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Treatment of pulmonary hypertension

Last literature review version 17.3: September 2009  |  This topic last updated: October 7, 2009   (More)

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 such as epoprostenol, endothelin receptor antagonists, phosphodiesterase 5 inhibitors such as sildenafil, or certain calcium channel blockers (eg, a dihydropyridine or diltiazem).

Assessment of disease severity, primary therapy, and advanced therapy are 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" and "Diagnostic evaluation of pulmonary hypertension" 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", section on 'Classification'.)

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

  • The functional significance of the PH is determined by measuring exercise capacity. From the exercise capacity, the patient's World Health Organization (WHO) functional class can be determined (table 2) [4].
  • Pulmonary artery systolic pressure and right ventricular function can be estimated by echocardiography, and then used to make a presumptive diagnosis of PH. Right heart catheterization must be performed to accurately measure the hemodynamic parameters and confirm that PH exists. However, right heart catheterization is often deferred until advanced therapy is indicated because it is an invasive procedure. (See 'Advanced therapy' below.)

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

PRIMARY THERAPY — 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, and drug use (table 1). (See "Overview of pulmonary hypertension", 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, including systolic dysfunction, diastolic dysfunction, and valvular heart disease (table 1). (See "Overview of pulmonary hypertension", 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 therapy in 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", section on 'Classification'.)

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

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

  • A trial randomly assigned 87 patients with COPD, a history of right ventricular dysfunction, and a PaO2 below 60 mmHg to receive either oxygen therapy for 15 hours per day or no oxygen therapy [5]. Oxygen therapy decreased five-year mortality (46 versus 67 percent), but the survival advantage did not appear until after 500 days of therapy. Pulmonary vascular resistance did not increase in the oxygen group, but increased in the group without oxygen (graph 1).
  • The Nocturnal Oxygen Therapy Trial (NOTT) compared continuous (19 hours per day) to nocturnal (12 hours per day) oxygen administration [6]. The population included 203 patients with COPD and either a PaO2 below 55 mmHg or a PaO2 below 60 mmHg with coexisting polycythemia, leg edema, or cor pulmonale on the electrocardiogram. The three-year mortality rate was lower with continuous oxygen than nocturnal oxygen (22 versus 42 percent) (graph 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, 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) [7].

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

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

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

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", 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 — Diuresis will diminish hepatic congestion and peripheral edema. However, it should be performed 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 either 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]. 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], hereditary PAH [1], drug-induced PAH [1], or group 4 PH. However, most of the evidence comes from observational studies of patients with IPAH [1,10-12]. 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 [13].

The anticoagulant of choice is warfarin, with a therapeutic goal of an International Normalized Ratio (INR) of approximately two.

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 nonvalvular atrial fibrillation" and "Indications for anticoagulation in heart failure".)

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

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

Exercise — Exercise training appears to be beneficial for patients with PH [16,17]. 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 [16]. 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 such as epoprostenol, endothelin receptor antagonists, phosphodiesterase 5 inhibitors such as sildenafil, or certain calcium channel blockers (eg, a dihydropyridine or diltiazem).

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) [1,18]. (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.

  • Group 1 PAH — Advanced therapy is often needed for patients with group 1 PAH because there are no effective primary therapies.
  • Group 2 PH — There are a few situations in which advanced therapy may be considered for group 2 PH (eg, patients with persistent PH due to mitral stenosis who have undergone mitral valve replacement). However, for most patients with group 2 PH, advanced therapy should be avoided because it may be harmful.

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

  • Group 3 PH — Advanced therapy is not approved by the United States Food and Drug Administration (FDA) for patients with group 3 PH. However, it but may be 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.

The tendency of advanced therapy to worsen ventilation-perfusion mismatch and increase hypoxemia in patients with group 3 PH may be formulation- and disease-specific. Inhaled nitric oxide, inhaled iloprost, and oral sildenafil have been shown in small studies to decrease pulmonary vascular resistance without increasing hypoxemia, while epoprostenol appears to decrease pulmonary vascular resistance but increases hypoxemia [19-21]. As an example, an open-label trial randomly assigned 16 patients with group 3 PH due to pulmonary fibrosis to receive oral sildenafil or intravenous epoprostenol [19]. Both treatments decreased pulmonary vascular resistance in one hour, but oral sildenafil was also associated with a decrease in shunt fraction and improved arterial oxygenation, while epoprostenol therapy resulted in increased pulmonary shunting and decreased arterial oxygenation.

  • Group 5 PH — 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 [22], while another study reported that carefully selected patients can be transitioned from prostanoid infusion to oral bosentan [23].

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 ) [1].

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 [8]. 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 [24]:

  • 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 (table 3).
  • Inhaled nitric oxide administered at 10 to 20 ppm is selective for the pulmonary vasculature. Thus, it is often better tolerated than the intravenous agents (table 3) [25-29]. (See "Inhaled nitric oxide in adults with pulmonary hypertension".)

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 [1,9]. 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 [1].

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 [10,30-32]. 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 [10]. 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 [32]. 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 [33]. 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 [34,35]. Loss of hypoxic vasoconstriction can worsen ventilation-perfusion mismatch and hypoxemia. CCBs may also be associated with deterioration of right ventricular (RV) function [33]. (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, and inhaled iloprost [36,37]. All of the prostanoid formulations have the limitations of a short half-life and a heterogeneous response to therapy.

Epoprostenol — Intravenous epoprostenol (Flolan) is the advanced therapy that has been best studied. It improves hemodynamic parameters, functional capacity, and survival in patients with IPAH [38-42]. 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 [43-46].

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 [40]. 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)(calculator 1).

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 [47].

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 [48].

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 or greater than 30 mmHg with exertion, 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 (Remodulin) can be given intravenously or subcutaneously, although subcutaneous administration is uncommon due to severe pain at the injection site (table 3). Inhaled treprostinil (Tyvox) has more recently been approved, specifically for patients with group 1 PAH who are WHO functional class III (table 2).

Treprostinil improves hemodynamic parameters, symptoms, exercise capacity, and survival in patients with group 1 PAH [37,49-51]. 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 [52,53]. Reciprocally, epoprostenol can be given if the desired effect is not achieved with treprostinil.

Iloprost — Inhaled iloprost (Ventavis) 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 [54]. 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 — Endothelin-1 is a potent vasoconstrictor and smooth muscle mitogen. High concentrations of endothelin-1 have been recorded in the lungs of patients with both IPAH and other etiologies of group 1 PAH, including scleroderma and congenital cardiac shunt lesions [55]. Endothelin receptor antagonism emerged as an initial therapy for group 1 PAH in the late 1990s.

A meta-analysis of five randomized trials (482 patients) evaluated the impact of endothelin receptor antagonists (bosentan or sitaxsentan) on patients with PAH [56]. The endothelin receptor antagonists improved exercise capacity, dyspnea, and hemodynamic measures (pulmonary artery pressure, pulmonary vascular resistance, and cardiac index).

Bosentan — Bosentan (Tracleer), a nonselective endothelin receptor antagonist, improves hemodynamics and exercise capacity in patients with group 1 PAH and delays clinical worsening (table 3) [57-60]. The mortality of bosentan-treated IPAH patients appears favorable compared to historical controls [55,59]. Mortality has not been studied in patients with other types of PH. The major advantage of bosentan is its oral administration.

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, 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 [58]. Bosentan improved symptoms, the six-minute walking distance, and the WHO functional class (graph 3).
  • Another double-blind trial randomly assigned 185 patients with moderate group 1 PAH to receive bosentan or placebo twice daily for six months [2]. The bosentan was administered at a dose of 62.5 mg twice daily for four weeks and then increased to 125 mg twice daily. Bosentan improved pulmonary vascular resistance and the mean six-minute walk distance, although the latter was not statistically significant. A limitation of this trial was its failure to follow the principle of intention to treat.

Selective agents — Ambrisentan (Letaris) and sitaxsentan (Thelin) are selective type A endothelin-1 receptor antagonists that are administered orally. The evidence suggests that ambrisentan [61,62] or sitaxsentan [63-66] improves exercise tolerance, WHO functional class, hemodynamics, and quality of life in patients with PAH. Ambrisentan is available in the United States. Sitaxsentan is not yet available in the United States, but is available in Europe. Both agents are dosed once daily.

Adverse effects — The main adverse effect of the endothelin receptor antagonists is hepatotoxicity, which appears to be more severe at higher doses. Ambrisentan may be a safe and effective alternative for patients who previously discontinued bosentan or sitaxsentan due to abnormal liver function test results according to one observational study [67], suggesting the hepatotoxicity may differ among the endothelin receptor antagonists. Liver function tests should be closely monitored during therapy and endothelin receptor antagonists should be avoided in patients with moderate or severe hepatic dysfunction, or in conjunction with cyclosporine or glyburide.

Peripheral edema is the most common side effect that requires attention. Mild cases can be managed with diuretics, but more severe cases warrant discontinuation of the medication. Endothelin receptor antagonists are also potent teratogens, requiring meticulous contraception if used by women who have childbearing potential.

PDE5 inhibitors — Sildenafil (Viagra, Revatio), tadalafil (Cialis, Adcirca), and vardenafil (Levitra) 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 improves pulmonary hemodynamics and exercise capacity in patients with group 1 PAH [68-71]. However, its effect on mortality has not been adequately evaluated. An illustrative trial randomly assigned 278 patients with group 1 PAH to receive sildenafil (20, 40, or 80 mg) or placebo three times daily for 12 weeks [70]. 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. The effect of sildenafil on patients with other types of PH is uncertain.

Tadalafil also appears to improve outcomes in patients with group 1 PAH. A trial randomly assigned 405 such patients to receive tadalafil (2.5, 10, 20, or 40 mg) or placebo once daily for 16 weeks [72]. 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.

There appear to be substantial differences in the effects of various PDE5 inhibitors. This was illustrated in a randomized trial that compared the acute effects of sildenafil, tadalafil, and vardenafil in patients with IPAH [73]. The three medications varied substantially in their rate of onset, pulmonary vascular selectivity, and effect on oxygenation. Only sildenafil was associated with improved arterial oxygenation.

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 plus either epoprostenol or treprostinil — Limited experience suggests that bosentan can be used safely and effectively added to epoprostenol or treprostinil therapy [51,74]. A trial randomly assigned 22 patients with group 1 PAH who were receiving epoprostenol to have either bosentan or placebo added for 16 weeks [74]. 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.
  • Sildenafil plus 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 [75]. 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 plus 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 [76]. 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.
  • Iloprost plus sildenafil — The combination of iloprost plus sildenafil may improve outcomes compared to either agent alone [77,78]. This was illustrated by a prospective cohort study of 73 patients with group 1 PAH who were receiving long-term inhaled iloprost [77]. 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 [79]. 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 [80]. 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.

Selection of an agent — The number of pharmacologic agents available for advanced therapy continues to increase, making selection of an appropriate agent increasing 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) [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. 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]. 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.

ATRIAL SEPTOSTOMY — Creation of a right-to-left shunt by atrial septostomy has been performed in some patients with syncope or severe right heart failure in an attempt to increase systemic blood flow by bypassing the pulmonary vascular obstruction [81-89].

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 [81,84]. However, procedure-related mortality may be as high as 15 to 20 percent [81,87]. 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 [88,90]. It may also be considered in patients who have signs of impaired systemic blood flow (such as syncope) due to reduced left heart filling. Stepwise balloon dilatation is the procedure of choice [8].

Patients with the most advanced PAH appear more likely to die or get worse with atrial septostomy [88]. This includes patients with markedly elevated mean right atrial pressure (eg, greater than 20 mmHg) [8], extremely low cardiac output, and a resting arterial oxyhemoglobin saturation less than 80 percent. In addition, older age and impaired renal function were associated with early adverse outcomes in one series [81].

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 [8,91]. Bilateral lung or heart-lung transplantation is the procedure of choice [8].

The timing of transplantation is critical, since survival from severe IPAH refractory to medical therapy is poor and the availability of suitable organs for transplantation is limited. The three year survival of patients who had a lung or heart-lung transplant for IPAH is approximately 50 percent [88,92].

Guidelines for when to refer a patient for transplant evaluation are as follows [93]:

  • 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 [81]. 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 [94]. 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 therapy should be directed at the underlying cause of the PH (see 'Primary therapy' above. In addition, the need for diuretic, oxygen, and anticoagulant therapy should be assessed:

  • For patients with fluid retention due to PH, we suggest diuretics (Grade 2B). (See 'Diuretics' 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. Advanced therapy is treatment that is directed at the PH itself, rather than the underlying cause of the PH. (See 'Patient selection' 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.)

All patients selected for advanced therapy should undergo right heart catheterization and most of those who have group 1 PAH should also undergo vasoreactivity testing (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, or phosphodiesterase 5 inhibitors (Grade 2C). Patients who respond to such therapy should be reassessed after three to six months of treatment. (See 'General approach' 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). Non-CCB agents include prostanoids, endothelin receptor antagonists, and phosphodiesterase 5 inhibitors. (See 'General approach' above.)

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

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