New Developments in the Treatment of PAH

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New Developments in the Treatment of PAH  CME/CE

Disclosures

Susan P. Steinbis, MSN, NP-C   

A progressive vasculopathy is the wording used to describe pulmonary arterial hypertension (PAH). Pulmonary hypertension is a disease that affects the pulmonary vasculature, leading to right ventricular failure with devastating consequences for those affected. Historically, treatment has been limited and complex with the continuous intravenous (IV) administration of epoprostenol. The end of 2001 introduced the first oral therapy, bosentan, and then 2002 produced treprostinil, a continuous, subcutaneous prostacyclin analogue. Since then, numerous studies have been conducted evaluating new therapies, subsequently leading to the approval of newer agents.

What's New?

So what is in our arsenal now in 2005? This year has been an exciting year for new therapies in the treatment of PAH. Iloprost, another prostacyclin analogue, was approved for the treatment of World Health Organization (WHO) class I PAH with New York Heart Association (NYHA) functional class III or IV. Like epoprostenol and treprostinil, it exerts its effect on the prostacyclin pathway but is administered via inhalation through the Prodose AAD System, a breath-actuated drug delivery device. It is given in 6 daily doses with the option to administer up to 9 times a day, if needed. The side-effect profile is better than that for other prostanoids as iloprost is not administered systemically, but headache, cough, and flushing are common. Syncope has been reported but is thought to be secondary to sudden activity in the morning before the first therapy is administered. In a randomized, double-blind study, at Week 12, iloprost was shown to have a 40-meter improvement in 6-minute walk distance (6MWD) from baseline when compared to placebo. The endpoint of the clinical trial was at least a 10% increase in 6MWD when compared to baseline and improvement of at least 1 NYHA functional class vs baseline with no death or clinical worsening. When all these endpoints were combined, iloprost demonstrated a 19% improvement over placebo.

Treprostinil was first approved as a subcutaneous therapy in 2002 and is now available in an IV preparation. Vallery McLaughlin, MD, reported the 1-year data on IV treprostinil at CHEST 2005. After receiving an infusion lasting 48 hours with a half-life of 4.5 hours, 16 de novo patients experienced an 80-meter increase in 6MWD at 12 weeks. At 1 year, the de novo group had a total improvement in 6MWD of 125 meters with a decrease in mean pulmonary artery pressure (mPAP), an increase in cardiac index, and a decrease in pulmonary vascular resistance (PVR) by half. Thirty-four of 41 patients in the transition group (IV epoprostenol to IV treprostinil) completed the 1-year study. At the end of the 12 months, the transition group maintained stability in 6MWD and in hemodynamics. Chronic IV treprostinil therefore is assumed to provide sustained improvement in exercise capacity and hemodynamics. Of note, more than twice the dose was needed for treprostinil when compared to epoprostenol, with a mean dose of 98 ng/kg/min in the de novo group and 111 ng/kg/min in the transition group.[1]

Multiple Pathways

Much discussion has centered around the multiple pathways involved in pulmonary hypertension. The nitric oxide pathway has been the most recently addressed pathway in the treatment of PAH. Sildenafil was approved this year as a PDE-5 inhibitor. At CHEST 2005, Lalaine Corate, MD, and Namita Sood, MB, BCh, discussed the use of sildenafil in patients with right heart failure and PAH. Both noted improvements with either 50 mg or 100 mg every 8 hours. The use of sildenafil in the acute setting with long-term follow-up demonstrated a mean increase in 6MWD at > 4 weeks with a mean decrease in oxygen by 2 LPM. There was also improvement in WHO functional class but 4 of 14 patients on the 100-mg regimen needed additional therapy at 5 or more months and 1 patient died before the end of 1 year secondary to progression of disease.[2,3]

David Badesch, MD,[4] reviewed data from the SUPER-1 study, a clinical trial involving 278 patients who received 20-, 40-, or 80-mg doses of sildenafil citrate; 6MWD was used as an endpoint. At the end of the 12-week period, patients on the 20-mg dose had a 45-meter improvement in 6MWD and the 80-mg group had a 50-meter improvement in distance. The sildenafil group also experienced an improvement in NYHA functional class vs the placebo group. The mPAP and PVR demonstrated continued improvement with 80 mg sildenafil vs 20 mg, and the cardiac output also increased to a greater degree with 80 mg than with 20 or 40 mg. The side-effect profile includes headache, flushing, diarrhea, and dyspepsia.

Martin C. Brown, MD,[5] reviewed data evaluating the long-term benefits of sildenafil on the quality of life (QOL) in patients with PAH. The same patients that were enrolled in SUPER-1 were evaluated, and data were collected using the SF-36 and the EuroQoL (EQ-5D) questionnaires. Improvements in physical functioning, general health, and vitality were statistically significant after 24 weeks on sildenafil. The utility index and current health state also demonstrated a statistically significant improvement (sildenafil vs placebo), and the effect for all areas mentioned was maintained for the 24-week period and, in some domains, for up to 6 months. The physical health domains were the ones most significantly impacted by sildenafil use.

Preliminary data were released on another oral agent, sitaxsentan, a selective endothelin receptor antagonist awaiting approval from the US Food and Drug Administration (FDA). Dr. David Badesch[6] reviewed the results of STRIDE-1, a clinical trial comparing placebo, 100 mg, and 300 mg daily dosing of sitaxsentan. Two patients experienced elevation of liver function tests (LFT) to > 3 times the upper limit of normal (ULN). At week 12, both doses demonstrated an increase in 6MWD, a decrease in mPAP, an increase in cardiac index, and a decrease in PVR. However, researchers felt that the 300-mg dose was a significant overdosing of the medication since the 100-mg dose did not demonstrate an increase in LFT over the 12-week period. In the extension study, 4 of 79 patients experienced an elevation of LFT > 3 times ULN. Adverse events included headache, peripheral edema, nausea, nasal congestion, and elevated international normalized ratio (INR). Final data for STRIDE-2 are still pending, but preliminary data suggest that sitaxsentan at a dose of 100 mg daily may improve the time to clinical worsening for NYHA functional class II-IV.

In STRIDE-2, there were 4 arms of the study evaluating placebo, 50 mg sitaxsentan, 100 mg sitaxsentan, and traditional dosing of bosentan (for adults, 62.5 mg twice daily for 4 weeks, then increased to 125 mg twice daily; and for patients who weigh less than 40 kg [88 lbs] and who are over 12 years of age, 62.5 milligrams twice daily). Warfarin dosing must be monitored with this medication, and if the patient is on warfarin at the time of initiation of sitaxsentan, the dose should be decreased by 80% with monitoring of INR until therapeutic again on anticoagulant therapy. If warfarin and sitaxsentan are initiated together, warfarin should be initiated at a dose of 0.5 to 1 mg and titrated up to the goal INR.[6]

With these new therapies now available, the question becomes, "Where are we going with therapy now, and is combination therapy a good option?" Quite a few lectures at CHEST 2005 discussed combination therapy and associated outcomes. Vallery McLaughlin, MD,[7] discussed the addition of iloprost to bosentan in the STEP study. The objective of this trial was to evaluate safety and efficacy of dual therapy. Participants were randomized to receive iloprost (n = 32) or placebo (n = 33). The first part of the trial consisted of a 12-week blinded study with patients on stable-dose bosentan for a minimum of 16 weeks. Most patients were NYHA functional class III. The iloprost group experienced a 30-meter increase in 6MWD at the end of the 12 weeks, and the placebo group demonstrated a minimal increase of 4 meters. At 12 weeks, the iloprost group also demonstrated a 34% improvement in NYHA functional class vs 6% in the placebo group.

Sildenafil add-on therapy for patients receiving bosentan for the treatment of PAH, WHO class I, was reviewed by Stephen Mathai, MD.[8] Of the 98 patients receiving bosentan, 26 also received sildenafil for clinical worsening of symptoms. The patients were NYHA functional class II-IV. Of the 26 patients receiving sildenafil, 14 had idiopathic pulmonary arterial hypertension (IPAH) and 12 of those had scleroderma-associated PAH. At the end of the clinical trial, those with IPAH receiving bosentan and sildenafil demonstrated improvement in 6MWD whereas the 12 with scleroderma-associated PAH did not improve. There were 2 deaths in the scleroderma group. More than 20% of the patients stopped therapy secondary to side effects from sildenafil. Limitations of the study, Mathai stated, were the limited number of patients, lack of hemodynamics prior to the addition of sildenafil, selection bias, and the fact that it was not a controlled study.[8]

On the Horizon

So what's on the horizon for the treatment of PAH? While the FDA analyzes data from the STRIDE-1 and -2 studies and we await approval of sitaxsentan, other therapies are being evaluated. Myogen is currently conducting studies with ambrisentan, another selective endothelin receptor antagonist. Lewis Rubin, MD,[9] reviewed preliminary 12-week data that showed a decrease in right atrial pressure, mPAP, and PVR and an increase in cardiac index with ambrisentan use. Dr. Badesch later elaborated on this study, explaining that the 4 doses of ambrisentan that were evaluated (1.0, 2.5, 5.0, and 10.0 mg) resulted in an increase in 6MWD of at least 32 meters at Week 12. Data from all doses combined at Week 24 demonstrated approximately a 50-meter increase in 6MWD, with the IPAH group demonstrating greater improvement than the secondary PAH group. WHO functional class was also noted to improve. Adverse events noted were peripheral edema, upper respiratory infection, nasal congestion, headache, nausea, and flushing, with < 4% elevation of LFT.[4]

Inhaled treprostinil is also being evaluated and tadalafil, a long-acting PDE-5 inhibitor, has drawn attention. Clearly, further studies will have to be conducted and the PAH community will continue to strive to find the right medication combinations for those affected by this devastating condition. Research will also focus heavily on the cause of PAH as more is understood about the underlying pathophysiology. Future areas of study may also center around 2-methoxyestradiol, vasoactive intestinal polypeptide, and maybe even imatinab mesylate.

References

McLaughlin V. One year experience with intravenous treprostinil in pulmonary arterial hypertension patients. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 1722.Corate L, The use of sildenafil in the acute treatment of patients with severe pulmonary arterial hypertension and right heart failure. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 1729Sood N. Sildenafil I acutely decompensated right heart failure secondary to pulmonary arterial hypertension. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 1729.Badesch D. Long-term management of pulmonary arterial hypertension. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 963.Brown M. Long-term benefits of sildenafil treatment on health-related quality of life in patients with pulmonary arterial hypertension. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 10-31-05 ID# 1722Badesch D. Sitaxsentan improves the time to clinical worsening in patients with pulmonary arterial hypertension. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 1722.McLaughlin V. A randomized, double-blind, placebo-controlled study of iloprost inhalation as add-on therapy to bosentan in pulmonary arterial hypertension. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 1722.Mathai S. The addition of sildenafil to bosentan therapy in the treatment of pulmonary arterial hypertension. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 1722.Rubin L. The changing world of pulmonary arterial hypertension therapies: a focus on the patient. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 965.
 

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