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Disclosures: William Hopkins, MD Speaker's Bureau: Merck [Atherosclerosis]; Actelion [Pulmonary Hypertension (Bosentan, Opsimut, Epoprostenol, Iloprost)]; Bayer [Pulmonary Hypertension (Riociguat)]. Lewis J Rubin, MD Consultant/Advisory Boards: Actelion; United Therapeutics; Gilead; GeNO [pulmonary hypertension (macitentan, selexipag, treprostinil, beraprost, ambrisentan, nitric oxide)]. Equity Ownership/Stock Options: GeNO [inhaled NO system]. Jess Mandel, MD Nothing to disclose. Geraldine Finlay, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
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 "Overview of pulmonary hypertension in adults" and "Clinical features and diagnosis of pulmonary hypertension in adults" and "Pathogenesis of pulmonary hypertension".)
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 "Overview 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) .
●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 "Overview 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 "Overview 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 due to systolic dysfunction" and "Treatment and prognosis of diastolic heart failure" and "Course and management of chronic aortic regurgitation in adults" and "Overview of the management of chronic mitral regurgitation" and "Medical management and indications for intervention in 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 "Overview 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 . 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 . 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) .
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 "Overview 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 . 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 for pulmonary thromboendarterectomy' and "Chronic thromboembolic pulmonary hypertension: Surgical treatment", section on 'Pulmonary thromboendarterectomy'.)
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 "Overview of pulmonary hypertension in adults", section on 'Classification'.)
All groups — Several therapies should be considered in all patients with PH. They include diuretic, oxygen, anticoagulant, and digoxin therapy, as well as exercise.
Diuretics — Diuretics are used to treat fluid retention due to PH because diuresis will diminish hepatic congestion and peripheral edema . However, they should be administered with caution to avoid decreased cardiac output (due to decreased right and/or left ventricular preload), arrhythmias induced by hypokalemia, and metabolic alkalosis. Fluid can also be removed by dialysis or ultrafiltration if necessary.
Oxygen therapy — Continuous oxygen administration remains the cornerstone of therapy in patients with group 3 PH, as discussed above. 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 [1,9,10]. 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 . (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 — Patients with PH are at increased risk for intrapulmonary thrombosis and thromboembolism, due to sluggish pulmonary blood flow, dilated right heart chambers, venous stasis, and a sedentary lifestyle. Even a small thrombus can produce hemodynamic deterioration in a patient with a compromised pulmonary vascular bed that is unable to dilate or recruit unused vasculature.
It is generally accepted that anticoagulation is indicated in patients with IPAH [1,9,10], hereditary pulmonary artery hypertension (PAH) [1,9], drug-induced PAH [1,9], or group 4 PH. Limited experience with newer anticoagulants makes warfarin the anticoagulant of choice, with a therapeutic goal of an international normalized ratio (INR) of approximately two.
Support for the use of warfarin in patients with PH largely comes from observational studies of patients with IPAH [1,12-15]. In a systematic review of seven observational studies that evaluated the effect of warfarin in patients with group 1 PAH, five studies found a mortality benefit .
The risk of bleeding on vitamin K antagonists 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 . Compared to idiopathic PAH and chronic thromboembolic disease-associated PAH, connective tissue disease-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 PH subtypes. Prospective studies with subset analysis are required to accurately assess whether increases in bleeding risk offset the apparent benefit of anticoagulation in these patient groups.
Patients with pulmonary hypertension frequently have other risk factors for thromboembolism (eg, atrial fibrillation, severe left heart failure) that may warrant anticoagulation. These conditions are discussed separately. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization" and "Antithrombotic therapy in patients with heart failure".)
Digoxin — Digoxin therapy has been shown to have both beneficial effects and drawbacks:
●Digoxin improves the right ventricular ejection fraction of patients with group 3 PH due to COPD and biventricular failure . 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 . Verapamil is preferred for multifocal atrial tachycardia, unless there is concurrent left ventricular failure. (See "Control of ventricular rate in atrial fibrillation: Pharmacologic therapy".)
Exercise — Exercise training appears to be beneficial for patients with PH [20-24]. A crossover trial randomly assigned 30 patients who were receiving advanced therapy for severe PH to either an exercise training group or a sedentary control group . After 15 weeks, the mean six-minute walk distance increased in the exercise training group and decreased in the sedentary group (+96 versus -15 meters). Following crossover, the sedentary group also improved their mean six-minute walk distance (+74 meters). The improved distances exceed those described for all types of advanced therapy. Exercise training improved the WHO functional class and peak oxygen consumption. Despite the functional benefits, exercise training did not improve hemodynamic abnormalities, measured as the Doppler-derived pulmonary artery systolic pressure. This study suggests that skeletal muscle training may play a major role in the treatment of patients with PH.
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.
Overview — Advanced therapy is directed at the pulmonary hypertension (PH) itself, rather than the underlying cause of the PH. It includes treatment with prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, soluble guanylate cyclase stimulants 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 [1,25]. (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 PAH is shown in the figure (algorithm 1). (See 'Patient selection' below.)
Most patients initially receive monotherapy and are followed up within four to six weeks to evaluate the clinical and hemodynamic response. Patients with refractory PAH may require combination therapy, although data are limited. (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 . (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) [1,25]. 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. Extrapolation to other patient populations must be done with caution. 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).
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) . 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 .
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 . Despite this, it is occasionally considered for patients who remain WHO functional class III or IV (table 2) despite correction of hypoxemia and optimization of the underlying disease, especially if the severity of the PH is out of proportion to the severity of the parenchymal lung disease.
Advanced therapy for patients with group 3 PH should only be initiated at specialized centers and administered cautiously due to its potential to worsen ventilation-perfusion mismatch and increase hypoxemia, an effect that may be formulation- or disease-specific. As examples, small observational trials of patients with pulmonary fibrosis suggest that epoprostenol increases hypoxemia while inhaled nitric oxide, inhaled iloprost, and oral sildenafil do not appear to have this effect in the same population [26,27]. However, while oral sildenafil did not worsen hypoxemia in patients with group 3 PH due to pulmonary fibrosis, it was associated with worsened hypoxemia in patients with group 3 PH due to chronic obstructive pulmonary disease [26,28].
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 series of eight patients described a favorable response to intravenous epoprostenol in most patients , while another study reported that carefully selected patients can be transitioned from prostanoid infusion to oral bosentan . 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. (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) [1,9,25]. 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 toxic 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 [1,25]:
●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 [27-31]. (See "Inhaled nitric oxide in adults with pulmonary hypertension".)
●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 3).
●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 [1,10]. 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 .
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.
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 — Preferred agents include oral ambrisentan, bosentan, macitentan, sildenafil, tadalafil, or riociguat. (See 'Endothelin receptor antagonists' below and 'PDE5 inhibitors' below and 'Guanylate cyclase stimulant' below.)
Class III — Preferred agents include oral ambrisentan, bosentan, macitentan, sildenafil, tadalafil, or riociguat. As an alternative for patients with rapid progression or other markers of poor clinical prognosis, we occasionally initiate intravenous epoprostenol, intravenous or subcutaneous treprostinil, or inhaled iloprost (eg, echocardiographic evidence of severe right ventricular dilatation and dysfunction or the presence of a pericardial effusion). (See "Overview of pulmonary hypertension in adults", section on 'Prognostic factors' and 'Endothelin receptor antagonists' below and 'PDE5 inhibitors' below and 'Guanylate cyclase stimulant' below and 'Prostanoids' below.)
Class IV — Patients with severe PH who are WHO functional class IV should be treated with an intravenous prostanoid. Most clinicians consider intravenous epoprostenol as the preferred agent. Intravenous treprostinil is a reasonable alternative. Inhaled iloprost is an option for patients who decline or cannot receive intravenous therapy. (See 'Prostanoids' 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 [1,9,25]. It should consist of two agents with different mechanisms of action. Thus, agents from any two of the following three classes can be used in combination: prostanoids, endothelin receptor antagonists, and nitric oxide enhancer (PDE5 inhibitors or guanylate cyclase stimulant). Rarely, a third agent is used and importantly, a PDE5 inhibitor should not be used in conjunction with a guanylate cyclase stimulant because both stimulate nitric oxide.
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 [12,31-33]. 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 . 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).
A more recent 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 . 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.
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 3). 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 . 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 [35,36]. Loss of hypoxic vasoconstriction can worsen ventilation-perfusion mismatch and hypoxemia. CCBs may also be associated with deterioration of right ventricular (RV) function . (See "Major side effects and safety of calcium channel blockers".)
Prostanoids — Prostanoid formulations used to treat PH include intravenous epoprostenol (prostacyclin), intravenous treprostinil, subcutaneous treprostinil, inhaled treprostinil, and inhaled iloprost [37,38]. All of the prostanoid formulations have the limitations of a short half-life and a heterogeneous response to therapy.
Epoprostenol — Intravenous epoprostenol is the advanced therapy that has been best studied. It improves hemodynamic parameters, functional capacity, and survival in patients with IPAH [39-44]. 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 [45-48].
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 . 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 3).
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 .
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 [50,51].
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.
Epoprostenol may also be reimbursed for the treatment of patients with other types of PH, if the clinician can demonstrate that the PH is out of proportion to the associated disease (eg, parenchymal lung disease) or is the major cause of symptoms. This is also true for the other pharmacologic agents used for advanced therapy.
Treprostinil — Treprostinil 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 3). 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 [38,52-55]. 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 [56,57]. 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) [58,59]. In one trial, 349 patients with PAH, not on other advanced therapy, were randomly assigned to gradually increasing doses of treprostinil or placebo . 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 — Inhaled iloprost has theoretical advantages in targeting the lung vasculature and does not require intravenous administration (table 3). 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 . 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).
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 . 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:
●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) [62-66].
A meta-analysis of 12 randomized trials (1471 patients) evaluated the impact of the ERAs (bosentan or sitaxsentan) on patients with PAH . 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) . 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 [2,66,69-75]. 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 [70-72]. 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 . 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 associated with interstitial lung disease", section on 'Advanced therapy'.)
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 [69,77-79]. The mortality of bosentan-treated IPAH patients appears favorable compared to historical controls [61,78]. 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 . Bosentan improved symptoms, the six-minute walking distance, and the WHO functional class (figure 3).
●Another double-blind trial randomly assigned 185 patients with moderate group 1 PAH to receive bosentan or placebo twice daily for six months . 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) . 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). 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 .
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 [80-83]. 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 . 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 . 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.
Other — Tadalafil and vardenafil also appear 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 . 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 . 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 . 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.
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) . This trial (CHEST-1) is discussed separately. (See "Chronic thromboembolic pulmonary hypertension: Medical treatment".)
Patients with PAH (group 1) may also benefit from riociguat. 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) [88,89]. 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 (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).
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. Clinical studies have begun to evaluate combination therapy:
●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 [54,90]. 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 . 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 . 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) [58,92]. 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 . 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 bosentan – The benefits of adding sildenafil to bosentan therapy are more certain among patients with IPAH than those with scleroderma-associated PAH. A 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 . 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.
●Sildenafil added to iloprost – The combination of iloprost plus sildenafil may improve outcomes compared to either agent alone [95,96]. This was illustrated by a prospective cohort study of 73 patients with group 1 PAH who were receiving long-term inhaled iloprost . 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 . 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 . 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.
SPECIAL POPULATIONS — Select populations including pregnant women and those at high altitude require special consideration.
Pregnancy — Endothelin receptors (eg, bosentan) and guanylate cyclase stimulants (riociguat) are absolutely contraindicated in pregnancy (FDA category X). 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).
For women of childbearing age with known PAH, pregnancy should be avoided due to the risk of worsening pulmonary vascular hemodynamics. Consequently, estrogen-containing contraceptives should be avoided. Surgical (patient or partner) methods of contraception are preferred but dual barrier contraception is an acceptable alternative.
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 91 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 "Overview of pulmonary hypertension in adults", section on 'Surgical risk'.)
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 [99-109]. 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 [99,102]. However, procedure-related mortality may be as high as 15 to 20 percent [99,105]. 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 [106,110]. 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 .
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) , 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 .
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 . 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 [8,111,112]. Bilateral lung or heart-lung transplantation is the procedure of choice .
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 [106,113].
Guidelines for when to refer a patient for transplant evaluation are as follows :
●World Health Organization (WHO) functional class III or IV
●Mean right atrial pressure >10 mmHg
●Mean pulmonary arterial pressure >50 mmHg
●Cardiac index <2.5 L/min per m2
●Failure to improve functionally despite medical therapy
●Rapidly progressive disease
Hyperbilirubinemia is a late manifestation of pulmonary hypertension caused by chronic passive hepatic congestion and cardiac cirrhosis . 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 . 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 idiopathic pulmonary arterial hypertension (IPAH), hereditary PAH, drug-induced (eg, anorexigens) PAH, or group 4 PH, we suggest anticoagulant therapy (Grade 2B). (See 'Anticoagulation' above.)
•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 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. (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 prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, or guanylate cyclase stimulant (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 depends on the functional severity of disease (algorithm 1 and table 2). For patients who are WHO functional class II or III, oral agents rather than intravenous prostanoids are preferred (Grade 2B); options include oral endothelin receptor antagonists (ambrisentan, bosentan or macitentan), oral phosphodiesterase inhibitors (sildenafil or tadalafil), and oral guanylate cyclase inhibitors (riociguat). Alternative agents, particularly for patients with functional class III include 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). 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. (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. (See 'Progressive or refractory disease' above.)
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