Initial Triple Combination Therapy for Intermediate-and High-Risk Pulmonary Arterial Hypertension: Standard of Care or Still Too Soon to Tell?

To the Editor:

Current guidelines recommend initial oral combination therapy for patients with low- or intermediate-risk pulmonary arterial hypertension (PAH) and initial combination therapy including intravenous prostacyclin for high-risk patients, but whether dual or triple combination therapy is preferable remains an open question (1, 2). We read with great interest the perfect retrospective study from Boucly and colleagues (3), which investigated the impact of initial treatment strategy on the long-term prognosis of PAH by a comprehensive subgroup analysis and propensity score matching method and demonstrated tremendous survival benefits of initial triple combination therapy including parenteral prostacyclin for high-risk patients with PAH at the time of diagnosis. Excitingly, this is the first study showing a favorable profile of initial triple combination therapy with parenteral prostacyclin in intermediate-risk patients with PAH. However, the initial triple combination strategy is highly controversial among patients with intermediate- and high-risk PAH.

Three differential signaling pathways integrated in triple combination therapy, namely, the endothelin, nitric oxide, and prostacyclin pathways, may complement each other and produce superimposed or even synergistic effects (1). Gone are the days when patients with PAH had no available effective medicines, and with multiple accessible drugs advancing side by side and vying for the light, we have ushered in a new era of prosperity, so why not choose an optimized initial triple combination strategy? Moreover, a high proportion of triple combination therapies (including epoprostenol) enabled Japanese patients with idiopathic/heritable PAH to obtain a good long-term prognosis, with a 10-year survival rate of nearly 80%, suggesting more effectiveness of a relatively aggressive treatment strategy to rapidly reach low-risk status or hemodynamic normalization, especially for intermediate- and high-risk PAH (4). Additionally, although initial dual combination of PAH-targeted medications brought clinical benefits (5), the overall 10-year survival rate reported in the related study was only 43%, with 25% of patients with PAH receiving initial dual therapy escalated to triple combination therapy after a median follow up of 17 months (3), indicating the former strategy may result in disease progression and delayed optimal treatment.

Nonetheless, medication administration complexity, high drug expenses, targeted agent accessibility, and various adverse effects make initial triple combination strategy contentious and challenging. Unlike widely accepted oral medication, subcutaneous or intravenous administration of treprostinil requires complex up-titration to achieve an optimally tolerated dose. Regarding cost burden and drug accessibility, bosentan, macitentan, riociguat, and selexipag were already covered by Chinese national health insurance in 2019, but treprostinil has not been included. Furthermore, epoprostenol is not currently marketed in China, thus greatly limiting the therapeutic measures of critically ill patients. Last but not least, 19.0% of patients with PAH treated with selexipag, in the post hoc analysis of GRIPHON Study (evaluating a selexipag add-on to background dual combination therapy), prematurely discontinued their study regimen because of an adverse event, implying more side effects with more drugs (6).

Further prospective, multicenter, randomized controlled trials are needed to conclusively determine the optimal triple drug combination, and the role of initial triple therapy in other PAH subtypes, such as congenital heart disease or connective tissue disease–associated PAH, is also worth exploring.