Version January 2024
INTRODUCTION — Pulmonary hypertension (PH) is classified into five groups based upon etiology. Patients in the first group are considered to have pulmonary arterial hypertension (PAH), whereas patients in the remaining four groups are considered to have PH (table 1 and table 2 and table 3). In this topic, we discuss PAH-specific therapy, while general measures for treating PAH, as well as pathogenesis, diagnosis, classification, and prognosis of PAH, are discussed separately. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)" and "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)
Our approach for the most part is in keeping with several guideline groups [1].
DEFINITION — PAH-specific therapy (also known as PAH-targeted or PAH-directed therapy) is directed at the PAH itself rather than the underlying cause of the PAH. PAH-specific agents include prostacyclin pathway agonists, endothelin receptor antagonists, nitric oxide-cyclic guanosine monophosphate enhancers, or, rarely, select calcium channel blockers (table 4).
PRETREATMENT EVALUATION (AGENT SELECTION) — Patients with PAH should be referred to a specialized center for evaluation and management since the administration of PAH-specific therapy can be harmful. Before PAH-specific therapy is administered:
●The diagnosis of PAH, and any potential associated etiology, should be in place, since PAH-specific therapy has not been found to be beneficial in most other forms of PH and may, in fact, be harmful. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)
●When indicated, vasoreactivity testing should be performed. (See 'Vasoreactive patients' below.)
●The baseline risk of disease progression and death should be assessed. (See 'Vasoreactivity testing (select patients)' below.)
Vasoreactivity testing (select patients) — Select patients with PAH (ie, group 1 PH) (table 1) should undergo acute vasoreactivity testing (AVT) to identify the small subset of PAH patients (10 to 20 percent) who may respond to calcium channel blocker (CCB) therapy. This includes patients with idiopathic PAH (IPAH), heritable PAH, and drug/toxin-induced PAH (ie, patients who are most likely to be vasoreactive).
Patients with associated forms of PAH are rarely vasoreactive, and, as such, vasoreactivity testing is not indicated [2]. This includes patients with PAH due to connective tissue disease, congenital heart disease, human immunodeficiency virus (HIV), portal hypertension, and schistosomiasis and patients with suspected pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis.
Contraindications to AVT include low systemic blood pressure (eg, systolic BP <90 mmHg), low cardiac index (cardiac index <2 L/min/m2), or presence of severe (functional class IV) symptoms (table 5) since hypotension and occasionally cardiovascular collapse can occur with the administration of the vasodilator. Caution should also be exercised if it is suspected that patients have a component of group 2 PH (ie, cardiovascular causes of PH (table 1)).
Patients with a positive vasoreactivity test are candidates for a trial of CCB therapy (see 'Calcium channel blockers (trial)' below). In contrast, CCB therapy should be avoided in patients with a negative test since CCBs can have serious adverse effects, including systemic hypotension and death, in this population. Choice of therapy in nonvasoreactive patients is discussed below. (See 'Nonvasoreactive patients' below.)
AVT involves the administration of a short-acting vasodilator followed by measurement of the hemodynamic response using a right heart catheter. Agents commonly used for vasoreactivity testing include inhaled nitric oxide, epoprostenol, adenosine, and inhaled iloprost:
●Inhaled nitric oxide is the most common agent used and is administered at 10 to 20 ppm. It is selective for the pulmonary vasculature with minimal systemic effects and is therefore better tolerated than other agents [3-7]. Procedure and efficacy details are provided separately. (See "Inhaled nitric oxide in adults: Biology and indications for use".)
●Epoprostenol is infused at a starting rate of 1 to 2 ng/kg per minute and increased by 2 ng/kg per minute every 5 to 10 minutes until a clinically significant fall in blood pressure, an increase in heart rate, or adverse symptoms (eg, nausea, vomiting, headache) develop (table 4).
●Adenosine is administered intravenously in doses of 50 mcg/kg per minute and increased every two minutes until uncomfortable symptoms develop or a maximal dose of 200 to 350 mcg/kg per minute is reached.
●Inhaled iloprost, while in theory can be used as an AVT agent, is not frequently administered for this purpose.
The test is considered positive if mean pulmonary artery pressure decreases at least 10 mmHg and to a value less than or equal to 40 mmHg, with an increased or unchanged cardiac output, and a minimally reduced or unchanged systemic blood pressure. "Borderline" results are considered as nonreactive.
Baseline risk assessment
Our approach — In patients with PAH, the baseline risk of disease progression and death should be assessed prior to the initiation of PAH-specific therapy. Risk stratification determines the initial regimen chosen and is also used to determine disease progression and response to therapy (algorithm 1). Without an agreed-upon optimal approach, our strategy is to choose an agent primarily based upon AVT and World Health Organization (WHO) functional class (table 5). This approach is practical since WHO functional class is a major determinant of outcome; consequently, regulatory approvals have been traditionally based upon WHO functional class. We subsequently individualize that therapy according to additional factors. These include established factors known to increase the risk of disease progression and death (eg, symptoms, evidence of right heart failure, right heart catheter hemodynamics) (table 6), as well as patient preferences, approval status of the chosen drug, cost, route of administration, side effect profile, presence of comorbidities, and potential interaction with other drugs (table 7). Specific drug interactions and management suggestions may be determined by using Lexicomp drug interactions, the drug interactions program included with UpToDate.
High- versus low-/intermediate-risk multiparameter risk assessment models — Guidelines put forth by several societies suggest allocation of PAH-specific therapy based upon high-risk and low- or intermediate-risk categories [1]. In essence, patients assigned to the low- or intermediate-risk category should receive combination oral therapy similar to that described for WHO class II/III (with similar exceptions for alternate combination oral strategies and single-agent therapy) (see 'WHO functional class II and III or low/intermediate risk (combination oral therapy)' below) while high-risk patients should be placed on combination therapy that contains a parenteral prostanoid. (See 'WHO functional class IV or high risk (parenteral prostanoid-containing combination regimen)' below.)
Several groups have proposed other models for risk stratification. However, all of the proposed models have limitations and are not routinely or consistently used. These include the United States Registry to Evaluate Early and Long-term PAH disease management (REVEAL), the Swedish PAH Registry (SPAHR), The Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), the French Pulmonary Hypertension Network (FPHN), the European Cardiology Society/European Respiratory Society (ECS/ERS) guidelines group, and the World Symposium of Pulmonary Hypertension (figure 1 and table 6 and algorithm 2) [1,8]. Most of these models predict survival and involve a multidimensional approach that includes elements of clinical, biochemical (eg, brain natriuretic peptide), functional (eg, exercise capacity, WHO functional class), and hemodynamic parameters (echocardiography and pulmonary arterial catheter) that have prognostic significance (table 6). However, it must be noted that all regulatory approvals are based in part on WHO functional class and none of these multi-risk assessment models have been used as an outcome to assess treatment in any PAH trial. As examples:
●The one-year survival of patients with newly diagnosed group 1 PAH may be predicted using a risk score derived from the REVEAL registry data [9-12]. The risk score is the sum of points derived from clinical data including group 1 subgroup, demographics, and comorbidities; functional class, vital signs, six-minute walk distance (6MWD), and brain natriuretic peptide level; and echocardiogram, pulmonary function tests, and right heart catheterization findings (figure 1) (calculator 1). Data were prospectively collected from 504 patients with a mean 6MWD of 308 meters, 62 percent of whom were classified as WHO functional class III (table 5). One-year survival correlated with risk score: 1 to 7 (95 percent), 8 (92 percent), 9 (89 percent), 10 to 11 (72 percent), and ≥12 (66 percent). Although not agreed upon, a score of 1 or less is considered low risk, a score between 2 and 9 is considered moderate risk, and a score of 10 or greater is high risk.
●Prognosis was reported using data derived from the COMPERA database [13]. Patients were risk stratified using a model that incorporated WHO functional class, 6MWD, brain natriuretic peptide levels, right atrial pressure, cardiac index, and mixed venous oxygen saturation. Mortality rates in patients at one year after diagnosis was 3 percent for low-risk patients, 10 percent for intermediate-risk patients, and 21 percent for high-risk patients (table 8). A four-stratum risk profile has also been reported using refined cutoff levels for the same parameters in the original model [14]. Survival rates one year after diagnosis were 100 percent for low-risk patients, 98 percent for intermediate-/low-risk patients, 91 percent for intermediate-/high-risk patients, and 78 percent for high-risk patients.
VASOREACTIVE PATIENTS
Calcium channel blockers (trial) — For patients with PAH who are vasoreactive, we administer an initial trial of calcium channel blocker (CCB) therapy (eg, one to three months). This only applies to patients with World Health Organization (WHO) class I to III since patients with WHO functional class IV do not typically undergo acute vasoreactivity testing nor are they generally candidates for oral therapy.
●Efficacy – Approximately 10 to 20 percent of PAH patients who undergo testing demonstrate a positive vasoreactive response. Among patients who are vasoreactive, approximately one-half clinically respond to CCB therapy. Among those who clinically improve, the response is generally short-lived, eventually requiring the addition of another agent of a different class. Long-term response is defined as an improvement in WHO functional class that is sustained for at least one year while on CCB therapy only (ie, same or better than that achieved in the initial vasoreactivity test and usually to an mean pulmonary artery pressure <30 mmHg with increased or normal cardiac output) [15]. Only a proportion of vasoreactive patients have a long-term response (approximately 5 percent) [16-19].
The evidence suggesting that CCB therapy is beneficial in terms of survival is limited by the absence of randomized trials comparing CCB therapy to no therapy in vasoreactive patients only. Without such trials, it is uncertain whether vasoreactive patients who receive CCB therapy truly benefit from the therapy or are predisposed to a better outcome, with vasoreactivity potentially being a marker of a better prognosis. However, in our experience, vasoreactive patients who experience a sustained lowering of pulmonary artery pressure feel remarkably better while on CCB therapy. Improved survival was reported in an observational study of 64 patients with idiopathic PAH (IPAH) that reported that the five-year survival was greater among patients who received CCB therapy (primarily nifedipine) compared with a control group of patients (comprised nonvasoreactive IPAH patients and historical controls) [16]. Another observational study of 557 patients with IPAH found that only 13 percent had a positive vasoreactivity test and only 54 percent of the vasoreactive patients with IPAH who received CCB therapy maintained functional improvement after one year [19]. Responders were more vasoreactive (ie, had a greater decrease of mean pulmonary arterial pressure during the vasoreactivity test) and had less severe disease at baseline.
●Agent and dosing – CCB therapy can be initiated as an outpatient with either long-acting nifedipine (30 mg/day) or diltiazem (120 mg/day), which is then increased to the maximal tolerated dose over days to weeks (table 4). Short-acting nifedipine should not be used. Systemic blood pressure, heart rate, and oxygen saturation should be carefully monitored during titration. Sustained release preparations of both nifedipine and diltiazem are available. Their use minimizes the adverse effects of therapy, especially systemic hypotension. Amlodipine, a long-acting dihydropyridine, is a useful alternative for patients who are intolerant of the other CCB agents.
Patients who respond to CCB therapy should be reassessed after three to six months of treatment with a similar approach to that described below (see 'Follow-up' below). A poor response to therapy necessitates evaluation for non-CCB PAH-specific medication; in such patients, CCB therapy is generally stopped once patients demonstrate the need for double or triple therapy. (See 'Nonvasoreactive patients' below.)
●Adverse effects – Adverse effects are common among patients with PAH who are administered CCBs. Many of the adverse effects are a result of the potent systemic vasodilatory properties of CCBs (eg, hypotension and peripheral edema) [20,21]. Paradoxically, while pulmonary vasodilation from CCB therapy may reduce hypoxic vasoconstriction, loss of hypoxic vasoconstriction can worsen ventilation-perfusion mismatch and hypoxemia [22,23]. CCBs may also be associated with deterioration of right ventricular function due to the negative inotropic effect of CCBs [24]. (See "Major side effects and safety of calcium channel blockers".)
NONVASOREACTIVE PATIENTS — For patients with PAH who are typically nonvasoreactive (eg, connective tissue disease-PAH, human immune deficiency PAH) and have not undergone vasoreactive testing (see 'Vasoreactivity testing (select patients)' above) and for patients who are nonvasoreactive or are vasoreactive and have failed CCB therapy, we generally use the World Health Organization (WHO) functional classification for selection of a suitable agent(s). WHO functional class and additional factors that influence agent selection are provided above (table 7 and table 6) (see 'Pretreatment evaluation (agent selection)' above). An alternate selection process is also suggested above (see 'High- versus low-/intermediate-risk multiparameter risk assessment models' above). Agent selection described in this section assumes treatment-naïvety.
PAH-specific therapy consistently improves hemodynamic measures, WHO functional class, and six-minute walk distance (6MWD) [25,26] and likely improves survival. Best illustrating this is a meta-analysis of 21 randomized trials (3140 patients) that found that therapy with a prostanoid, an endothelin receptor antagonist, or a phosphodiesterase-5 inhibitor improves mortality compared with no therapy (1.5 versus 3.8 percent; risk reduction 0.57, 95% CI 0.35-0.92) [25]. However, the average duration of treatment in trials was only 14 weeks. In addition, the same survival benefits may not apply to all patient subgroups within group 1 PAH. For example, although survival from systemic sclerosis-associated PAH has improved in the era of PAH-directed therapy, it is worse than that for idiopathic PAH (IPAH) and the mortality remains high, particularly when PH is associated with coexistent interstitial lung disease. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Prognosis' and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis", section on 'Pulmonary arterial hypertension-directed therapy' and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'Prognosis'.)
WHO functional class I (monotherapy) — Patients rarely present with functional class I (because they are typically asymptomatic) and, in fact, this class is more likely to reflect patients on therapy who originally presented with a higher functional class. However, there is a small proportion of high-risk patients that undergo screening echocardiography that may present with WHO functional class I (eg, patients with scleroderma, patients with congenital heart disease and patients with known heritable PAH mutations). In practice, while some patients in this category, may be monitored closely for disease progression to a functional level that warrants therapy (eg, class II), we generally start PAH-specific monotherapy, particularly when patients have "high-risk" features (table 6) or when significant elevations in the pulmonary artery pressure (PAP) is observed (eg, systolic PAP >50 mmHg and mean PAP >35 mmHg). This approach is based upon the rationale that PAH is progressive if left untreated and that therapy should prevent/slow disease progression [27]. There is no preference or data that support selecting one class of agent, and selection is usually at the discretion of the prescribing PH-specialist. Any coexisting conditions that worsen PH should also be treated (eg, obstructive sleep apnea). Despite these indications for single-agent therapy, pragmatically, there has been a paradigm shift in treatment in this group that advocates for combination therapy earlier in the disease process to stave off progression; thus, the threshold to add in a second agent should be low as the disease progresses.
WHO functional class II and III or low/intermediate risk (combination oral therapy) — For patients with functional class II and III PAH or have low- or intermediate-risk PH, who are drug-naïve, we initially administer dual combination therapy with an endothelin receptor antagonist (ERA) and an agent that targets the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway, typically a phosphodiesterase 5 inhibitor (PDE5I). Occasionally, a third agent (eg, selexipag) may be administered if escalated therapy is required during follow-up. (See 'Follow-up' below.)
Combination oral therapy — In patients with WHO functional class II and III or with low- or intermediate-risk PH, we and other experts prefer the combination of the ERA ambrisentan and the PDE5I tadalafil because it has been shown in this population to result in a significant reduction in the rate of clinical failure compared with monotherapy with either drug alone (see 'Tadalafil plus ambrisentan' below). For those who have a contraindication to either agent, another oral agent in the same class can be substituted (provided that two agents from the same class are not combined [eg, PDE5Is and riociguat] (table 4)). However, such combinations are less well proven and drug interactions can potentially limit the outcome. Combination therapy may be administered as two agents initiated together (initial combination therapy; preferred by the authors of this topic) or as "add-ons" (ie, one followed by another; sequential combination therapy [eg, two to three weeks apart]) [28,29]. Some combinations are available as a single oral tablet (eg, macitentan-tadalafil combination).
Some patients may require triple-agent combination therapy, but we do not recommend triple agent therapy as an initial strategy.
Tadalafil plus ambrisentan — One randomized trial (AMBITION) of 500 drug-naïve patients with group 1 PAH (mostly idiopathic and connective tissue disease [CTD]-related) who had class II or III symptoms compared the combination of 10 mg of ambrisentan (ERA) and 40 mg of tadalafil (PDE5I) with either agent alone [30]. The combined regimen, administered on average for 18 months, resulted in a 50 percent reduction in the rate of clinical failure (18 percent versus 31 percent) and improved exercise capacity (49 versus 24 meters). The reduction in clinical failure rate was primarily driven by decreased hospitalizations for progressive PAH (which portends a poor prognosis), rather than by improved survival or WHO functional class. Adverse events (eg, edema, headache, nasal congestion, anemia, and syncope) were reported more frequently in those receiving combination therapy (45 versus 30 percent), but rates of hypotension were similar.
This trial is the basis for recommending this particular combination in PAH patients with class II or III symptoms. However, clinicians should be aware that substituting with other drugs within the same family (eg, sildenafil plus bosentan) may not be associated with the same improved outcomes. As an example, the increased metabolism and consequent reduction in plasma concentration of sildenafil by bosentan may partly explain the contradictory outcomes associated with this combination [31]. In contrast, the lack of drug interaction between tadalafil and ambrisentan may also explain why the outcomes reported in AMBITION were more robust. (See 'Alternate oral combinations' below.)
Alternate oral combinations — Other combination oral regimens of two agents from a different class (table 4) are feasible in patients not suited to the ambrisentan and tadalafil combination (eg, contraindications to the drug or adverse effects).
The strongest level of data support the following combinations:
●Macitentan plus sildenafil – The SERAPHIN trial compared the oral ERA macitentan to placebo in 250 patients with moderate to severe PAH; 85 percent of patients had IPAH or CTD-PAH, and the majority were functional class II or III [32,33]. Approximately 60 percent of patients were already on a PDE5I (ie, combined therapy), mostly sildenafil, and 40 percent were treatment-naïve (ie, single-agent therapy with macitentan). Over a two-year period, fewer patients treated with macitentan (3 mg or 10 mg daily) progressed or died on therapy (38 and 31 percent, respectively versus 46 percent) [32]. Exercise capacity and WHO functional class also improved with macitentan treatment. This benefit was observed independent of whether patients were on combination or single-agent oral therapy for PAH. The study was not powered to show a benefit in mortality as an independent outcome.
●Tadalafil plus bosentan – The PHIRST trial randomly assigned 405 patients with mostly functional class II and III PAH, one-half of whom were on bosentan, to receive tadalafil (2.5, 10, 20, or 40 mg) or placebo once daily for 16 weeks [34]. Tadalafil (40 mg) significantly increased the 6MWD and the time to clinical worsening, while also decreasing the incidence of clinical worsening and improving health related quality of life. In an uncontrolled extension trial, PHIRST-2, the improvement of the 6MWD was sustained for an additional 52 weeks [35].
●Riociguat plus bosentan – A multicenter randomized placebo-controlled trial of riociguat (PATENT-1) studied 443 patients with symptomatic PAH (mostly WHO functional class II and III) [36]. Approximately 50 percent were treatment-naïve and the remainder were on PAH-specific therapy, primarily the ERA, bosentan. Twelve weeks of oral riociguat (2.5 mg three times daily) resulted in a modest increase in the 6MWD (increase by 30 meters versus decrease by 6 meters) compared with placebo. Riociguat also resulted in improvements in pulmonary vascular resistance, symptoms, WHO functional class, and time to clinical worsening. This benefit was observed regardless of whether patients were receiving concurrent or single-agent PAH-specific therapy. A follow-up long-term extension study (PATENT-2) reported sustained benefits and a similar safety profile for riociguat when administered for up to two years [37,38].
●Selexipag plus ERA and/or PDE5I – In a large trial (GRIPHON), 1156 patients with group 1 PAH and WHO classification II or III were randomly assigned to receive placebo or selexipag (200 to 1600 micrograms twice daily) for a median duration of 1.4 years [39]. The majority (approximately 80 percent) were receiving a stable dose of an ERA, a PDE5I, or both and the remainder were drug-naïve. Selexipag resulted in a benefit that was largely driven by a reduction in hospitalizations (14 versus 19 percent) and disease progression (7 versus 17 percent), rather than by improved survival (mortality, 5 versus 3 percent). The effect of selexipag as an add-on on double combination background therapy had a similar effect [40].
Other combinations have less robust evidence to support their use:
●Bosentan plus sildenafil – Unlike ambrisentan and tadalafil, results from trials that combine sildenafil and bosentan have been contradictory. In one prospective study, the addition of sildenafil to bosentan in PAH patients who developed clinical deterioration, improved symptoms, exercise capacity, and WHO functional class [41]. Improvement was more frequent and of greater magnitude in patients with IPAH, compared with patients with scleroderma-associated PAH. In a second study of patients failing monotherapy with either bosentan or sildenafil, the addition of either agent also resulted in improved functional class and survival in those with IPAH, compared with those with connective tissue-associated PAH [42]. In contrast, a larger placebo-controlled trial reported no benefit when bosentan was added to sildenafil in a similar population, although the inclusion of patients with repaired congenital heart disease may have impacted the outcome [43].
●Oral treprostinil plus ERA, riociguat, or PDE5I – The addition of oral treprostinil in patients with group 1 PAH on an ERA and/or a phosphodiesterase-5 inhibitor did not improve the 6MWD at 16 weeks (FREEDOM-C and FREEDOM C-2) [44-46]. A study drug discontinuation rate of 22 percent was noted in the treprostinil group and was attributed to the high incidence (>40 percent) of side effects of headache, nausea, vomiting, diarrhea, flushing, and jaw pain. Significant improvements were noted in dyspnea and exercise capacity. Another randomized trial (FREEDOM-EV) reported that oral treprostinil added to any other oral agent (most were on a PE5I or riociguat) resulted in a greater proportion of patients with improved time to clinical worsening when compared with the addition of placebo (26 versus 36 percent) [47]. However, the magnitude of the improvement was small.
Combinations of PDE5Is and riociguat are not recommended based upon post-trial data that demonstrated increased rates of hypotension (PATENT-PLUS) among patients taking this combination [48]. Consequently, the US Food and Drug Administration issued a warning against combining PDE5Is and guanylate cyclase stimulants [49].
Single-agent therapy — Occasionally, single-agent oral therapy may be appropriate for patients with very early class I/II disease who have a low-risk profile (see 'WHO functional class I (monotherapy)' above) and for patients who have been stable on monotherapy for a prolonged period (eg, 5 to 10 years). Other possible indications include patients >75 years old with multiple risk factors for heart failure, patients suspected to have pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis, patients with contraindications to combination therapy (eg, severe liver disease), patients with portopulmonary hypertension and human immune deficiency virus (ie, patients who were not included in the combination trials), or patients who decline combination therapy. Selecting an agent is at the discretion of the prescribing PH-specialist.
For patients with functional class III symptoms who have rapid progression or other markers of poor clinical prognosis (eg, echocardiographic evidence of severe right ventricular dilatation and dysfunction or the presence of a pericardial effusion (table 6)), we frequently initiate a parenteral or inhaled prostanoid, although starting an oral prostanoid (eg, selexipag, treprostinil) is reasonable as an initial trial. In the latter situation, the threshold to switch to a parenteral agent should be low if patients worsen rapidly. (See 'Parenteral prostanoid' below.)
Endothelin receptor antagonists — Endothelin-1 is a potent vasoconstrictor and smooth muscle mitogen. Endothelin receptors A and B are targeted by endothelin receptor antagonists (ERAs). Nonselective dual-action ERAs include bosentan and macitentan, while ambrisentan is a selective antagonist of endothelin receptor A. Sitaxsentan was withdrawn from the European Union, Canada, and Australia in 2010 following several fatal cases of hepatoxicity [50-54].
Data supporting a role for individual ERAS as single-agent therapy include the following:
●ERAs as a group – In a Cochrane meta-analysis of 16 randomized trials that compared ERAs with placebo in patients with functional class II/III, patients receiving ERAs had improved exercise capacity (mean increase of 25 m), functional class (odds ratio [OR] 1.41, 95% CI 1.16-1.70), and symptoms, and reduced odds of functional class deterioration (OR 0.43, 95% CI 0.26-0.72) [55]. There was low certainty evidence of a possible reduction in mortality from ERA use (OR 0.78, 95% CI 0.58, 1.07).
●Ambrisentan – Randomized placebo-controlled studies (eg, ARIES-1 and ARIES-2) of patients with moderate to severe idiopathic and CTD–related PAH (mostly WHO functional class II and III) consistently reported that ambrisentan, administered for up to two years, delayed disease progression and clinical worsening [56-58]. In addition, ambrisentan has been associated with improved exercise tolerance, WHO functional class, pulmonary vascular hemodynamics, and quality of life.
●Bosentan – Bosentan has been shown in patients with group 1 PAH to delay clinical worsening and improve pulmonary vascular hemodynamics and exercise capacity [59-62]. The mortality of bosentan-treated IPAH patients appears favorable compared with historical controls [61,63].
●Macitentan – In the SERAPHIN trial that compared oral macitentan with placebo in 250 patients with moderate to severe PAH (mostly, WHO functional class II and III), the benefits that were observed in the patients taking combined therapy (eg, slower disease progression and lower mortality, improved exercise tolerance) were also seen in subgroup of patients that were on single-agent therapy with macitentan [32,33]. This trial is discussed in more detail above. (See 'Alternate oral combinations' above.)
The main adverse effects of ERAs are hepatotoxicity and peripheral edema [32,54,56-58,60,64,65].
●Hepatotoxicity – Reports suggest that mild elevations in aminotransferase levels occur in less than 6 percent of patients on bosentan, ambrisentan, and macitentan. Ambrisentan appears to be the least hepatotoxic. For macitentan, rates of liver function test abnormalities were shown in trials to be no different between the treatment and placebo groups (3 to 4 percent), although post-marketing analysis suggests an increased risk of liver injury [66]. It is prudent to monitor liver function tests monthly during treatment with bosentan and occasionally with ambrisentan and macitentan. The duration of monitoring is indefinite for bosentan. In patients with moderate or severe hepatic dysfunction or patients on cyclosporine or glyburide, we avoid or use caution when administering ERAs (eg, use ambrisentan rather than bosentan).
●Peripheral edema – Peripheral edema is the most common side effect in patients taking bosentan and ambrisentan (up to 17 percent of patients); edema appears to be less of an issue with macitentan. Mild cases can be managed with diuretics, but more severe cases warrant discontinuation of the medication.
●Others – ERAs are also potent teratogens, requiring meticulous, double method contraception if used by women with childbearing potential. Macitentan may also be complicated by nasopharyngitis (15 percent) and anemia (8 percent) [32].
Ambrisentan should not be used in patients with concurrent idiopathic pulmonary fibrosis since one randomized trial reported that ambrisentan was associated with an increased risk of disease progression and hospitalizations [67]. This trial and treatment of interstitial lung disease-associated PH are discussed separately. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Endothelin receptor antagonists' and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis".)
Nitric oxide-cyclic guanosine monophosphate enhancers — Agents in this class enhance the production or function of nitric oxide (NO), a potent vasodilator, and include phosphodiesterase inhibitors (PDE5Is) and the guanylate cyclase stimulant, riociguat.
●PDE5Is – One meta-analysis of 36 studies (2999 patients) reported that patients with group 1 PAH treated with PDE5Is were more likely to improve their WHO functional class (OR 8.59, 95% CI 3.95-18.72) and less likely to die (OR 0.088, 95% CI 0.07-0.68) [68].
•Sildenafil – Sildenafil improves pulmonary hemodynamics and exercise capacity in patients with group 1 PAH [69-72]. However, its effect on mortality has not been adequately evaluated. An illustrative trial (SUPER-1) randomly assigned 277 patients with group 1 PAH to receive sildenafil (20, 40, or 80 mg) or placebo three times daily for 12 weeks [71]. The sildenafil group demonstrated significant improvement in hemodynamics and 6MWD, which persisted during one year of follow-up. Mortality was not reported. A follow-up open-label, three-year extension trial (SUPER-2) [73] reported persistent improvement in the 6MWD and WHO functional class in 46 and 29 percent of patients, respectively; the estimated three year survival rate was 79 percent.
•Tadalafil – In the PHIRST-1 and -2 trials that included 405 PAH patients, one-half of whom were treatment naïve, tadalafil (40 mg) increased the 6MWD the time to clinical worsening, when compared with placebo [34,35]. These trials are discussed in detail above. (See 'Alternate oral combinations' above.)
•Vardenafil – Vardenafil is not approved by the US Food and Drug Administration for the treatment of PAH but in PAH patients has been reported to increase the mean 6MWD and cardiac index, while decreasing the mean pulmonary arterial pressure, pulmonary vascular resistance, and number of clinical worsening events [74].
Adverse effects of PDE5Is and precautions that should be taken in those being treated with PDE5Is are similar to those in patients being treated for erectile dysfunction. Common side effects include headache, gastrointestinal upset, flushing, and muscle and joint pains. Further details are provided separately. (See "Treatment of male sexual dysfunction", section on 'Adverse effects'.)
●Guanylate cyclase stimulant — Riociguat is an oral soluble guanylate cyclase stimulant that has reported benefit in patients with inoperable and persistent chronic thromboembolic PH (group 4) (see "Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy"), but patients with group 1 PAH may also benefit from riociguat [29,37,38]. In trials of WHO class II and III PAH patients (PATENT-1 and -2), one-half of whom were treatment-naïve, riociguat (2.5 mg three times daily) improved the exercise tolerance, pulmonary vascular resistance, symptoms, WHO functional class, and time to clinical worsening for up to two years of treatment [37,38]. Riociguat had a favorable safety profile and was well tolerated, with syncope as the most frequent reported side effect (4 versus 1 percent). Hemoptysis from pulmonary hemorrhage was rare. This study is discussed in detail above. (See 'Alternate oral combinations' above.)
Oral prostacyclin receptor agonists — Selexipag is an oral selective non-prostanoid prostacyclin receptor (IP receptor) agonist that results in vasodilation of the pulmonary vascular bed and may benefit patients with PAH who have WHO functional class II and III [39,75]. Selexipag possesses high selectivity for the IP receptor over other prostanoid receptors distinguishing it from prostacyclin and prostacyclin analogs currently used in the management of PAH [76]. Best illustrating efficacy is a randomized trial (GRIPHON), where selexipag was associated with a reduction in hospitalizations and slower disease progression; however, only 20 percent of PAH patients were treatment naïve and the remainder were on other oral agents [39]. This study is discussed in more detail above (see 'Alternate oral combinations' above). An intravenous formulation is available for patients who are unable to temporarily take the oral formulation [77].
An oral formulation of treprostinil, a prostacyclin analogue, has also been shown to improve exercise capacity in treatment-naïve PAH patients who have functional class II and III symptoms [78-82]. In contrast, conflicting data exist on the addition of oral treprostinil to other oral agents (FREEDOM trials) [44-46]. These data are discussed above. (See 'Alternate oral combinations' above.)
WHO functional class IV or high risk (parenteral prostanoid-containing combination regimen) — Patients with severe PAH who are WHO functional class IV or high-risk PH should be treated with a parenteral prostanoid-containing combination regimen. Most of these patients are already receiving single or combination oral therapy from treatment administered for class III symptoms and the parenteral prostanoid is added to that regimen (resulting typically in triple combination therapy). Most clinicians consider intravenous (IV) epoprostenol as the preferred agent. IV or subcutaneous treprostinil is a reasonable alternative. For patients who decline or cannot receive IV or subcutaneous therapy, inhaled treprostinil or iloprost is an option. It is prudent in this population to refer patients for lung transplantation evaluation. (See 'Lung transplantation' below.)
Parenteral prostanoid — Several parenteral prostanoids are available with the strongest evidence of efficacy in favor of IV epoprostenol. A meta-analysis of 17 trials (765 patients with PAH), patients on prostacyclin agonists were over twice as likely to have improved WHO functional class, 6MWD (19.5 meters, 95% CI 14.82-24.19), and pulmonary hemodynamics, compared with a control group of PAH patients (placebo, any other treatment or usual care) [83]. Mortality was improved in patients receiving IV agents (OR 0.29, 95% CI 0.12-0.69; risk of death 6 per 100). However, many of the studies were small or open-label randomized studies, which limit the certainty of the effect.
Epoprostenol
●Efficacy – In patients with PAH, IV epoprostenol (prostacyclin; PGI2) consistently improves hemodynamic parameters and functional capacity, but only patients with IPAH have been shown to have improved survival with this drug; studies in other populations of PAH patients were limited [83-93]. The efficacy of IV epoprostenol was illustrated by a landmark trial that randomly assigned 81 patients with WHO class III or IV IPAH (three-quarters and one-quarter, respectively) to receive IV epoprostenol as single-agent therapy or standard therapy (typically oral therapy) for 12 weeks [86]. IV epoprostenol improved quality of life, mean pulmonary arterial pressure (-8 versus +3 percent), pulmonary vascular resistance (-21 versus +9 percent), and exercise capacity (+47 versus -66 meters). Eight patients died during the trial, all of whom were in the standard therapy group.
●Dosing and administration – Epoprostenol is delivered continuously through a permanently implanted central venous catheter using a portable infusion pump. It is usually initiated, as an outpatient, at doses of 1 to 2 ng/kg per minute and increased by 1 to 2 ng/kg per minute every one to two days depending on symptoms and adverse effects. Once an initial level of 6 to 10 ng/kg per minute is achieved (usually within one to two weeks), most patients require dose increases of 1 to 2 ng/kg per minute every two to four weeks to sustain the clinical effect (table 4). The rate at which the dose can be increased and peak dose varies from patient to patient and depends upon disease severity, symptoms, and adverse effects. For example, in some patients, a "plateau" is reached between 20 and 40 ng/kg per minute, while in others the dose may need further titration [94].
A maximal dose has not been established. Patients who have been receiving therapy for many years may receive doses as high as 150 to 200 ng/kg per minute with sustained clinical and hemodynamic benefit. Excess doses may produce high-output cardiac states. In this situation, the dose should be reduced, while monitoring for rebound PH [95].
●Adverse effects – Side effects include jaw pain, diarrhea, flushing, and arthralgias. More severe adverse effects are usually attributable to the complex delivery system including thrombosis, pump malfunction, and interruption of the infusion. Central venous catheter infection occur in approximately 2 percent of patients annually and can also contribute to the morbidity and mortality of continuous epoprostenol therapy [83,96-98]. While interruption of the infusion can precipitate a life-threatening crisis from rebound PH, it is less commonly encountered now that patients are also frequently taking oral meds. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'Management of acute pulmonary hypertensive crisis'.)
Treprostinil — Treprostinil is a prostacyclin analog that can be given IV or subcutaneously (table 4). An inhaled and oral formulation are also available. Advantages of parenteral treprostinil, compared with epoprostenol, include the option of continuous subcutaneous rather than IV delivery for a small percentage of patients, a longer half-life such that cartridges only need changing every 48 rather than 24 hours. For patients who desire the advantages associated with treprostinil administration, it can be offered as first-line therapy. Patients who are already receiving epoprostenol can generally be transitioned to treprostinil (subcutaneous or intravenous) without a significant loss of clinical efficacy [99,100]. Reciprocally, epoprostenol can be given if the desired effect is not achieved with treprostinil.
●Efficacy – IV and subcutaneous treprostinil improve hemodynamic parameters, symptoms, exercise capacity, and, possibly, survival in patients with group 1 PAH [78-82]. Trials comparing epoprostenol with treprostinil have not been performed.
●Dosing – Treprostinil is delivered continuously through a subcutaneous or IV catheter using a portable infusion pump. It is usually initiated, as an outpatient. Subcutaneous or IV dosing infusions are started at 0.625 to 1.25 ng/kg per minute. The dose is increased in increments of 1.25 ng/kg per minute per week for first four weeks, followed by increments of 2.5 ng/kg per minute per week for remainder of therapy. Similar to epoprostenol, the maximal dose has not been established.
Rapid uptitration of treprostinil has been described in 17 pregnant women with severe PAH/PH crisis [101]. IV treprostinil was started at 1.25 ng/kg per minute and increased by 1.5 to 2.5 ng/kg per minute every three hours to a maximum dose of 10 ng/kg per minute during the first 24 hours. During the next 24 hours the dose was similarly increased to a median maximum dose of 15 ng/kg per minute (interquartile range, 15 to 20 ng/kg per minute). Fifteen patients survived to discharge, and only two died of their PH crisis.
●Adverse effects – The adverse effects of treprostinil are similar to those of epoprostenol. Subcutaneous administration is used less often than in the past due to severe pain at the injection site.
Studies describing the efficacy of inhaled treprostinil are discussed below. (See 'Combination therapy containing a parenteral agent' below.)
Iloprost — Inhaled iloprost, a prostacyclin analogue, has theoretical advantages in that it specifically targets the lung vasculature and does not require IV administration (table 4). The main disadvantages are the need for frequent administration (six to nine times per day), peaks and lows of drug concentration, and inability to dose during sleep.
One trial randomly assigned 203 patients with PAH (including a variety of types) who were WHO class III or IV to receive iloprost (2.5 to 5 mcg, six to nine times per day) or placebo for 12 weeks [102]. Greater improvements in WHO class and in the 6MWD was reported in the iloprost group compared with the placebo group (17 versus 5 percent).
Combination therapy containing a parenteral agent — While in the past, single-agent therapy was common, most patients now with WHO functional class IV are on combination therapy from treatment administered for class III symptoms and, in general, previous medications are not discontinued. Among the possible combinations, many experts prefer IV epoprostenol added to a PDE5I (eg, sildenafil, tadalafil).
Several combinations have been shown to be beneficial in patients with PAH:
●Sildenafil added to epoprostenol – One trial randomly assigned 267 patients with group 1 PAH who were receiving epoprostenol to have sildenafil or placebo added for 16 weeks [103]. Most patients were WHO functional class III at the beginning of the trial. Sildenafil improved hemodynamic parameters, exercise capacity, quality of life, and time to clinical worsening, compared with placebo.
●Bosentan added to either epoprostenol or treprostinil – One trial (BREATHE-2 trial) randomly assigned 22 patients with group 1 PAH who were receiving epoprostenol to have either bosentan or placebo added for 16 weeks [104]. Epoprostenol improved hemodynamic parameters, exercise capacity, and functional class, compared with baseline. The addition of bosentan improved these outcomes to a greater degree than the addition of placebo, although the difference was not statistically significant [81,104].
●Inhaled treprostinil added to either bosentan or sildenafil – In one trial (TRIUMPH), 235 patients with group 1 PAH who were deteriorating despite bosentan or sildenafil therapy were randomly assigned to receive the addition of either inhaled treprostinil or placebo for 12 weeks [105]. The treprostinil group had a significant improvement in their 6MWD and quality of life, but there were no differences in the time to clinical worsening, dyspnea, or WHO functional class.
●Sildenafil added to inhaled iloprost – Several studies have shown that in patients with group 1 PAH have reported that the addition of sildenafil to inhaled iloprost resulted in an improvement in exercise capacity, WHO functional class, and hemodynamics [106,107].
●Bosentan plus inhaled iloprost – The effect of combining bosentan with iloprost is less clear. Early observational studies suggested that the combination was both safe and effective when bosentan was added to preexisting inhaled iloprost therapy [108]. However, a subsequent trial that randomly assigned 40 patients with IPAH to receive bosentan alone or bosentan plus iloprost for 12 weeks, demonstrated no difference in the 6MWD [109]. The results of the trial may have been skewed by three outliers in the combination therapy group.
●Others – Small numbers of patients with functional class IV PAH were included in PATENT (riociguat) and SERAPHIN (macitentan) and are insufficient to draw conclusions [32,36]. These trials are discussed above. (See 'Alternate oral combinations' above.)
FOLLOW-UP — Initiation of PH-specific therapy (including calcium channel blocker [CCB] therapy) requires close follow-up. Frequent reassessment is necessary because of the complex nature of the disease and its treatments, as well as the tendency of PAH to progress.
Outpatients visits — Patients should be seen as an outpatient in a PH center, but patient logistics may dictate alternative forms of follow-up, such as frequent telephone contact and co-management with local clinicians.
The initial visit usually occurs within the first six weeks. Thereafter, patients should ideally be seen every three months. However, for patients receiving parenteral or combination therapy and patients who have advanced symptoms, right heart failure, or advanced hemodynamic abnormalities, more frequent visits are typical.
Follow-up visits should ideally include a thorough history and examination to assess symptoms of right heart failure, exercise tolerance, and resting and ambulatory oximetry. The frequency of follow-up testing with brain natriuretic peptide (BNP or N-terminal pro-BNP [NT-proBNP]), six-minute walk distance (6MWD), echocardiogram, and right heart catheterization should be determined on a case-by-case basis and varies among centers. We usually obtain a 6MWD at each visit and an echocardiogram every 12 months, or sooner if clinically indicated. In addition, we typically repeat a right heart catheterization after the initiation of therapy (eg, at 3, 6, or 12 months), as well as when the patient deteriorates. The threshold to obtain BNP or NT-proBNP should be low, especially in patients with a deterioration in clinical status [110,111].
Patients should be warned not to stop their medication suddenly, particularly intravenous epoprostenol, since abrupt increases in pulmonary pressures may occur resulting in acute deterioration, especially if they are receiving single-agent therapy. Patient education and medication-alert devices for this purpose are prudent. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'Management of acute pulmonary hypertensive crisis'.)
For patients who require surgery or a procedure, perioperative/procedural management of PAH-specific medications should be done in conjunction with a PH expert and anesthesiologist, the details of which are discussed separately. (See "Anesthesia for noncardiac surgery in patients with pulmonary hypertension or right heart failure" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'Management of acute pulmonary hypertensive crisis' and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'Surgical or periprocedural care'.)
Goal-oriented therapy — A good response to therapy is typically considered one that involves improvement in all of the following:
●Functional class, preferably to class I or low-risk category
●Clinical symptoms
●Echocardiographic and biochemical evidence of right heart failure (ie, "goal-oriented" therapy)
Improvements should be notable within the first six weeks of therapy but may continue to occur over three to six months or longer. Rare patients have an extraordinary response, but de-escalation of therapy is not routinely recommended. However, for patients who experience a suboptimal response (eg, minor improvement, stabilize without progression), or develop progressive symptoms on therapy (even after a period of stability), escalation therapy is warranted.
Escalation therapy — Escalation therapy involves increasing the dose of a current medication and/or the addition of a second agent (for patients on monotherapy) or a third agent (for patients on double combination therapy). CCBs are not generally considered part of double or triple therapy. Importantly, combining two agents from the same class is contraindicated (eg, phosphodiesterase 5 inhibitor [PDE5I] and riociguat or oral selexipag and parenteral prostanoid).
Escalation of therapy and transitioning from one agent to another, which is sometimes needed (eg, for adverse effects or noncompliance), should always be done under the supervision of an expert in PAH.
Switching to another agent in the same class may be an option for those on nitric oxide-cyclic guanosine enhancers. One preliminary study suggested that switching from a PDE5I to riociguat was safe and a potential approach to escalation therapy [112]. In that study, 293 patients on a PDE5I were randomly switched to riociguat or continuation of their PDE5I. More patients in the riociguat group improved compared with those who stayed on their PDE5I (41 versus 21 percent).
Patients who are rapidly deteriorating despite therapy should be referred for lung transplantation (eg, patient may have unrecognized pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis). (See 'Lung transplantation' below.)
REFRACTORY PATIENTS — PAH is a progressive disease, and, in some cases, patients progress to a point where they are refractory to PAH-specific therapy. Such patients have a high mortality. Lung transplantation is a definitive form of therapy for such cases, while the creation of a right-to-left shunt is a temporizing measure only.
Lung transplantation — Guidelines for lung transplant referral are as follows [113]:
●World Health Organization (WHO) functional class III or IV during escalating therapy
●Rapidly progressive disease (prior to or on therapy)
●Use of parenteral prostanoid therapy regardless of functional class symptoms
●Known or suspected pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis
Bilateral lung or heart-lung transplantation is the procedure of choice [114]. Selection of suitable patients for lung transplantation is discussed separately. (See "Lung transplantation: General guidelines for recipient selection" and "Lung transplantation: An overview".)
Post-transplantation management for idiopathic PAH (IPAH) is similar to management for other conditions requiring transplantation, although the incidence of obliterative bronchiolitis appears to be higher in IPAH patients undergoing transplantation [115]. An elevated bilirubin has been associated with a high postoperative mortality in heart-lung transplant recipients, and the likelihood of successful transplantation is poor if the bilirubin elevation persists after the patient's cardiopulmonary status is optimized. Recurrence of IPAH after transplantation has not been reported. (See "Lung transplantation: Procedure and postoperative management".)
Although lung transplantation has been successfully performed in patients with IPAH and is considered a definitive therapy [114,116,117], it is not necessarily associated with improved survival. The three-year survival of patients who had a lung or heart-lung transplant for IPAH is approximately 50 percent [118,119].
Indications for liver transplantation in patients with portopulmonary hypertension are discussed separately. (See "Portopulmonary hypertension", section on 'Liver transplantation'.)
Right-to-left shunt — Creation of a right-to-left shunt is a temporizing (eg, as a bridge to transplant) or palliative measure. It is typically reserved for patients with severe symptomatic PAH and right heart failure, despite aggressive advanced therapy and maximal diuretic therapy [118,120]. It may also be considered in patients who have signs of impaired systemic blood flow (such as syncope) due to reduced left heart filling. The purpose of right-to-left shunting is to avoid these undesirable outcomes by diverting blood flow to bypass the pulmonary vascular bed and enter the systemic circulation, thereby elevating systemic blood flow and maintaining tissue perfusion, albeit with less oxygenated blood. They are rarely performed in the United States but more commonly performed in countries where transplant is an infrequent option.
Procedures that have been used to generate a right-to-left shunt in adults with PAH are atrial septostomy and placement of a Potts shunt via a transcatheter approach [118,121-130]. Importantly, a preexisting patent foreman ovale or atrial septal defect (may act as a natural right-to-left shunt in those with severe PAH) should not be percutaneously or surgically closed in a patient with significant PH.
Shunts are not reversible and require surgical closure at the time of transplant.
Atrial septostomy — Atrial septostomy is a right-to-left shunt that connects right and left atrial cavities. Although arterial desaturation follows the procedure, it may be offset in some patients by increased cardiac output and augmentation of systemic oxygen delivery [121,124,131]. However, procedure-related mortality may be as high as 15 to 40 percent [121,127]. Stepwise balloon dilatation is the procedure of choice [114].
In a meta-analysis of 16 trials (204 patients), balloon atrial septostomy resulted in a reduction in right atrial pressure (-2.77 mmHg), increase in cardiac index (0.62 L/M/m2) and left atrial pressure (1.68 mmHg), and decrease in arterial saturation (-8.45 percent) [131]. Mortality at 30 days was 38 percent.
Patients with the most advanced PAH appear more likely to die or get worse with atrial septostomy. This includes patients with markedly elevated mean right atrial pressure (eg, greater than 20 mmHg) [114], extremely low cardiac output, and a resting arterial oxyhemoglobin saturation less than 80 percent. In addition, older age and impaired renal function were associated with early adverse outcomes in one series [121].
Transcatheter Potts shunt — Surgical placement of a right-to-left shunt between the left pulmonary artery and the descending aorta (Potts shunt) has been described as a palliative measure in children with PAH. However, mortality from general anesthesia and surgery in adult patients with severe PAH is considerably higher. Placement of a transcatheter Potts shunt (TPS) under fluoroscopic guidance has been performed in one pilot study [130]. TPS involves retrograde needle perforation of the aorta, with subsequent placement of a covered stent between the aorta and left pulmonary artery. Of four adults studied (18 to 47 years old), two died and two survived at 4 and 10 months with symptomatic improvement. The use of TPS should be reserved for patients enrolled in clinical trials until further studies confirm its safety and efficacy in this population.
PROGNOSIS — The prognosis of PAH is discussed separately. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'Prognosis'.)
INVESTIGATIONAL THERAPIES — Investigational therapies include the following:
●Sotatercept – Mutations in bone morphogenetic protein receptor type 2 (BMPR2) play a known role in the pathogenesis of PAH. BMP is a member of the transforming growth factor (TGF) beta family of proteins. Sotatercept acts as a ligand trap for members of the TGF-beta superfamily, and restores balance between the growth-promoting activin pathway and the growth-inhibiting BMP pathway [132]. Preliminary data in phase 2 trials reported benefit from sotatercept [133,134]. In a phase 3 trial of 320 PAH patients on stable background therapy and with stable functional class II and III symptoms, sotatercept was compared with placebo [135]. Sotatercept resulted in improved six-minute walk distance (6MWD) at 24 weeks (median change 34.4 versus 1 meter). Improvements were also reported in pulmonary vascular resistance, N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, WHO functional class, and time to death or clinical worsening. The most common adverse effects were headache, diarrhea, and peripheral edema. Specific to sotatercept were also increased hemoglobin level, thrombocytopenia, bleeding, telangiectasis, and hypertension. While encouraging, these patients were clinically stable; many had already received two or three other medications, and the majority had idiopathic or heritable PAH. Thus, generalizability to sicker, less clinically stable, or treatment-naïve patients is unknown.
●Pulmonary artery denervation – Pulmonary artery denervation (PADN) has been studied in PAH. In one study of 128 patients, PADN in intermediate high-risk patients who were treated with a combination of PADN and PDE-5 inhibitors had greater improvement in the 6MWD, NT-proBNP, and pulmonary vascular resistance compared with those treated with sham plus PDE-5 inhibitor [136].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults".)
SUMMARY AND RECOMMENDATIONS
●Pulmonary arterial hypertension (PAH)-specific therapies – PAH-specific therapy (also known as PAH-targeted or PAH-directed therapy) is directed at the PAH itself rather than the underlying cause of the PAH. PAH-specific agents include prostacyclin pathway agonists (epoprostenol, treprostinil, iloprost, selexipag), endothelin receptor antagonists (ERAs; ambrisentan, bosentan, macitentan), nitric oxide-guanosine monophosphate (NO-cGMP) enhancers (phosphodiesterase 5 inhibitors [PDE5Is; sildenafil, tadalafil]), or, rarely, calcium channel blockers (CCBs; nifedipine, diltiazem) (table 4). (See 'Definition' above.)
●Agent selection – Patients with PAH should be referred to a specialized pulmonary hypertension (PH) center for evaluation and management. The diagnosis of PAH (and any potential associated etiology) should be in place and, when indicated, acute vasoreactivity testing (AVT) should be performed (idiopathic PAH, heritable PAH, and drug-induced PAH). Although agent selection based upon several risk stratification models has been proposed, we prefer to select PAH-specific therapy based upon AVT and World Health Organization (WHO) functional class (table 5) and, subsequently, individualize that therapy according to additional factors that can affect risk and patient preference (table 6 and table 7 and algorithm 1). (See 'Pretreatment evaluation (agent selection)' above.)
●Positive vasoreactivity – For patients who have a positive vasoreactivity test and WHO class I to III symptoms, we suggest a trial of CCB therapy with extended-release nifedipine or extended-release diltiazem (Grade 2C). The rationale for a CCB trial is based upon the lower toxicity profile when compared with other PAH-specific therapies. However, the response rate is often suboptimal and typically not sustained. Patients who respond to CCB therapy should be reassessed after three to six months of treatment. Patients with WHO functional class IV do not generally undergo AVT and would be treated as if they were nonvasoreactive. (See 'Calcium channel blockers (trial)' above.)
●Nonvasoreactive – For patients with PAH who are typically nonvasoreactive (eg, connective tissue disease-PAH, human immune deficiency PAH) and have not undergone vasoreactive testing and for patients who are nonvasoreactive or are vasoreactive and have failed CCB therapy, PAH-specific therapy with a non-CCB agent depends upon WHO functional class (algorithm 1). (See 'Nonvasoreactive patients' above.)
•WHO functional class I – For patients with WHO functional class I symptoms, we suggest monotherapy with a PAH-specific agent (eg, PDE5I, ERA, or riociguat) rather than no treatment (Grade 2C). This is particularly important for "high-risk" patients (table 6), based upon the rationale that, if left untreated, PAH will progress. Agent selection is at the discretion of the treating PH specialist. (See 'WHO functional class I (monotherapy)' above.)
•WHO functional class II/III – For patients with WHO functional class II or III symptoms (ie, low- or intermediate-risk PH), we suggest dual combination oral therapy rather than monotherapy (Grade 2B). Combination therapy generally consists of an ERA and an agent that targets the NO-cGMP pathway, typically a PDE5I. Combination therapy appears to improve exercise capacity and reduce the rates of disease progression and hospitalization compared with monotherapy, although a mortality benefit has not been clearly demonstrated. Monotherapy may be suitable for a select group (eg, patients with very early class I/II disease). (See 'WHO functional class II and III or low/intermediate risk (combination oral therapy)' above.)
•For patients with WHO functional class IV – For patients with WHO functional class IV symptoms (ie, high-risk PH), we suggest treatment with a parenteral prostanoid-containing combination regimen rather than oral therapy (Grade 2C). Combination therapy is typically triple or, less commonly, double therapy. Among the options for parenteral prostanoids, we suggest intravenous (IV) epoprostenol rather than other agents (Grade 2C). The rationale for this choice is that limited data support a possible survival advantage with epoprostenol therapy. IV or subcutaneous treprostinil is a reasonable alternative. Inhaled treprostinil or iloprost is an option for patients who decline or cannot receive IV or subcutaneous therapy. Early referral for lung transplantation is prudent in this population. (See 'WHO functional class IV or high risk (parenteral prostanoid-containing combination regimen)' above.)
●Follow-up – After starting PAH-specific therapy, patients should be followed up within the first six weeks. Thereafter, patients should ideally be seen every three months. However, for patients receiving parenteral or combination therapy and patients who have advanced symptoms, right heart failure, or advanced hemodynamic abnormalities, more frequent visits are typical.
A good response to therapy is typically considered one that involves improvement in functional class (preferably to class I), clinical symptoms, and echocardiographic and biochemical evidence of right heart failure (ie, "goal-oriented" therapy). For patients who experience a suboptimal response (eg, minor improvement, stabilize without progression), or develop progressive symptoms on therapy, escalation therapy is warranted (eg, dual or triple combination therapy). (See 'Follow-up' above.)
●Refractory patients – For patients who are refractory to medical therapy, lung transplantation is a definitive form of therapy, while the creation of a right-to-left shunt is a temporizing measure only. (See 'Refractory patients' above.)
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