Pharmacotherapy for Idiopathic Pulmonary Arterial Hypertension During the Past 25 Years

Anna M. Hackman, Pharm.D.; Thomas E. Lackner, Pharm.D., FASCP


Pharmacotherapy. 2006;26(1):68-94. 

In This Article

Treatment Options

A MEDLINE search was conducted by coupling the key search term idiopathic pulmonary arterial hypertension with each pharmacologic agent used in the treatment of IPAH. Because most of the advances in treating IPAH have occurred since the NIH patient registry was begun in 1981, the search was limited to the period from January 1981-September 2005. In addition, information regarding upcoming and ongoing IPAH clinical trials was retrieved through searches of the NIH medical research Web site ( and the United States Food and Drug Administration (FDA) Center for Drug Evaluation and Research Web site (

Identified primary research articles, as well as primary research referenced by IPAH review articles, were examined for relevance to the pharmacotherapy for IPAH. Articles were excluded from the literature review if they pertained to studies of pharmacologic agents in the treatment of conditions other than IPAH (e.g., bosentan for the treatment of systemic hypertension), if the studies were conducted in animals, if the articles were not in English, and if the research was performed in neonatal populations, as this group can be affected by persistent pulmonary hypertension of the newborn, which has a different etiology and treatment options than those of IPAH.

The literature search identified 365 articles, of which 178 met the stated selection criteria and were reviewed. Seventy-five articles were deemed appropriate for use in developing this review. These articles consisted of 56 primary research articles, 5 review articles, 4 case reports, 3 consensus panel statements, 4 package inserts, 1 report, 1 editorial, and 1 letter.

Warfarin has been shown to improve survival in patients with IPAH, resulting in a significant increase in the number of patients surviving to 3 years.[2,17] Dilated right heart chambers and sluggish pulmonary blood flow, in addition to the characteristic finding of in situ thrombosis in this disease, are indications for anticoagulation in patients with IPAH. Because these patients have a compromised pulmonary vasculature with little indicated, indefinite therapy with warfarin (goal ability to dilate or recruit unused vessels, even international normalized ratio [INR] of 1.5-2.5) minor pulmonary obstruction by a thrombus can is recommended in adults and children with be life threatening. Therefore, unless contra-right-sided heart failure or a hypercoagulable state with IPAH. Anticoagulation with warfarin also should be considered in children with IPAH without right-sided heart failure or a hypercoagulable state; if such children are younger than 5 years of age, the dosage should be adjusted to maintain a lower target INR.[10]

During diagnostic testing for IPAH, patients are typically given an acute vasodilator challenge with use of a short-acting pulmonary vasodilator (e.g., intravenous epoprostenol, inhaled nitric oxide, or intravenous adenosine). Patients who respond with a decrease in mean pulmonary artery pressure of at least 10 mm Hg over baseline and an increased or unchanged cardiac output are considered responders. For these patients, calcium channel blockers such as nifedipine or diltiazem are an appropriate and effective first-line therapy, in the absence of right-sided heart failure.[17,18]

Results of a prospective, open-label, parallel-group study showed a 94% 5-year survival rate for responders treated with high-dose calcium channel blockers compared with a 55% survival rate among nonresponders treated with conventional therapy (digoxin, diuretics, and/or warfarin), and a 38% survival rate in the historical control group.[17] Unfortunately, only approximately 25% of all patients with IPAH experience a positive acute vasodilator trial and are able to benefit from high-dose calcium channel blocker therapy. Indeed, in patients with fixed or late-stage IPAH, the only treatment effect of high-dose calcium channel blockers is systemic hypotension, causing a decrease in an already compromised cardiac output, with potentially disastrous consequences. In addition, the high doses of nifedipine (up to 180 mg/day) and diltiazem (up to 720 mg/day) necessary to produce beneficial effects in patients with IPAH, and the nonselectivity of calcium channel blockers for the pulmonary vasculature, may result in dose-limiting systemic hypotension even in patients for whom calcium channel blocker therapy is an option.[10,17]

Although diuretics can reduce fluid overload associated with right-sided heart failure, the right ventricle is highly dependent on preload. Cautious use of diuretics must be exercised to avoid a deleterious decrease in cardiac output with resultant systemic hypotension, syncope, and renal insufficiency.[10] Various diuretics have been used to treat clinical signs of right-sided heart failure in patients with IPAH, including furosemide, hydrochlorothiazide, metolazone, and bumetanide. A less aggressive, potassium-sparing diuretic such as triamterene, however, may be the preferred agent, particularly in early stages of the disease or with concomitant use of digoxin. In patients not receiving digoxin, spironolactone is an attractive agent because of its aldosterone-inhibiting properties in the setting of sympathetic nervous system and renin-angiotensin-aldosterone system activation due to increased right-sided heart filling pressure and upstream venous congestion in patients with IPAH.[20] Spironolactone's ability to increase digoxin concentrations, however, may complicate therapy if these drugs are coadministered. Patients requiring additional diuresis can receive low-dose loop diuretics, with dosage titrated to maximum effect, with metolazone added in refractory cases. To tread the line between symptom amelioration and compromised cardiac output, careful monitoring of blood pressure, fluid status, serum electrolyte levels, and renal function is critical.

Limited data suggest that digoxin may be useful in mitigating the negative inotropic effects of calcium channel blockers in the treatment of IPAH, as well as improving cardiac output in patients with IPAH and refractory right ventricular failure.[21] As in left-sided heart failure, however, a long-term survival benefit has never been shown with digoxin therapy in patients with IPAH. If used, serum digoxin concentrations must be carefully monitored due to the increased risk of digoxin toxicity when hypoxemia or diuretic-induced hypokalemia is present. Rhythm disturbances associated with digoxin toxicity are of particular concern in patients with IPAH, as their compromised right ventricular function presents an increased baseline risk for sudden cardiac death.

Because hypoxemia can lead to pulmonary vasoconstriction, supplemental oxygen therapy may provide a degree of pulmonary-specific vasodilation in patients with IPAH. In a recent study, treatment with 100% oxygen provided a significant decrease in mean pulmonary artery pressure and increase in cardiac output.[22] In addition, some patients with IPAH experience significant nocturnal hypoxemia and may benefit from supplemental oxygen therapy at night to help attenuate vasoconstrictive disease progression and provide symptomatic relief. Current recommendations advise use of supplemental oxygen to maintain oxygen saturations of greater than 90% at all times.[10]

Despite conventional medical therapy, IPAH inevitably will progress to New York Heart Association (NYHA) functional class III or IV right-sided heart failure in most patients, necessitating lung or heart-lung transplantation.[23] The paucity of donor organs, however, limits the usefulness of this treatment option, and the reality of the organ distribution system often dictates whether the procedure is a single lung, bilateral lung, or heart-lung transplant. Mortality among patients while waiting on transplant lists is high, and the procedure itself has an in-hospital mortality rate of approximately 15%. Reports of 4-year survival rates vary from 55-100%, and studies show a dramatic reduction in mean pulmonary artery pressure after transplantation, as well as appreciable improvements in quality of life.[24,25] The rate of survival to transplantation can be improved with atrial septostomy, a surgical procedure that creates a right-to-left shunt in the heart by forming a hole in the atrial septum. This improves cardiac output and can provide a bridge to lung or heart-lung transplantation in patients with end-stage IPAH.[26]

Epoprostenol. Epoprostenol is a prostaglandin (or prostacyclin) that activates intracellular adenylate cyclase, causing increased cyclic adenosine 3',5'-monophosphate (cAMP) concentrations ( Table 1 ). Increased cAMP mediates vasodilation of the pulmonary vasculature, as well as inhibition of platelet aggregation. Synthesized in the body from arachadonic acid through the cyclooxygenase pathway, prostacyclin is released by vascular endothelial cells. In patients with IPAH, however, production of prostacyclin is depressed, resulting in impaired pulmonary vasodilation and increased platelet activation.[15]

Epoprostenol initially was used only as a diagnostic agent in acute vasodilator trials, but the focus changed to treatment when it became apparent that continuous intravenous infusion of epoprostenol could provide a life-saving bridge to lung transplantation in patients with IPAH.[18,27] Eventually its long-term efficacy was proved in clinical trials, and it is now considered a long-term alternative to transplantation. In one study, 70% of lung transplant candidates treated with epoprostenol were removed from the transplant list or transplantation was deferred because of clinical improvement.[27] As a first-line treatment option in patients who do not exhibit a positive response to acute vasodilator challenge and who, therefore, are not candidates for high-dose calcium channel blocker therapy, epoprostenol improves mean pulmonary artery pressure, pulmonary vascular resistance, cardiac output, exercise tolerance, quality of life, and survival. Several key studies elucidate these findings ( Table 2 ).[28,29,30,31,32,33]

In 1990, the first controlled study was conducted to investigate the effects of treatment with epoprostenol on pulmonary hemodynamics and exercise tolerance in patients with IPAH.[28] The 8-week trial randomly assigned 11 patients to conventional therapy (warfarin plus digoxin, supplemental oxygen, diuretics, methyldopa nitroglycerin ointment, and/or oral vasodilators such as diltiazem or nifedipine) plus continuously administered intravenous epoprostenol, whereas 12 patients received conventional therapy alone. During the trial, three patients from the conventional treatment group and one patient from the epoprostenol group died. Results from the remaining patients showed significant favorable hemodynamic changes from baseline in the epoprostenol group, including a decrease in total pulmonary resistance of 36%, and an 18% increase in cardiac output. Changes in exercise tolerance, as measured by the distance covered in a 6-minute walk, increased in the epoprostenol group by 54%. In contrast, except for an increased mean 6-minute-walk distance, none of these parameters showed statistically significant changes in the conventional treatment group. Epoprostenol dosages were individualized based on the greatest hemodynamic benefit achieved without significant adverse effects in each patient and were found to require repeated escalation to maintain symptom control. Similar reports of tachyphylaxis have been documented in other trials.[29,30] Although this study represented only a short-term trial of epoprostenol, it indicated that unambiguous clinical benefits existed over conventional therapy.

A larger, 12-week trial compared intravenous epoprostenol plus conventional treatment with conventional therapy alone in 81 patients with IPAH in NYHA class III or IV.[29] Exercise capacity significantly improved over baseline in 41 patients treated with epoprostenol (mean distance covered during the 6-min walk increased from 316 to 348 m) compared with 40 patients receiving conventional therapy, who experienced a significant decline in exercise capacity (mean 6-min-walk distance decreased from 272 to 257 m). The NYHA class in the epoprostenol group improved in 40% of the patients, was unchanged in 48%, and worsened in 13%. By contrast, NYHA class in the conventional therapy group improved in only 3%, was unchanged in 87%, and worsened in 10% of patients. Significant decreases in the mean pulmonary artery pressure and pulmonary vascular resistance favored patients receiving epoprostenol.

Mortality was evaluated as a secondary end point: eight patients (10%) died during the 12-week study; all were in the conventional treatment group. As previously noted, frequent dosage increases of epoprostenol were necessary to maintain the beneficial effects of therapy. The initial mean ± SD dose of 5.3 ± 0.5 ng/kg/minute was increased to 9.2 ± 0.8 ng/kg/minute by the end of the study. Again, clinical benefits from epoprostenol therapy were recognized, and additional knowledge was being gained, but longer term studies were needed before epoprostenol could offer genuine hope for patients with IPAH.

A separate analysis of the same patient population studied the effects of epoprostenol on echocardiographic measures of right ventricular structure and function.[34] Patients treated with epoprostenol had a significantly smaller increase in right ventricular end-diastolic area (an indication of right ventricular dilatation associated with a loss of contractile function), as well as a significantly lower maximal tricuspid regurgitant jet velocity (reflecting a lower pulmonary artery systolic pressure), when compared with those receiving conventional therapy. The epoprostenol group also exhibited significantly greater improvement in the eccentricity index in both systole and diastole (indicative of the degree of curvature of the ventricular septum caused by elevated right ventricular pressures and resulting in abnormal left ventricular filling dynamics) compared with the conventional therapy group. This analysis indicated that therapy with epoprostenol could result in beneficial changes in right-sided heart structure and function, in addition to previously shown clinical benefits.

Through the mid-1990s, conventional wisdom suggested that optimal epoprostenol dosing required an aggressive treatment protocol to overcome the inevitable effects of tachyphylaxis. In a case series considering the effectiveness of such an epoprostenol regimen, dosages were increased as soon as tolerance developed or at any time a reduction in adverse effects permitted a dosage increase.[30] The goal was to maintain the 27 study participants at the highest tolerated dose throughout the trial period of 16.7 months. In seven of eight participants who initially exhibited minimal or no response to acute vasodilator challenge, an unexpected 39% reduction in pulmonary vascular resistance was achieved with long-term epoprostenol therapy, indicating that epoprostenol may have the potential to reverse vascular remodeling in addition to possessing vasodilatory properties. In addition, significant decreases of 22% in mean pulmonary artery pressure and 53% in pulmonary vascular resistance, as well as a significantly increased cardiac output of 70% over baseline, were demonstrated.

By 1999, however, it had become apparent that patients may experience adverse effects from being maintained in a state of continually elevated cardiac output during epoprostenol therapy. Although individuals with untreated IPAH typically have reduced cardiac output at presentation, the development of a treatment-induced, long-term high output state could have deleterious effects on cardiac function, resulting in dangerous arrhythmias. In addition, it has been postulated that a persistently elevated cardiac output may, itself, induce tolerance due to neurohormonal activation.[31] Increasing a patient's epoprostenol dosage would overcome this tachyphylaxis until further neurohormonal activation again negated it.

In an attempt to ameliorate these consequences of epoprostenol treatment, another case series evaluated the possible benefits of a more conservative dosage regimen.[31] The study followed 12 patients with IPAH who had been successfully treated with long-term epoprostenol therapy for 39 ± 20 months, as evidenced by an improvement in NYHA rating from class III or IV to class I or II, as well as an average decrease in mean pulmonary artery pressure of 25% and a reduction in pulmonary vascular resistance of 71%. Throughout this initial period of epoprostenol treatment, patients had periodically experienced a return of IPAH symptoms that required dosage escalations. After each dosage increase, patients' symptoms of IPAH were alleviated, but adverse events related to epoprostenol (jaw pain, leg pain, diarrhea, severe flushing) were reported to have worsened. In addition, each patient was found to have a relatively high cardiac output (mean ± SD cardiac index 5.5 ± 1.1 L/min/m2).

The mean ± SD epoprostenol dose during this period was 98 ± 61 ng/kg/minute. Investigators hypothesized that the dosage of epoprostenol could be tapered downward, under direct hemodynamic monitoring, to a dosage that prevented rebound pulmonary hypertension while achieving the goal of maintaining patients' cardiac index below 4 L/minute/m2 (upper limit of normal). They successfully accomplished a downward titration in 11 of 12 patients over 6-24 hours, with a mean dose reduction of 39%. Although dyspnea in one patient limited dose reduction, rebound pulmonary hypertension did not occur in any patient, and mean pulmonary artery pressure did not significantly increase (45 ± 12 vs 46 ± 10 mm Hg after reduction).

After initial dose reduction, patients were followed as outpatients over a mean of 13.6 months, during which time further dose reductions were possible in three patients, two patients required no further dosage changes, and six patients required minor increases in dosage. Throughout the follow-up period, all patients reported an improvement in epoprostenol-related flushing, with some study participants also describing a significant reduction in treatment-related leg pain. In addition, patients were able to maintain a lower, more normalized cardiac output, with a significantly reduced rate of tolerance development. The investigators concluded that epoprostenol dosing could be optimized without compromising clinical efficacy, thereby maintaining the patient's cardiac index within normal limits and relieving some of the adverse effects associated with epoprostenol therapy. Optimal dosing can be monitored during periodic heart catheterizations, with dosage being adjusted based on a target cardiac index of 2.5-4.0 L/minute/m2.[32]

In a case series from 1991-2001, 162 patients treated with epoprostenol were followed for an average of 36.3 months (range 1-122 mo).[32] The objective of this case series was to determine the long-term effects of epoprostenol on survival in patients with IPAH. All patients were NYHA class III (46%) or IV (54%), despite optimal conventional medical therapy. During the study, 70 patients (43.2%) died, 11 (6.8%) underwent lung or heart-lung transplantation, and 3 (1.9%) elected to discontinue epoprostenol. Researchers realized that, due to the high mortality rate associated with advanced IPAH and the demonstrated short-term efficacy of epoprostenol, it was no longer considered ethical to conduct a long-term randomized trial using epoprostenol. Therefore, study investigators compared survival in this case series with predicted survival determined by a prognostic equation derived from data from the NIH registry. This equation incorporates three key hemodynamic variables in IPAH: mean pulmonary artery pressure, right atrial pressure, and cardiac index.[1,33] Results from the case series showed a significant improvement in survival among patients treated with epoprostenol (87.8% survival at 1 yr, 76.3% at 2 yrs, and 62.8% at 3 yrs) compared with predicted survival (58.9% at 1 yr, 46.3% at 2 yrs, and 35.4% at 3 yrs).[32]

This large-scale trial provided evidence for the American College of Chest Physicians' guideline recommendation that in patients with IPAH who are in NYHA class III and who are not candidates for calcium channel blocker therapy, epoprostenol should be considered as a first-line treatment alternative, and that in patients in NYHA class IV who are not candidates for calcium channel blocker therapy, epoprostenol should be regarded as the treatment of choice, particularly if their condition is unstable.[10]

Although studies indicate that epoprostenol improves survival and quality of life in patients with IPAH,[29,32] its use is not without serious limitations. Because epoprostenol is unstable at pH values below 10.5, it is inactivated by the low pH of the stomach and cannot be given orally. In addition, with a half-life of only 3-5 minutes, rapid metabolism in the systemic circulation necessitates administration by continuous intravenous infusion. The delivery system is complex and cumbersome, using a portable infusion pump connected to a permanent, indwelling catheter inserted into either the subclavian or jugular vein. A backup drug delivery system is required in case of pump malfunction because of the risk of rebound pulmonary hypertension, rapid hemodynamic and symptomatic deterioration, and potentially life-threatening pulmonary hypertensive crisis if the epoprostenol infusion is interrupted for even a brief period of time.[28,32,35] Patients or caregivers must learn to mix the drug each day, including a backup supply in case of problems, by using an aseptic technique. Because epoprostenol is light and temperature sensitive, the infusion pump and medicine cassette must be placed in a bag containing ice packs to keep the drug cool.

Instruction in sterile technique, catheter care, drug administration, and infusion pump maintenance is critical, as most serious adverse effects of long-term epoprostenol therapy are related to the delivery system and include infusion pump failure, catheter-related infection and/or sepsis, and catheter thrombosis, dislodgment, or perforation. One study reported 119 local infections at the catheter site (0.24/person-yr), 70 episodes of sepsis (0.14/person-yr), 10 tunnel infections (0.02/person-yr), and 72 instances in which the catheter had to be replaced (0.15/person-yr).[32] In the same study, four patients (2.5%) died of sepsis, which may have been related to the catheter, and one patient (0.6%) died after interruption of the epoprostenol infusion. In addition to these medical consequences, there are psychosocial ramifications of epoprostenol therapy, since it commits the patient and their family to a way of life that focuses on ensuring uninterrupted delivery of the drug. The cost of epoprostenol treatment, including the drug as well as pump rental and supplies, can exceed $60,000/year and may be a consideration for some patients contemplating treatment options.

Adverse drug events are frequent and include diarrhea, headache, jaw pain, and cutaneous flushing.[28,29,30,31] Other common adverse events are nausea and vomiting, anxiety and nervousness, and muscle pain.[35] In addition, even with careful monitoring, tachyphylaxis can be a common event, requiring frequent dose escalations.

Treprostinil. Treprostinil was approved by the FDA in May 2002 and is indicated for patients with IPAH who are in NYHA classes II-IV to diminish symptoms associated with exercise ( Table 1 ).[36] A structural analog of prostacyclin, treprostinil exhibits the same mechanism of action (i.e., an increase in cAMP leading to vasodilation of the pulmonary vasculature and inhibition of platelet aggregation). However, treprostinil is considerably longer acting, with a half-life of 2-4 hours, and is chemically stable at room temperature and a neutral pH.[36] These characteristics permit continuous subcutaneous infusion with a pager-sized microinfusion device and small, self-inserted subcutaneous catheters similar to those used by patients with diabetes mellitus to administer insulin with an insulin pump. Treprostinil comes prepared as a sterile solution intended for administration without dilution. Therefore, many of the risks associated with epoprostenol therapy, such as sepsis, thrombosis, or drug delivery failure, are not associated with treprostinil. Studies comparing epoprostenol with treprostinil, as well as studies crucial to FDA approval of treprostinil, are summarized in Table 3 .[37,38,39]

In a study that consisted of a series of three sequential trials, the feasibility of long-term subcutaneous infusion of treprostinil in patients with IPAH was assessed.[37] The first two trials were multicenter, open-label, cross-over designs; the third was a controlled study. Trial 1 evaluated the short-term effects of intravenous epoprostenol and intravenous treprostinil to determine maximum tolerated doses and comparative efficacy with the same route of administration. Similar increases in cardiac output and similar decreases in mean pulmonary artery pressure and pulmonary vascular resistance were demonstrated. In addition, dose-limiting adverse events (headache, nausea, chest pain, jaw pain, backache, and restlessness) were similar with both treatments.

Trial 2 compared the hemodynamic effects and pharmacokinetics of intravenous treprostinil with those of subcutaneous treprostinil. Results from trial 2 showed similar changes in hemodynamic parameters in both the intravenous and subcutaneous treprostinil groups, suggesting that the favorable effects observed from intravenous treprostinil in trial 1 could be reproduced with subcutaneous administration. The pharmacokinetic data obtained from trial 2 found that the half-life of intravenous treprostinil ranged from 26-42 minutes, compared with 55-117 minutes for subcutaneous treprostinil.

Trial 3 was an 8-week pilot study that compared subcutaneous treprostinil with placebo. Although treprostinil had a favorable effect on hemodynamics and exercise tolerance, none of these effects reached statistical significance. The most common adverse events with subcutaneous treprostinil were infusion-site pain and erythema. In addition, headache, diarrhea, flushing, foot pain, and jaw pain were seen with treprostinil therapy, adverse events that are also common with epoprostenol.

Treprostinil was approved by the FDA based on the results of two controlled studies that enrolled a total of 470 patients (NYHA classes II-IV) with IPAH or PAH associated with connective tissue disease or congenital systemic-to-pulmonary shunts.[36,40] All subjects received either conventional therapy plus continuous subcutaneous treprostinil or conventional therapy plus continuous infusion of placebo during a 12-week period. The studies were identical in design and were conducted simultaneously. Results of both studies were analyzed and reported by using individual as well as pooled data, which tended to confound interpretation of study results.[36,38,41] The primary end point of the studies was exercise capacity after 12 weeks of treatment. Pooled study results showed a median change from baseline of only 10 m for the treprostinil group, compared with no change in the control group;[36] this treatment effect was not statistically significant. In addition, no difference was noted in the results between the two groups regarding principal reinforcing end points of mortality, lung transplantations, or clinical deterioration.[38,40] However, the subjectively scored Dyspnea-Fatigue Rating, Borg Dyspnea Score, and composite score for signs and symptoms of pulmonary hypertension, also defined as principal reinforcing end points, improved significantly in the treprostinil group compared with the placebo group.

The secondary end points of mean pulmonary artery pressure, pulmonary vascular resistance index, and cardiac index were significantly improved as well. Ultimately, although the study did not achieve its primary end point, FDA approval was granted based on an improvement in perceived quality of life and a reduction in clinical symptoms, coupled with a lack of safety concerns.

In the current study, a significant difference was noted in the frequency of adverse events with treprostinil compared with placebo.[38] These effects included infusion-site pain, infusion-site reaction (including erythema, induration, or rash), diarrhea, jaw pain, vasodilatation, and edema. Infusion-site pain was the most common adverse effect related to treatment with treprostinil, occurring in 85% of the patients. Eighteen treprostinil-treated participants (8%) discontinued their study treatment due to intolerable infusion-site pain, compared with only one patient in the placebo group. Infusion-site pain was variably relieved by the use of topical cold and hot compresses, topical and oral analgesics, antiinflammatory drugs, and narcotics. In addition, rotation of the infusion site every 3 days rather than every day helped to minimize infusion-site adverse events.[36]

Treprostinil may be an alternative therapy for patients who, although stable while receiving epoprostenol, have experienced life-threatening catheter or delivery system complications or who cannot tolerate dosage escalations. In an open-label study, a cohort of eight such patients was successfully transitioned from intravenous epoprostenol to subcutaneous treprostinil.[39] All of the patients had experienced initial clinical improvement with long-term epoprostenol therapy (3-15 mo), as well as an improvement in NYHA class. The transition to treprostinil was prompted by severe complications of epoprostenol therapy, including recurrent central catheter-related sepsis (five patients); severe headache, jaw pain, abdominal cramping and diarrhea that prevented an increase in epoprostenol dosage in the face of deteriorating clinical condition (one patient); recurrent cerebral air emboli (one patient); and several episodes of syncope related to accidental disconnections of the intravenous line (one patient). Transitions were performed over 21-96 hours in an intensive care or telemetry inpatient setting. The clinical status and NYHA class of all patients were unchanged after the transition from epoprostenol to treprostinil. A 6-minute-walk test was performed in five patients able and willing to participate at 1 week before and 6-8 weeks after transition and showed a nonsignificant change (from 496 ± 45 to 486 ± 29 m). All of the patients experienced pain, swelling, and erythema at the subcutaneous injection site. The pain was rated as moderate-to-severe in 7 patients (88%) and was treated with cold compresses, corticosteroid or nonsteroidal antiinflammatory drug (NSAID) ointments, acetaminophen, or oral NSAIDs. Two patients were treated briefly with acetaminophen-codeine preparations, and two patients received short courses of oral prednisolone 2 mg/kg/day, which appeared to be very effective.

The local infusion-site pain markedly improved after several weeks in all but two patients, but all study participants reported an improved sense of comfort and well being after changing to treprostinil. Follow-up ranged from 4-11 months. In seven patients, clinical state, functional class, and 6-minute-walk distance remained unchanged. One patient, whose clinical condition had been deteriorating while receiving intravenous epoprostenol, continued to deteriorate after the transition despite continually increasing dosages of treprostinil.

These studies indicate that although treprostinil may not be appropriate as first-line therapy for IPAH, patients in NYHA class II or III may consider a trial with treprostinil, particularly if other treatment options have failed. Patients in NYHA class IV should be advised to use intravenous epoprostenol due to the lack of proven long-term mortality benefit with treprostinil.[9]

Iloprost. The possibility of a therapy for IPAH that could be administered directly to the lungs through inhalation has been an attractive concept for many years. Iloprost, an aerosolized analog of epoprostenol, has been studied as a treatment for IPAH for nearly 2 decades. Recently approved by the FDA, it is the only inhalation therapy available ( Table 1 ). Iloprost is a powerful vasodilator, selectively acting on the pulmonary vascular bed through ventilation-matched alveolar deposition of the drug, theoretically preventing systemic hypotension. The effects last for 60-120 minutes, which necessitates inhalation using a jet nebulizer 6-9 times/day (without interruption of bed rest at night), with each treatment lasting approximately 10 minutes. Studies following the development of iloprost are detailed in Table 4 .[42,43,44]

In order to compare efficacy, an uncontrolled, open-label study looked at the effects of short-term administrations of oxygen, inhaled nitric oxide, intravenous prostacyclin (epoprostenol), inhaled prostacyclin, and inhaled iloprost in six patients (four with IPAH and two with PAH associated with CREST syndrome [calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia]).[42] All patients were in NYHA class III or IV. Each agent was administered as a single dose followed by a washout period sufficient to allow a return to stable baseline. Hemodynamic measurements were taken before, during, and after administration of each agent.

As expected, hemodynamic variables were only slightly affected by oxygen administration, but inhalation of nitric oxide, an endogenous vasodilator, resulted in marked improvements in mean pulmonary artery pressure, pulmonary vascular resistance, and cardiac output, with little impact on systemic arterial pressure. The beneficial effects of nitric oxide, however, ended 2-5 minutes after the dose. Intravenous prostacyclin significantly decreased pulmonary vascular resistance and increased cardiac output, resulting in a modest decline of pulmonary artery pressure but a substantial decrease in mean systemic arterial pressure and an increase in heart rate due to peripheral vasodilation. Inhaled prostacyclin, acting selectively on the pulmonary vascular bed, caused significant improvements in mean pulmonary artery pressure, pulmonary vascular resistance, and cardiac output, with only a minimal effect on mean systemic arterial pressure. These beneficial effects lasted 10-30 minutes after the end of the inhaled prostacyclin dose. Finally, in all patients, inhalation of the stable prostacyclin analog iloprost provided nearly identical changes in hemodynamics to those seen with inhaled prostacyclin (data not provided by the study authors), but the iloprostinduced changes were maintained for 60-120 minutes after inhalation.

In another uncontrolled, open-label study, 24 patients with NYHA class III or IV IPAH received inhaled iloprost 6-8 times/day over 1 year to assess long-term changes in exercise capacity and hemodynamics.[43] At 3 months, significant improvements compared with baseline were noted in the mean distance covered during a 6-minute-walk test, as well as in mean pulmonary artery pressure and pulmonary vascular resistance. These changes were sustained at the end of 12 months, at which time a significant increase compared with baseline was also noted in cardiac output. All hemodynamic measurements were taken before the first iloprost inhalation of the day, suggesting that mechanisms other than vasodilation may contribute to its therapeutic effect, and at all times there was further improvement in these variables immediately after inhalation of iloprost. Treatment was well tolerated by all patients, with reports of flushing, headache, and jaw pain in five patients (21%). Coughing during inhalation was common initially but spontaneously resolved during the first 4 weeks of therapy.

A multicenter, double-blind, randomized study followed 203 patients with IPAH or selected forms of secondary pulmonary hypertension.[44] Patients were randomly assigned to receive either aerosolized iloprost or placebo, in addition to conventional therapy. The primary end point was fairly rigorous and consisted of a composite of a 10% or greater increase in 6-minute-walk distance evaluated 30 minutes after inhalation of the study drug, and improvement of one NYHA class (e.g., from class III to class II), in the absence of clinical deterioration or death during the 12-week study. Secondary end points included each component of the primary end point individually, as well as hemodynamic values, and Mahler Dyspnea Index Scores. During the study, the mean frequency of inhalation was 7.5 times/day. Nine percent of patients received 2.5 µg/inhalation, and 91% received 5 µg/inhalation, corresponding to a median inhaled dose of 30 µg/day. Tolerance did not appear to occur at any time during the study.

The primary end point was met by 17 (16.8%) patients in the iloprost group, compared with just 5 (4.9%) of the placebo group. Of the secondary end points, changes in NYHA class and Mahler Dyspnea Index Scores showed statistically significant differences between treatment groups. Five patients receiving iloprost met the criteria for clinical deterioration (including one death), compared with 12 patients (with four deaths) in the placebo group. Although nearly 40% of iloprost-treated patients increased their 6-minute-walk distance by greater than 10%, more than 25% in the placebo group did as well, rendering the between-group difference statistically insignificant.

The placebo group showed significant worsening in pulmonary vascular resistance and cardiac output at the end of 12 weeks compared with baseline. In the iloprost group, the same parameters were significantly improved compared with baseline. However, even at 12 weeks, hemodynamic measurements preceding the first daily inhalation of iloprost were largely unchanged from baseline, suggesting sub-therapeutic concentrations during overnight, drug-free periods, and a potential drawback to inhaled iloprost therapy.

This limitation of treatment with aerosolized iloprost may be ameliorated with the use of other agents in combination with iloprost. Polypharmacy approaches have been investigated with promising results,[45,46] but larger, long-term studies are indicated. As no studies have yet evaluated the mortality benefits of iloprost, it should be considered second-line therapy, even though its noninvasive, easy administration and relative lack of serious adverse effects may make it an attractive treatment alternative for some patients.

Bosentan. An increasing understanding of the multiple pathogeneses of IPAH led to the discovery of another target for drug therapy, and bosentan was subsequently developed as the first endothelin-receptor antagonist available for IPAH ( Table 1 ). Endothelin-1 is a peptide produced in endothelial cells and vascular smooth muscle cells. It binds to two types of receptors, ETA and ETB. When bound by endothelin-1, ETA receptors located on vascular smooth muscle cells activate phospholipase C, which mediates an increase in intracellular calcium through the inosital 1,4,5-triphosphate pathway, resulting in potent vasoconstriction by the vascular smooth muscle cells.[47,48] In a parallel cascade of events, endothelin-1 binding to ETA receptors also leads to cell proliferation and vascular remodeling by increasing concentrations of diacylglycerol, thereby stimulating protein kinase C.[47] Similar to ETA receptors, some ETB receptors are located on vascular smooth muscle cells, where they are involved, although to a much lesser extent, in vasoconstriction. However, ETB receptors are also found in substantial numbers on the vascular endothelium, where they conversely mediate vasodilation through the release of nitric oxide and play a role in the clearance of endothelin-1 from the circulation.[49]

Bosentan is a competitive antagonist of endothelin-1 at both ETA and ETB receptors, leading to reductions in vasoconstriction and ascular remodeling. Because it is a nonpeptide, bosentan is not hydrolyzed by peptidases in the systemic circulation and gastrointestinal tract, making oral administration possible. Given the clinically significant improvements in exercise capacity, functional class, and hemodynamics seen with bosentan, it may be considered a potential first-line treatment option in patients who are not candidates for high-dose calcium channel blocker therapy.[10,50,51]

However, bosentan has caused dose-related, reversible hepatic toxicity during clinical trials, with elevated aminotransferase concentrations in as many as 11% of patients.[40,52] These results are of particular concern in patients with IPAH. Patients frequently have advanced disease at presentation, including compromised hepatic function as a result of right-sided heart failure. The risk of increased hepatic insult has led to implementation of a monitoring program by the manufacturer that requires liver function tests before therapy begins and at monthly intervals. Bosentan is also an FDA category X teratogen, necessitating the exclusion of pregnancy both before therapy begins and monthly thereafter. Information about the potential for liver injury and the contraindication regarding pregnancy are included in a black box warning in the package insert.[52] Finally, bosentan has been shown to cause hypochromic anemia (> 15% decrease in hemoglobin level).[52,53]

Bosentan has the potential for numerous drug interactions, particularly among cytochrome P450 (CYP) 3A4 and CYP2C9 substrates.[52,53] Coadministration of cyclosporine (which may increase bosentan concentrations by up to 30-fold) or glyburide (which increases risk of hepatotoxicity) with bosentan is contraindicated, whereas caution is indicated for concomitant use with tacrolimus (which may increase bosentan concentrations), ketoconazole (which may increase bosentan concentrations), and warfarin (which may decrease warfarin concentrations). Although specific drug studies have not been performed to evaluate the effect of bosentan on hormonal contraceptives (including oral, parenteral, transdermal, and implantable forms), many of these drugs are metabolized by CYP3A4, and the possibility of contraceptive failure exists; a second form of birth control should be used at all times by women of childbearing age who are taking bosentan. Additional drug interactions may be the result of bosentan's CYP3A4- and CYP2C9-inducing potential and include drugs primarily metabolized by these CYP enzymes. Examples include glipizide, simvastatin, and sildenafil; such drugs should be monitored clinically during concomitant administration of bosentan.[52,53,54,55,56]

Two critical studies examined the clinical implications of bosentan ( Table 5 ).[50,51] A 12-week controlled study of bosentan (dosage titrated to 125 mg twice/day) was conducted in 32 patients with IPAH or PAH associated with scleroderma who were in World Health Organization (WHO) functional class III despite optimal medical therapy.[50] A significant increase in walking distance of 70 m was realized in the bosentan group compared with a reduction of 6 m in the placebo group. A significantly greater improvement in WHO functional class was observed in the bosentan group compared with the placebo group. The hemodynamic variables most closely correlated with mortality in patients with IPAH (i.e., mean pulmonary artery pressure, mean right atrial pressure, and cardiac index) showed significantly greater improvement in patients receiving bosentan versus placebo.[1,50]

Finally, study investigators reported that the frequency of adverse events between groups did not differ significantly. Nine (43%) of 21 patients receiving bosentan experienced an adverse event compared with 7 (64%) of 11 patients in the placebo group. The only information provided regarding the type of adverse events indicated that increases in aminotransferase concentrations were seen in two patients treated with bosentan, but that these increases were asymptomatic and self-limiting. This initial small study provided the first indication that a new drug target could be effectively exploited in the treatment of IPAH. Although secondary end points showed promising evidence for therapy with bosentan, a long-term mortality benefit had yet to be proved.

The Bosentan Randomized Trial of Endothelin Antagonist Therapy (BREATHE-1) was designed to evaluate the effect of bosentan on exercise capacity and WHO functional class in patients with PAH, as well as to compare the efficacy and adverse effect profiles of two different bosentan dosages.[51] This controlled study randomly assigned 213 patients with WHO classes III and IV disease (both primary and associated with connective tissue disease) into three groups: bosentan dosage titrated to 125 mg twice/day, bosentan dosage titrated to 250 mg twice/day, or placebo. At the end of 16 weeks, all patients continued their assigned study drug in a double-blinded manner until the completion of the study period, the day the last enrolled patient finished the assessment at week 16. This second time period lasted up to 12 additional weeks. At the end of the study, all participants were eligible to enter an open-label study of bosentan.

At the end of 16 weeks, the 6-minute-walk test was significantly improved in the bosentan groups compared with the placebo group. The increase was more pronounced in the bosentan 250-mg group than in the 125-mg group (54 vs 35 m, respectively), but the difference between the bosentan treatment groups was not significant. Although patients treated with bosentan exhibited a greater improvement in WHO functional class than that in the placebo group, the significance of this difference was not reported; overall, although 42% of the patients treated with bosentan showed an improvement in functional class, 30% of the placebo group did as well. Finally, with the exception of abnormal hepatic enzymes seen in both bosentan groups, the type and frequency of adverse events were similar among all three treatment groups and most often involved headache, dizziness, cough, and flushing. Study results showed increases in aminotransferase concentrations to greater than 8 times the upper limit of normal in two patients (3%) in the bosentan 125-mg group and five patients (7%) in the bosentan 250-mg group, leading to premature discontinuation of the study drug by three patients.[51]

In addition, in a published letter replying to readers comments,[57] the investigators reported that 10 patients (13.5%) treated with bosentan 125 mg twice/day experienced increases in aminotransferase concentrations of more than 3 times the upper limit of normal. None of these patients elected to withdraw from the study, and bosentan therapy was continued at either the same dosage or at a reduced dosage of 62.5 mg twice/day. Aminotransferase concentrations returned to values that were less than twice the upper limit of normal in 7 of the 10 patients and decreased progressively in the remaining 3 patients. All 10 patients participated in the open-label elective phase of the study.[57]

Although the study's primary end point, an increase in 6-minute-walk distance, was achieved, there are no trials yet that prove a long-term mortality benefit with bosentan therapy, and safety concerns may limit its use. The American College of Chest Physicians' guidelines, however, recommend that patients with IPAH who are in NYHA class III should consider long-term therapy with bosentan as a treatment alternative, and the substantially lessened effect on quality of life with oral bosentan over intravenous epoprostenol must be taken into account in devising a treatment plan.

A recently published subanalysis of the BREATHE-1 trial assessed the effects of bosentan on cardiac structure and function in 85 patients (84% with IPAH, 16% with PAH associated with connective tissue disease) over a 16-week period.[58] In the 56 patients randomly assigned to receive bosentan, echocardiographic results revealed a smaller mean increase in right ventricular end-diastolic area, indicating less contractile function loss, than in patients assigned to placebo, although this change failed to reach statistical significance. A decrease in septal displacement reflected by reduced systolic and diastolic eccentricity indexes was also observed in this group, reflecting lower right ventricular pressures and resulting in improved left ventricular filling dynamics. Doppler measurements included right ventricle ejection time, left ventricle stroke volume, cardiac index, and maximal tricuspid regurgitant velocities, all of which were significantly improved over that of the placebo group, with the exception of maximal tricuspid regurgitant velocity, an indicator of pulmonary artery pressure. These data suggest that bosentan treatment may improve right-sided heart function, but not to an extent that would be expected to reverse structural anomalies.

The BREATHE-2 trial was a double-blind, randomized study of the safety and efficacy of oral bosentan combined with intravenous epoprostenol.[59] Patients received intravenous epoprostenol for 48 hours and were then randomly assigned to receive in addition either bosentan or placebo for 4 months. Results indicated that the combination of bosentan and epoprostenol was well tolerated, and both groups showed an improvement in the primary end point of total pulmonary resistance. However, the change from baseline in total pulmonary resistance did not reach statistical significance between the epoprostenol-placebo and epoprostenol-bosentan groups. Because the two drugs possess different mechanisms of action, the possibility of combining their effects is an attractive treatment option that requires additional research.

Sildenafil. In an attempt to exploit another target for drug therapy, researchers have focused on the nitric oxide pathway. Production of nitric oxide is impaired in patients with IPAH,[14] resulting in decreased production of cyclic guanosine monophosphate (cGMP), a potent mediator of vascular smooth muscle relaxation and vasodilation. Although inhaled nitric oxide has been shown to decrease pulmonary vascular resistance,[42] ambulatory delivery is cumbersome. Another strategy is to prolong the circulation of existing cGMP by inhibiting phosphodiesterase type 5, an enzyme that rapidly hydrolyzes cGMP. Because phosphodiesterase type 5 is selective for penile and pulmonary tissue, phosphodiesterase type 5 inhibitors increase cellular concentrations of cGMP in these tissues, causing preferential vasodilation with minimal reductions in systemic blood pressure. Numerous anecdotal reports have described successful treatment of IPAH with the phosphodiesterase type 5 inhibitor sildenafil ( Table 1 ), either singly or in combination with other drugs.[60–63] More recently, studies have been conducted to evaluate the efficacy, safety, and optimal dosage of sildenafil. These are reviewed below and summarized in Table 6 .[64–66]

A case series followed five patients with PAH (four with IPAH and one with Eisenmenger's syndrome) who were treated with oral sildenafil 50 mg every eight hours.[64] All patients were NYHA class II or III and received conventional therapy (diuretics, warfarin, and/or calcium channel blockers) in addition to sildenafil. At the end of the 3-month study, NYHA class had improved by one class in every patient. Exercise capacity had increased significantly, as evidenced by a 34% increase in 6-minute–walk distance. Mean pulmonary artery pressure and pulmonary vascular resistance index decreased 25.7% and 41.5%, respectively, with no significant change in systolic blood pressure. In addition, right ventricular mass, as measured by magnetic resonance imaging in three patients, decreased 16.2%, apparently reversing the pathologic septal shift seen in patients with IPAH. Although this was a small, uncontrolled study, it suggested that due to sildenafil's potential efficacy, simplicity, and safety profile, further controlled studies were warranted.

In a double-blind, randomized, crossover study, 22 patients with IPAH (NYHA class II or III) were randomly assigned to receive either sildenafil or placebo, in addition to conventional therapy.[65] After 6 weeks, each group was given the alternate therapy, with no washout period, for another 6 weeks. Sildenafil dosage was based on body weight: patients weighing 25 kg or less received 25 mg 3 times/day, patients weighing 26-50 kg received 50 mg 3 times/day, and patients weighing 51 kg or greater received 100 mg 3 times/day. The primary end point was the change in exercise capacity, as measured by time (sec) on a treadmill using the Naughton protocol. Secondary end points included changes in cardiac index and pulmonary artery systolic pressure as assessed by Doppler echocardiography. When considering the combined values of both groups, exercise time increased significantly, rising from a mean of 475 seconds at the end of the placebo phase to 686 seconds after 6 weeks of treatment with sildenafil. Likewise, cardiac index significantly improved from 2.80 to 3.45 L/minute/m2. The decrease in pulmonary artery systolic pressure, however, was not statistically significant. One of the limitations of this study was the absence of a washout period between crossover phases, allowing the sildenafil treatment effect to be carried over into the placebo phase in the sildenafil-first group and effectively blunting the beneficial effect of sildenafil therapy. In spite of this, the study achieved its primary end point. One patient in the placebo-first group died one week after randomization and one patient had syncope at rest while in the placebo phase. In addition, one patient in the sildenafil-first group elected not to continue 1 week after randomization. All other patients tolerated sildenafil therapy well except for minor adverse effects (headache, backache, constipation, and numbness in hands and feet).

A prospective, open-label study also looked at the efficacy and optimal dosage of sildenafil in patients with IPAH.[66] Over an 8-week period, 15 patients with IPAH (NYHA class III or IV) participated in a step-up therapeutic protocol. In addition to conventional therapy, patients received sildenafil 50 mg twice/day during the first 4 weeks and 100 mg twice/day for the next 4 weeks. Primary end points were changes in 6-minute-walk distance, NYHA class, and Borg Dyspnea Index. Results showed significant improvements in all primary end points with sildenafil 50 mg twice/day at 4 weeks. Six-minute-walk distance increased by 61%, NYHA class improved by 58%, and the Borg Dyspnea Index decreased by 45% (lower score means less dyspnea). In all but one patient, increasing the dosage to 100 mg twice/day did not provide any additional clinical benefit.

Based on a priority review of data from a 3-month, randomized, double-blind, placebo-controlled study involving 278 patients, the FDA approved sildenafil for the treatment of IPAH in June 2005. The study participants were patients with IPAH (63%), PAH associated with connective tissue disease (30%), and PAH following surgical repair of congenital heart defects (7%); all patients but one were in NYHA classes II and III.[67] Patients were randomly assigned to receive either placebo or sildenafil 20, 40, or 80 mg 3 times/day. Although full results of the study (Sildenafil Use in Pulmonary Arterial Hypertension [SUPER-1]) have not yet been published, preliminary analyses indicate that the sildenafil groups showed significant improvements in both 6-minute-walk distance and NYHA functional class. Because differences in walk distance were not significant between sildenafil dosage groups, the approved dosage is limited to 20 mg 3 times/day. In addition, initial data from a 1-year, uncontrolled extension of the SUPER-1 study were recently presented at the 2005 International Conference of the American Thoracic Society. Results from SUPER-2 suggest that patients who experienced a treatment benefit at 3 months continued to see this clinical improvement when taking sildenafil long term.[68] Finally, of the 259 patients who elected to participate in the SUPER-2 extension, 96% were still alive at the end of 1 year, suggesting a mortality benefit with long-term sildenafil therapy.[69] A more thorough evaluation of the SUPER-1 and -2 studies must be undertaken before any recommendations can be made; however, in view of its convenient oral administration and relative safety profile (the most common adverse effects are headache, nasal congestion, and visual disturbances), sildenafil's potential role as monotherapy or adjunctive therapy for IPAH may soon be fully realized.

Sitaxsentan. Like bosentan, sitaxsentan is an endothelin1-receptor antagonist, but unlike bosentan, it is specifically an ETA-receptor antagonist. By preferentially blocking ETA receptors, sitaxsentan preserves the vasodilatory and endothelin1-clearing properties of ETB receptors, theoretically resulting in less vasoconstriction as well as lower circulating endothelin-1 concentrations. In a small, 12-week, open-label trial involving 20 patients with PAH (8 with IPAH and 12 with PAH secondary to either collagen vascular disease or congenital systemic-to-pulmonary shunts), sitaxsentan significantly improved exercise capacity as measured by the 6-minute-walk distance, as well as mean pulmonary artery pressure and pulmonary vascular resistance index (mean pulmonary vascular resistance/body surface area); there was, however, no significant change in cardiac output.[70] Clinically important adverse events during the trial included anemia, increased prothrombin time or INR, systemic hypotension, pulmonary edema, and asymptomatic increases in serum transaminase levels. At the end of the trial, any study participants who had not deteriorated during the trial were eligible to continue taking sitaxsentan during an extension phase of the study. Unfortunately, at weeks 16 or 17, two patients developed acute hepatitis. One patient immediately discontinued sitaxsentan administration, and serum transaminase levels returned to baseline approximately 9 weeks later. The other patient chose to reduce the dosage of sitaxsentan, but after 3 weeks serum transaminase levels continued to increase. Acute fulminant hepatitis was diagnosed, and despite discontinuation of sitaxsentan administration, the patient died. The extension phase of the trial was terminated early due to these serious adverse events.

Recently, the Sitaxsentan to Relieve Impaired Exercise (STRIDE-1) trial randomly assigned 178 patients with PAH (94 with IPAH, 42 with PAH related to connective tissue disease, and 42 with PAH associated with congenital systemic-to-pulmonary shunts) to receive sitaxsentan 100 mg, sitaxsentan 300 mg, or placebo daily for 12 weeks.[71] The primary end point, percentage of predicted peak oxygen consumption during cycle ergometry, was significantly increased in the 300-mg group only. Secondary end points included 6-minute-walk distance, NYHA class, hemodynamic parameters (mean pulmonary artery pressure, mean right atrial pressure, pulmonary vascular resistance, and cardiac index), and time to clinical worsening (death, epoprostenol rescue, atrial septostomy, or transplantation). Compared with the placebo group, significant improvements were seen in all secondary end points in both the 100- and 300-mg groups, with the exception of mean pulmonary artery pressure, which showed no significant change between the 100-mg group and the placebo group, and time to clinical worsening, in which no differences were seen among any of the three arms of the study.

Adverse events reported by more than 10% of the patients receiving sitaxsentan and occurring more frequently than in the placebo group were headache, peripheral edema, nausea, increased INR or prothrombin time, nasal congestion, and dizziness. However, of greater concern was the high rate of liver enzyme abnormalities, defined as aminotransferase concentrations greater than 3 times the upper limit of normal. Increased liver enzyme levels were found in 10% of the sitaxsentan 300-mg group (6/63), resulting in discontinuation of the study by three patients, compared with 3% of the placebo group (2/59), resulting in discontinuation of the study by one patient, and none of the group receiving 100 mg of sitaxsentan.

Although possibly warranted because of the significant improvements in clinical status demonstrated thus far, future studies evaluating the safety and efficacy of sitaxsentan will require careful monitoring of liver enzyme levels. A phase III trial comparing sitaxsentan and bosentan is planned.

Beraprost. Beraprost is an orally active, chemically stable analog of epoprostenol. It has been approved in Japan for treatment of patients with IPAH, where a multicenter case series study evaluated survival rates in patients receiving beraprost plus conventional therapy (24 patients) compared with patients receiving only conventional therapy (calcium channel blockers, nitrates, digitalis, and diuretics; 34 patients).[72] The results showed significantly higher 1-, 2-, and 3-year survival rates of 96%, 85%, and 76%, respectively, in the beraprost treatment group, compared with 77%, 47%, and 44% in the group receiving only conventional therapy.

A small, uncontrolled European study involving 13 patients with IPAH and PAH secondary to thromboembolic disease or Eisenmenger's syndrome showed significant improvements over baseline in NYHA class, 6-minute-walk distance, and pulmonary artery pressure with beraprost administration during a 12-month period.[73] More recently, the Arterial Pulmonary Hypertension and Beraprost European Trial (ALPHABET) group conducted a 12-week controlled study in 130 patients with IPAH or PAH associated with collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, or HIV infection.[74] After 12 weeks, the patients treated with beraprost showed significant improvement over the control group in 6-minute-walk distance. A subgroup analysis comprised only of patients with IPAH showed an even greater improvement in the beraprost group compared with placebo. Similarly, IPAH symptoms, as measured subjectively by the Borg Dyspnea Score, improved significantly by -0.94 (a lower score indicates fewer symptoms) in the beraprost group compared with the control group. However, cardiopulmonary hemodynamics showed no significant changes.

A United States study of oral beraprost was conducted over 9 months in 116 patients with IPAH (86 patients) or PAH related to either collagen vascular disease (12 patients) or congenital systemic-to-pulmonary shunts (18 patients).[75] After 6 months, the primary end point of disease progression (death, transplantation, epoprostenol rescue, or > 25% decrease in peak oxygen consumption) was significantly lower with beraprost compared with placebo. However, this treatment effect was not significantly different from placebo at either the 3- or 9-month follow-up evaluations. The beraprost treatment group also performed significantly better on the 6-minute walk at months 3 and 6 but showed no significant difference at the 9-month follow-up. Composite changes in WHO functional class between the beraprost and placebo groups were significant only at the 6-month interval. Hemodynamic variables and quality-of-life indicators were not significantly improved at any time during the study.

The benefits of beraprost seen during early phases of this trial may have dissipated due to an inability to adequately increase the dosage regimen. Dose-limiting adverse events (headache, jaw pain, flushing, and diarrhea) were more common in the beraprost-treated group, although serious adverse events (fatal or life-threatening incidents or events requiring hospitalization) occurred more frequently in the control group.