2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension

Authors, Journal, Affiliations, Type, DOI

• Authors: Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Huggins GS, Jais X, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S; ESC/ERS Scientific Document Group
• Journal: European Heart Journal
• Affiliations: Multi-national ESC/ERS Task Force; corresponding authors Rosenkranz S (ESC) and Delcroix M (ERS)
• Type: Joint ESC/ERS Clinical Practice Guideline
• DOI: https://doi.org/10.1093/eurheartj/ehac237

Overview

The 2022 ESC/ERS PH Guidelines represent a landmark update to the 2015 iteration, with the most impactful change being a lower haemodynamic diagnostic threshold for pulmonary hypertension (mPAP >20 mmHg, PVR >2 WU), replacing the prior ≥25 mmHg threshold, and the formal reintroduction of exercise PH as a defined entity. The five-group clinical classification is maintained but refined, with PVOD/PCH and persistent PH of the newborn incorporated into Group 1, a new CTEPD category introduced for thromboembolic disease without PH, and risk stratification at follow-up expanded from 3 to 4 strata. Key treatment advances include initial combination ERA + PDE5i as Class I for most low-to-intermediate-risk PAH patients, balloon pulmonary angioplasty (BPA) upgraded to Class I for inoperable CTEPH, supervised exercise training upgraded from IIa to Class I, iron deficiency correction upgraded to Class I, and PDE5i designated Class III in HFpEF-related isolated post-capillary PH.

Keywords

Pulmonary hypertension, pulmonary arterial hypertension, CTEPH, haemodynamic definition, right heart catheterization, risk stratification, ERA, PDE5i, balloon pulmonary angioplasty, exercise training, iron deficiency, SSc screening

Key Takeaways

Haemodynamic Definitions (Section 3.1)

• New PH threshold: mPAP >20 mmHg at rest (lowered from ≥25 mmHg), supported by upper limit of normal studies and prognostic data.
• Pre-capillary PH: mPAP >20 mmHg + PAWP ≤15 mmHg + PVR >2 WU. PAWP ≤15 mmHg maintained as the pre/post-capillary threshold.
• Post-capillary PH: mPAP >20 mmHg + PAWP >15 mmHg. Subdivided into: isolated post-capillary PH (IpcPH, PVR ≤2 WU) and combined post- and pre-capillary PH (CpcPH, PVR >2 WU).
• Exercise PH (reintroduced): mPAP/CO slope >3 mmHg/L/min between rest and exercise. Not physiological in subjects <60 years. Associated with impaired prognosis in exercise dyspnoea and multiple cardiovascular conditions.
• Unclassified PH: mPAP >20 mmHg + PVR ≤2 WU + PAWP ≤15 mmHg; often from elevated pulmonary blood flow (CHD, liver disease, hyperthyroidism). Clinical follow-up recommended.
• Drug threshold caveat: All approved PAH drugs have been studied only in patients with mPAP ≥25 mmHg and PVR >3 WU — no efficacy data exist for lower-threshold patients.

Clinical Classification (Section 3.2)

• 5 PH groups maintained: Group 1 (PAH), Group 2 (LHD), Group 3 (lung disease/hypoxia), Group 4 (PA obstructions, primarily CTEPH), Group 5 (unclear/multifactorial).
• Group 1 updates: PVOD/PCH and persistent PH of the newborn (PPHN) moved into Group 1. IPAH subclassified into non-responders and acute responders to vasoreactivity testing.
• Group 3 update: 'Sleep-disordered breathing' replaced by 'hypoventilation syndromes' (isolated nocturnal OSA not considered a cause of PH).
• Group 4 update: Renamed 'PH associated with pulmonary artery obstructions'; CTEPD (chronic thromboembolic pulmonary disease without PH) formally introduced as a clinical entity.

Epidemiology (Section 4)

• Global PH prevalence: ~1% of global population; LHD (Group 2) is the leading cause globally; COPD is second most common.
• PAH (Group 1): Incidence ~6 cases/million adults; prevalence 48–55 cases/million adults (developed countries). IPAH accounts for 50–60% of PAH cases; historically female-predominant, but now increasingly diagnosed in older patients with equal sex distribution.
• CTEPH (Group 4): Incidence 2–6 cases/million adults; prevalence 26–38 cases/million adults. Cumulative incidence post-acute PE: 0.6% (all PE patients), 3.2% (survivors), 2.3% at 2 years in prospective data.
• PH-LHD (Group 2): Post-capillary PH affects ≥50% of HFpEF patients; PH present in 60–70% of severe symptomatic mitral valve disease; up to 50% of symptomatic aortic stenosis.
• Group 3: 1–5% of advanced COPD have mPAP >35–40 mmHg; mPAP ≥25 mmHg in 8–15% of IPF patients initially, rising to >60% in end-stage disease.

Diagnosis (Section 5)

• Echocardiography: First-line non-invasive investigation (Class I/B); assigns echocardiographic probability of PH based on TRV (threshold maintained at >2.8 m/s) plus additional signs. Echocardiography alone insufficient to confirm PH — RHC required.
• Diagnostic algorithm: Three-step process: Step 1 (suspicion: GP evaluation — ECG, BNP/NT-proBNP, O₂ sat); Step 2 (detection: echocardiography, PFTs, ABG); Step 3 (confirmation: referral to PH centre, RHC).
• RHC: Required for PH confirmation; mandatory before PAH therapy initiation; recommended in suspected PH-LHD if aids management; recommended in severe tricuspid regurgitation before valve intervention.
• Imaging: V/Q or perfusion scintigraphy recommended in unexplained PH to screen for CTEPH (Class I/C); CT pulmonary angiography recommended in suspected CTEPH (Class I/C).
• Warning signs for immediate hospitalisation: WHO-FC III/IV rapid progression, signs of RV failure, syncope, low CO state, poorly tolerated arrhythmias, haemodynamic compromise.

Screening (Section 5.3)

• Systemic sclerosis (SSc): Annual evaluation of PAH risk recommended (Class I/B); DETECT algorithm recommended when disease duration >3 years, FVC ≥40%, and DLCO <60% (Class I/B). Prevalence 5–19%; annual incidence 0.7–1.5%.
• BMPR2 carriers: Annual screening including ECG, NT-proBNP, DLCO, echocardiography, CPET recommended; multimodal approach — echocardiography alone insufficient. Lifetime PAH risk ~20% (42% in females, 14% in males).
• Portal hypertension: Echocardiography recommended for liver transplant assessment (Class I/C). PoPH prevalence 1–2%.
• Post-PE follow-up: In persistent/new dyspnoea after PE, further evaluation for CTEPH/CTEPD recommended (Class I/C); referral to PH/CTEPH centre for mismatched perfusion defects beyond 3 months of anticoagulation (Class I/C).

PAH Risk Stratification (Section 6.2)

• 3-strata model at diagnosis: Low / Intermediate / High risk; based on WHO-FC, 6MWD, NT-proBNP, echocardiography, RHC haemodynamics.
• 4-strata model at follow-up: Low / Intermediate-Low / Intermediate-High / High risk. Adds sub-stratification within the intermediate range to guide escalation decisions.
• Treatment goal: Achieving and maintaining low-risk status is the primary treatment target.
• Key haemodynamic parameters for low-risk status: RAP <8 mmHg, CI ≥2.5 L/min/m², SVI ≥38 mL/m², mixed venous O₂ saturation >65%.

General Measures (Section 6.3.1)

• Supervised exercise training: Class I/A (upgraded from IIa) — RCT in 116 PAH/CTEPH patients showed +34.1 m 6MWD improvement.
• Iron deficiency correction: Class I/C — iron deficiency common in PAH; i.v. supplementation recommended in anaemia; repletion without anaemia is Class IIb.
• Anticoagulation: IIb (individual basis only) — not generally recommended; potentially harmful in SSc-PAH; conflicting evidence for IPAH.
• ACEi/ARB/ARNI/SGLT-2i/beta-blockers/ivabradine: Class III — not recommended in PAH unless required by comorbidities (hypertension, CAD, left HF, arrhythmias).
• Diuretics: Class I/C — for signs of RV failure and fluid retention.
• Oxygen: Class I/C — long-term oxygen when PaO₂ <8 kPa (60 mmHg).
• Pregnancy: strongly discouraged — maternal mortality 11–25% even with modern treatment; ERAs and riociguat contraindicated (teratogenic; Class III/B); CCBs/PDE5i/prostacyclin analogues considered safe.

Calcium Channel Blockers (Section 6.3.3.1)

• CCBs: Class I/C — only for vasoreactive patients (acute responders) with IPAH, HPAH, or DPAH; <10% of patients qualify.
• Adequate CCB response defined as WHO-FC I/II + marked haemodynamic improvement (mPAP <30 mmHg and PVR <4 WU) at 3–6 month reassessment.
• CCBs not recommended in non-responders (Class III/C) — risk of severe hypotension, syncope, RV failure.

PAH Drug Therapy Algorithm (Section 6.3.3 and GRADE Recommendations)

• Initial combination therapy (ERA + PDE5i): Class I/B for low-to-intermediate-risk IPAH/HPAH/DPAH (GRADE: Low evidence, Conditional recommendation).
  • Ambrisentan + tadalafil (AMBITION trial): Class I — the primary evidence base for initial combination.
  • Macitentan + tadalafil: Class I (new) — new recommendation in 2022.
  • Other ERA + PDE5i combinations: Class IIa.
• Initial triple therapy including i.v./s.c. prostacyclin: may be considered in intermediate-risk patients with severe haemodynamic impairment (RAP ≥20 mmHg, CI <2.0 L/min/m², SVI <31 mL/m², and/or PVR ≥12 WU).
• Selexipag (oral prostacyclin receptor agonist): approved for PAH combination therapy.
• Bosentan + sildenafil: Class III (downgraded from IIb — not recommended).
• Escalation: reassessment at 3–6 months; if intermediate-high/high risk, add parenteral prostacyclin or consider lung transplantation.

CTEPH Management (Section 10)

• Lifelong anticoagulation: Class I/C — for all CTEPH patients; VKA preferred in antiphospholipid syndrome (Class I); antiphospholipid syndrome testing recommended (Class I).
• Multidisciplinary CTEPH team review: Class I — operability assessment and multimodality management planning required.
• PEA (pulmonary endarterectomy): Class I — treatment of choice for patients with accessible fibrous obstructions; performed in deep hypothermia circulatory arrest.
• BPA: Class I (upgraded from IIb) — recommended for technically inoperable patients or those with residual PH after PEA and distal obstructions amenable to BPA. Pre-BPA medical therapy should be considered (Class IIa).
• Riociguat (sGC stimulator): Class I — for symptomatic inoperable CTEPH or persistent/recurrent PH after PEA.
• CTEPD without PH: Anticoagulation Class IIa (individual basis); PEA or BPA Class IIa in selected symptomatic patients.
• Multimodality approach (riociguat/PDE5i + ERA + prostacyclin): Class IIb for persistent PH after PEA or inoperable CTEPH.
• Treprostinil s.c.: Class IIb for WHO-FC III–IV inoperable or residual/recurrent CTEPH.

PH Associated with Left Heart Disease (Group 2; Section 8)

• RHC: Class I — recommended in suspected PH-LHD when results aid management; also recommended in severe tricuspid regurgitation.
• Referral to PH centre: Class I — for patients with LHD, suspected severe pre-capillary component (features of PH with RV dysfunction).
• PDE5i in HFpEF with isolated post-capillary PH: Class III — not recommended (GRADE: Low evidence, Conditional recommendation against).
• PDE5i in ILD-associated PH: Class IIb (individual decision at PH centres).
• Borderline PAWP (13–15 mmHg) with HFpEF features: exercise or fluid challenge testing may be considered (Class IIb) to unmask post-capillary PH.
• In CpcPH with severe pre-capillary component (PVR >5 WU): individualised approach Class I.

PH Associated with Lung Disease (Group 3; Section 9)

• Optimise underlying lung disease treatment: Class I — including hypoxia, sleep-disordered breathing, alveolar hypoventilation.
• Referral to PH centre: Class I — for lung disease with suspected severe PH or uncertainty about treatment.
• Individualised PAH therapy: Class I — in lung disease with severe PH.
• Inhaled treprostinil: Class IIb — may be considered in PH associated with ILD.
• Ambrisentan: Class III — not recommended in PH associated with IPF.
• Riociguat: Class III — not recommended in PH associated with IIP.

Genetics of PAH (Section 5.1.10)

• BMPR2: Most common gene in HPAH (~80%); penetrance ~20% overall (42% female, 14% male). Annual multimodal screening recommended for carriers.
• Other validated PAH genes: ATP13A3, AQP1, ABCC8, KCNK3, SMAD9, Sox17, CAV1, TBX4, EIF2AK4, KDR, ENG, ACVRL1 (HHT), GDF2. TBX4, ALK1, and ENG found in top 6 most common findings in adults with previously diagnosed IPAH.
• Genetic counselling: Class I — prior to genetic testing and for asymptomatic family members.
• Next-generation sequencing gene panels now standard; composition changes as discoveries advance.

Limitations of the Document

• New haemodynamic threshold (mPAP >20 mmHg) not yet validated by drug trial evidence: All approved PAH drugs studied only in patients with mPAP ≥25 mmHg and PVR >3 WU; no trial data for the lower-threshold zone (mPAP 21–24 mmHg, PVR 2–3 WU). Clinical implications of the expanded definition remain unclear.
• BPA evidence base remains limited: Upgraded to Class I but evidence quality is Low (GRADE); most BPA data from Japanese single-centre registries; external validity in non-specialised centres uncertain.
• Anticoagulation recommendation inconsistency: Downgraded to IIb for IPAH/HPAH despite meta-analyses suggesting survival benefit; no RCT data available; registry data are conflicting. Recommendation reflects expert opinion more than evidence.
• Risk stratification validation gap: The 4-strata follow-up model is clinically pragmatic but not validated against hard outcomes in prospective cohorts at the time of publication; individual risk score weightings are expert-derived.
• CTEPD definition and management: CTEPD without PH is newly formalised but prevalence unknown; management recommendations (BPA/PEA for symptomatic patients) are Class IIa with limited supportive evidence.
• Exercise PH: Reintroduced but mPAP/CO slope thresholds are age-dependent; reproducibility and prognostic thresholds in clinical practice require further validation.

Key Concepts Mentioned

• concepts/PAH-Risk-Stratification — 3-strata at diagnosis; 4-strata at follow-up; low-risk target
• concepts/Pulmonary-Hypertension-Classification — 5-group clinical classification; pre/post-capillary definitions
• concepts/Right-Heart-Catheterization — gold standard for PH confirmation and haemodynamic assessment

Key Entities Mentioned

• entities/Pulmonary-Hypertension — main entity; diagnostic threshold, classification, management overview
• entities/CTEPH — Group 4; PEA/BPA/riociguat therapeutic algorithm
• entities/Heart-Failure — Group 2 PH-LHD; HFpEF + PH; PDE5i Class III in post-capillary PH

Wiki Pages Updated

• entities/Pulmonary-Hypertension — created
• entities/CTEPH — created
• concepts/PAH-Risk-Stratification — created
• entities/Heart-Failure — added Group 2 PH-LHD section
• wiki/wikiindex.md — PHT-ESC-2022 entry added