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Combination Therapy with Sildenafil and Bosentan and Epoprostenol Weaning in Patients with Pulmonary Arterial Hypertension

Robert Frantz

Thomas DeZiel

Luanne Koenig

Michael McGoon


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Conference: 2006 International PHA Conference and Scientific Sessions

Release Date: 06.23.2006

Presentation Type: Abstracts

Robert P. Frantz, MD, Thomas A. DeZiel RN, Luanne J. Koenig RN, Michael D. McGoon MD,

Mayo Clinic College of Medicine, Rochester MN USA

BACKGROUND. The endothelin receptor antagonist bosentan and the phosphodiesterase-5 inhibitor sildenafil have each been shown to improve 6 minute walk distance, WHO functional class and hemodynamics in patients with PAH.  It has been hypothesized that combination therapy might be more effective than monotherapy. However, the randomized trials of each of these agents excluded patients receiving the other agent, and there is extremely limited reported experience with combination therapy.  Accordingly we reviewed our initial experience with this combination of therapy.

METHODS.   The records of all patients with PAH attending the Mayo Pulmonary Hypertension Clinic and receiving treatment with both bosentan and sildenafil who had signed Health Insurance Portability and Accountability Act authorization were reviewed. Combination therapy was initiated because of persistent exercise limitation despite monotherapy, persistent severe elevation in pulmonary artery pressure despite monotherapy, or with the goal of reducing or eliminating intravenous epoprostenol therapy. Sildenafil was initiated at 25 mg tid and titrated upward to a maximum dose of 100 mg tid. Bosentan was initiated at 62.5 mg bid and uptitrated at 1 month to 125 mg bid. Descriptive statistics include frequencies and percentages for categorical data and mean ± standard deviation for continuous data. Six minute walk distances, echo estimated PA systolic pressure, and WHO functional class before and at least 6 months after addition of the second oral agent (296 ± 161 days for six minute walks and 338 ± 240 days for echocardiograms) were compared utilizing paired t-tests. All tests are two-sided and a p value of  < 0.05 was considered to be statistically significant.

RESULTSEighteen patients were studied (15 women and 3 men, age 50 ± 15 years).  Eight patients had idiopathic PAH , 8 had APAH, Venice classification 1.3: (2 with diet drug exposure, 4 with scleroderma, 1 with unrepaired atrial septal defect and 1 with  repaired ASD). Two patients had PH in the context of obstructive sleep apnea (Venice classification 3.3).  Six patients were receiving intravenous epoprostenol, with addition of bosentan and sildenafil being intended to permit reduction or cessation of epoprostenol therapy. Thirteen patients had sildenafil added to bosentan therapy, while 5 patients had bosentan added to sildenafil therapy. Duration of therapy with the first oral agent prior to adding the second oral agent was 13 ± 10 months. The patients have been followed on combination therapy for 12.6 ± 8.3 months. WHO class was unchanged in 10 patients, while 8 patients improved by one functional class (mean baseline WHO class 2.6 ± 0.8, and at follow-up 2.2 ± 0.8, p = .002) with 100% survival. Combination therapy was well tolerated. No patients developed LFT abnormalities. Six minute walk distance improved from 429 ± 119 m to 473 ± 132 m (p = 0.004), and estimated PA systolic pressure improved from 90 ± 14 mm Hg to 81 ± 21 mm Hg (p = 0.04).  Of the 6 patients who had been on epoprostenol, 5 were able to discontinue this therapy, while one was able to reduce his epoprostenol dose from 67 to 46 ng/kg/min. One patient subsequently resumed epoprostenol because of the finding of a drop in mean pulmonary artery pressure from 51 to 38 mm Hg with epoprostenol administered at time of follow-up catheterization. All of these patients reported significant lessening of symptoms related to epoprostenol therapy including resolution of diarrhea, jaw claudication, flushing, rash and lower extremity aching. Freedom from an indwelling venous catheter and 24 hour a day pump was also perceived as a significant benefit. Six minute walk distances actually improved in all 6 patients compared to their walks while on epoprostenol alone.

COMMENTS AND CONCLUSIONS. Highly selected epoprostenol-treated PAH patients are able to transition to combined oral therapy. In our preliminary experience, combined therapy of PAH with sildenafil and bosentan appears to be safe and may be more effective than oral monotherapy. However, double blind placebo controlled trials of oral combination therapy are essential in order to rigorously test this hypothesis.