Pulmonary Arterial Hypertension: Combination Therapy in Practice

Marsha Burks; Simone Stickel; Nazzareno Galiè


Am J Cardiovasc Drugs. 2018;18(4):249-257. 

In This Article

Abstract and Introduction


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.


Using combination therapy to target multiple pathogenic pathways is now considered the standard of care in pulmonary arterial hypertension (PAH). Strong evidence from randomized controlled trials (RCTs) and observational studies support this approach,[1] and both initial and sequential combination therapy have a prominent role in the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines on pulmonary hypertension (PH).[2,3] Combination therapy has been administered in clinical practice for > 15 years, and its use is increasing.[4–7] This is not surprising given that there is a strong scientific rationale for its use in PAH and the clear importance of this option for a disease that is progressive and ultimately fatal.[1,8] Given the rapid expansion of the evidence in the past few years and the strength of the ESC/ERS guideline recommendations, it is now clear that the benefits of combination therapy should be made available to the majority of PAH patients.

Combination therapy has been shown to be efficacious in the clinical trial setting, but it may also increase the practical challenges in clinical practice, and care must be taken to ensure that the benefit–risk ratio remains favorable for the patient. The robust clinical efficacy data supporting combination therapy and the role of risk stratification to guide clinical decision-making have recently been comprehensively reviewed.[9] However, practical advice for healthcare professionals regarding combination therapy management in the clinic is also required. For this review, we performed a search of the literature using PubMed to identify all published papers in the English language related to the use of combination therapy in PAH. With the help of this literature review, we identified some of the challenges associated with the use of combination therapy and drew on our clinical experience to provide advice on these practical aspects within this review article. This includes tailoring the treatment regimen to the needs of each patient, optimizing the protocol used for treatment initiation and appropriately managing side effects. By implementing these steps into the management of combination therapy, it is possible to strike the right balance between therapeutic safety and efficacy, in order to achieve the best possible outcome for patients.