PCCU Volume 17, Lesson 20

bosentan; endothelin; epoprostenol; prostacyclin; pulmonary arterial hypertension

Abbreviations

CCB = calcium channel blocker; cGMP = cyclic guanine monophosphate; ET-A = endothelin-A; FDA = Food and Drug Administration; INR = international normalized ratio; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; PPH = primary pulmonary hypertension; WHO = World Health Organization

Tremendous progress has been made in developing specific therapies for primary pulmonary hypertension (PPH) and pulmonary arterial hypertension (PAH) due to underlying scleroderma and CREST syndrome (calcinosis cutis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia). These previously refractory diseases have been clearly demonstrated to respond to these disease mechanism–based approaches. The advent of continuous IV epoprostenol (Flolan; Glaxo-Wellcome; Research Triangle Park, NC), followed by bosentan (Tracleer; Actelion Ltd; Allschwil, Switzerland) and treprostinil (Remodulin; United Therapeutics; Research Triangle Park, NC), as well as several other investigational candidates, are making an impact.

Definition and Classification

PPH is a rare disorder with a female predominance. Without therapy, the prognosis is poor, with an estimated median life expectancy of 2.8 years from the time of diagnosis.¹ PPH was defined by the National Institutes of Health registry working-group as a mean pulmonary artery pressure of >25 mm Hg at rest or 30 mm Hg with exercise and no proven underlying etiology.² Recently, the World Health Organization (WHO) symposium on PPH defined this entity as a systolic pulmonary artery pressure >40 mm Hg with a tricuspid regurgitation jet of 3 to 3.5 m/s by Doppler3 in the absence of secondary causes. It is of paramount importance to distinguish PAH from other types of pulmonary hypertension (PH). The WHO classification of PH is outlined in Table 1.³ PH due to other causes is thought to differ pathophysiologically from PAH, and is generally managed differently, always with a focus on the underlying cause. We will focus on newer forms of therapy used specifically for PAH. Therapy for other forms of PH will not be addressed. Conventional treatment for PAH includes the potential use of calcium channel blocker (CCB) therapy, anticoagulation, oxygen, digoxin, and diuretics. These will be very briefly addressed followed by a discussion of newer therapeutic modalities.

Conventional Therapy

When PH is diagnosed, it is important to determine both the cause and the severity. These will dictate the appropriate approach to therapy. Vasoconstriction is important in the pathogenesis of PAH but not the only critical factor. This is consistent with the finding that high-dose CCBs have been proven beneficial only in a minority of patients with PPH referred to as responders. Such patients usually show an acute response to a short-acting vasodilator challenge during right-heart catheterization.

CCBs (nifedipine, diltiazem, and amlodipine) are generally used. Treatment should be started with a low dose (eg, 30 mg of nifedipine or 90 mg of diltiazem per day), titrated up to higher doses as tolerated. It has been suggested that mortality may be improved in patients receiving CCB therapy if high doses can be tolerated. In the studies by Rich et al,⁴ these patients were discharged taking doses as high as 720 mg/d of diltiazem or 240 mg/d of nifedipine. It appears unusual, however, for patients to tolerate such high doses.

Sluggish blood flow and an imbalance of prostacyclin and thromboxane may create a procoagulant environment leading to in situ microvascular thrombosis.⁵ In addition, patients with decreased pulmonary vascular reserve could have significant hemodynamic deterioration even from a minor thromboembolic event. Patients with PAH should receive anticoagulant therapy unless it is contraindicated. It appears that chronic anticoagulation improves survival in patients with PPH.⁴ No evidence-based research exists to guide anticoagulation or the international normalized ratio (INR) goal; however, experts recommend warfarin with an INR goal of 1.5 to 2.5.⁶

Oxygen requirements should be assessed at rest and during exercise, and oxygen should be titrated to achieve a saturation of >90% at all times. Digoxin may be of benefit in the appropriate clinical setting, particularly if there is associated left ventricular systolic dysfunction or atrial fibrillation. Otherwise, its precise role in the setting of right ventricular failure from PAH is otherwise unclear. No randomized, controlled data exist to support the use of digoxin in PAH. Diuretics are used to help with lower-extremity edema and ascites.

Epoprostenol

Epoprostenol (prostacyclin, prostaglandin I₂, Flolan) represents the most significant advance in the treatment of PAH. It is not a new therapy, but is the cornerstone of treatment for patients with severe disease. A survival benefit was first observed in a study comparing patients who received prolonged continuous IV epoprostenol with historical control subjects from the National Institutes of Health PPH registry who received standard therapy.⁷ The landmark study that revolutionized the treatment of PAH compared continuous IV epoprostenol plus conventional therapy with conventional therapy alone in patients with New York Heart Association (NYHA) class III and IV symptoms. The IV infusion of epoprostenol resulted in improved exercise capacity, quality of life, survival, and hemodynamics at 3 months.⁸ Subsequently, a similarly conducted clinical trial demonstrated improved exercise capacity and hemodynamics in patients with PAH related to the scleroderma spectrum of diseases.⁹ These studies led to US Food and Drug Administration (FDA) approval for these indications.

Although it is a vasodilator, epoprostenol appears to result in smooth-muscle remodeling, as well as to reduce platelet aggregation and possibly impart anti-inflammatory and inotropic effects. Therapy is usually started in the hospital via a dedicated peripheral IV line and administered by a pump that can accommodate the low infusion rate of approximately 60 to 80 mL of epoprostenol delivered in a 24-h period. The starting dose is generally 2 ng/kg/min. It is titrated up by 1-ng/kg/min increments two to three times daily in the hospital and once to twice per week in the outpatient setting (Table 2). Before the patient is discharged from the hospital, central IV access is placed for chronic infusion, generally by means of a Hickman-type catheter tunneled under the skin into the subclavian vein. Education is crucial prior to discharge, with emphasis on pump operation, mixing the medication, and care of the central line. A family member or close friend should also be instructed.¹⁰ Occasionally, patients cannot effectively learn the required information, and they cannot receive this therapy unless a family member can be unequivocally relied upon to do the daily care. Dosing is guided by clinical symptoms, exercise testing, transthoracic echocardiography, oxygenation, and subjective dyspnea score. Right-heart catheterization is performed when clinically indicated, although some centers elect to perform it yearly as well. The usual adverse effects are hypotension, jaw pain, flushing/erythema, nausea, and diarrhea. More long-term side effects include skin rash and chronic lower-extremity pain. IV epoprostenol remains the mainstay of therapy for severe PAH. As with any unusual disease and therapy, patients with PAH requiring epoprostenol are best managed at medical centers handling large numbers of these patients. Frequent telephone contact by dedicated nurses are essential for dosing and monitoring side effects. Unfortunately, epoprostenol is expensive, costing as much as $50,000 to $100,000 per year. Newer therapies may offer increased hope of weaning patients off of epoprostenol.

Other Prostacyclins

Another advance in the treatment of PAH has been the advent of treprostinil (Remodulin). This stable prostacyclin analogue can be administered subcutaneously, but is administered by continuous infusion via a central catheter because of its short half-life. Catheter-related infections can also occur but appear less likely to cause bacteremia compared with IV epoprostenol. Treprostinil was recently approved by the FDA for the treatment of patients with PPH, as well as PAH associated with connective tissue disease or congenital systemic-to-pulmonary shunts with class II, II, or IV PAH symptoms. A 12-week, double-blind, placebo-controlled, multicenter trial demonstrated improved exercise capacity and hemodynamics.¹¹ Therapy is initiated at about 1.25 ng/kg/min and the dose is escalated by 0.625-ng/kg/min increments twice weekly until limited by side effects. Infusion site pain is common. The administration of treprostinil is less cumbersome than IV epoprostenol, and the pump used is smaller. The major adverse effect of treprostinil is pain at the subcutaneous injection site. This may prevent necessary dose increases.

Beraprost is an oral prostacyclin analog. It is not available in the United States. While an Asian and European study has appeared promising in PAH, a US study was discontinued early.¹² Iloprost is an inhaled prostacyclin analog approved for use in Europe. This is based on the results of the Aerosolized Iloprost Randomized (AIR) study, a European, randomized, controlled trial involving a total of 203 patients with NYHA class III or IV PAH. In this trial, iloprost was found to improve exercise capacity, improve functional status, and prevent deterioration in hemodynamics compared with placebo.¹³ Based on the drug’s relatively short half-life, 6 to 12 inhalations per day are needed, which is its major disadvantage. At this time, iloprost is not FDA-approved.

Bosentan

Endothelin-1 is a paracrine vasoactive peptide produced by endothelial cells in response to hypoxia, ischemia, and shear stress. It is a very potent vasoconstrictor. It is overexpressed in the plasma and lung tissue of patients with PPH and scleroderma. Its actions are mediated by endothelin-A (ET-A) and endothelin-B receptors located in the pulmonary vasculature and implicated in pulmonary vasoconstriction, inflammation, proliferation, and bronchoconstriction. Activation of endothelin-B receptors results in the production of nitric oxide and vasodilation. Activation of ET-A receptors results in vasoconstriction and smooth-muscle growth.

Bosentan is an oral dual endothelin receptor antagonist. It was first shown to improve exercise capacity and hemodynamics in a small randomized, controlled trial of patients with PPH and NYHA functional class III status.¹⁴ Next, the Bosentan Randomized trial of Endothelin Antagonist THErapy (BREATHE), a study of 213 patients with NYHA class III status, led to FDA approval for treatment of PAH, making it the first approved oral therapy for PAH. Bosentan improved exercise capacity and prolonged the time to clinical worsening in patients with either severe PAH or PH associated with connective-tissue disease.¹⁵ The initial dose of bosentan is 62.5 mg bid for 4 weeks. If well tolerated, the dose is increased to 125 mg bid. Liver function testing should be performed monthly, as dose-dependent hepatic dysfunction may occur. Bosentan therapy should not be used in patients with significant liver disease. Patients with previously abnormal liver function should be evaluated carefully on a case-by-case basis. The drug is, however, generally well tolerated. While cheaper than epoprostenol, it is still expensive, but it could in theory reduce or delay the need for epoprostenol. Bosentan is approved for use in patients with class III and IV symptoms. Future data may suggest whether earlier therapy is beneficial.

Nitric Oxide

When inhaled, nitric oxide acts as a selective pulmonary vasodilator. It is rapidly metabolized when it reaches the blood, which limits its effect to the lung and prevents systemic side effects. Because of technical difficulties with administering this gas, it is generally not used in the outpatient setting. It is often used for predicting the response to oral vasodilator therapy during right-heart catheterization in patients with PAH.¹⁶ It has been used as a bridge to lung transplantation in patients not responding to epoprostenol.¹⁷

Atrial Septostomy

Atrial septostomy is rarely performed. The procedure can be considered in patients with severe right heart failure and syncope. It may be used as a palliative measure or as a bridge to lung transplantation. The procedure is performed percutaneously; a defect is created in the atrial septum and sequentially dilated in an attempt to unload the right ventricle.¹⁸ Arterial desaturation is expected after the procedure, but it is difficult to predict which patients will benefit and experience increased cardiac output. Procedure-related mortality is a significant concern. Achieving a shunt of ideal size is difficult, and very severe hypoxemia can result.

Transplantation

Before the advent of epoprostenol, lung transplantation was the only option for patients with advanced PAH. There are no data comparing the effectiveness of transplantation and medical therapy. Transplantation should be considered for patients with poor functional status and poor predicted survival. A primary concern is the timing of the operation. Lung or heart-lung transplantation may be performed. If left ventricular function is preserved, heart transplantation generally is not needed.¹⁹ Congenital heart disease is addressed either with repair of the defect and bilateral lung transplantation or with heart-lung transplantation. There have not been any reported PPH recurrences after transplantation, but a higher incidence of bronchiolitis obliterans has been observed in these patients. Patients with progressive right ventricular failure despite maximal therapy including IV epoprostenol should be considered candidates for transplantation. It remains unclear whether patients should proceed to transplantation earlier or wait as long as possible to receive a transplant, thereby risking the possibility of more substantial deterioration and in turn potentially increasing the risk of the transplant procedure.

Choice of Therapy

WHO Class I and II

Patients with class I and II symptoms usually begin CCB treatment if they are found to be responsive to vasodilators during right-heart catheterization (Fig 1). Bosentan or treprostinil should be considered if clinical worsening is observed, or if the degree of response to vasodilators is suboptimal. It is not clear which should be tried first, but bosentan is an oral agent and is thus less cumbersome than treprostinil. Some consider it reasonable for a CCB and anticoagulation to be prescribed for nonresponders with class I symptoms; however, there are no data to support this approach. Nonresponders with class II symptoms should be considered for treatment with bosentan or treprostinil. Future studies should clarify the potential benefit of bosentan in Class II patients.

Figure 1. Algorithm for the therapeutic approach to PAH. For a more detailed discussion, see text. Modified from Tapson VF, McLaughlin VV, Robbins IM, Gaine SP, Rubin LJ. Adv Pulm Hypertension 2002; 1:1.

*Warfarin therapy should be undertaken if deemed safe. The generally accepted INR range is 1.5 to 2.5. Diuretics, digoxin, and oxygen are utilized on an individual basis.

†Right-heart catheterization is essential in determining initial and sometimes subsequent therapy. This, together with WHO classification, echocardiographic data, and exercise testing, is used in treatment decisions. The rate at which symptoms are progressing may play a role in the level of aggressiveness with therapy. The terms IIIa and IIIb denote early, stable class III patients and advanced class III patients, respectively.

‡Unresponsive class I–II patients are individualized; one option is enrollment in clinical research trials as in class IIIa. For vasoreactive patients, CCBs alone may be appropriate when the vasodilator response is exceptional.

§In those who respond to CCBs, but suboptimally, or who respond but worsen clinically, oral bosentan (Tracleer) should be strongly considered. This drug is approved for WHO class III–IV patients. There is no clear consensus on the use of this drug as it relates to presence or absence of vasodilator response. Bosentan should not be used in setting of liver disease.

||Treprostinil (Remodulin) is an investigational subcutaneous prostacyclin analogue (approvable letter for class II–IV PAH), and iloprost (not available in the United States) is an investigational inhaled prostacyclin analogue. Other investigational agents may be considered in stable class II–III patients in the setting of clinical research trials.

¶Epoprostenol (Flolan) is the FDA-approved intravenous prostacyclin for class III–IV patients and is the most effective form of therapy in these individuals. Bosentan is appropriate for most class IIIa patients before epoprostenol is considered, but in class IIIb–IV patients, epoprostenol is preferred. The distinction between class IIIb and class IV is essentially arbitrary as these patients are generally handled in the same manner. The relative roles of bosentan and treprostinil are not as well defined in this more severely ill population, and the latter awaits final approval. Combined therapy with the addition of bosentan and/or sildenafil could be considered but would be investigational; clinical trials are ongoing or planned.

#Very few centers have extensive experience with atrial septostomy. When used, this is intended to serve as a bridge to transplantation. The timing of lung transplant referral is individualized at different centers. This depends in part upon the waiting time at the listing institution.

WHO Class III and IV

Class III encompasses the majority of patients with PAH, thus including a broad range of symptoms. Class III patients with less severe, stable symptoms are sometimes referred to as class IIIa. CCB therapy is usually initiated in these patients if they are vasodilator responders at catheterization. Bosentan or treprostinil can also be considered for these patients. Nonresponders with class IIIa symptoms should receive bosentan or treprostinil. In these patients, epoprostenol can be considered if deterioration is noted. In class III patients with more advanced symptoms (sometimes referred to as class IIIb) and in class IV patients, epoprostenol treatment should be instituted. It is feasible that the addition of bosentan would be of benefit in patients whose symptoms are advanced enough to require epoprostenol, and this is under investigation.

Future Therapy

Phosphodiesterase-5 is an enzyme abundant in both lung and penile tissue that hydrolyzes cyclic guanine monophosphate (cGMP). Blocking this enzyme increases cGMP levels, resulting in vasodilation. There is emerging evidence that this phosphodiesterase-5 inhibitor may be effective for PAH.²⁰ A large clinical trial with sildenafil is underway in PAH patients.

Selective ET-A receptor antagonism might offer an advantage over dual endothelin receptor antagonism. An open-label pilot study suggested that the selective ET-A receptor antagonist sitaxsentan may be effective in treating PAH.²¹ This drug, and another selective ET-A receptor antagonist, ambrisentan, will undergo further study.

The beneficial effects of the new medications for PAH are mediated through different mechanisms and pathways. Epoprostenol, treprostinil, and iloprost work through cyclic adenosine monophosphate; sildenafil and nitric oxide act via cGMP; and bosentan and sitaxsentan antagonize endothelin receptors. Combining medications that work through different pathways may yield additive or synergistic effects. Several clinical trials will evaluate the effects of combination therapy.
New therapy targeted against endothelial proliferation is under way in experimental models using elastase inhibitors.²² Experiments on arginine and citruline to generate nitric oxide in vivo are also under way. Finally, the discovery of a region on chromosome 2 encoding bone morphogenetic protein receptor type 2 associated with familial PPH and many cases of sporadic PPH may pave the way for more therapeutic options.²³

Conclusions

The future for patients with PAH appears much more optimistic than ever before. While progression of the disease to death or the need for transplantation still occurs, new therapeutic modalities, potentially used in combination, offer more hope. Referral to experienced PAH centers for guidance in management is crucial.

New Treatment for Pulmonary Arterial Hypertension

Objectives

Key words

Abbreviations