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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, 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:
Once the severity of the patient's pulmonary hypertension has been determined, primary therapy can be considered.
PRIMARY THERAPY — 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, chronic hemolytic anemia, 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:
Thus, continuous oxygen therapy improves survival in patients with COPD and a PaO2 below 55 mmHg, despite seemingly mild effects on pulmonary hemodynamics. 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), 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'.)
Primary therapy is directed at the underlying cause.
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 [1,12-14]. 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 "Antithrombotic therapy to prevent embolization in atrial fibrillation" and "Indications for antithrombotic therapy in heart failure".)
Digoxin — Digoxin therapy has been shown to have both beneficial effects and drawbacks:
Exercise — Exercise training appears to be beneficial for patients with PH [19-23]. 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.
ADVANCED THERAPY — Advanced therapy is directed at the PH itself, rather than the underlying cause of the PH. It includes treatment with prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, or, rarely, certain calcium channel blockers. Guanylate cyclase stimulants are not yet available.
Patient selection — Advanced therapy is considered for patients who have evidence of persistent PH and a World Health Organization (WHO) functional class II, III, or IV despite adequate primary therapy (table 2) [1,24]. (See 'Primary therapy' above.)
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 administered advanced therapy only at specialized centers where clinicians are experienced in the evaluation and management of patients with PH.
There are special considerations for each group of pulmonary hypertension.
General approach — Patients with PH who are selected for advanced therapy should undergo an invasive hemodynamic assessment prior to the initiation of advanced therapy. It is recommended that patients with group 1 PAH also undergo a vasoreactivity test with intravenous adenosine, intravenous epoprostenol, or inhaled nitric oxide (patients with IPAH and anorexigen-induced PAH are the most likely to respond) .
Patients with a positive vasoreactivity test can be given a trial of oral calcium channel blocker therapy with a dihydropyridine or diltiazem. In contrast, patients with a negative vasoreactivity test require advanced therapy with a prostanoid, endothelin receptor antagonist, or phosphodiesterase 5 inhibitor. Combination advanced therapy may be appropriate in refractory cases, although data are limited. Some patients are refractory to all medical interventions. In such cases, lung transplantation or creation of a right to left shunt by atrial septostomy may be considered . An algorithm for advanced therapy is shown in the figure (algorithm 1).
The discussion that follows will address the following issues: the acute vasoreactivity test; the various therapeutic agents that are available to treat PH; and the clinical trials that support the use of the various agents (most included only patients with group 1 PAH). Finally, we describe selection of a pharmacologic agent.
Vasoreactivity test — It is recommended that patients with group 1 PAH undergo a vasoreactivity test (patients with IPAH and anorexigen-induced PAH are the most likely to respond). This involves the administration of a short-acting vasodilator and then measurement of the hemodynamic response using a right heart catheter. Agents commonly used for vasoreactivity testing include epoprostenol, adenosine, and inhaled nitric oxide :
An acute vasoreactivity 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 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".)
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 [12,37-39]. 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 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.
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 [41,42]. 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 [43,44]. 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 [45-49]. 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 [50-53].
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, 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 [55,56].
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:
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 uncommon 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 [44,57-60]. 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 [61,62]. Reciprocally, epoprostenol can be given if the desired effect is not achieved with treprostinil.
Oral formulations of treprostinil are not commercially available, but have been examined in clinical trials [63,64]. As an example, 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 statistically significant but not clinically impressive 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:
Among these agents, only bosentan (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) [67-71]. Macitentan is not yet commercially available in the United States.
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 [2,71,74-80]. 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.
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 (table 3) [74,81-83]. The mortality of bosentan-treated IPAH patients appears favorable compared to historical controls [66,82]. 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):
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 [75-77]. 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 PAH. 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'.)
Macitentan — Macitentan is an oral agent with dual endothelin receptor antagonist function that has been studied in patients with idiopathic and connective tissue disease-related PAH. One randomized trial compared oral macitentan to placebo in 250 patients with moderate to severe PAH (WHO functional class II-IV) . 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. This drug is not yet commercially available in the United States.
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) .
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.
Guanylate cyclase stimulant — Stimulators of the nitric oxide receptor, soluble guanylate cyclase (sGC) have 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, not yet available, that has been studied as a therapy for patients with PAH (group 1) and chronic thromboembolic pulmonary hypertension (CTEPH; group 4) [93-96]. Results from multicenter randomized placebo-controlled trials of riociguat reported benefit in patients with PAH (PATENT-1) and inoperable CTEPH (CHEST-1) [95,96]. PATENT-1 studied 443 patients with symptomatic PAH. 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). Similar improvements were reported in patients with inoperable CTEPH (CHEST-1). This trial is discussed separately. (See "Chronic thromboembolic pulmonary hypertension: Medical treatment", section on 'Outcomes'.)
This agent, which is not yet available, holds promise as a therapy for patients with PAH and inoperable CTEPH, pending approval by the United States Federal Drug Administration.
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:
Selection of an agent — The number of pharmacologic agents available for advanced therapy continues to increase, making selection of an appropriate agent increasingly complex. The following strategy categorizes the initial choice of agents according to WHO functional class (table 2). It is just one reasonable approach to selecting an agent. However, it is supported by moderate and high quality evidence. It is also consistent with the algorithm developed during the 4th World Symposium on Pulmonary Hypertension (algorithm 1) . Clinicians with expertise in the treatment of patients with advanced PH may deviate from this algorithm based on their clinical experience.
Combination therapy is appropriate in cases refractory to monotherapy [1,9]. It should consist of two agents with different mechanisms of action. In other words, it should consist of agents from any two of the following three classes: prostanoids, endothelin receptor antagonists, and PDE5 inhibitors.
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.
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 [106-116].
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 [106,109]. However, procedure-related mortality may be as high as 15 to 20 percent [106,112]. 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 [113,117]. 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 [8,118,119]. 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 [113,120].
Guidelines for when to refer a patient for transplant evaluation are as follows :
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".)
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