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Treatment of pulmonary hypertension in adults
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Treatment of pulmonary hypertension in adults
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Literature review current through: Jul 2017. | This topic last updated: Apr 21, 2017.

INTRODUCTION — Early identification and treatment of pulmonary hypertension (PH) is generally suggested because advanced disease may be less responsive to therapy [1-3]. Treatment begins with a baseline assessment of disease severity, followed by primary therapy. Primary therapy is directed at the underlying cause of the PH.

Some patients progress to advanced therapy, which is therapy directed at the PH itself, rather than the underlying cause of the PH. It includes treatment with prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, soluble guanylate cyclase stimulant or, rarely, certain calcium channel blockers.

Assessment of disease severity, primary therapy, and advanced therapy will be reviewed here. The definition, classification, epidemiology, etiology, pathogenesis, clinical manifestations, diagnosis, natural history and prognosis of PH are discussed separately. (See "Classification and prognosis of pulmonary hypertension in adults" and "Clinical features and diagnosis of pulmonary hypertension in adults" and "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)".)

NOMENCLATURE — The World Health Organization (WHO) classifies patients with PH 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). When all five groups are discussed collectively, PH is generally used. We adhere to this nomenclature in the discussion that follows. The WHO classification system is described in detail elsewhere. (See "Classification and prognosis of pulmonary hypertension in adults", section on 'Classification'.)

BASELINE ASSESSMENT — The baseline severity of PH should be determined prior to the initiation of therapy. This assessment is essential because the response to therapy will be measured as the change from baseline. Functional impairment and hemodynamic derangement are the key determinants of disease severity:

The functional significance of the PH is determined by measuring exercise capacity. From the exercise capacity, the patient's World Health Organization (WHO) functional class can be determined (table 2) [4].

Pulmonary artery systolic pressure and right ventricular function can be estimated by echocardiography, and then used to make a presumptive diagnosis of PH. Right heart catheterization must be performed to accurately measure the hemodynamic parameters and confirm that PH exists. However, right heart catheterization is often deferred until advanced therapy is indicated because it is an invasive procedure. (See 'Advanced therapy' below.)

Once the severity of the patient's pulmonary hypertension has been determined, primary therapy can be considered.

PRIMARY THERAPY FOR PH — Primary therapy refers to treatment that is directed at the underlying cause of the PH. It is warranted in nearly all patients with PH. The disease severity should be reassessed following primary therapy, in order to determine whether advanced therapy is indicated.

Group 1 PAH — Patients with group 1 pulmonary arterial hypertension (PAH) have idiopathic pulmonary arterial hypertension (IPAH, formerly called primary pulmonary hypertension), hereditary PAH, or PAH due to diseases that localize to small pulmonary arterioles, such as connective tissue diseases, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and drug use (table 1). (See "Classification and prognosis of pulmonary hypertension in adults", section on 'Classification'.)

There are no effective primary therapies for most types of group 1 PAH. As a result, advanced therapy is often needed. (See 'Advanced therapy' below.)

Group 2 PH — Patients with group 2 PH have PH secondary to left heart disease with chronic left atrial and pulmonary venous hypertension, including systolic dysfunction, diastolic dysfunction, and valvular heart disease (table 1). (See "Classification and prognosis of pulmonary hypertension in adults", section on 'Classification'.)

Primary therapy for group 2 PH consists of treatment of the underlying heart disease, which is discussed in detail separately. (See "Overview of the therapy of heart failure with reduced ejection fraction" and "Treatment and prognosis of heart failure with preserved ejection fraction" and "Natural history and management of chronic aortic regurgitation in adults" and "Management of chronic primary mitral regurgitation" and "Medical management and indications for intervention for mitral stenosis" and "Medical management of asymptomatic aortic stenosis in adults".)

Group 3 PH — Patients with group 3 PH have PH secondary to various causes of hypoxemia, such as chronic obstructive pulmonary disease, interstitial lung disease, other pulmonary diseases with a mixed restrictive and obstructive pattern, sleep-disordered breathing, or alveolar hypoventilation disorders (table 1). (See "Classification and prognosis of pulmonary hypertension in adults", section on 'Classification'.)

Primary therapy for group 3 PH consists of treatment of the underlying cause of hypoxemia and correction of the hypoxemia with supplemental oxygen. (See "Management of stable chronic obstructive pulmonary disease" and "Treatment of idiopathic pulmonary fibrosis" and "Management of obstructive sleep apnea in adults".)

Oxygen is the only modality with proven mortality benefit in some patients with group 3 PH. This has been established by two large trials studying patients with COPD, the most common cause of group 3 PH:

A trial randomly assigned 87 patients with COPD, a history of right ventricular dysfunction, and a PaO2 below 60 mmHg to receive either oxygen therapy for 15 hours per day or no oxygen therapy [5]. Oxygen therapy decreased five-year mortality (46 versus 67 percent), but the survival advantage did not appear until after 500 days of therapy. Pulmonary vascular resistance did not increase in the oxygen group, but increased in the group without oxygen (figure 1).

The Nocturnal Oxygen Therapy Trial (NOTT) compared continuous (19 hours per day) to nocturnal (12 hours per day) oxygen administration [6]. The population included 203 patients with COPD and either a PaO2 below 55 mmHg or a PaO2 below 60 mmHg with coexisting polycythemia, leg edema, or cor pulmonale on the electrocardiogram. The three-year mortality rate was lower with continuous oxygen than nocturnal oxygen (22 versus 42 percent) (figure 2). Oxygen therapy was also associated with a slight reduction of pulmonary vascular resistance.

Thus, continuous oxygen therapy improves survival in patients with COPD and a PaO2 below 55 mmHg. While the trial suggested seemingly mild effects on pulmonary hemodynamics, in our experience, some patients with chronic hypoxia experience a marked reduction in pulmonary artery pressure with continuous oxygen therapy. Predictors of a long-term response to continuous supplemental oxygen therapy include a decrease of the mean pulmonary artery pressure greater than 5 mmHg after 24 hours of 28 percent oxygen therapy and a high peak oxygen consumption (VO2) after symptom-limited exercise (>6.5 cc/kg per min as determined by a 30 second collection of expired gas in an airtight collection bag) [7].

Group 4 PH — Patients with group 4 PH have PH due to thromboembolic occlusion of the proximal or distal pulmonary vasculature (eg, chronic thromboembolic disease) (table 1). (See "Classification and prognosis of pulmonary hypertension in adults", section on 'Classification'.)

Anticoagulation is primary medical therapy for patients with group 4 PH. The value of anticoagulant therapy for group 4 PH is an extrapolation of the clinical evidence that anticoagulation prevents recurrent pulmonary embolism. Data suggesting that anticoagulation is beneficial in patients with group 4 PH are lacking.

Surgical thromboendarterectomy is primary surgical therapy for selected patients with thromboembolic obstruction of the proximal pulmonary arteries [8]. Perioperative mortality for this procedure is less than 10 percent when performed in selected centers and the hemodynamic response may be dramatic and sustained. Prior to proceeding with this invasive approach, a three-month period of anticoagulation is required and patients must remain severely incapacitated due to PH. (See "Chronic thromboembolic pulmonary hypertension: Surgical treatment", section on 'Indications' and "Chronic thromboembolic pulmonary hypertension: Surgical treatment", section on 'Surgical technique'.)

Group 5 PH — Group 5 PH is uncommon and includes PH with unclear multifactorial mechanisms. Examples include PH caused by hematologic disorders (eg, myeloproliferative disorders and chronic hemolytic anemia), systemic disorders (eg, sarcoidosis), metabolic disorders (eg, glycogen storage disease), and miscellaneous causes (table 1). (See "Classification and prognosis of pulmonary hypertension in adults", section on 'Classification'.)

All groups — Several therapies should be considered in patients with PH including diuretic, oxygen, anticoagulant, and digoxin therapy, as well as exercise. These therapies should be administered taking into consideration the underlying cause as well as the risks and benefits associated with each therapy.

Diuretics — Patients with fluid retention from PH-related right ventricle failure (RV) may benefit from diuretics. [9]. Diuretics diminish hepatic congestion, peripheral edema, and pleural effusions and may be of particular benefit in those in whom interventricular sepal deviation from elevated RV pressure impairs left ventricle output.

However, diuretics should be administered with caution. Since patients with PH are pre-load dependent, over-diuresis may result in under-filling of the RV, and a decline in RV stroke volume, thereby reducing left ventricle (LV) stroke volume resulting in systemic hypotension and sometimes shock. In addition, diuretics can be associated with arrhythmias induced by hypokalemia, and metabolic alkalosis (which can depress ventilation).

Most diuretic is administered orally in the chronic setting. However, diuresis may be more effective in the acute setting, when it can be given as a bolus dose or a continuous infusion (which may be better tolerated hemodynamically in those with borderline blood pressure).

Occasionally, the increased right ventricular pressure is so severe that diuretics are ineffective; in such cases, ultrafiltration may be beneficial.

Oxygen therapy — Continuous oxygen administration remains the cornerstone of therapy in patients with group 3 PH, as discussed above. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis", section on 'Conventional and supportive therapies'.)

It is inferred that oxygen may benefit other groups of patients with PH and resting, exercise-induced, or nocturnal hypoxemia. However, long-term data do not exist.

Oxygen should be considered for all patients with PH plus hypoxemia (table 3) [1,9-11]. The flow of oxygen needed to correct hypoxemia should be determined by measurement of the oxygen saturation. Oxygen is generally administered at 1 to 4 L/min via nasal prongs and adjusted to maintain the oxygen saturation above 90 percent at rest and, if possible, with exercise and sleep [12]. (See "Long-term supplemental oxygen therapy".)

Supplemental oxygen will not significantly improve the oxygen saturation of patients who have congenital heart disease with a right-to-left shunt (Eisenmenger physiology).

Anticoagulation — Anticoagulation is indicated in patients with group 4 PH (eg, chronic thromboembolic pulmonary hypertension [CTEPH]) and not typically administered to those with group 2, 3, or 5. However, anticoagulation in patients with group 1 PAH is controversial. Studies that report outcomes associated with anticoagulation in patients with group 1 PAH are hampered by their methodologic limitations including retrospective design, high dropout rates, and variable practice among centers. Reflecting variable practice among centers are reports suggesting that following diagnosis, only 50 percent or less of those with group 1 PAH actually receive anticoagulation [13,14]. In general, most experts agree that anticoagulation should be avoided in patients with systemic sclerosis (SSc)-associated PAH due to a lack of benefit or potential harm. In contrast, experts disagree on whether or not patients with idiopathic, hereditary, HIV- and drug-induced-PAH should be anticoagulated; in this population, we suggest that anticoagulant therapy be administered on a case-by-case basis according to the clinician's assessment of the risks and benefits. Patients with PAH from portopulmonary hypertension are generally not anticoagulated.

Traditionally, many patients with group 1 PAH were anticoagulated, particularly those with idiopathic, hereditary, connective tissue disease (CTD)-associated- and drug-induced-PAH [1,9-11,13,15,16]. This practice was based upon the increased risk for intrapulmonary vascular thrombosis and venous thromboembolism, the observation that even a small thrombus can produce hemodynamic collapse in those with a compromised pulmonary vascular bed, and early studies that suggested a mortality benefit. However, evidence from registry-based studies have since reported conflicting outcomes in patients with idiopathic PAH (IPAH) and potential harm in those with SSc-PAH [14]. As examples:

In a 2006 systematic review of seven observational studies that evaluated the effect of warfarin in patients with group 1 PAH, five studies found a mortality benefit, while two did not show benefit [16].

In the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), anticoagulation was associated with an improved three-year survival in patients with IPAH compared with those who had other forms of PAH (mostly CTD-associated PAH; hazard ratio [HR]; 0.79; 95% CI 0.66-0.94) [13]. In a post-hoc analysis of those with SSc-PAH there was a statistically nonsignificant trend towards worse survival among those taking anticoagulants compared with patients not on anticoagulant therapy (three-year survival 62 versus 74 percent; HR, 1.82; 95% CI 0.94-3.54).

In the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL), there was no survival advantage associated with warfarin use in patients with IPAH compared with matched warfarin-naïve PAH controls, even when adjusted for disease severity [14]. However, a fifty percent increase in mortality (mostly from progressive disease) was reported in SSc-PAH patients receiving warfarin, when compared with PAH patients who were not anticoagulated.

Limited experience with direct oral anticoagulants (eg, direct thrombin or factor Xa inhibitors) makes warfarin the anticoagulant of choice, with a therapeutic goal of an international normalized ratio (INR) of approximately 2.0. Many centers in the US target a range of 1.5 to 2.5 with no bridging for temporary interruptions while many European centers target a range of 2.0 to 3.0 with bridging anticoagulant for interruptions. One retrospective study of 366 patients with PAH reported that 50 percent had had at least one of the three major risk factors for bioaccumulation of direct oral anticoagulants, such that therapy with these agents should be individualized and mainly be administered in those with proven indications [17]. (See "Warfarin and other VKAs: Dosing and adverse effects" and "Perioperative management of patients receiving anticoagulants" and "Direct oral anticoagulants and parenteral direct thrombin inhibitors: Dosing and adverse effects".)

The risk of bleeding on anticoagulation (warfarin) may differ among patients with different types of PH. As an example, a retrospective study of 198 patients with PH receiving anticoagulation reported major bleeding events in 23 percent [18]. Compared to IPAH and CTEPH, CTD-related PAH had a higher bleeding event rate (19 versus 5.4 and 2.4 events per 100 patient-years, respectively). This suggests that differences in bleeding risk may alter the risk-benefit ratio of anticoagulation in CTD-related PAH. Although registry studies report that most deaths in SSc patients on anticoagulants are due to progressive disease [13,14], randomized studies are required to accurately assess whether increases in bleeding risk offset the potential benefit of anticoagulation in this population.  

Patients with PH frequently have other risk factors for thromboembolism (eg, atrial fibrillation, severe left heart failure) that may warrant anticoagulation. Anticoagulation for these conditions should be assessed independently and are discussed separately. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization" and "Antithrombotic therapy in patients with heart failure" and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)

Digoxin — Digoxin therapy has been shown to have both beneficial effects and drawbacks:

Digoxin improves the left ventricular ejection fraction of patients with group 3 PH due to COPD and biventricular failure [19]. However, these patients may be more sensitive than most patients to digitalis toxicity and require close monitoring.

Digoxin helps control the heart rate of patients who have supraventricular tachycardias associated with right ventricular dysfunction [20]. Verapamil is preferred for multifocal atrial tachycardia, unless there is concurrent left ventricular failure. (See "Control of ventricular rate in atrial fibrillation: Pharmacologic therapy".)

No data are available on the long-term effects of digoxin in patients with group 1 PAH [1].

In the acute setting (eg, shock due to right ventricular failure), intravenous inotropic support may be appropriate. Such patients are best managed in a center with expertise since management of inotropic agents in the acute setting can be challenging due to their altered hemodynamic effects on pulmonary vascular resistance. Dobutamine and milrinone are the most widely available agents, while experience with levosimendan is limited and it is less widely available. All of the agents increase RV contractility, as well as decrease RV afterload by inducing pulmonary vasodilation, a feature that may enhanced by inhaled nitric oxide or inhaled epoprostenol [21,22]. The primary side effects of intravenous inotropic agents are tachycardia and systemic hypotension. The hypotension induced by these agents generally occurs at low doses, and then resolves as the dose is increased. Since most patients are hypotensive when the inotropic agent is initiated, we first increase systemic blood pressure by administering norepinephrine by continuous infusion and then begin the inotropic agent. As we adjust the dose of the inotropic agent, we attempt to lower the dose of norepinephrine so that the patient is left receiving the inotropic agent alone. If this is not possible, consideration for adding phenylephrine or vasopressin should be made [23]

Exercise — Exercise training appears to be beneficial for patients with PH [24-28]:

In a meta-analysis of five randomized trials that included mostly patients with group 1 PAH, exercise programs ranging from 3 to 15 weeks resulted in improved exercise capacity (increase by 60 meters in the six-minute walk distance [6MWD]) peak oxygen uptake (increase 2.4 mL/kg/minute), and health-related quality of life [29].

In a randomized crossover trial, 15 weeks of exercise training resulted in an improved 6MWD when compared with sedentary controls (+96 versus -15 meters) [24]. Following crossover, the sedentary group also improved their mean 6MWD (+74 meters). Exercise training improved the World Health Organization (WHO) functional class and peak oxygen consumption. However, exercise training did not improve hemodynamic abnormalities, measured as the Doppler-derived pulmonary artery systolic pressure.

Vaccinations — Pulmonary hypertension is considered a chronic disease and as such, patients should be immunized with all age-appropriate as well as influenza and pneumococcal pneumonia vaccines.

Surgical risk — Patients with pulmonary hypertension, in particular those with pulmonary arterial hypertension (PAH) and significant right ventricular dysfunction, are at high risk of complications and death when undergoing anaesthesia, mechanical ventilation, and major surgery [30-32]. The perioperative management can be complicated by hemodynamic instability resulting in severe hypoxemia, acute right heart failure/circulatory collapse and death [33]. In addition, medication-related complications can increase surgical risk of bleeding (eg, anticoagulants and prostanoids).

The degree of surgical risk was described in an international, prospective study that collected data from 114 patients with PAH undergoing noncardiac and nonobstetric surgery [33]. Major complications and perioperative mortality were seen in 6 and 3.5 percent, respectively, with the highest mortality in those requiring emergency procedures (15 percent).

The following risk factors predicted major complications [34]:

Emergency surgery (odds ratio [OR] 2.4, 95% CI 1.4-3.6)

Elevated right atrial pressure (>7 mmHg) (OR 1.1, 95% CI 1.0-1.3)

Six-minute walking distance (≤399 meters) (OR 2.2, 95% CI 1.1-3.7)

Perioperative use of vasopressors (OR 1.5, 95% CI 1.2-2.7)

There is no standard approach to the management of these patients in the perioperative period. However, we typically apply simple measures such as careful monitoring of anticoagulants, fluid balance, oxygenation, blood pressure, and heart rate. Preoperative medications for PAH generally should be continued without interruption. The value of this approach, as well as right heart catheterization for the perioperative management of PAH, is unknown and requires further study. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults", section on 'Patients undergoing high risk surgery' and "Evaluation of preoperative pulmonary risk", section on 'Pulmonary hypertension'.)

ADVANCED THERAPY

Overview — Advanced therapy is directed at the pulmonary hypertension (PH) itself (PH-targeted therapy), rather than the underlying cause of the PH. It includes treatment with prostacyclin pathway agonists, endothelin receptor antagonists, nitric oxide (NO)-cGMP enhancers, or rarely, certain calcium channel blockers. Patients with persistent PH with World Health Organization (WHO) functional class II, III, or IV despite treatment of the underlying cause of the PH should be referred to a specialized center to be evaluated for advanced therapy.

Advanced therapy should not be administered unless a diagnostic right heart catheterization (RHC) and extensive investigations for the etiology of PH have been performed. Additionally, most patients with group 1 PAH, in particular, those with idiopathic PAH, heritable PAH, and anorexigen-induced PAH, should also undergo vasoreactivity testing during RHC which facilitates agent selection [1,11]. (See 'Vasoreactivity test' below.)

Advanced therapy is widely accepted for many patients with group 1 pulmonary arterial hypertension (PAH). In contrast, it should only be administered on a case-by-case basis for patients with group 3 PH, group 4 PH, or group 5 PH, after carefully weighing the risks versus the benefits. Advanced therapy should NOT be administered to most patients with group 2 PH. An algorithm for advanced therapy for the treatment of group 1 PAH is shown in the figure (algorithm 1). (See 'Patient selection' below.)

After initiating therapy, most patients are followed up within four to six weeks to evaluate the clinical and hemodynamic response. Patients with refractory PAH may require alternate or combination therapy. (See 'Agent selection' below and 'Follow-up' below.)

For those who are refractory to all medical interventions, lung transplantation or creation of a right to left shunt by atrial septostomy are options [8]. (See 'Transplantation' below and 'Right to left shunt' below.)

Patient selection — Advanced therapy is considered for patients who have World Health Organization (WHO) functional class II, III, or IV PH despite adequate primary therapy (table 2) [1,11]. Advanced therapy is widely accepted for many patients with group 1 PAH. In contrast, it must be considered on a case-by-case basis for patients with group 3 PH, group 4 PH, or group 5 PH, after carefully weighing the risks versus the benefits. Advanced therapy should NOT be administered to most patients with group 2 PH.

Two issues deserve emphasis before selecting a patient for advanced therapy. First, the evidence supporting advanced therapy comes primarily from studies that included patients with idiopathic PAH or scleroderma-related PAH such that extrapolation to other patient populations must be done with caution. In addition, the administration of advanced therapy to patients with other forms of pulmonary hypertension (eg, idiopathic pulmonary fibrosis-related PAH) may be potentially harmful. Second, most clinicians agree that patients should be selected and advanced therapy administered only at specialized centers where clinicians are experienced in the evaluation and management of patients with PH.

Group 1 PAH — Advanced therapy is often needed for patients with group 1 PAH because there are no effective primary therapies. In addition, randomized trials show favorable outcomes in this population of PH patients (eg, improved survival, 6 minute walk distance, functional class, and pulmonary hemodynamics, as well as delayed time to disease progression) [35].

Group 2 PH — For most patients with group 2 PH (PH secondary to left heart disease), advanced therapy should be avoided because it may be harmful. However, there are a few situations in which advanced therapy may be considered for group 2 PH (eg, patients with persistent PH due to mitral valve disease who have undergone mitral valve replacement with normalization of left atrial pressure).

The potential harm of advanced therapy in this population of patients with PH was best illustrated by a trial that randomly assigned 471 patients with PH and severe left ventricular dysfunction to receive standard therapy with or without epoprostenol (a component of advanced therapy) [3]. The trial was terminated early because the epoprostenol group had a nonstatistically significant increase in mortality at three months (30 versus 24 percent) and six months (48 versus 37 percent). Possible explanations for the detrimental impact of epoprostenol include its significant positive inotropic effect and the inability of a compromised left heart to handle the increased flow across a newly dilated pulmonary vascular bed [4].

Group 3 PH — Advanced therapy is not approved by the United States Food and Drug Administration (FDA) for patients with group 3 PH (PH secondary to chronic lung disease or hypoxemia) and some guideline panels recommend against its use in this population, except in the context of a clinical trial [3]. In general, trials have either shown no clinically significant benefit or raised safety concerns (eg, worsening hypoxemia, increased mortality) when advanced therapy is used in this population. As an example, one trial of riociguat (a guanylate cyclase stimulant) in patients with PH associated with idiopathic pneumonia (RISE-IIP) was terminated early because of increased adverse events and mortality in patients treated with riociguat [36,37]. Similarly, in patients with idiopathic pulmonary fibrosis without associated PH, ambrisentan was associated with increased risk for disease progression and hospitalizations [38]. These data are discussed in detail separately. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis".)

Thus, we suggest that for most patients with PH secondary to or associated with significant lung disease, advanced PH-targeted therapy should not be used. (table 2). Advanced therapy for this population may only be considered in the setting of severe PH; it should only be initiated at specialized centers and administered cautiously due to its potential to worsen ventilation-perfusion mismatch and increase hypoxemia.

Group 4 PH — Pulmonary thromboendarterectomy is the only potentially curative therapy for group 4 PH (chronic thromboembolic PH; CTEPH). However, advanced therapy with riociguat, a soluble guanylate cyclase stimulant, can be considered for patients with WHO functional class II through IV CTEPH (table 2) who are not operative candidates or have a suboptimal hemodynamic outcome following thromboendarterectomy. It can also be administered to patients as a bridge to surgery. (See "Chronic thromboembolic pulmonary hypertension: Medical treatment", section on 'Indications and Outcomes'.)

Group 5 PH — The role of advanced therapy for patients in this category of PH due to unclear multifactorial mechanisms is unknown. Small studies have addressed the role of advanced therapy for patients with PH related to sarcoidosis. One retrospective study of 13 patients with sarcoidosis-related PH who were treated with intravenous prostacyclin (monotherapy or in combination oral therapies) reported improved cardiac output, pulmonary vascular resistance, and functional class at 12 months [39]. Another series of eight patients described similar results with intravenous epoprostenol monotherapy [40], while another study reported that carefully selected patients can be transitioned from prostanoid infusion to oral bosentan [41].

PH-specific therapy for PH associated with sickle cell disease has been administered on an individual basis but trials thus far have not yielded clinically significant effects, and the largest of the studies was terminated early (walk-PHaSST) because of increased adverse events. (See "Pulmonary hypertension associated with sickle cell disease".)  

Agent selection — There is no single best approach to selecting an agent for advanced therapy. Our strategy is to choose an agent based on multiple factors including WHO functional class, right ventricular function, hemodynamics, vasoreactivity test, and patient characteristics and preferences (table 2). It is supported by data from randomized trials and also consistent with the approach suggested by the 5th World Symposium on Pulmonary Hypertension and The American College of Chest Physicians (algorithm 1) [1,9,11]. Clinicians with expertise in the treatment of patients with advanced PH may also individualize therapy based on their clinical experience.

Vasoreactivity test — Prior to the initiation of advanced therapy, it is recommended that patients with group 1 PAH undergo a vasoreactivity test, particularly patients with idiopathic PAH, heritable PAH, and anorexigen-induced PAH who are the groups of patients most likely to respond; patients with associated forms of PAH (connective tissue disease, congenital heart disease, HIV, portal hypertension, and schistosomiasis) are rarely vasoreactive and as such vasoreactivity testing is not absolutely necessary in that population of group I PAH patients. Vasoreactivity testing facilitates agent selection by identifying those who may respond to calcium channel blockers (CCBs), which are less expensive and have fewer side effects than other forms of advanced therapy. Patients with a negative vasoreactivity test may be candidates for advanced therapy with a prostanoid, endothelin receptor antagonist, phosphodiesterase 5 inhibitor, or soluble guanylate cyclase stimulant (non-CCBs). (See 'Agents' below.)

Vasoreactivity testing involves the administration of a short-acting vasodilator followed by measurement of the hemodynamic response using a RHC. Agents commonly used for vasoreactivity testing include inhaled nitric oxide, epoprostenol, and adenosine [42]:

Inhaled nitric oxide is the commonly used agent 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 the intravenous agents listed below [43-47]. (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 min and increased by 2 ng/kg per min 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 min and increased every two minutes until uncomfortable symptoms develop or a maximal dose of 200 to 350 mcg/kg per min is reached.

The test is considered positive if mean pulmonary artery pressure decreases at least 10 mmHg and to a value less than 40 mmHg, with an increased or unchanged cardiac output, and a minimally reduced or unchanged systemic blood pressure. Patients with a positive vasoreactivity test are candidates for a trial of calcium channel blocker (CCB) therapy with a dihydropyridine or diltiazem [10,48]. In contrast, patients with a negative vasoreactivity test should be treated with an alternative agent because CCBs have not been shown to be beneficial in these patients and may be harmful [48].

Patients with portopulmonary hypertension are rarely vasoreactive and are at increased risk for adverse sequelae from pure vasodilator therapy. Therefore, neither vasoreactivity testing nor calcium channel blocker therapy is indicated in this group. (See "Portopulmonary hypertension".)

Contraindications to vasoreactivity testing include low systemic blood pressure, low cardiac index, or the presence of severe (functional class IV) symptoms (table 2) because hypotension and occasionally cardiovascular collapse can occur with the administration of the vasodilator. Thus, most clinicians agree that acute vasoreactivity testing should only be performed by clinicians who are experienced in the performance and interpretation of this procedure.

Importantly, patients should not be treated for PAH with CCBs without demonstration of acute vasoreactivity since CCBs in the absence of acute vasoreactivity may result in serious adverse events including systemic hypotension and death. (See 'Calcium channel blockers' below.)

WHO functional class

Class I — These patients do not require pharmacologic therapy; however, they should be monitored closely for disease progression to a functional level that may warrant therapy. Any co-existing conditions that worsen pulmonary hypertension should also be treated (eg, obstructive sleep apnea).

Class II and III — For patients in class II and III with a new diagnosis of PAH who are drug-naïve, many experts initially administer oral agents that target the endothelin and nitric oxide-cyclic guanosine monophosphate (cGMP) pathways in combination. The combination of ambrisentan and tadalafil is preferred because it is associated with a significant reduction in the rate of clinical failure compared to monotherapy with either drug alone. For those who have a contraindication to either agent, substitution with another oral agent in the same class is preferred, although such combinations are less well proven and drug interactions can potentially limit the outcome. (See 'Combination therapy' below.)

Other options include alternative combined oral regimens of two agents from a different class (prostacyclin pathway agonists, endothelin receptor antagonists, and nitric oxide cGMP pathway enhancers) or single agent oral therapy. Suitable oral agents include oral ambrisentan, bosentan, macitentan, sildenafil, tadalafil, riociguat, or selexipag (table 4). Whether sequential combination therapy results in similar long-term benefits compared with initial combination therapy is not known. (See 'Endothelin receptor antagonists' below and 'PDE5 inhibitors' below and 'Guanylate cyclase stimulant' below and 'Combination therapy' below.)

For patients with class III who have rapid progression or other markers of poor clinical prognosis, we occasionally initiate oral selexipag or intravenous epoprostenol, intravenous or subcutaneous treprostinil, or inhaled treprostinil or iloprost (eg, echocardiographic evidence of severe right ventricular dilatation and dysfunction or the presence of a pericardial effusion). (See "Classification and prognosis of pulmonary hypertension in adults", section on 'Prognostic factors' and 'Endothelin receptor antagonists' below and 'PDE5 inhibitors' below and 'Guanylate cyclase stimulant' below and 'Prostacyclin pathway agonists' below.)

Class IV — Patients with severe PH who are WHO functional class IV should be treated with a parenteral prostanoid. Most clinicians consider intravenous epoprostenol as the preferred agent. Intravenous or subcutaneous treprostinil is a reasonable alternative. Inhaled treprostinil or iloprost is an option for patients who decline or cannot receive intravenous therapy. (See 'Prostacyclin pathway agonists' below and 'Combination therapy' below.)

Progressive or refractory disease — For patients with disease that is refractory or poorly responsive to monotherapy, combination therapy with an agent of a different class is appropriate [1,9,11]. It should consist of two agents with different mechanisms of action. Agents from any two of the following three classes are typically used in combination: prostacyclin pathway agonists, endothelin receptor antagonists, nitric oxide (NO)-cGMP enhancers. Rarely, a third agent is used. Importantly, agents within the same class (eg, phosphodiesterase 5 inhibitors and guanylate cyclase stimulants) should not be used in combination due to the high risk of hypotension. Data to support specific combinations are limited and discussed below. (See 'Combination therapy' below.)

AGENTS — Data discussed in this section largely pertain to patients with group 1 pulmonary arterial hypertension.

Calcium channel blockers — Some patients who are vasoreactive and receive CCB therapy with a dihydropyridine or diltiazem can achieve prolonged survival, sustained functional improvement, and hemodynamic improvement [15,49-51]. This was illustrated by an observational study of 64 patients with IPAH that compared vasoreactive patients who received CCB therapy (primarily nifedipine) to a combined group that included patients who were not vasoreactive plus historical controls [15]. None of the patients in the combined group received a CCB. Five year survival was greater among patients who received CCB therapy (94 versus 55 percent).

Positive vasoreactive testing does not reliably predict those who are likely to experience a clinical improvement with CCB therapy. An 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 [51]. 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. In a small retrospective study of PAH patients of varying etiologies, those who had an acute vasoreactive response had a better survival compared with those without such acute hemodynamic change [52].

The evidence suggesting that CCB therapy is beneficial in terms of survival is limited by the absence of randomized trials comparing such therapy to no therapy in vasoreactive patients only. Without such trials, it is uncertain whether the vasoreactive patients who received CCB therapy in the observational trials truly benefited from the therapy or were 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 the pulmonary artery pressure feel remarkably better while on CCB therapy.

CCB therapy can be initiated with either long-acting nifedipine (30 mg/day) or diltiazem (120 mg/day), then increased to the maximal tolerated dose (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 agents. Patients who respond to CCB therapy with a dihydropyridine or diltiazem (defined as asymptomatic or minimal symptoms) should be reassessed after three to six months of treatment.

Adverse effects are common among patients with PH who are administered CCBs. In an observational study evaluating 12 patients with PH due to obliterative pulmonary vascular diseases who were administered verapamil, nifedipine, or hydralazine, severe short- and long-term side effects occurred in 11 of the 12 patients who received verapamil or nifedipine [53]. Many of the adverse effects are a result of the potent vasodilatory properties of CCBs. Systemic vasodilation may cause hypotension, while pulmonary vasodilation may reduce hypoxic vasoconstriction [54,55]. Loss of hypoxic vasoconstriction can worsen ventilation-perfusion mismatch and hypoxemia. CCBs may also be associated with deterioration of right ventricular (RV) function [53]. (See "Major side effects and safety of calcium channel blockers".)

Prostacyclin pathway agonists — Drug formulations used to treat PAH include intravenous prostacyclin (epoprostenol), synthetic analogs of prostacyclin (intravenous treprostinil, subcutaneous treprostinil, inhaled treprostinil, and inhaled iloprost), and non-prostanoid prostacyclin receptor agonists (selexipag).  

Epoprostenol — Intravenous epoprostenol (prostacyclin; PGI2) is the advanced therapy that has been best studied. It improves hemodynamic parameters, functional capacity, and survival in patients with IPAH [56-61]. In patients with other types of group 1 pulmonary arterial hypertension (PAH), intravenous epoprostenol improves hemodynamic parameters and functional capacity; however, survival has not been adequately evaluated due to limited sample sizes [62-65].

The efficacy of intravenous epoprostenol was illustrated by a trial that randomly assigned 81 patients with severe (ie, World Health Organization [WHO] class III or IV) IPAH to receive intravenous epoprostenol or standard therapy for 12 weeks [58]. Intravenous epoprostenol improved quality of life, mean pulmonary arterial pressure (-8 versus +3 percent), pulmonary vascular resistance (-21 versus +9 percent), and exercise capacity, as measured by a six-minute walk test (+47 versus -66 meters). Eight patients died during the trial, all of whom were in the standard therapy group.

We believe that epoprostenol should be considered the first-line agent in patients with severe disease (ie, WHO class IV) because only a small number of such patients were included in the clinical trials of the alternative agents. In less severe disease (ie, WHO class II or III), numerous choices exist, as discussed below.

Epoprostenol is delivered continuously through a permanently implanted central venous catheter using a portable infusion pump. It is usually initiated at doses of 1 to 2 ng/kg per min and increased by 1 to 2 ng/kg per min every one to two days as tolerated. The rate at which the dose can be increased varies from patient to patient and depends to a large extent on how well the drug is tolerated. Once an initial level of 6 to 10 ng/kg per min is achieved (usually within one to two weeks), most patients require dose increases of 1 to 2 ng/kg per min every two to four weeks to sustain the clinical effect (table 4).

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 min 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 pulmonary hypertension [66].

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 can also contribute to the morbidity and mortality of continuous epoprostenol therapy [67,68].

Most insurers in the United States now reimburse the cost of continuous intravenous epoprostenol for IPAH and group 1 PAH due to connective tissue diseases, portal hypertension, HIV infection, anorectic drug therapy, or congenital heart disease. In each of these conditions, the following criteria must be met:

Pulmonary hypertension has progressed despite medical or surgical treatment of the underlying disorder, AND

The mean pulmonary artery pressure is greater than 25 mmHg at rest, AND

Symptoms from PH are present, AND

Acute vasoreactivity testing was negative, CCB therapy with a dihydropyridine or diltiazem failed, or treatment with a CCB is contraindicated.

Treprostinil — Treprostinil is a prostacyclin analog that can be given intravenously or subcutaneously, although subcutaneous administration is used less often than in the past due to severe pain at the injection site (table 4). Inhaled treprostinil has more recently been approved, specifically for patients with group 1 PAH who are WHO functional class III (table 2).

Intravenous and subcutaneous treprostinil improve hemodynamic parameters, symptoms, exercise capacity, and possibly survival in patients with group 1 PAH [69-73]. It has not been evaluated in patients with other types of PH. Trials comparing epoprostenol to treprostinil have not been performed. Advantages of parenteral treprostinil, compared to epoprostenol, include the option of continuous subcutaneous delivery, a longer half-life that may make interruption of the infusion less immediately life threatening, and no need for refrigeration. All of these advantages allow more flexibility and easier administration. For patients who desire the advantages associated with treprostinil administration, it can be offered as first line therapy. Based upon preliminary results, patients who are already receiving epoprostenol generally can be transitioned to treprostinil (subcutaneous or intravenous) without a significant loss of clinical efficacy [74,75]. Reciprocally, epoprostenol can be given if the desired effect is not achieved with treprostinil.

Based on the results of two clinical trials, an oral formulation of treprostinil was approved by the US Food and Drug Administration (FDA) [76,77]. In one trial, 349 patients with PAH, not on other advanced therapy, were randomly assigned to gradually increasing doses of treprostinil or placebo [77]. After 12 weeks, the treprostinil group experienced a small but statistically significant increase in six minute walk distance. No significant effect was noted on the incidence of clinical worsening, but the overall rate of clinical worsening was low. The combination of oral treprostinil with other agents is described below. (See 'Combination therapy' below.)

Iloprost — Iloprost is a prostacyclin analog. Inhaled iloprost has theoretical advantages in targeting the lung vasculature and does not require intravenous administration (table 4). The main disadvantage is the need for frequent administration (six to nine times per day).

A trial randomly assigned 203 patients with PH (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 [78]. The primary endpoint (improvement in WHO class and >10 percent improvement in the six-minute walk test) was greater in the iloprost group compared to the placebo group (17 versus 5 percent).

Selexipag — 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 [79]. Both selexipag and its active metabolite possess high selectivity for the IP receptor over other prostanoid receptors distinguishing it from prostacyclin and prostacyclin analogs currently used in the management of PAH [80].

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 [79]. Approximately 20 percent of patients were drug-naïve and the remainder were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. Selexipag was associated with a significant 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). Adverse effects, that were mostly mild, were reported in up to two-thirds of patients and were consistent with the known side effects of prostacyclin (eg, headache, diarrhea, nausea, flushing, muscle aches, and jaw pain).

Endothelin receptor antagonists

Overview — Endothelin-1 (ET-1) is a potent vasoconstrictor and smooth muscle mitogen. High concentrations of ET-1 have been recorded in the lungs of patients with both idiopathic PAH and other etiologies of group 1 PAH, including scleroderma and congenital cardiac shunt lesions [81]. Endothelin receptor antagonism emerged as an initial therapy for group 1 PAH in the late 1990s.

There are two receptors (endothelin receptor A and B) that are targeted by endothelin receptor antagonists (ERAs). ERAs that have been tested in clinical trials include:

Nonselective dual action receptor antagonists – bosentan and macitentan

Selective receptor antagonists of endothelin receptor A – ambrisentan and sitaxsentan

Among these agents, only bosentan and macitentan (nonselective) and ambrisentan (selective) are available. Sitaxsentan was withdrawn from the European Union, Canada, and Australia in 2010 following several fatal cases of hepatoxicity (the drug was never approved in the United States) [82-86].

A meta-analysis of 12 randomized trials (1471 patients) evaluated the impact of the ERAs (bosentan or sitaxsentan) on patients with PAH [87]. The ERAs improved exercise capacity, dyspnea, and hemodynamic measures (pulmonary artery pressure, pulmonary vascular resistance, and cardiac index).

There is some evidence that the magnitude of the response to ERAs may vary according to gender and race; namely, an observational study of 1130 patients that used data extracted from randomized trials found that women had significantly greater improvement in their six-minute walk test than men (+29.7 m) and white individuals had a trend toward greater improvement in their six-minute walk test than black individuals (+43.6 m) [88]. While the data are too preliminary to alter current clinical practice, further investigation is warranted.

The main adverse effects of concern for ERAs are hepatotoxicity and peripheral edema [2,86,89-95]. ERAs are also potent teratogens, requiring meticulous, double method contraception if used by women with childbearing potential. Additional adverse events reported for individual ERAs are discussed in the sections below.

Hepatotoxicity differs among ERAs with sitaxsentan as the most hepatotoxic. Reports suggest that mild elevations in aminotransferase levels occur in less than 6 percent of patients on bosentan, ambrisentan, and macitentan. However, 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. Careful consideration should be given to the use of ERAs in patients with moderate or severe hepatic dysfunction, or in conjunction with cyclosporine or glyburide.

In our experience, peripheral edema is the most common side effect that requires attention with bosentan and ambrisentan and occurs in up to 17 percent of patients. Mild cases can be managed with diuretics, but more severe cases warrant discontinuation of the medication. Edema may be less of an issue with macitentan.

Ambrisentan — Ambrisentan is an oral selective type A endothelin-1 receptor antagonist. Randomized placebo-controlled studies (eg, the ARIES-1 and ARIES-2 trials) of patients with moderate to severe idiopathic and connective tissue disease–related PAH (WHO functional class II to IV) consistently reported that ambrisentan administered for up to two years delayed disease progression and clinical worsening [90-92]. In addition, ambrisentan has been associated with improved exercise tolerance, WHO functional class, pulmonary vascular hemodynamics, and quality of life.

Ambrisentan is the least hepatotoxic of the ERAs. However, there are concerns regarding the use of ambrisentan in patients with concurrent idiopathic pulmonary fibrosis (IPF). In one randomized placebo-controlled trial of patients with IPF, ambrisentan was associated with an increased risk of disease progression and hospitalizations [38]. However, this trial was not powered to examine efficacy or safety of ambrisentan as a therapy for PAH or ILD-associated PH. Further details regarding this trial and the use of ambrisentan as a treatment for ILD-associated pulmonary hypertension 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".)

Bosentan — Bosentan is an oral nonselective endothelin receptor antagonist that has been shown in patients with group 1 PAH to delay clinical worsening and improve pulmonary vascular hemodynamics and exercise capacity [89,96-98]. The mortality of bosentan-treated IPAH patients appears favorable compared to historical controls [81,97]. Mortality has not been studied in patients with other types of PH.

Bosentan appears to be effective in patients with severe group 1 PAH (WHO functional class III or IV) and may also be effective in patients with moderate group 1 PAH (WHO functional class II):

In a double-blind trial (BREATHE-1 trial), 213 patients with severe group 1 PAH were randomly assigned to receive bosentan (62.5 mg) or placebo twice daily for four weeks, followed by either of two doses of bosentan (125 or 250 mg) twice daily for a minimum of 12 weeks [89]. Bosentan improved symptoms, the six-minute walking distance, and the WHO functional class.

Another double-blind trial randomly assigned 185 patients with moderate group 1 PAH to receive bosentan or placebo twice daily for six months [2]. The bosentan was administered at a dose of 62.5 mg twice daily for four weeks and then increased to 125 mg twice daily. Bosentan improved pulmonary vascular resistance and the mean six-minute walk distance, although the latter was not statistically significant. A limitation of this trial was its failure to follow the principle of intention to treat.

Macitentan — Macitentan is an oral agent with dual endothelin receptor antagonist function that has been studied in patients with WHO group 1 PAH. The SERAPHIN trial compared oral macitentan to placebo in 250 patients with moderate to severe PAH (WHO functional class II-IV; approximately 85 percent of patients had IPAH or connective tissue disease associated PAH) [93,99]. 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 versus 46 percent) [93]. This benefit was observed independent of whether patients were receiving additional advanced oral therapy for PAH. Exercise capacity and WHO functional class also improved with macitentan treatment. The effects of this agent were not tested in patients receiving intravenous or subcutaneous prostanoid therapy, nor was this study powered to show a benefit in mortality as an independent outcome.

The rates of liver function test abnormalities were no different between the groups (3 to 4 percent). However, as compared with placebo, macitentan was associated with a higher rate of nasopharyngitis (15 versus 10 percent) and anemia (hemoglobin ≤8 g/dL; 8 to 13 versus 3 percent). The incidence of edema was not different in the placebo and macitentan treated groups [93].

Nitric oxide-cyclic guanosine monophosphate enhancers — 

PDE5 inhibitors — Sildenafil, tadalafil, and vardenafil are orally administered cyclic GMP phosphodiesterase type 5 (PDE5) inhibitors that prolong the vasodilatory effect of nitric oxide and are also used to treat erectile dysfunction.

Sildenafil — Sildenafil improves pulmonary hemodynamics and exercise capacity in patients with group 1 PAH [100-103]. However, its effect on mortality has not been adequately evaluated. An illustrative trial (the SUPER-1 trial) randomly assigned 277 patients with group 1 PAH to receive sildenafil (20, 40, or 80 mg) or placebo three times daily for 12 weeks [102]. The sildenafil group demonstrated significant improvement in hemodynamics and six-minute walk distances, which persisted during one year of follow up. Mortality was not reported. Patients who completed the SUPER-1 trial were eligible to participate in an uncontrolled, open-label, three-year extension called the SUPER-2 trial [104]. The trial enrolled 259 patients and, at the end of three years of therapy, found persistent improvement in the six-minute walk distance and WHO functional class of 46 and 29 percent of patients, respectively, compared with the baseline values measured prior to the SUPER-1 trial. The estimated three year survival rate was 79 percent. The effect of sildenafil on patients with other types of PH is uncertain.

Tadalafil — Tadalafil also appears to improve outcomes in patients with group 1 PAH. The PHIRST trial randomly assigned 405 such patients to receive tadalafil (2.5, 10, 20, or 40 mg) or placebo once daily for 16 weeks [105]. Tadalafil (40 mg) significantly increased the six-minute walk distance and the time to clinical worsening, while decreasing the incidence of clinical worsening and improving health related quality of life. This improvement of the six-minute walk distance was sustained for an additional 52 weeks in the PHIRST -2 trial, an uncontrolled extension trial [106].

Other — Similarly, another trial randomly assigned 66 patients with group 1 PAH to receive vardenafil (5 mg once daily for four weeks, then twice daily) or placebo for 12 weeks [107]. Vardenafil increased the mean six minute walking distance and cardiac index, while decreasing the mean pulmonary arterial pressure, pulmonary vascular resistance, and number of clinical worsening events. Vardenafil is not approved by the Food and Drug Administration for the treatment of PAH.

Guanylate cyclase stimulant — Stimulators of the nitric oxide receptor, soluble guanylate cyclase (sGC) have a dual mode of action. They increase the sensitivity of sGC to endogenous nitric oxide (NO), a pulmonary vasodilator, and they also directly stimulate the receptor to mimic the action of NO.

Riociguat is an oral sGC stimulant that has reported benefit in patients with inoperable and persistent chronic thromboembolic pulmonary hypertension (CTEPH; group 4) [108]. These data are discussed separately. (See "Chronic thromboembolic pulmonary hypertension: Medical treatment".)

Patients with PAH (group 1) may also benefit from riociguat [109-111]. A multicenter randomized placebo-controlled trial of riociguat (PATENT-1) studied 443 patients with symptomatic PAH (World Health Organization Class [WHO] II and III) (table 2) [108,112]. Compared to placebo, 12 weeks of oral riociguat (2.5 mg three times daily) was associated with a modest increase in the six-minute walking distance (6MWD; increase by 30 m versus decrease by 6 m). This benefit was observed regardless of whether patients were receiving concurrent advanced therapy during the study (prostanoids, endothelin receptors antagonists). Improvements in pulmonary vascular resistance, symptoms, WHO functional class, and time to clinical worsening were also reported in patients receiving the study drug. 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. A followup long-term extension study (PATENT-2) reported sustained benefits and a similar safety profile for riociguat when administered for up to two years in patients with PAH [109,110].

COMBINATION THERAPY — It has been proposed that combining pharmacologic agents with different mechanisms of action may produce an additive effect or may induce the same effect at lower doses of each agent [113]. Combination therapy may be administered as two agents initiated together or as "add-ons" (ie, one followed by another) [114]. The combination associated with the best efficacy is tadalafil and ambrisentan for patients with functional class II or III PAH.

Tadalafil plus ambrisentan – The combined oral regimen of tadalafil (phosphodiesterase-5 inhibitor) plus ambrisentan (endothelin receptor antagonist), improves outcomes in patients with WHO functional class II or III. One randomized trial (AMBITION) of 500 newly diagnosed patients with group 1 PAH (mostly idiopathic and connective tissue disease-related) who had class II or III symptoms compared the combination of 10 mg of ambrisentan and 40 mg of tadalafil with either agent alone [115]. The combined regimen administered on average for eighteen 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 including 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 [116]. In contrast, the lack of drug interaction between tadalafil and ambrisentan may also explain why the outcomes reported in AMBITION were more robust.

Sildenafil plus bosentan – Combining sildenafil and bosentan may be associated with improved outcomes but results from trials have been contradictory. One prospective cohort study followed 25 patients with group 1 PAH who were initially treated with bosentan monotherapy, but developed clinical deterioration and had sildenafil added [117]. Clinical improvement occurred after the addition of sildenafil, as measured by symptoms, exercise capacity, and WHO functional classification. Improvement was more frequent and of greater magnitude in patients with IPAH, compared to patients with scleroderma-associated PAH. In a second study of patients failing monotherapy with either bosentan or sildenafil, the addition of the other agent also resulted in improved functional class and survival in those with idiopathic PAH, when compared with those with connective tissue-associated PH [118]. 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 [119].

Bosentan added to either epoprostenol or treprostinil – Limited experience suggests that bosentan can be used safely and effectively added to epoprostenol or subcutaneous treprostinil therapy [72,120]. A 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 [120]. Epoprostenol improved hemodynamic parameters, exercise capacity, and functional class, compared to baseline. The addition of bosentan improved these outcomes to a greater degree than the addition of placebo, although the difference was not statistically significant.

Treprostinil added to either bosentan or sildenafil – The addition of inhaled treprostinil may improve the exercise capacity and quality of life of patients with persistent symptoms despite bosentan or sildenafil therapy. This was demonstrated by the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) trial [121]. In the trial, 235 patients with group 1 PAH, a WHO functional class III or IV, and a six minute walking distance (6MWD) of only 200 to 450 meters despite bosentan or sildenafil therapy were randomly assigned to receive either inhaled treprostinil or placebo for 12 weeks. The treprostinil group had a larger improvement in their six minute walking distance and quality of life, but there were no differences in the time to clinical worsening, dyspnea, or WHO functional class.

Oral treprostinil added to an endothelin receptor antagonist and/or a phosphodiesterase-5 inhibitor – The addition of oral treprostinil in patients with group 1 PAH already on an endothelin receptor antagonist and/or a phosphodiesterase-5 inhibitor did not improve the 6MWD at 16 weeks (FREEDOM-C and FREEDOM C-2) [76,122]. The 354 subjects were randomly assigned to oral treprostinil or placebo for 16 weeks. The dose of treprostinil was increased at intervals according to protocol to a median dose of 3 mg twice daily. 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 the secondary end-points of median dyspnea fatigue index score and combined 6MWD and Borg dyspnea score.

Sildenafil added to epoprostenol – The addition of sildenafil to long-term epoprostenol therapy improves clinical outcomes. A trial randomly assigned 267 patients with group 1 PAH who were receiving epoprostenol to have sildenafil or placebo added for 16 weeks [123]. 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 to placebo. There was no difference in dyspnea. Headache and dyspepsia were more common in the sildenafil group.

Sildenafil added to iloprost – The combination of iloprost plus sildenafil may improve outcomes compared to either agent alone [124,125]. This was illustrated by a prospective cohort study of 73 patients with group 1 PAH who were receiving long-term inhaled iloprost [124]. Clinical deterioration occurred in 14 patients, prompting the addition of sildenafil for 9 to 12 months. Among those patients who had sildenafil added to their iloprost regimen, there was improvement in exercise capacity, WHO functional class, and hemodynamics.

Bosentan plus 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 [126]. 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 six-minute walking distance, the trial's primary endpoint [127]. The results of the trial may have been skewed by three outliers in the combination therapy group. Thus, larger trials are needed to adequately evaluate the efficacy of bosentan and iloprost combination therapy.

Riociguat added to sildenafil – The safety of combining sildenafil and riociguat was examined in one trial (PATENT PLUS) where patients receiving sildenafil were randomized to placebo or riociguat (up to 2.5 mg three times daily) and treated for 12 weeks [128]. There were no differences observed in standing or supine blood pressure, pulmonary hemodynamics, or exercise capacity with riociguat plus sildenafil compared with sildenafil alone. However, when the combination was administered in a small number of patients beyond the study period, high rates of discontinuation (due to hypotension) and three deaths (thought not to be study drug-related) were reported. Due to the unfavorable safety profile, the US Food and Drug Administration issued a warning against combining PDE5 inhibitors and guanylate cyclase stimulants [129]. We agree that this combination is contraindicated and should not be administered in patients with PAH.

SPECIAL POPULATIONS — Select populations including pregnant women and those at high altitude require special consideration.

Pregnancy — Endothelin receptor antagonists (eg, bosentan) and guanylate cyclase stimulants (riociguat) are absolutely contraindicated in pregnancy (FDA category X) and in women who may become pregnant. A negative pregnancy test is required prior to treatment, monthly during treatment, and at one month after discontinuation of treatment. Although data are limited, using the same indications as the general population, most women who are pregnant and have pulmonary arterial hypertension (PAH) should be treated with a prostanoid (functional class III, IV), usually epoprostenol. Consultation with an expert is warranted in women with PAH due to the complexity of drug administration and potential fetal and maternal complications associated with PH itself and the delivery (eg, fetal hypoxia, acute cardiovascular collapse).

A retrospective review of 49 pregnant women with PH (30 had World Health Organization [WHO] group 1 PAH) from four major academic medical centers in the United States reported a mortality of 16 percent (eight women). Seven of the eight deaths occurred in women with group 1 PAH; six of whom had severe PH (defined as mean pulmonary artery pressure ≥50 mmHg) [130]. Three deaths occurred following pregnancy termination procedures and five deaths occurred postpartum, four in those who delivered by caesarian section compared with one who delivered vaginally. There were no neonatal deaths. Seventy three percent of women with severe PH received advanced therapies for pulmonary hypertension including vasopressors, inotropes, pulmonary vasodilators, and extracorporeal membrane oxygenation (ECMO).

For women of childbearing age with known PAH, pregnancy should be avoided due to the risk of worsening pulmonary vascular hemodynamics. In addition, estrogen-containing contraceptives should be avoided. Surgical (patient or partner) methods of contraception are preferred but dual barrier contraception (eg, progesterone implanted intrauterine device) is an acceptable alternative. (See "Contraceptive counseling and selection".)

Altitude and air travel — Patients with exposure to high altitude or patients planning air travel should continue their routine PH medications. Supplemental oxygen (2 to 4 L per minute) can also be administered to maintain oxygen saturations above 90 percent. Assessment of patients for air travel and the effects of high altitude are discussed separately. (See "Assessment of adult patients for air travel", section on 'Pulmonary' and "Traveling with oxygen aboard commercial air carriers" and "High altitude illness: Physiology, risk factors, and general prevention" and "High altitude, air travel, and heart disease".)

Patients requiring surgery — Patients with symptomatic pulmonary hypertension and right ventricular dysfunction, in particular those with pulmonary arterial hypertension (PAH), are at high risk of cardiovascular collapse and death when undergoing anesthesia, mechanical ventilation, and major surgery, such that patients should avoid nonessential surgery. For those in whom surgery is necessary, preoperative medications for PAH should be continued without interruption. Perioperatively, patients should be managed by a multidisciplinary team that includes a cardiovascular anesthesiologist and PH expert with careful monitoring of fluid balance, oxygenation, blood pressure and heart rate. (See 'Surgical risk' above.)

FOLLOW-UP — Patients should ideally be seen every three months (or more frequently) if they are receiving parenteral or combination therapy [9,10]. The same is true of patients who have advanced symptoms, right heart failure, or advanced hemodynamic abnormalities. Less ill patients should be seen every three to six months. Such frequent reassessment is necessary because of the complex nature of the disease and its treatments. Patient logistics may dictate alternative forms of follow-up, such as frequent telephone contact.

Follow-up visits should ideally include a thorough history to assess symptoms of right heart failure, exercise tolerance, and medication side effects; physical examination for signs of right heart failure; and resting and ambulatory oximetry. The frequency of follow-up testing with a brain natriuretic peptide (BNP), six minute walk test (6MWT), echocardiogram, and invasive hemodynamic assessment (right heart catheterization) should be determined on a case by case basis. We usually obtain a 6MWT at each visit and an echocardiogram every 12 months, or sooner if clinically indicated. The frequency of right heart catheterization (RHC) is made on a case-by-case basis. It is common to repeat a RHC early after the initiation of therapy (3, 6 or 12 months), when the patient deteriorates, and when combination therapy is initiated.  

RIGHT TO LEFT SHUNT — Creation of a right to left shunt is not routinely recommended as therapy for the treatment of pulmonary arterial hypertension (PAH). However, in adults with severe symptomatic PAH, such a procedure can be considered. 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 [131-141]. Importantly, a preexisting patent foreman ovale (PFO) or atrial septal defect (ASD) should never be percutaneously or surgically closed in a patient with significant PH.

Patients with severe PAH face significant morbidity and mortality due to progressive right heart failure. Severely high pulmonary vascular resistance leads to a reduction in left ventricular preload and consequently, systemic pressure, that can precipitate significant syncope and death (from obstructive shock). 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.  

Atrial septostomy — Atrial septostomy is a right to left shunt that connects right and left atrial cavities. As a direct result of high right atrial pressures; the right-to-left shunting and consequent arterial desaturation that follow the procedure are offset in some patients by increased cardiac output and augmentation of systemic oxygen delivery by up to 27 percent [131,134]. However, procedure-related mortality may be as high as 15 to 20 percent [131,137]. It is difficult to predict which patients will benefit and which will deteriorate after this therapy.

Atrial septostomy may be considered in individuals with refractory severe pulmonary arterial hypertension (PAH) and right heart failure, despite aggressive advanced therapy and maximal diuretic therapy [138,142]. It may also be considered in patients who have signs of impaired systemic blood flow (such as syncope) due to reduced left heart filling. Stepwise balloon dilatation is the procedure of choice [8].

Patients with the most advanced PAH appear more likely to die or get worse with atrial septostomy [138]. This includes patients with markedly elevated mean right atrial pressure (eg, greater than 20 mmHg) [8], 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 [131].

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 pulmonary artery hypertension (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 [141]. TPS involves retrograde needle perforation of the aorta, with subsequent placement of a covered stent between the aorta and left pulmonary artery. Of four patients studied (18 to 47 years old), two died and two survived at four and ten 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.  

TRANSPLANTATION — Transplantation has been performed in patients with idiopathic pulmonary arterial hypertension (IPAH) and is considered by some to be the final effective treatment for selected patients with IPAH [8,143,144]. Bilateral lung or heart-lung transplantation is the procedure of choice [8].

The timing of transplantation is critical, since survival from severe IPAH refractory to medical therapy is poor and the availability of suitable organs for transplantation is limited. The three year survival of patients who had a lung or heart-lung transplant for IPAH is approximately 50 percent [138,145].

Guidelines for when to refer a patient for transplant evaluation are as follows [146]:

World Health Organization (WHO) functional class III or IV during escalating therapy

Rapidly progressive disease

Use of parenteral targeted pulmonary arterial hypertension (PAH) therapy regardless of symptoms or New York Heart Association (NYHA) functional class

Known or suspected pulmonary veno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis

Importantly, referral to a transplant center for the above indications does not infer that transplant is associated with improved survival, particularly for patients on parenteral therapy with functional class II or III. The decision to transplant patients with PAH should be individualized and is discussed separately. (See "Lung transplantation: General guidelines for recipient selection" and "Lung transplantation: An overview".)

Hyperbilirubinemia is a late manifestation of pulmonary hypertension caused by chronic passive hepatic congestion and cardiac cirrhosis [131]. 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.

Post-transplantation management for 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 [147]. Recurrence of IPAH after transplantation has not been reported. (See "Lung transplantation: Procedure and postoperative management".)

SUMMARY AND RECOMMENDATIONS

The World Health Organization (WHO) classifies patients with pulmonary hypertension (PH) 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). (See 'Nomenclature' above.)

Initial (primary) therapy should be directed at the underlying cause of the PH. In addition, the need for diuretic, oxygen, and anticoagulant therapy should be assessed (see 'Primary therapy for PH' above):

For patients with fluid retention due to PH, we suggest diuretics (Grade 2B). (See 'Diuretics' above.)

For patients with group 4 PH, anticoagulant therapy is indicated. For patients with systemic sclerosis–associated PAH, we suggest that anticoagulant therapy not be administered (Grade 2C). For patients including those with idiopathic pulmonary arterial hypertension (IPAH), hereditary PAH, and HIV-and drug-induced PAH, we suggest administering anticoagulant therapy on a case-by-case-basis. (See 'Anticoagulation' above and "Chronic thromboembolic pulmonary hypertension: Medical treatment", section on 'Summary and recommendations'.)

For patients with group 3 PH and resting or exercise hypoxemia, we recommend supplemental oxygen (Grade 1A). For patients with other types of PH, we suggest supplemental oxygen if resting, exercise, or nocturnal hypoxemia exists (Grade 2B). (See 'Oxygen therapy' above and 'Group 3 PH' above.)

Patients with persistent PH whose WHO functional class is II, III, or IV despite treatment of the underlying cause of the PH should be referred to a specialized center to be evaluated for advanced therapy (algorithm 1). Advanced therapy is treatment that is directed at the PH itself, rather than the underlying cause of the PH. (See 'Advanced therapy' above.)

Advanced therapy is widely accepted for many patients with group 1 PAH. In contrast, it must be considered on a case-by-case basis for patients with group 4 PH or group 5 PH, after carefully weighing the risks versus the benefits. Advanced therapy should NOT be administered to most patients with group 2 or group 3 PH. (See 'Patient selection' above.)

Advanced therapy should not be administered until a diagnostic right heart catheterization (RHC) and extensive investigations for the etiology of PH have been performed. Additionally, most patients with group 1 pulmonary arterial hypertension (PAH), in particular, those with idiopathic PAH, heritable PAH, and anorexigen-induced PAH, should also undergo vasoreactivity testing during RHC which facilitates agent selection. (See 'Vasoreactivity test' above.)

-For patients who have a positive vasoreactivity test, we suggest a trial of calcium channel blocker (CCB) therapy with a dihydropyridine or diltiazem prior to the initiation of therapy with prostacyclin pathway agonists, endothelin receptor antagonists, or nitric oxide-cyclic guanosine monophosphate enhancers (cGMP) (Grade 2C). Patients who respond to such therapy should be reassessed after three to six months of treatment. (See 'Calcium channel blockers' above.)

-For patients with idiopathic pulmonary arterial hypertension (IPAH) who have a negative vasoreactivity test or fail CCB therapy with a dihydropyridine or diltiazem, we recommend advanced therapy with a non-CCB agent (Grade 1A). For patients with another type of group 1 PAH who have a negative vasoreactivity test or fail CCB therapy with a dihydropyridine or diltiazem, we suggest advanced therapy with a non-CCB agent (Grade 2B). (See 'Agents' above.)

-For patients in whom a non-CCB agent is chosen, the preferred agent(s) depends on the functional severity of disease (algorithm 1 and table 2). Patients with WHO functional class I do not require therapy but should be monitored for disease progression and contributing causes of PH should be treated. For patients who are WHO functional class II or III, oral agents rather than intravenous prostanoids are preferred (Grade 2B). Classes of suitable agents include oral endothelin receptor antagonists (ambrisentan, bosentan, or macitentan), oral phosphodiesterase inhibitors (sildenafil or tadalafil), oral guanylate cyclase stimulants (riociguat), and oral prostacyclin pathway agonists (selexipag). Among the options, we suggest ambrisentan and tadalafil rather than other combinations or single agent therapy (Grade 2B). For patients with functional class III who have rapid progression or other markers of poor clinical prognosis, some experts administer oral selexipag, intravenous epoprostenol, inhaled iloprost, intravenous treprostinil, or subcutaneous treprostinil. For patients who are WHO functional class IV, we suggest intravenous epoprostenol, rather than any alternative agent (Grade 2B). (See 'Agent selection' above and 'Agents' above.)

-For patients with refractory disease, combination therapy with a second, and rarely third, agent of a different class is appropriate, with the exception of combining PDE5 inhibitors and guanylate cyclase stimulants, which is contraindicated due to an unfavorable safety profile. (See 'Progressive or refractory disease' above.)

Atrial septostomy and lung transplantation are reserved for patients who are refractory to medical therapy. (See 'Right to left shunt' above and 'Transplantation' above.)

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