence of harm in both groups (see Choose Initial Treatment).^[1]^[12]
Prescribing a direct oral anticoagulant (apixaban, rivaroxaban, or similar) as PAH-specific anticoagulation — there is no supporting evidence for this in PAH; warfarin remains the guideline-supported choice where anticoagulation is indicated specifically for PAH.^[1]
Anticoagulating connective-tissue-disease-, HIV-, portal-hypertension-, or congenital-heart-disease-associated PAH the same way as idiopathic PAH — the guideline recommends against routine anticoagulation in these specific subgroups (see Special Populations).^[1]
Treating new pulmonary edema after starting a vasodilator or calcium channel blocker as simple drug intolerance rather than a red flag for occult PVOD/PCH.
Allowing any interruption in a continuous IV epoprostenol infusion to go unaddressed — its roughly 6-minute half-life means abrupt cessation can cause rapid, severe rebound PH and death.^[1]
Skipping bosentan's mandatory monthly liver enzyme monitoring, or applying its monthly schedule loosely to ambrisentan or macitentan (or vice versa) — the monitoring intensity genuinely differs by agent.^[6]
Listing a portopulmonary hypertension patient for liver transplant without addressing moderate-to-severe PH first — it is a contraindication to transplant until adequately treated.^[1]
Treating oral monotherapy as a permanent, "set and forget" plan — low-risk patients still need scheduled reassessment, and most contemporary intermediate- or high-risk patients need initial combination therapy rather than a monotherapy trial first.^[1]
Deferring lung transplant referral until no medical options remain, rather than referring once persistent severe PH or RV failure is established despite maximal therapy.^[1]

Clinical Decision Algorithm

Algorithm A — From unexplained dyspnea to a confirmed PAH diagnosis

Unexplained exertional dyspnea, +/- syncope, edema, or exam findings of PH

Transthoracic echocardiography — estimate sPAP, assess RA/RV size and function, screen for left-sided pathology^[1]

Left heart disease signs (LVH, LV dysfunction, significant valve disease)

Group 2 — treat the underlying cardiac disease; PAH-specific vasodilators not indicated

No left heart disease; PFTs/HRCT show significant lung disease or hypoxia

Group 3 — optimize the underlying lung disease; PAH-specific vasodilators not routinely indicated

No left heart or significant lung disease

V/Q scan to screen for CTEPH^[1]

V/Q scan positive/high probability

Group 4 — refer to a CTEPH/PEA-experienced multidisciplinary centre for operability assessment

V/Q scan normal

Right heart catheterization to confirm precapillary PH: mPAP >20 mmHg, PAWP <=15 mmHg, PVR >2 Wood units^[2]

Group 1 PAH confirmed — proceed to acute vasodilator testing and risk stratification^[1]

Algorithm B — Risk-stratified initial therapy for confirmed PAH

Group 1 PAH confirmed by RHC in a PH centre

Acute vasodilator testing (inhaled NO, IV epoprostenol, or adenosine) in IPAH/HPAH/DPAH candidates^[1]

Marked positive response (mPAP fall >=10 mmHg to <40 mmHg, stable/increased CO)

High-dose calcium channel blocker (diltiazem); confirm sustained low-risk status at follow-up RHC

Negative, or not eligible for testing

Multiparametric risk stratification: functional class, 6MWD, BNP/NT-proBNP, hemodynamics, imaging^[2]

Low risk

Initial oral monotherapy: ERA, PDE5 inhibitor, or riociguat

Intermediate risk

Initial dual oral combination: ERA + PDE5 inhibitor^[5]

High risk / functional class IV

Initial combination including IV epoprostenol (preferred) or SC/IV treprostinil

Reassess at 3-4 months — goal is achieving and maintaining low-risk status^[1]

Low-risk status achieved

Continue; reassess every 6-12 months

Low-risk status not achieved

Escalate — add a drug class or intensify to/within parenteral prostacyclin; reassess transplant candidacy

Algorithm C — Which PH patients should not receive PAH-specific vasodilator therapy

PH confirmed — which group?

Group 2 — left heart disease

Do not start PAH-targeted therapy — optimize filling pressures and treat the underlying cardiac disease^[1]

Group 3 — mild-moderate, no RV failure

Do not start PAH-targeted therapy or routine RHC — optimize the underlying lung disease^[1]

Group 3 — moderate-severe and/or RV failure

Refer to a PH centre — individualized specialist decision only (e.g., possible PDE5 inhibitor in severe PH-ILD)^[2]

Group 4 CTEPH is the exception — riociguat is guideline-recommended for inoperable or residual/recurrent disease after PEA assessment^[1]

Drug Tables

Endothelin Receptor Antagonists (ERAs)

Block endothelin-1-mediated vasoconstriction and smooth-muscle proliferation. All three are teratogenic and require monthly pregnancy testing and effective contraception in anyone of reproductive potential. See Choose Initial Treatment for the full risk-based combination-therapy rationale.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Bosentan	62.5 mg PO twice daily x4 weeks, then 125 mg PO twice daily maintenance	Dose-dependent hepatotoxicity (ALT/AST at least 3x ULN in ~11% of trial patients), peripheral edema, anemia, teratogenicity	Contraindicated with cyclosporine (bosentan levels increased ~30-fold) and glyburide (increased hepatotoxicity risk); reduces hormonal contraceptive and warfarin effect via CYP3A4/CYP2C9 induction	The only ERA with a mandatory monthly liver-enzyme monitoring requirement for the full duration of treatment
Ambrisentan	5 mg PO once daily, may increase to 10 mg once daily	Peripheral edema/fluid retention (more prominent than other ERAs), anemia, teratogenicity	Fewer clinically significant CYP interactions than bosentan	The ERA studied together with tadalafil in the AMBITION upfront-combination trial
Macitentan	10 mg PO once daily — single fixed dose, no titration	Anemia, headache, nasopharyngitis, teratogenicity	Fewer clinically significant CYP interactions than bosentan	The only ERA with randomized-trial evidence of a reduced composite morbidity/mortality endpoint (SERAPHIN)

Nitric Oxide-cGMP Pathway: PDE5 Inhibitors and the sGC Stimulator Riociguat

PDE5 inhibitors and riociguat both act on the nitric oxide-cGMP pathway and must never be combined with each other or with any nitrate — the combination carries a real risk of severe, symptomatic systemic hypotension.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Sildenafil	20 mg PO three times daily	Headache, flushing, dyspepsia, epistaxis, visual disturbance	Contraindicated with riociguat and with any nitrate (severe hypotension); avoid with strong CYP3A4 inhibitors	PDE5 inhibitor — combination-therapy backbone alongside an ERA for intermediate-risk PAH
Tadalafil	40 mg PO once daily	Headache, flushing, myalgia, back pain, dyspepsia	Contraindicated with riociguat and with any nitrate (severe hypotension)	Once-daily PDE5 inhibitor; the agent studied together with ambrisentan in the AMBITION trial
Riociguat	Start 1 mg PO three times daily; titrate by 0.5 mg three times daily no more often than every 2 weeks, by systolic BP and tolerability, to a maximum of 2.5 mg three times daily (maximum total daily dose 7.5 mg)	Hypotension, headache, dyspepsia, peripheral edema, hemoptysis, gastritis	Contraindicated with any PDE5 inhibitor and with any nitrate/nitric oxide donor (severe hypotension); switching from a PDE5 inhibitor requires a washout (24h+ sildenafil, 48h+ tadalafil)	The one PAH-class agent with a second, distinct indication in inoperable or residual/recurrent CTEPH

Prostacyclin Pathway Agents

Replace deficient endogenous prostacyclin, producing vasodilation plus antiplatelet and antiproliferative effects. Reserved for higher-risk PAH; delivery method (continuous parenteral, inhaled, or oral) is itself a major treatment decision — see Choose Initial Treatment.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Epoprostenol	Continuous IV infusion via a permanent central venous catheter; start ~2 ng/kg/min, titrate upward by symptoms/tolerability with no fixed ceiling	Flushing, headache, jaw/bone pain, nausea, diarrhea, catheter-related infection, rebound PH with interruption	Additive hypotension with other vasodilators	~6-minute half-life — any unplanned infusion interruption is a medical emergency; the only PAH agent with RCT-demonstrated survival benefit as monotherapy in the highest-risk population
Treprostinil	SC/IV: start ~1.25 ng/kg/min, titrate by symptoms; also available as inhaled and oral extended-release formulations	Infusion-site pain (SC, often treatment-limiting), flushing, headache, jaw pain, diarrhea	Additive hypotension with other vasodilators	SC delivery avoids the infection risk of an indwelling central catheter; the most delivery-flexible agent in this pathway
Selexipag	Start 200 mcg PO twice daily; increase by 200 mcg twice-daily increments approximately weekly, as tolerated, to a maximum of 1600 mcg twice daily	Headache, jaw/bone pain, flushing, diarrhea, nausea — dose-related, most prominent during uptitration	Avoid strong CYP2C8 inhibitors/inducers, which affect levels of the active metabolite	Oral, non-prostanoid IP-receptor agonist; reduced a composite morbidity/mortality endpoint in the GRIPHON trial
Iloprost	Inhaled, 2.5-5 mcg via nebulizer, 6-9 times daily	Flushing, headache, jaw/bone pain, cough, nausea	Additive hypotension with other vasodilators	Short duration of action requires frequent daily nebulized dosing — a genuine adherence burden; not currently published in the Pharmasist Drug Database

Calcium Channel Blockers — Confirmed Acute Vasodilator Responders Only

Appropriate only for the roughly 10-15% of idiopathic, heritable, or drug/toxin-induced PAH patients with a documented positive acute vasodilator response on RHC. Dangerous and contraindicated in a non-responder.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Diltiazem	High-dose, individualized and uptitrated in a PH expert centre	Hypotension, bradycardia, peripheral edema — dangerous in a non-vasoresponder	Additive bradycardia/hypotension with other rate- or pressure-lowering agents	Appropriate only for confirmed acute vasodilator responders (see Choose Initial Treatment)
Amlodipine	High-dose, individualized and uptitrated in a PH expert centre	Hypotension, peripheral edema — dangerous in a non-vasoresponder	Additive hypotension with other vasodilators	An alternative to diltiazem for confirmed vasoresponders; not currently published as a standalone monotherapy entry in the Pharmasist Drug Database

Supportive Therapy

Anticoagulation, diuretics, and oxygen are individualized to PAH subtype and clinical status rather than given routinely to every patient — see Choose Initial Treatment for which PAH subgroups should, and should not, receive anticoagulation.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Warfarin	Individualized to target INR 2-3	Bleeding	Numerous — confirm the full medication list, including any interacting ERA (bosentan reduces warfarin effect via CYP induction)	Reasonable only in selected idiopathic, heritable, or drug/toxin-induced PAH without elevated bleeding risk; not recommended in CTD-, HIV-, portal-hypertension-, or CHD-associated PAH
Furosemide	Individualized to volume status and renal function	Electrolyte disturbance, renal function changes, hypotension	Additive hypotension with PAH-specific vasodilators	Titrate carefully — both under- and over-diuresis can worsen right ventricular filling and cardiac output

Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.