Pulmonary Arterial Hypertension: Combination Therapy in Practice

Abstract

Combination therapy is now regarded as the standard of care in pulmonary arterial hypertension (PAH) and is becoming widely used in clinical practice. Given the inherent complexities of combining medications, there is a need for practical advice on implementing this treatment strategy in the clinic. Drawing on our experience and expertise, within this review, we discuss some of the challenges associated with administration of combination therapy in PAH and how these can be addressed in the clinic. Despite their differing modes of action, all of the currently available classes of PAH therapy induce systemic vasodilation. In initial combination therapy regimens in particular, this may lead to additive side effects and reduced tolerability compared with monotherapy. However, approaches such as staggered treatment initiation and careful up-titration may reduce the risk of additive side effects and have been used successfully in clinical practice, as well as in clinical trials and registry studies. When combination therapy regimens are initiated, it is important that patients are monitored regularly for the presence of any side effects and that these are then managed promptly and appropriately. For patients to attain the best outcomes, the treatment regimen must be tailored to the individual’s specific needs, including consideration of PAH etiology, the presence of comorbidities and concomitant medications beyond PAH therapy, and patient lifestyle and preference. It is also vital that individuals are managed at expert care centers, where multidisciplinary teams have a wealth of specialist experience in treating PAH patients. Adherence to therapy can be a concern in a chronic disease such as PAH, and as treatment regimens become increasingly complex, maintaining good treatment adherence may become more challenging. It is essential that patients are educated on the importance of treatment adherence, and this is a key role for the PAH nurse specialist. For patients who are managed carefully in expert centers with combination therapy regimens that are tailored to their specific needs, a favorable benefit–risk ratio can be achieved. With individual and carefully managed approaches, the excellent results observed with combination therapy in clinical trials can be obtained by patients in a real-world setting.

Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis

“…In line with findings in the AMBITION trial,12 peripheral oedema was more common with combination therapy than monotherapy. In patients receiving multiple therapies, a greater number of side effects compared with patients undergoing single therapy are possible, particularly therapies associated with vasodilation 32…”

Sex-specific differences and survival in patients with idiopathic pulmonary arterial hypertension 2008–2016

“…An early positive treatment response, with improvement of clinical, functional, and haemodynamic parameters [1], has been shown to result in a similar survival benefit as having a stable low-risk profile at the time of diagnosis [2, 20–22]. Thus, access to several treatment options and better understanding of treatment strategies, including the benefits of combination therapy [23, 24], might have contributed to reducing, not only the total mortality, but also the sex-related differences in survival seen in previous studies [25]. It has been suggested that women may benefit more from ERAs than men and that men may benefit more from a PDEi than women [25, 26]; however, findings from studies with a direct comparison between an ERA and PDEi did not support this [27, 28].…”

Combination Therapy in Pulmonary Arterial Hypertension: Gleaning a Practical Approach from the Randomized Trials

“…The practical application of combination therapy in PAH has recently been summarized. 19 Among other useful points is that all PAH patients may not tolerate the simultaneous initiation of a PDE-5 inhibitor and an endothelin receptor antagonist, that is, combination therapy may need to be initiated in a stepped approach. For those patients intolerant of oral IP receptor agonists, for example, in whom an oral IP receptor was initiated because of a decrease in 6MWD or an increase in NTproBNP as opposed to progression to functional Class IV, the clinician can consider a trial of either inhaled treprostinil or iloprost to improve functional capacity.…”