Oral therapies for the treatment of pulmonary arterial hypertension: a population-based cost-minimization analysis

Abstract

Dranitsaris and Mehta[1] reported that, for patients with New York Heart Association functional class (NYHA FC) II/III pulmonary arterial hypertension in Canada, ambrisentan provides the same clinical benefit and is less costly than the other endothelin receptor antagonists (ERAs), bosentan and sitaxentan, and therefore should be considered as the ERA of choice. Their findings were based on a cost-minimization analysis (CMA) and, as they acknowledge, "the primary requirement of a CMA is that all clinical outcomes be equivalent between comparator treatments." From a literature review they identified nine randomized clinical trials of four oral treatments for pulmonary arterial hypertension - ambrisentan,[2,3] bosentan,[4-6] sitaxentan[7,8] and sildenafil[9,10] - to be included in their study. Based on a meta-regression analysis of efficacy data from these trials (improvements from baseline in placebo-corrected 6 minute walk distance, the Borg dyspnoea index and NYHA FC as well as absolute rates of time to clinical worsening) they concluded that "the assumption of clinical equivalence is reasonable" between agents. Based on the data identified, absolute rates of improvement in NYHA FC versus baseline (imNYHA) appear to be broadly in the range of 13-43% for the drugs included in the analysis. Indeed, the authors reported "the independent variable 'drug' in the meta-regression model failed to reach statistical significance with respect to the RR [relative risk] for imNYHA (p = 0.001)." However, the conclusion of clinical equivalence is misleading. Clear treatment differences between placebo and active drug in terms of NYHA FC improvement versus baseline have been reported across the trials for bosentan in patients originally in NYHA FC III (placebo-corrected improvement: 7-33.8%) and sildenafil in patients initially in NYHA FC II-IV and treated with the approved dose of 20 mg three times a day (placebo-corrected improvement: 21%) but not for ambrisentan (placebo-corrected improvement: -2.5% to 4.5%), as shown in the data provided by the authors in table IV. Indeed, for bosentan, sitaxentan and sildenafil, the improvements in NYHA FC versus placebo were statistically significant.[4,5,7,9] In contrast, "treatment effects observed were due primarily to less WHO [NYHA] functional class deterioration in patients receiving ambrisentan compared with patients receiving placebo."[2] We would like to ask the authors to explain this disconnect. It is also worth mentioning that expert consensus does not view these agents as clinically equivalent. In the recent guidelines issued by the experts following the 4th World Symposium on Pulmonary Hypertension in Dana Point, CA, USA in 2008, sitaxentan was given a lower grading (moderate recommendation [B]) than the other agents (strong recommendation [A]).[11] Furthermore, an inconsistent effect on the time to clinical worsening has been shown with ambrisentan[2] and an effect on this outcome has never been shown with sitaxentan.[7,8] In contrast, bosentan has consistently been shown to significantly increase the time to clinical worsening compared with placebo.[4,5] Alternative pharmacotherapy, after discontinuation of initial treatment, appears to be the main cost driver in this study. These costs were $Can1175 for ambrisentan versus $Can8279 for bosentan per patient for 3 years of therapy and were based on two assumptions that may be flawed. 1. The discontinuation rate due to adverse events (AEs) used in the CMA for bosentan 125 mg twice daily (6%) was approximately twice that used for ambrisentan 5 mg daily (3.1%). The discontinuation rates due to AEs for bosentan range from 0% over 20 weeks,[4] 5% over 16 weeks[6] to 6% over 16 weeks.[5] Discontinuation rates due to AEs for ambrisentan range from 0% to 4.1% over 12 weeks.[2,3] The authors provide no rationale as to why they used discontinuation data from only two studies,[3,5] one on bosentan and one on ambrisentan, and why they selected the highest percentage of discontinuations for bosentan, which was the combined rate for the twice daily 125 mg and 250 mg doses. …