The application of up-front combination therapy in PAH has drawn analogies to other diseases for which this strategy is commonly used, such as malignancy and Human Immunodeficiency Virus (HIV) infection [1, 2]. However, the molecular basis for this analogy is unclear. Monotherapy treatment for malignancy is associated with increased risk of de novo somatic mutations giving rise to resistant cellular clones; combination chemotherapy up-front decreases the chance of resistance, and prolongs survival in many forms of cancer [3]. Similarly, HIV may develop resistance to anti-retroviral therapy, which is prevented by the use of combination therapy [4]. However, there is no evidence that aberrant pulmonary vascular cells in patients with PAH develop escape mechanisms that are, in turn, resistant to therapy, much less that such patterns of resistance may be altered by up-front combination therapy.

Alternatively, the sequential addition of therapy allows evaluation of the individual clinical response to each medication, including allowing titration of the dose to optimize the benefit versus side effect profile. If the clinical response is (a) harm or (b) inadequate with the first medication, the initial medication can be removed or substituted, and/or a second class of medication added, with further optimization of the second medication before additional advancement of therapy as required. In this manner, tolerability and benefit are systematically optimized for each patient, with a clear assessment of response to each medication.

Such personalized therapy is important, as a fraction of patients will have a suboptimal response to any single medication. This fact of biologic variability is demonstrated by the data in Fig. 17.2, which reports the change in 6 min walk distance (6MWD) reported for PAH patients treated with riociguat in the recently published PATENT-1 trial [6]. In this study, 76 % of patients had a net positive improvement in 6MWD from baseline to the last study visit at 12 weeks, while 24 % of patients had a decline in 6MWD. The heterogeneity in clinical response will be compounded with the use of multiple medications, particularly if multiple medications are started simultaneously, some of which may be beneficial and some of which may be harmful; the net result may be partial or suboptimal, with great difficulty determining if one or more medications may actually be causing harm. Thus, sequential combination therapy has a strong biologic and practical rationale.

To date, 14 double-blind randomized clinical trials investigating the use of combination therapy in PAH have been published. Thirteen of these studies investigated the use of medications added sequentially (Table 17.1). In these studies, sequential addition of therapy was typically performed in the context of background PAH-specific therapy, with the exception of Iversen and colleagues, who assessed the effect of non-selective endothelin receptor antagonist therapy initiation with bosentan, followed by randomization of patients to placebo or sildenafil in a cross-over design [10].