Pulmonary Arterial Hypertension Management

Evaluation

Clinical and hemodynamic assessments are important in determining prognosis and consequent management.

Tests for Assessment of Pulmonary Hypertension Severity  

The following tests are indicated to establish baseline severity as well as for follow-up of therapy:  

6-Minute Walk Test (6MWT)  

A 6-minute walk test is an objective assessment of exercise capacity. It is influenced by several factors, including sex, age, height, weight, comorbidities, need for O₂, learning curve and motivation. The distance walked, exertional dyspnea (Borg scale), and finger O₂ saturation are measured. A walking distances of <332 meters or <250 meters and O₂ desaturation >10% indicate a poor prognosis.

Cardiopulmonary Exercise Testing (CPET)  

Cardiopulmonary exercise testing is also an objective assessment of exercise capacity but is less acceptable and less frequently used than 6MWT. Gas exchange and ventilation are continuously recorded while on incremental exercise. O₂ uptake at anaerobic threshold and at peak exercise, peak work rate, peak heart rate, O₂ pulse, and ventilator efficiency are reduced according to PH severity. Peak oxygen uptake (VO₂) is the most widely used for therapeutic decision-making. It provides useful information to further stratify patients with PAH at intermediate risk when associated with stroke volume index (SVI).  

Biochemical Markers  

Biochemical markers are a non-invasive tool for assessment and monitoring of RV dysfunction in patients with PH. Serum uric acid is a marker of impaired oxidative metabolism of ischemic peripheral tissue, where high values relate to poor survival in IPAH. BNP and NT-proBNP are directly proportionate to RV dysfunction, which is the major cause of death in PAH.  

Cardiac Magnetic Resonance Imaging (cMRI)  

Cardiac MRI provides accurate and reproducible assessment of RV size and function. RV volumes, RV ejection fraction (RVEF) and SV are essential prognostic determinants in PAH. The SV ≤25 mL/m², RV end-diastolic volume ≥84 mL/m², LV end-diastolic volume ≤40 mL/m², and PA stiffness as measured by change <16% in relative cross-sectional area all corresponds to poor prognosis.  

Echocardiography  

Echocardiography generates indices that have good prognostic value, such as pericardial effusion, indexed right atrium area, LV eccentricity index and RV Doppler index.  It makes possible the measurement of combined parameters such as the tricuspid annular plane systolic excursion (TAPSE)/systolic PAP (sPAP) which is closely linked to RV-PA coupling and predicts outcome.  

Right Heart Catheterization (RHC)  

The mean right atrial pressure (RAP) (mRAP), cardiac index (CI), and mPAP are predictive of survival and may be used together with PaO₂ saturation, PVR, and a marked vasoreactivity response for prognostication.

Definition of Patient Status  

The use of a three-strata model (low, intermediate, and high risk) is recommended for stratification of risk at the time of diagnosis using all available date including hemodynamics. The use of a four-strata model (low, intermediate-low, intermediate-high, and high risk) is recommended for stratification of risk during follow-up based on WHO-FC, 6MWT, and BNP/NT-proBNP and additional values as necessary.  

Assessment of patient risk depends on the following factors: WHO-FC, 6MWT and BNP/NT-proBNP are the strongest prognostic predictors, and at least these 3 variables are recommended to stratify risk.

Reference: 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.
^◊VE/VCO2: Ventilatory equivalents for carbon dioxide.
*RVESVI: RV end-systolic volume index

Assessment of patient risk during follow-up depends on the following factors:

Reference: 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.  

Stable and Satisfactory  

Such patients on oral therapy are evaluated every 3 to 6 months with FC assessment and 6MWT done every clinic visit, echocardiogram done every 12 months, and RHC done on clinical deterioration.  

Stable and Not Satisfactory  

The patient, although stable, has not fulfilled all the characteristics of the stable and satisfactory patient status. A complete reassessment and consideration for additional or different treatment is recommended. A complete re-evaluation done on clinical deterioration and every 3 to 4 months after initiation or changes in therapy should be done until the patient becomes stable and satisfactory.  

Unstable and Deteriorating  

Such patients on IV Epoprostenol and/or combination therapy are evaluated every 1 to 3 months with FC assessment and 6MWT done every clinic visit, echocardiogram done every 6 to 12 months, and RHC done on clinical deterioration and every 6 to 12 months.

Acute Vasoreactivity Test  

Pulmonary vasoreactivity testing is recommended in patients with WHO-FC I-III with IPAH, HPAH or DPAH. Vasoreactivity testing in PAH helps in the identification of acute vasoreactive responders who may be candidates for treatment with high-dose calcium channel blockers. A positive result may be considered as a decrease in mPAP of at least 10 mmHg to ≤40 mmHg with an increase or unchanged CO during acute challenge with inhaled NO, inhaled Iloprost, intravenous (IV) Epoprostenol or IV Adenosine. Patients with a positive result, including PAH associated with scleroderma or CHD (without right heart failure) should be considered for trial therapy with a calcium antagonist. Adequate response should be confirmed with complete reassessment, including RHC after 3 to 4 months of treatment. An additional acute vasoreactivity testing is recommended at reassessment to determine persistent vasodilator response supporting the use of high doses of calcium antagonists. This is not indicated in patients with overt right heart failure, hemodynamic instability, WHO-FC IV, and significantly elevated left heart filling pressures.

Principles of Therapy

The achievement and maintenance of a low-risk profile on optimized medical therapy is the recommended treatment goal in patients with PAH. Treatment plans for patients with IPAH, HPAH, DPAH or PAH with CTD should be stratified based on the presence or absence of cardiopulmonary comorbidities and according to disease severity evaluated by risk stratification. Patients with cardiopulmonary comorbidities respond less to PAH therapy. Treatment escalation depends on the risk assessment during follow-up and general treatment strategies. Discontinuation of causative agent is recommended in patients with suspected drug- or toxin-associated PAH.  

Treatment Strategy  

Step 1  

This includes general care, patient education, and supportive therapy. Acute vasoreactivity testing should be done prior to initiation of calcium antagonist therapy.  

Step 2  

This includes initiation of pharmacologic therapy. Initial combination therapy is considered in non-vasoreactive and treatment-naive high-risk patients. The choice of therapy will depend on the approval status/availability of the drug, route of administration, side effect profile, patient preference and practitioner’s experience.  

Step 3  

This depends on the patient’s response to initial treatment, which includes pharmacologic combination therapy and interventional treatments.

Pharmacological therapy

Patients with Positive Acute Vasoreactivity  

Calcium Antagonists  

Example drugs: Amlodipine, Diltiazem, Felodipine, Nifedipine  

The choice of agent should be based on the patient’s heart rate (HR) at baseline. Nifedipine and Amlodipine are preferred in those with relative bradycardia, and Diltiazem is favored in those with relative tachycardia.   Of the vasodilators studied in PAH patients, calcium antagonists have been the most successful. It has shown hemodynamic and functional status improvements of >1 year. High doses are recommended in patients with IPAH, HPAH or DPAH. Patients with IPAH and without right heart failure who demonstrate an acute response to vasodilator testing should be considered for a trial of oral calcium antagonist.  

If patients with PAH associated with underlying processes such as scleroderma or CHD have had positive acute vasoreactivity tests, a trial of calcium antagonists should be attempted. A single-agent treatment with calcium antagonists should only continue in patients showing clinical and hemodynamic response. High doses of calcium antagonists should be continued in patients with IPAH, HPAH or DPAH with WHO-FC I or II with marked hemodynamic improvement (mPAP <30 mmHg and PVR <4WU). Patients with WHO-FC III or IV or without marked hemodynamic improvement despite treatment with high doses of calcium antagonists are recommended PAH therapy initiation. The continuation of calcium antagonist therapy should be considered in patients with positive vasoreactivity tests with insufficient long-term response to calcium antagonists and require additional PAH treatment. Patients with positive acute vasoreactivity and are treated with calcium antagonists should be reassessed initially after 3 to 4 months of therapy with RHC then followed closely for drug safety and efficacy.

Patients with Negative Acute Vasoreactivity or Non-Responders to Calcium Antagonists  

INITIAL MONOTHERAPY  

Initial monotherapy is considered as residual agents for:

• IPAH patients >75 years old and with multiple risk factors for left heart disease
• Non-vasoreactive patients with WHO-FC I-II and remain stable on monotherapy
• Patients with PAH associated with HIV, portal hypertension, or uncorrected heart disease
• PAH patients with high suspicion for PVOD or PCH
• Patients with contraindications to combination therapy or unavailability of combination therapy

Initial monotherapy with a PDE5i or an ERA should be considered in non-vasoreactive patients with IPAH, HPAH or DPAH who present with cardiopulmonary comorbidities.

Endothelin Receptor Antagonists (ERAs)  

Example drugs: Ambrisentan, Bosentan, Macitentan  

Endothelin receptor antagonism is a promising treatment approach due to increased evidence of the pathogenic role of endothelin-1 in PAH. Endothelin-1 is a potent vasoconstrictor and a smooth muscle mitogen that might contribute to the increase in vascular tone and the pulmonary vascular hypertrophy associated with PAH.  

Ambrisentan  

Ambrisentan is a relatively selective antagonist of the ETA receptor. It demonstrated efficacy on symptoms, exercise capacity (6MWT), hemodynamics, and time to clinical worsening of patients with PAH. This is recommended for the improvement of 6MWT results in WHO-FC II-III patients who cannot tolerate combination therapy. An increased incidence of peripheral edema has been reported with Ambrisentan use. This requires a monthly LFT assessment.

Bosentan  

Bosentan is an orally active dual ETA and ETB receptor antagonist. It should be considered in PAH patients in WHO-FC II-III who are not candidates for or who have failed calcium antagonists and is recommended for WHO-FC II-III patients intolerant of combination therapy to delay disease progression, improve 6MWT and reduce hospital stay due to PAH-related complications. This is recommended in symptomatic patients with Eisenmenger syndrome to improve exercise capacity. It improves exercise capacity, functional class, hemodynamics, and time to clinical worsening in patients with PAH. LFT should be checked monthly and hematocrit checked every 3 months. Barrier methods of contraception are recommended over hormonal methods because they may reduce the efficacy of hormonal agents and are potentially teratogenic.  

Macitentan  

Macitentan is a dual ETA and ETB receptor antagonist. It prevents endothelin-1 from binding to ETA and ETB. This should be considered for treatment of PAH patients and for long-term therapy of PAH patients with WHO-FC II-III to delay disease progression and improve functional class. It may be used as an additional treatment agent for PAH patients with WHO-FC III-IV who remain symptomatic despite optimal doses of PDE5i or inhaled prostacyclin analogs to improve functional class, 6MWT and delay time to clinical worsening. A modified version using the same structure of Bosentan, has shown improvements in efficacy and with lesser adverse effects. Studies have shown increased exercise capacity, slower disease progression, and decreased hospitalization in PAH patients on Macitentan therapy.

Guanylate Cyclase Stimulator  

Riociguat  

Riociguat is a soluble guanylate cyclase stimulator, an enzyme that helps regulate NO. It is a treatment option used to improve exercise capacity and hemodynamics, functional class, and delay clinical worsening in patients with WHO-FC II-III.  It may be used as an additional treatment agent for PAH patients with WHO-FC III-IV who remain symptomatic despite optimal doses of Ambrisentan, Bosentan or inhaled prostacyclin analogs to improve functional class, 6MWT and delay time to clinical worsening. This is indicated for therapy of symptomatic inoperable or recurrent CTEPH patients.  

Phosphodiesterase-5 Inhibitors (PDE5i)  

Sildenafil (Oral or IV)  

Sildenafil is an orally active, potent, and selective inhibitor of cGMP phosphodiesterase type-5 that exerts its pharmacological effect by increasing intracellular concentration of cGMP, inducing relaxation and antiproliferative effects on vascular smooth muscle cells. It is recommended for the improvement of 6MWT results and improved functional class in WHO-FC II-III patients who cannot tolerate combination therapy. It may be used as an additional treatment agent for PAH patients with WHO-FC IV who remain symptomatic despite optimal doses of Epoprostenol IV to improve 6MWT. Sildenafil has shown favorable effects in IPAH, PAH associated with CTD, CHD and CTEPH on exercise capacity, symptoms and hemodynamics in clinical studies. Long-term data (available only at a dose of 80 mg 8 hourly) in patients completing 1 year of treatment with Sildenafil monotherapy showed sustained improvement at 1 year in the 6MWT.  

Tadalafil  

Tadalafil is a longer-acting selective PDE5i recommended for patients with WHO-FC II-III for the improvement of 6MWT results, improved functional class and delayed time to clinical worsening, especially those who cannot tolerate combination therapy. It has shown favorable results on exercise capacity, symptoms, hemodynamics, and time to clinical worsening at the largest dose in the study while demonstrating the durability of these effects. The side effect profile is similar to Sildenafil.

Vardenafil  

Vardenafil is a selective PDE5i which may stimulate vascular relaxation by increasing cGMP concentrations in smooth muscles. It is currently under study for its use in the treatment of PAH. Previous studies conducted showed an increase in the 6MWT, improved hemodynamics, and reduced time to disease progression. The side effect profile is similar to Sildenafil.  

Prostacyclin Analogs  

Example drugs: Beraprost, Epoprostenol, Iloprost, Treprostinil  

Prostacyclin is produced mainly by endothelial cells, which can induce potent vasodilation of all vascular Beds. It also inhibits platelet aggregation and has cytoprotective and antiproliferative activities. Prostacyclin analogs have been included in the pharmacotherapy of PAH for more than a decade. Treatment with IV or inhaled prostanoids should only be considered in patients with WHO-FC II who are intolerant to first-line agents or those previously treated but with unsatisfactory treatment results. In patients with WHO-FC III with evidence of rapid disease progression or poor clinical prognosis, initial therapy using a parenteral prostanoid should be considered. Parenteral and inhaled prostanoids should also be considered if the patient remains unresponsive despite treatment with 1 to 2 classes of oral prostanoids.  

Beraprost (Oral)  

Beraprost is the first chemically stable and orally active prostacyclin analog. It is a monotherapy option for patients with WHO-FC III who are intolerant to first-line agents or those previously treated but with unsatisfactory treatment results. An increase in exercise capacity has been shown, but this effect persists only up to 3 to 6 months of therapy with no hemodynamic benefits.  

Epoprostenol (IV)  

Epoprostenol is a synthetic prostacyclin that has shown symptomatic and hemodynamic improvements as well as survival in patients with IPAH in WHO-FC III-IV. Continuous IV Epoprostenol should be considered in patients with WHO-FC III with rapid disease progression or poor clinical prognosis, patients with WHO-FC IV, those who remain unresponsive despite treatment with 1 to 2 classes of oral prostanoids, and those with PAH associated with scleroderma to improve functional status and exercise capacity. It is a treatment of choice for PAH WHO-FC IV patients who are not candidates for or who have failed calcium antagonist therapy and preferred by most experts for class IV patients with unstable conditions because of its proven survival improvement, worldwide experience and rapidity of action. Its exact mechanism of action is still unknown but has shown pulmonary vasodilator properties. The disadvantage of this therapy is the need to administer it by continuous IV infusion.  

Iloprost (Inhaled)  

Iloprost is a chemically stable prostacyclin analog for IV, oral and aerosol administration. Inhaled Iloprost should be considered in patients who remain symptomatic despite correct and appropriate treatment with other prostacyclin analogs or PDE5i. This may be used as an additional treatment agent for PAH patients with WHO-FC III who remain symptomatic on stable and optimal doses of ERA or PDE5i to delay time to clinical worsening. Iloprost may be used as an additional treatment agent for PAH patients with WHO-FC III-IV who remain symptomatic on stable and optimal doses of ERA or PDE5i to delay time to improve exercise capacity. Studies have shown an increase in exercise capacity and improvement of symptoms, time to disease progression, peripheral vascular resistance (PVR) and clinical events with inhaled therapy. A continuous IV administration appears to be as effective as Epoprostenol in a small series of patients with PAH and CTEPH. It is a more potent pulmonary vasodilator than acute inhaled NO. Approved for use in WHO-FC III and IV PAH. The disadvantage of inhaled therapy is the short duration of action and therefore 6 to 9 inhalations/day are needed.

Treprostinil (Inhaled, IV, SC or Oral)  

Treprostinil is a stable tricyclic benzidine analog of Epoprostenol with a half-life of about 4.5 hours. It is administered via micro-infusion pumps and small SC catheters similar to those used for the administration of Insulin. This was recently approved as an inhaled prostacyclin analog, to be used on patients who remain symptomatic despite correct and appropriate treatment with other prostacyclin analogs or PDE5i. Treprostinil is recommended as an additional treatment agent for PAH patients with WHO-FC III-IV who remain symptomatic on stable and optimal doses of ERA or PDE5i to improve 6MWT. It has been shown to improve exercise capacity, hemodynamics and clinical events. Those who benefited the most are those who were more compromised at baseline and subjects who could tolerate the higher dose. A continuous IV and SC Treprostinil should be considered in patients with WHO-FC III with rapid disease progression or poor clinical prognosis and in patients with WHO-FC IV to improve the patient’s 6MWT. IV Treprostinil should be considered in patients who remain unresponsive despite treatment with 1 to 2 classes of oral PDE5i or ERA to improve exercise capacity. Oral preparation is US FDA-approved for PAH monotherapy. It has been shown to improve exercise capacity in treatment-naive PAH patients with WHO-FC II or III.  The disadvantages of therapy are pain and erythema occurring at the infusion site.  

Prostacyclin Receptor Agonist  

Selexipag  

Selexipag is a selective prostacyclin IP receptor agonist that in turn triggers smooth muscle vasodilation and inhibits platelet aggregation. Studies have shown that Selexipag may decrease pulmonary vascular resistance and morbidity/mortality events (eg death, disease progression, need for hospitalization and surgery). It is recommended for use in PAH patients with WHO-FC II and III.    

COMBINATION THERAPY  

Combination therapy is recommended for non-vasoreactive patients not responding adequately to monotherapy but should be instituted by expert centers only. An additional PAH medication may be considered in non-vasoreactive patients with IPAH, HPAH or DPAH with cardiopulmonary comorbidities who present at intermediate or high risk of death under PDE5i or ERA monotherapy. The safety and efficacy of combination therapy in PAH is a subject of active investigation.  

Initial Combination Therapy for Patients Without Cardiopulmonary Comorbidities  

Example drugs: Ambrisentan + Tadalafil, Bosentan + Sildenafil + Epoprostenol IV, Bosentan + Epoprostenol IV

This is recommended for non-vasoreactive patients with WHO-FC II-III. An initial combination therapy with an ERA and a PDE5i is recommended in patients with IPAH or HPAH or DPAH or CTD-associated PAH with low or intermediate risk of death. This is associated with improved functional class, exercise capacity, cardiac biomarkers and reduced hospitalization. A combination therapy with Ambrisentan and Tadalafil or Macitentan and Tadalafil is recommended. The AMBITION trial showed that Ambrisentan/Tadalafil combination therapy improved exercise capacity and decreased hospitalizations in treatment-naive PAH patients with WHO-FC II-III. Macitentan/Tadalafil combination therapy has been shown to significantly improve exercise capacity, cardiopulmonary hemodynamics, and functional capacity in treatment-naive PAH patients in the TRITON study. A combination therapy with other ERAs and PDE5is may be considered. Macitentan/Sildenafil combination therapy has been shown to improve exercise capacity and WHO functional class in the SERAPHIN trial.  

An initial triple combination therapy with an ERA and a PDE5i plus an IV/SC prostacyclin analog should be considered in patients with high risk of death and in patients with intermediate risk presenting with severe hemodynamic dysfunction (RAP ≥20 mmHg, CI <2.0 L/min/m², SVI <31 mL/m², and/or PVR ≥12 WU). This is associated with better long-term survival compared to monotherapy or dual therapy. IV treatments may be used in WHO-FC IV PAH patients who are unresponsive to oral formulations.  

Sequential Combination Therapy for Patients Without Cardiopulmonary Comorbidities  

Example drugs: Macitentan added to Sildenafil, Riociguat added to Bosentan, inhaled Treprostinil added to Sildenafil or Bosentan, Sildenafil added to Epoprostenol or Bosentan, Ambrisentan added to Sildenafil, Iloprost added to Bosentan, Tadalafil added to Bosentan, Tadalafil added to Ambrisentan, Bosentan added to Epoprostenol, Riociguat added to Sildenafil or other phosphodiesterase inhibitor  

Combination therapy is used for WHO-FC II-IV PAH patients unresponsive to initial combination oral and IV therapies. It may improve 6MWT, WHO-FC, and time to disease progression. A continuation of treatment is recommended in patients who achieve low risk status under initial PAH therapy.  

The recommended sequential combination therapies to reduce the risk of morbidity and mortality include:

• PDe5i or oral/inhaled prostacyclin analog plus Macitentan
• ERAs and/or PDE5is plus Selexipag
• ERA or PDE5i or Riociguat monotherapy plus oral Treprostinil

Epoprostenol plus Sildenafil is the recommended sequential combination therapy to improve exercise capacity.  

The sequential combination therapies which should be considered to improve exercise capacity include:

• Sildenafil or Bosentan monotherapy plus inhaled Treprostinil
• Bosentan plus Riociguat

The sequential combination therapies which may be considered to improve exercise capacity include:

• Bosentan plus inhaled Iloprost or Sildenafil or Tadalafil
• Sildenafil plus Ambrisentan or Bosentan

An addition of Selexipag to patients with IPAH, HPAH or DPAH with intermediate-low risk of death while on ERA and PDE5i combination therapy should be considered to reduce the risk of clinical worsening. An addition of IV or SC prostacyclin analog and referral for lung transplantation evaluation should be considered in patients with IPAH, HPAH or DPAH with intermediate-high to high risk of death while on ERA and PDE5i combination therapy. Switching to Riociguat may be considered in patients with IPAH, HPAH or DPAH with intermediate-low risk of death while on ERA and PDE5i combination therapy. Sotatercept is a subcutaneously administered activin signaling inhibitor indicated for the treatment of adults with PAH to increase exercise capacity, improve WHO FC and reduce the risk of clinical worsening events. It may be used as an add-on to background PAH therapy in symptomatic patients with WHO-FC II and III.  

Supportive Therapy  

Oral Anticoagulant  

Example drug: Warfarin  

Oral anticoagulation is associated with improved survival in IPAH patients and should also be considered in heritable PAH, PAH due to anorexigen use and associated PAH (APAH). Anticoagulation in patients with PAH associated with underlying diseases such as scleroderma or CHD is controversial, and one must consider risk-benefit ratio before starting Warfarin. Patients on long-term IV Epoprostenol in the absence of contraindications should be anticoagulated to prevent catheter-associated thrombosis. The therapeutic INR can vary depending on the center (1.5 to 2.5 or 2.0 to 3.0). The decision to start anticoagulation must be individualized.  

Diuretics  

Diuretics are recommended in patients with PAH with signs of RV failure and fluid retention. The symptomatic and clinical benefits are seen in PAH patients with right heart failure. The choice and type of diuretics need to be individualized. Loop diuretics, thiazides and mineralocorticoid receptor antagonists (MRA) may be used as monotherapy or in combination, depending on the patient's clinical need and kidney function. Serum electrolytes and renal function should be monitored closely in those receiving diuretics.  

Digoxin  

Digoxin produces favorable acute hemodynamic effects in patients with right heart failure and PAH with atrial tachyarrhythmia. Long-term benefits are unknown. The use of Digoxin should be based on the judgment of the practitioner.  

O₂ Therapy  

Long-term O₂ therapy is recommended in patients with PAH with PaO₂ <60 mmHg on at least 2 occasions to achieve PaO₂ >60 mmHg. Ambulatory O₂ may be given when there is improvement of symptoms and desaturation during exercise is corrected.  

Iron Supplements  

IV iron supplementation is recommended in patients with severe iron deficiency anemia (Hb <7-8 g/dL).

Nonpharmacological

Lifestyle Modification  

General Care  

Maintenance of Intravascular Volume  

Near-normal intravascular volume is important in the long-term management of IPAH. A sodium-restricted (<2,400 mg/day) diet, fluid restriction, and judicious use of diuretics reduce volume overload in patients with PH and RV hypertension. Monitor renal function and blood biochemistry in patients to avoid hypokalemia and the effects of decreased intravascular volume leading to prerenal failure.  

Hemoglobin (Hb) Levels and Iron Status  

PAH patients are extremely sensitive to decreases in Hb levels. Anemias should be promptly treated. Phlebotomies should be done if hematocrit >65% in symptomatic patients (headache, poor concentration). Regular monitoring of iron status (serum iron, ferritin, transferrin saturation, soluble transferrin receptors) is recommended because iron deficiency in patients with PAH is associated with impaired myocardial function, aggravated symptoms, and increased risk of mortality.  

Concomitant Medications  

Avoid drugs that interfere with oral anticoagulants or increase the risk of GI bleeding. Empiric use of ACE inhibitors or beta-blockers should be discouraged, as this may result in hypotension and right heart failure.  

Prevention of Infection  

Due to the potentially devastating effects of respiratory tract infection in patients with PH, immunization with influenza, pneumococcal, and coronavirus disease 2019 (COVID-19) vaccines is warranted. Respiratory tract infection should be treated aggressively.  

Patient Education  

Genetic Testing/Counseling  

Genetic testing/counseling should be offered to relatives of patients with familial PAH, if available. IPAH patients should be advised regarding the availability of genetic testing and counseling for their relatives.

Pulmonary Arterial Hypertension_Management 1

Pulmonary Arterial Hypertension_Management 2

Surgery

Interventional Therapies  

Balloon Atrial Septostomy (BAS) and Potts Shunt  

Creation of a right-to-left shunt may be done with balloon atrial septostomy, wherein an interatrial shunt is made, and Potts shunt wherein the left PA is connected to the descending aorta. Several experimental and clinical observations suggest that an atrial defect may be of benefit in the setting of PH as it would allow right-to-left shunting which increases systemic output. This would increase systemic arterial O₂ saturation. It also decompresses the right atrium and ventricle, therefore decreasing signs and symptoms of right heart failure.  

At present, indications for right-to-left shunt are:

• Patients who are in WHO-FC IV with severe syncope and/or right heart failure despite all available medical treatments
• Palliative bridge to lung transplantation
• Sole treatment modality when other options are not available
• Considered in PAH associated with surgically corrected CHD, CTD, distal CTEPH, PVOD and PCH
• This may be considered before severe hemodynamic compromise and end-organ dysfunction occur

This should be performed only at institutions with significant procedural and clinical experience. This is avoided in patients with a baseline mean RAP >20 mmHg and O₂ saturation at rest of <85% on room air.  

Transplantation  

There is no agreement on the optimal type of transplantation for patients with PAH, whether single lung, double lung, or combined heart and lung. This is indicated in PAH patients when they have an unacceptable response to PAH therapies seen in WHO-FC III or IV. Due to a lack of effective medical therapeutic regimens, patients with PVOD and PCH should be candidates for transplantation at diagnosis.  

The criteria for referral for lung transplantation include:

• Known or suspected high-risk variants (eg PVOD, PCH, systemic sclerosis, large and progressive PA aneurysms)
• Necessity for treatment with IV or SC prostacyclin analog
• Progressive disease or recent hospitalization due to worsening PAH
• Signs of secondary liver or kidney impairment due to PAH or other life-threatening complications (eg recurrent hemoptysis)
• With ECS/ERS intermediate-high or high risk or Registry to Evaluate Early and Long-term PAH disease management (REVEAL) risk score >7 on appropriate PAH therapy

The criteria for listing a patient for lung transplantation include:

• Patient is fully evaluated and prepared for transplantation
• Progressive hypoxemia particularly in patients with PVOD or PCH
• Progressive but without end-stage liver or kidney impairment due to PAH or life-threatening hemoptysis
• With ECS/ERS high risk or REVEAL risk score >10 on appropriate PAH therapy which usually include IV or
• SC prostacyclin analog

Overall, a 5-year survival rates in PAH patients following transplant have been recorded at 45-50% and are continually increasing. Recent records showed 52-75% at 5 years and 45-66% at 10 years.