6. Galie N, Beghetti M, Gatzoulis MA, et al. Bosentan therapyin patient with Eisenmenger syndrome: a multicenter,double-blind, randomized, placebo-controlled study.Circulation 2006; 114: 48-54

7. Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapyfor pulmonary arterial hypertension. Am J Respir CritCare Med 2004; 169: 441-7

8. Barst RJ, Langleben D, Badesch D, et al. Treatment ofpulmonary arterial hypertension with the selectiveendothelin-A receptor antagonist sitaxsentan. J Am CollCardiol 2006; 47: 2049-56

9. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citratetherapy for pulmonary arterial hypertension. N Engl JMed 2005; 353: 2148-57

10. Lewis GD, Shah R, Shahzad K, et al. Sildenafil improvesexercise capacity and quality of life in patients with systolicheart failure and secondary pulmonary hypertension.Circulation 2007; 116: 1555-62

11. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hyper-tension. J Am Coll Cardiol 2009; 54 (1 Suppl.): S78-84

12. Galie N, Hoeper MM, Humbert M, et al. Guidelines for thediagnosis and treatment of pulmonary hypertension. Thetask force for the diagnosis and treatment of pulmonaryhypertension of the European Society of Cardiology (ESC)and the European Respiratory Society (ERS), endorsed bythe International Society of Heart and Lung Transplanta-tion (ISHLT). Eur Heart J 2009 Oct; 30 (20): 2493-537

13. Garin MC, Clark L, Chumney EC, et al. Cost-utility oftreatments for pulmonary arterial hypertension: a Markovstate-transition decision analysis model. Clin Drug Investig2009; 29 (10): 635-46

The Authors’ Reply

We would like to thank Lefebvre andHunsche[1] for their interesting comments regard-ing our cost-minimization analysis (CMA) offour oral therapies for the treatment of pulmon-ary arterial hypertension (PAH).[2] The two mainissues of debate are related to our assumption ofclinical equivalence between drugs and the eco-nomic impact of secondary therapies that wereused following adverse-effect-induced discontin-uations of the initial agent.

The four oral therapies evaluated in our studywere sildenafil, bosentan, sitaxsentan and am-brisentan, the latter three being part of the en-dothelin receptor antagonist (ERAs) class. Allexcept one of the pivotal placebo-controlled,double-blind randomized clinical trials (RCTs) ofthese PAH agents measured the improvement indistance walked in 6 minutes (6MWD) after

12–16 weeks of therapy as the primary endpoint.Improvement in New York Heart Association(imNYHA) functional classification was a sec-ondary endpoint. PAH is a rare condition with aprevalence of 26 patients per 1 million popula-tion.[3] As a result, head-to-head trials betweenactive drugs would require prohibitively largesample sizes, making their successful completiondifficult. Therefore, indirect statistical techniquesare the best approach to compare efficacy be-tween two or more drugs when randomized trialdata are not available.[4]

The indirect statistical comparison across thestudies of the four drugs clearly showed no statis-tically significant differences between the placebo-corrected changes in 6MWD and imNYHA over12–16 weeks, with the p-values being 0.34 and0.11, respectively (not p = 0.001 as suggested byLefebvre and Hunsche[1]). Despite statisticallysignificant imNYHA with some of the drugs re-lative to placebo in the original trials, the typicalimprovement was less than 0.5 of a class/subject(i.e. less than half of the subjects improved by oneclass) for all drugs. Hence, there is no clear sta-tistically significant difference in imNYHA be-tween active drugs as suggested by our indirectstatistical comparison. We acknowledge that lackof statistical significance does not necessarilyimply comparable efficacy. But it does suggestsmall (if any) differences that are unlikely to beclinically relevant. Therefore, these findings sup-ported our decision to conduct a CMA thatcompared direct costs between the four drugs.

Lefebvre and Hunsche[1] are correct that si-taxsentan was only given a ‘B’ recommendationby the Dana Point Expert Consensus State-ment.[5] However, it should be recognized thatsitaxsentan is currently approved for PAH ther-apy in Canada, Australia and the EU. Moreover,our idea of clinical equivalence of sildenafil andthe three ERAs is supported by the recentlypublished guidelines of the European Society ofCardiology (ESC) and the European RespiratorySociety (ERS), which gave all four drugs an ‘A’recommendation for the most common, NYHAIII PAH patients.[6]

Our results determined that, among the threeERAs, ambrisentan was the most economically

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ª 2010 Adis Data Information BV. All rights reserved. Appl Health Econ Health Policy 2010; 8 (1)

attractive from the perspective of the Canadianhealthcare system. The Canadian Common DrugReview (CDR) process conducts objective andrigorous reviews of the clinical and cost effec-tiveness of drugs, and provides formulary listingrecommendations to the publicly funded drugplans in the country. All new oral products inCanada must undergo a CDR review prior toprovincial formulary entry. The CDR reviewedour economic analysis, conducted their owninternal evaluation and essentially acceptedour conclusions. Ambrisentan was subsequentlygiven a positive recommendation for provincialformulary listing by the Canadian CDR process.

The second main issue highlighted by Lefebvreand Hunsche[1] was the rates of adverse effect-induced drug discontinuations and the choice ofsecondary therapies used in our model. Dis-continuations were obtained from those studiesthat evaluated each drug over the longest timeperiod. Hepatotoxicity is the most serious ad-verse effect of the ERA class of agents, but variesfrom the highest risk (11–14%) for bosen-tan, to £4% for sitaxsentan and 1–2% for ambri-sentan. Sitaxsentan also significantly interfereswith the metabolism of commonly used drugssuch as warfarin.[7,8] In contrast, clinical trialdata for ambrisentan suggest no relevant inter-actions with drugs commonly used in PAH.[9]

Moreover, ambrisentan can be safely used as arescue therapy in PAH patients who had bo-sentan or sitaxsentan discontinued because ofliver function abnormalities.[10] Similarly, second-line sitaxsentan after a bosentan failure has alsobeen reported to be safe.[11] There are no suchdata to support the use of bosentan for patientswho cannot tolerate first-line ambrisentan or si-taxsentan due to adverse effects such as hepato-toxicity. Therefore, in our model, ambrisentanwas used as a secondary therapy after a bosentanor sitaxsentan toxicity-induced discontinuation.This assumption is reasonable.

Notwithstanding the scenarios evaluated inour sensitivity analysis or other possible evalua-tions that could have been performed, it was clearthat the primary economic driver was daily drugcost, which was responsible for approximately 90%of the total economic impact. Therefore, modest

variations in secondary therapies and drug dis-continuation rates would not have altered theprimary conclusions of our study. When theclinical situation indicates that an ERA wouldbe the preferred agent, ambrisentan would becost saving because of its reduced daily drugcost, low rates of liver toxicity and minimal inter-actions with other medicines commonly used totreat PAH.

We wish to emphasize the theoretical nature ofour analysis with the overall intent being to guidehealth policy decision making. At the bedsidelevel, clinical decisionmaking is a complex process,based on many factors, including drug effective-ness and a risk-benefit analysis of therapy in eachpatient, as well as cost. Our analysis was based ona clearly stated assumption of clinical equiva-lence, supported by an indirect statistical com-parison of published placebo-controlled trialdata for each agent. However, it is critical to ap-preciate the serious and highly fatal nature ofPAH, and thus, the therapeutic goal is not justimprovement over a short-term period, but sus-tained benefit over several years. Although thereare important clinical data to support the bene-fit of PAH therapy over the long term, they areunblinded and uncontrolled, and thus cannotbe compared in an analysis such as ours. There-fore, well designed long-term trials are urgentlyneeded.

Finally, wewelcome and look forward to furtheropen scientific debate on the cost effectivenessof these important PAH therapies, given thattheir significant clinical benefits are achieved at ahigh cost.

George Dranitsaris1 and Sanjay Mehta2

1 Augmentium Pharma Consulting, Toronto,Ontario, Canada

2 London Health Sciences Centre, VictoriaHospital, London, Ontario, Canada

Acknowledgements

George Dranitsaris has acted as consultant to Glaxo-SmithKline Canada Inc. to develop this cost-minimizationmodel. GlaxoSmithKline did not contribute in any way to themethodology employed or to the interpretation of the results.Sanjay Mehta has received consulting and speaking fees from

72 Letter to the Editor

ª 2010 Adis Data Information BV. All rights reserved. Appl Health Econ Health Policy 2010; 8 (1)

pharmaceutical firms (Actelion Pharmaceuticals, Encysive,GlaxoSmithKline, Northern Therapeutics, Pfizer), and clin-ical investigator fees from pharmaceutical firms (Actelion,Encysive, Lilly, Pfizer, United Therapeutics) that own, marketand distribute pharmacological agents for the treatment ofpulmonary hypertension.

References1. Lefebvre M-C, Hunsche E. Oral therapies for the treatment

of pulmonary arterial hypertension: a population-basedcost-minimization analysis [letter]. Appl Health EconHealth Policy 2010; 8 (1): 69-71

2. Dranitsaris G, Mehta S. Oral therapies for the treatment ofpulmonary arterial hypertension: a population-based cost-minimization analysis. Appl Health Econ Health Policy2009; 7 (1): 43-59

3. Peacock AJ, Murphy NF, McMurray JJ, et al. An epide-miological study of pulmonary arterial hypertension. EurRespir J 2007; 30: 104-9

4. Song F, Altman DG, Glenny AM, et al. Validity of indirectcomparison for estimating efficacy of competing interven-tions: empirical evidence from published meta-analyses.BMJ 2003; 326: 472

5. Barst R, Simin J, Gibbs R, et al. Updated evidence-basedtreatment algorithm in pulmonary arterial hypertension.J Am Coll Cardiol 2009; 54: S78-84

6. Galie N, Hoeper MM, Humbert M, et al. Guidelines forthe diagnosis and treatment of pulmonary hypertension.Eur Heart J 2009; 30: 2493-537

7. Rubin L, Badesch DB, Barst RJ, et al. Bosentan therapy forpulmonary arterial hypertension. N Engl J Med 2002; 346:896-903

8. Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapyfor pulmonary arterial hypertension. Am J Respir CritCare Med 2004; 169: 441-7

9. Kingman M, Ruggiero R, Torres F. Ambrisentan, an endo-thelin receptor type A-selective endothelin receptor anta-gonist, for the treatment of pulmonary arterial hypertension.Expert Opin Pharmacother 2009; 10: 1847-58

10. McGoon MD, Frost AE, Oudiz RJ, et al. Ambrisentantherapy in patients with pulmonary arterial hypertensionwho discontinued bosentan or sitaxsentan due to liverfunction test abnormalities. Chest 2009; 135: 122-9

11. Benza R,Mehta S, Keogh A, et al. Sitaxsentan treatment forpatients with pulmonary arterial hypertension discontinu-ing bosentan. J Heart Lung Transplant 2007; 26: 63-9

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ª 2010 Adis Data Information BV. All rights reserved. Appl Health Econ Health Policy 2010; 8 (1)