Erum Naqvi obtained her Ph.D. in Molecular Medicine from Hannover Medical School (Germany) after completing her Masters in Biomedical Science and Bachelors in Microbiology from University of Delhi (India). She has several years of experience as a science writer.
With the increase in knowledge about pulmonary arterial hypertension (PAH) and the development of new drugs, several organizations and expert committees have developed or updated evidence-based guidelines for PAH treatment over the years. These include the joint committee of the European Society of Cardiology and the European Respiratory Society (ESC/ERS),1 the World Symposium on Pulmonary Hypertension (WSPH),2 and the American College of Chest Physicians (ACCP).3
General Guidelines for Patients With PAH
All 3 guidelines – ESC/ERS, WSPH, and ACCP – recommend some general measures and supportive care recommendations for patients diagnosed with PAH. These include recommendations to receive pneumococcal and influenza vaccinations, avoid pregnancy in female patients and get counseling about suitable birth control methods, participate in supervised exercise programs to improve exercise tolerance, avoid nonessential surgery to prevent perioperative complications, and use epidural anesthesia instead of general anesthesia due to the increased risk of hemodynamic imbalance.4
All 3 guidelines recommend patient referral to an expert PAH center in the management of patients with PAH. Those with an oxygen saturation less than 90% are recommended to receive supplemental oxygen. Diuretics are recommended to prevent volume overload and excess fluid retention. Those traveling by airplane are cautioned and recommended to undergo altitude simulation testing to determine if in-flight oxygen administration is required to maintain an oxygen saturation greater than 90%. Patients with idiopathic PAH (IPAH), heritable PAH (HPAH), or drug-induced PAH can be considered for use of warfarin (anticoagulation) based on individual cases.4
Pulmonary Vasodilator Testing
Patients with IPAH, HPAH, or drug-induced PAH are recommended to undergo pulmonary vasodilator challenge testing using vasodilators, such as inhaled nitric oxide, during right heart catheterization (RHC) before starting PAH-targeted therapy. Patients who show a positive vasodilator response, defined as a reduction in mPAP by ≥ 10 mmHg to a value of ≤ 40 mmHg with unchanged or improved cardiac output, often respond favorably to treatment with high-dose calcium channel blockers (CCBs) and have a better overall prognosis.1,5 Those patients who do not respond or respond negatively in the acute vasodilator testing should be treated with PAH-specific therapies.
According to the 2015 ESC/ERS guidelines, the initial treatment is determined by risk stratification (into low-, intermediate-, and high-risk categories) using assessment of several clinical factors, such as clinical parameters, exercise capacity, right ventricular function, and hemodynamic parameters, to evaluate the probability of 1-year mortality.
Patients who are at low- or intermediate risk are recommended oral monotherapy, such as an endothelin receptor antagonist (ERA; ambrisentan, bosentan, or macitentan), a phosphodiesterase type-5 inhibitor (PDE5i; sildenafil, tadalafil, or vardenafil), a guanylate cyclase stimulator (riociguat), or an oral prostacyclin receptor agonist (selexipag).1,6
The guidelines recommend that high-risk patients be treated with intravenous prostacyclin, preferably intravenous epoprostenol, in combination with a PDE5i or ERA.
In all cases, the guidelines recommend that patients should be closely followed-up and undergo comprehensive assessment after 3-6 months of treatment. If the treatment does not benefit, ie, fails to achieve or maintain low- or intermediate-risk status, additional therapies are added sequentially. If patients still progress to high-risk status despite triple therapy (including parenteral prostacyclin), they are referred for assessment for lung transplantation.1,6
Sixth WSPH Guidelines
The 2019 sixth WSPH proposed changing the definition of pulmonary hypertension (PH) to a mean pulmonary arterial pressure (mPAP) of ≥ 20 mm Hg instead of ≥ 25 mm Hg.2
Unlike the 2015 ESC/ERS guidelines that recommend monotherapy for patients at low- or intermediate risk, the sixth WSPH guidelines recommend up-front use of combination therapy with an ERA and PDE5i in low- and intermediate-risk patients (based on the findings of the AMBITION trial7,8). However, combination therapy is not recommended for patients with high chances of pulmonary veno-occlusive disease, those with a risk for left ventricular diastolic dysfunction, or those with a type of PAH not studied in the AMBITION trial, such as PAH associated with portal hypertension or very mild PAH.4
Patients who are in the high-risk category or functional class (FC) IV are recommended to receive intravenous epoprostenol in combination with a PDE5i.
Similar to the 2015 ECS/ERS guidelines, the 2019 WSPH guidelines use the risk stratification approach to guide initial as well as follow-up treatment. However, prognostic parameters other than those used in the 2015 ECS/ERS guidelines may be used to determine the risk status.4
The 2019 ACCP guidelines, similar to the 2019 WSPH guidelines, recommend initiating combination oral therapy with an ERA and a PDE5i, specifically ambrisentan and tadalafil, for patients with mild or moderate disease (FC II or III) and intravenous prostacyclin for patients with severe disease (FC IV). However, the ACCP guidelines use the patient FC to determine disease severity instead of the comprehensive risk assessment.3
Response to Therapy
All 3 guidelines recommend evaluating response to therapy after 3-6 months by performing complete assessment, including RHC. The ESC/ERS and WSPH guidelines recommend that if patients respond favorably to the therapy, ie, low-risk status has been achieved or maintained, current therapy should be continued, while patients who are in the intermediate- or high-risk categories even after 3-6 months of therapy should be treated with an additional agent.
The ACCP guidelines determine the treatment response by using the World Health Organization (WHO) FC. Patients with WHO FC III or IV symptoms despite treatment with 2 classes of PAH drugs should be treated with an additional third agent. Those who fail to improve despite maximal medical therapy should be considered for lung transplant evaluation.3,4
- Galiè N, Humbert M, Vachiery JL, et al.; ESC Scientific Document Group. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119. doi:10.1093/eurheartj/ehv317
- Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1):1801913. Published 2019 Jan 24. doi:10.1183/13993003.01913-2018
- Klinger JR, Elliott CG, Levine DJ, et al. Therapy for pulmonary arterial hypertension in adults: update of the CHEST guideline and expert panel report. Chest. 2019;155(3):565-586. doi:10.1016/j.chest.2018.11.030
- Vazquez ZGS, Klinger JR. Guidelines for the treatment of pulmonary arterial hypertension. Lung. 2020;198(4):581-596. doi:10.1007/s00408-020-00375-w
- Sitbon O, Humbert M, Jaïs X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111(23):3105-3111. doi:10.1161/CIRCULATIONAHA.104.488486
- Lan NSH, Massam BD, Kulkarni SS, Lang CC. Pulmonary arterial hypertension: pathophysiology and treatment. Diseases. 2018;6(2):38. doi:10.3390/diseases6020038
- Galiè N, Barberà JA, Frost AE, et al.; AMBITION Investigators. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373(9):834-844. doi:10.1056/NEJMoa1413687
Vachiéry JL, Galiè N, Barberá JA, et al.; AMBITION Study Group. Initial combination therapy with ambrisentan + tadalafil on pulmonary arterial hypertension‒related hospitalization in the AMBITION trial. J Heart Lung Transplant. 2019;38(2):194-202. doi:10.1016/j.healun.2018.11.006
Reviewed by Kyle Habet, MD, on 7/1/2021.