New clinical guidelines for the diagnosis and treatment of patients with pulmonary hypertension (PH) include an algorithm for earlier detection in the community and a recommendation for expedited referral for high-risk or complex patients. The guidelines were published simultaneously in the European Respiratory Journal and the European Heart Journal.
The 2022 guidelines from the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) integrate recent developments in detecting and managing PH and are an update to the 2015 version.
Created by a task force that included cardiologists, pneumologists, a thoracic surgeon, methodologists, and patients, the 2022 guidelines cover the entire spectrum of PH, with an emphasis on diagnosing and treating pulmonary arterial hypertension (PAH) and chronic thrombo-embolic pulmonary hypertension (CTEPH). The guidelines were developed with use of the Grading of Recommendations, Assessment, Development, and Evaluations approach and the Evidence to Decision framework.
Updated definitions, indicators, and cut-offs
The classification of PH has been updated, and the risk-stratification table includes additional echocardiographic and cardiac magnetic resonance imaging prognostic indicators. Recommendations for initial drug therapies have been simplified, and those for managing PH associated with left heart disease (PH-LHD) and lung disease have been revised. Other changes include a definition of exercise PH (mean pulmonary arterial pressure [mPAP]/cardiac output slope >3 mm Hg/L/min between rest and exercise).
The hemodynamic definition of PH has been updated (to mPAP >20 mmHg), and the definition of PAH implies a pulmonary vascular resistance (PVR) greater than 2 Wood units (WU) and pulmonary arterial wedge pressure at least 15 mm Hg. “These cutoff values better reflect the limits of normal ranges, but do not yet translate into new therapeutic recommendations, since the efficacy of PAH therapy in patients with pulmonary vascular disease and an mPAP 21-24 mm Hg and/or PVR 2-3 WU is still unknown,” noted the guideline authors.
Updated PH algorithm
The main diagnostic algorithm for PH now follows a 3-step approach: step 1, suspicion by first-line physicians; step 2, detection with echocardiography; and step 3, confirmation at a PH center when an intermediate/high probability of PH is established or in the presence of risk factors for PAH or a history of pulmonary embolism (PE).
Right heart catheterization
Among the new and revised recommendations with a class I grade, the task force advises that right heart catheterization (RHC) should comprise a complete set of hemodynamics and be conducted according to standardized protocols. Inhaled nitric oxide, inhaled iloprost, or intravenous epoprostenol are now recommended for vasoreactivity testing.
The updated guidelines recommend assigning an echocardiographic probability of PH, based on an abnormal tricuspid regurgitation velocity (TRV) and presence of other echocardiographic signs indicating PH, as well as to maintain the current threshold for TRV (>2.8 m/s) for echocardiographic probability of PH according to the updated hemodynamic definition.
DETECT algorithm for SSc
Patients with systemic sclerosis (SSc) are advised to have an annual evaluation of PAH risk. For adults with SSc of more than 3 years’ duration, a forced vital capacity of at least 40%, and a lung diffusion capacity for carbon monoxide less than 60%, the DETECT algorithm is recommended to identify asymptomatic patients with PAH. Among patients with SSc in which breathlessness is unexplained after noninvasive assessment, RHC is recommended to exclude PAH.
For patients who have persistent or new-onset dyspnea or exercise limitation after a PE, further diagnostic evaluation is recommended to assess for CTEPH/chronic thrombo-embolic pulmonary disease. Symptomatic patients with mismatched perfusion lung defects beyond 3 months of anticoagulation for acute PE are recommended to be referred to a PH/CTEPH center after considering the results of echocardiography, brain natriuretic peptide (BNP)/N-terminal (NT)-proBNP, and/or cardiopulmonary exercise testing.
Counseling is recommended for the risk of PAH, and annual screening is advised in individuals who test positive for PAH-causing mutations and in first-degree relatives of patients with heritable pulmonary arterial hypertension (HPAH).
Use of a 3-strata model (low, intermediate, and high risk) is recommended for risk stratification at diagnosis, while considering all available data including hemodynamics. For risk stratification during follow-up, use of a 4-strata model (low, intermediate-low, intermediate-high, and high risk) based on World Health Organization functional class (WHO-FC), 6-minute walking distance, and BNP/NT-proBNP is recommended, with consideration of other variables as necessary.
Women of childbearing potential
Women of childbearing potential with PAH are recommended to have counseling at diagnosis regarding the risks and uncertainties associated with becoming pregnant. The guidelines recommend providing women of childbearing potential with PAH with clear contraceptive advice, noting that the implications of contraceptive failure are significant in PAH. Women with PAH who consider pregnancy or who become pregnant should receive prompt counseling in an experienced PH center to facilitate genetic counselling and shared decision-making and to provide psychological support to the patients and their families when needed. Women with PAH having termination of pregnancy are advised to have this counseling at a PH center, with psychological support provided to the patient and her family.
The guidelines recommend continuing high doses of calcium channel blockers in patients with idiopathic pulmonary arterial hypertension (IPAH), HPAH, or drug- or toxin-associated PAH in WHO-FC I or II with marked hemodynamic improvement (mPAP <30 mm Hg and PVR <4 WU).
For initial oral drug combination therapy in patients with idiopathic, heritable, or drug-associated PAH without cardiopulmonary comorbidities, initial combination therapy with ambrisentan and tadalafil is recommended, as is initial combination therapy with macitentan and tadalafil.
Regarding sequential drug combination therapy in patients with idiopathic, heritable, or drug-associated PAH, the guidelines recommend basing treatment escalations on risk assessment and general treatment strategies. Also, the addition of macitentan to phosphodiesterase 5 inhibitors (PDE5is) or oral/inhaled prostacyclin analogues is recommended to lower the risk of morbidity and mortality. The addition of oral treprostinil to endothelin receptor antagonist or PDE5i/riociguat monotherapy is also recommended to decrease the risk of morbidity and mortality.
The guidelines recommend diagnosing drug- or toxin-associated PAH in patients with relevant exposure and in whom other causes of PH have been excluded. Patients with suspected drug- or toxin-associated PAH are advised to discontinue the causative agent immediately when possible.
Liver disease and transplantation
Echocardiography is recommended in patients with liver disease or portal hypertension with signs or symptoms indicating PH and as a screening tool in those assessed for liver transplantation or transjugular portosystemic shunt. For patients who are referred for liver transplantation, echocardiography is recommended as a screening test for PH.
Children with PH
For children with PH, the guidelines recommend that the diagnostic work-up, including RHC and acute vasodilator testing, and treatment occur at centers with specific expertise in pediatric PH. Children with PH are advised to have a comprehensive work-up for confirming diagnosis and specific etiology similar to that of adults but adapted for age.
The guidelines recommend lifelong therapeutic doses of anticoagulation in all patients with CTEPH. Also, antiphospholipid syndrome testing is recommended in patients with CTEPH. For patients with CTEPH and antiphospholipid syndrome, anticoagulation with vitamin K antagonists is recommended. All patients with CTEPH are advised to be assessed by a CTEPH team for the use of multimodality management.
Supervised exercise training is recommended for patients with PAH under medical therapy. Immunization is recommended for those with PAH against SARS-CoV-2, influenza, and Streptococcus pneumoniae. In cases of iron-deficiency anemia, correction of iron status is recommended in patients with PAH. In-flight oxygen administration is recommended for patients using oxygen therapy or who have arterial blood oxygen pressure <8 kPA (60 mm Hg) at sea level.
“Health professionals are encouraged to take the ESC/ERS guidelines fully into account when exercising their clinical judgement, as well as in determining and implementing preventive, diagnostic, or therapeutic medical strategies,” stated the task force. “However, the ESC/ERS guidelines do not override, in any way, the individual responsibility of health professionals to make appropriate and accurate decisions in considering each patient’s health condition and in consulting with that patient or the patient’s caregiver where appropriate and/or necessary.”
The guidelines are endorsed by the International Society for Heart and Lung Transplantation and the European Reference Network on rare respiratory diseases.
Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2022;43(38):3618-3731. doi:10.1183/13993003.00879-2022
Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731. doi:10.1093/eurheartj/ehac237