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Upfront triple therapy for pulmonary arterial hypertension: is three a crowd or critical mass?

Even the most enthusiastic reviews about progress in the pharmacotherapeutic management of pulmonary arterial hypertension (PAH) either begin or conclude with the sad acknowledgement that no treatment strategy comes close to being considered a “cure.” There is little doubt, however, that the cumulative discovery, clinical testing, approval and integration of an expanding armamentarium of medications has led to improvement in patients’ general well-being and life expectancy. Based on survival as a benchmark, the state of patients with PAH, as well as those with more narrowly and homogeneously defined idiopathic/heritable/toxin-induced PAH, has progressively improved from when no specific drug treatment was available, to when calcium channel blockers were used, to the introduction and use of intravenous epoprostenol, to the current era, in which multiple drugs are available and are frequently employed in combination [1–8]. Whereas median survival in 1986 for idiopathic PAH (then called primary pulmonary hypertension) was 2.8 years [2], it now exceeds 7 years [1].

The corollary of a beneficially widening array of therapeutic options is the complexity of guiding the multiple possible permutations of their use with an algorithm based on credible clinical studies, experience, and recognition of possible adverse effects as well as of expected degree and type of benefit. The Fifth World Symposium on Pulmonary Hypertension provided an updated treatment algorithm that summarises the options for treatment of PAH of varying degrees of symptomatic severity by World Health Organization (WHO) functional class, and attached a strength of recommendation and level of evidence grade to each group of options [9]. Thus, for example, any of the following medications (listed in politically neutral alphabetical order) are regarded as I-A or B for initial treatment of WHO functional class III PAH: ambrisentan, bosentan, intravenous epoprostenol, inhaled iloprost, macitentan, riociguat, …