Ask the Expert: Are Newer Management Approaches Increasing the Economic Burden of Treating Pulmonary Arterial Hypertension?

In a recent op-ed article published in the New York Times, Nobel Prize-winning economist Paul Krugman described the slowing of overall health care spending over the past few years, and attributed the lower cost increases recorded by Medicare Part D in part to the “absence of new blockbuster drugs.”1 Medical care providers for patients with pulmonary arterial hypertension (PAH) would be excused for seeing the world differently after what might reasonably be called a blockbuster past year. As described in the main articles of this issue of Advances, 3 new oral medications were approved in 2013,23 and implantable hemodynamic monitoring and implantable pump delivery systems are poised to change our understanding of disease severity, response to treatment, as well as delivery of intravenous prostacyclin.34 There is also news regarding additional treatments in the therapeutic pipeline and recent data supporting first-line double5 and triple combination6 medication therapy. These developments are raising the question: is the economic burden of treating PAH continually increasing, and if so, is it worth the additional cost?

The comparison at hand considers whether cost-conscious care providers mindful of the increasing focus on containing health care expenditures will favor the newer innovative management approaches (referred to as “innovations” in the subsequent discussion) over the traditional standard care, which may be lower cost. As explained within the Health Economics Resource Center (HERC) of the US Department of Veterans Affairs introduction to cost-effectiveness analysis,7 “If one of these alternatives saves costs and improves outcomes, it is favored; this principle is called dominance. The dominance principle can favor the innovation or standard care. When one of the alternatives is more costly and yields better outcomes, dominance provides no guidance. The decision maker will approve of its adoption only if the additional effectiveness justifies its additional cost.” While there are inadequate data currently available to definitively settle this issue, the remainder of this discussion will focus briefly on 3 key cost-effectiveness analysis questions relevant to PAH: (1) is there evidence of better outcomes with these innovations; (2) are the innovations higher or lower cost than previous standards; and (3) are there benefits that may justify a potential higher cost of innovations?

Considering the first of these questions, there is increasing evidence that innovative management approaches result in better outcomes in terms of survival and time to first clinical failure event. The multicenter Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) published in 20128 observed survival rates of 85% at 1 year, 68% at 3 years, and 57% at 5 years that compare favorably with the National Institutes of Health registry survival rates of 68% at 1 year, 48% at 3 years, and 34% at 5 years published in 1991.9 These data regarding improved survival with innovations involve historical comparisons that may be subject to significant bias in interpretation; however, other very recent data further support the argument for improved outcomes with innovations. The newly released initial results of the AMBITION trial showed a 50% reduction in the clinical failure rate, defined as time from randomization to the first occurrence of all-cause death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term clinical response.5 In AMBITION, first-line treatment with a combination endothelin receptor antagonist (ERA, ambrisentan) and concomitant phosphodiesterase type 5 inhibitor (PDE-5i, sildenafil) was compared with either medication alone as first-line therapy for World Health Organization (WHO)/New York Heart Association (NYHA) functional class II-III symptoms. This represents a significant innovation (with possible cost implications) compared to present guidelines that have recommended first-line combination therapy only for PAH patients with severe symptoms.10

If AMBITION represents a potential paradigm shift in the approach to first-line PAH therapy, it is relatively easy to understand concerns regarding rising PAH management costs. However, the discussion of the second question related to overall cost of innovations in PAH also requires a consideration of potential cost offsets.11 Medications for PAH are universally considered expensive, and use of first-line combination medication therapy may rapidly increase the up-front costs. Whether innovations such as new medication strategies pay for themselves over time largely depends on the avoidance (or minimization) of other costly events, a prime example of which include PAH-related hospitalizations. Data from the REVEAL Registry showed that 56.8% of the patients studied (n=862) had one or more hospitalizations, of which 52.4% were PAH-related.12 These hospitalizations represent a substantial economic burden and hence reducing them an equally substantial cost savings or offset. Based on an analysis of a large US insurance claims database, Lacey and colleagues estimated a hospitalization for the principal diagnosis of PAH was $73,880 (SD, $188,354).13 This was more than double the all-cause hospitalization mean cost of $34,123 (SD, $107,005). The recent SERAPHIN Trial examining the novel ERA therapy macitentan on a composite endpoint that included PAH-related deaths or hospitalizations observed that PAH patients treated with 10 mg macitentan daily experienced a 55% reduction in both hospitalizations (12 vs 27 per 100 patient-years for macitentan-treated group compared with placebo) and length of stay (mean of 2.7 hospital days for macitentan-treated group compared with 5.5 days with placebo).14 Additional research will ideally provide the basis for a comprehensive analysis of beneficial offsets resulting from innovations in PAH care.

The third and final question to address is whether a potential increase in PAH management costs may yet be worth accepting when considering the expected benefits. It would be convenient at this point in the discussion to be able to enumerate the data supporting improved quality of life based on innovative therapy. Data regarding health-related quality of life (HRQoL) in PAH are quite limited, however, as PAH-specific instruments to assess HRQoL are still in development, and effect of treatment on HRQoL has generally been studied only as a secondary or exploratory endpoint.15 This leads back to the previously cited clinical data, which offer a strong argument to utilize innovative therapy even if the cost offset leaves a higher economic burden. As summarized by Zhang and Soumerai in their analysis in Health Affairs, “It is important to emphasize that development of new medications can still provide net benefits to society, even in the absence of a cost offset. Some medications might have important nonpecuniary [financial] advantages relative to older drugs, such as higher life expectancy, better health outcomes, or reduced sick days, even if they do not reduce overall costs.”11 The functional benefits resulting from innovations in PAH management may in the future be shown to allow patients to remain in the workforce and to be more interactive outside their homes. This would likely alleviate some of the financial burden experienced by PAH patients and their families and reduce social isolation—important and valuable corollary benefits.15

In summary, assessing the economic burden of newer management strategies compared to traditional and potentially increasing generic medications requires more than a simple tally of up-front medication costs. Data suggesting better patient outcomes and possible substantial cost savings from these innovations continue to emerge. Specifically, data from recent longer-duration clinical trials measuring robust indicators of disease progression arguably provide indirect data suggesting there is also a quality of life benefit; however, an improved HRQoL has yet to be directly and convincingly shown. If utilizing innovations in present-day PAH care has improved survival, reduced hospitalizations, and slowed disease progression—even with a potential increase in costs—their use may well be justified.