A paradigm shift in pulmonary arterial hypertension management

At the end of 2013 clinicians managing pulmonary arterial hypertension (PAH) patients have many more treatment options available to them than they did two decades ago. Basic and clinical research continue to expand treatment options but, in a changing PAH environment, there is a need to move away from trials with primary end-points that merely demonstrate short-term improvements in function to large scale trials utilising robust end-points that reflect long-term morbidity and mortality [1].

The reviews in this issue of the European Respiratory Review discuss this evolution of study design and management of patients with PAH. The authors, all experts in the field of pulmonary hypertension, delivered the presentations upon which the articles are based at the 12th International Pulmonary Hypertension Forum in April 2013 in Hamburg, Germany. This annual platform for the exchange of knowledge and experience among clinicians and researchers was attended by over 1000 healthcare professionals from all over the world, highlighting the continuing interest in PAH.

All oral therapies currently available for the management of PAH have been approved based on change in 6-min walk distance (6MWD) over a short 12–16-week study period [2–6]. The 6MWD is a simple, inexpensive, reproducible test that has allowed the rapid expansion of therapeutic options in PAH, and remains a valuable, clinically important measure of symptomatic improvement. However, in today's more advanced PAH field, its utility as a primary end-point has been challenged. In their review, Gaine and Simonneau [7] will discuss the limitations of the 6MWD, including its reduced sensitivity in patients with milder disease [8] and the reduced ability to detect a treatment effect in patients already receiving PAH therapy [9]. With a diminishing pool of treatment naïve PAH patients this is particularly important as new agents will be evaluated in patients remaining symptomatic on initial therapy [10]. In addition, a meta-analysis of 22 randomised controlled trials found that change in 6MWD, the primary end-point employed in registration trials of PAH therapies, was not correlated with longer term outcomes [11].

To date, national PAH registries or single-centre cohort studies have been the only source of long-term outcome data. Although the information provided by such studies is valuable, prospective randomised controlled trials are required. The limitations of 6MWD have led to the use of composite primary end-points, consisting of morbidity and mortality events, being recommended [1]. Recommendations have been made on clinically relevant components that would comprise a composite primary end-point and mandating independent adjudication of all components [1]. As discussed in the review by Preston et al. [12], in the event-driven SERAPHIN study [13] these recommendations were refined further to produce a robust end-point and ensure that this study demonstrated a real benefit in clinically important long-term outcomes, namely a significant reduction in the risk of morbidity or mortality. Even with a composite end-point such trials need to recruit large numbers of patients, which is a challenge in a rare disease such as PAH. However, the SERAPHIN trial highlights that such trials can be conducted and other phase III, event-driven, long-term morbidity and mortality trials in PAH are ongoing, e.g. GRIPHON (oral selexipag; NCT01106014 [14]), COMPASS-2 (bosentan and sildenafil versus sildenafil monotherapy; NCT00303459 [15]) and AMBITION (first-line tadalafil and ambrisentan; NCT01178073 [16]). These trials will all be completed within the next 2 years and have the potential to inform on the design of all future clinical trials in PAH.

All drugs approved for the management of PAH target established pathogenic pathways; the endothelin, nitric oxide (NO) and prostacyclin pathways [17, 18]. Targeting these three pathways facilitates combination therapy, which is established in the treatment of PAH and has improved the outlook for PAH patients. However, despite the availability of several therapeutic options the long-term prognosis for patients with PAH remains unsatisfactory [19–21]. Ongoing research efforts focused on identifying targets within novel pathogenic pathways and improved drugs acting on known pathways are discussed in the review by Galiè and Ghofrani [22]. New drugs that are in advanced development and target existing pathways are macitentan (endothelin pathway), selexipag (prostacyclin pathway) and riociguat (NO pathway). Imatinib is the first non-vasoactive drug to enter phase III clinical development. Preclinical and small clinical studies are evaluating future candidate therapies that target new pathways.

PAH is a rapidly progressing disease, even in patients with mild symptoms [23], underlining the need for prompt diagnosis. Early diagnosis is confounded by the subtle, nonspecific nature of symptoms and by a low index of suspicion. However, as discussed in the review by Schwaiger et al. [24], screening of at-risk patient populations can identify PAH earlier, facilitating earlier treatment and improving prognosis [25]. The recently published DETECT study systematically evaluated 112 noninvasive screening tests in 466 systemic sclerosis patients who had undergone right heart catheterisation (RHC). The resulting algorithm is highly sensitive and misses fewer diagnoses than the European Society of Cardiology/European Respiratory Society guidelines [26]. The challenge with screening in PAH is to strike the right balance between the rate of missed diagnoses and the rate of RHC. The DETECT algorithm will help rheumatologists decide in which patients referral for RHC is warranted, which in turn should optimise resource utilisation.

PAH is a disease characterised by a progressive increase in pulmonary vascular resistance. However, it has subsequent effects on the right ventricle that ultimately lead to death [27]. Measures of right ventricular function are important in determining prognosis and in some cases evaluating response to treatment [28–32]. As a consequence it is critical to monitor right ventricular function. In the review by Peacock and Vonk Noordegraaf [33], the authors compare cardiac magnetic resonance imaging (CMRI) with other modalities for monitoring PAH patients. They highlight inherent difficulties in assessing the complex structure of the right ventricle based on two-dimensional images obtained with conventional echocardiography, which is compounded by inter-operator variability. They suggest that given the key role of the right ventricle in the progression of PAH, three-dimensional CMRI alone or in combination with other noninvasive tools is likely to become increasingly important in the routine assessment and monitoring of PAH patients and, with validation, may become a routine measure in clinical trials.

Guillevin et al. [34] report the results of a survey that examined the substantial financial, emotional and social impact of PAH on patients and their caregivers. Their study highlights the need for PAH patients not only to receive appropriate medical and surgical care but also psychological and emotional support from their communities.

Finally, Dimopoulos [35] highlights an often neglected patient population; patients with PAH due to congenital heart disease (CHD). Patients with PAH-CHD are initially under the care of a small number of specialised paediatric cardiologists. However, due to advances in therapy these patients are living longer and transitioning to the care of specialists who deal with adult patients. As such, they present a unique challenge not shared with other forms of PAH. Dimopoulos [35] presents the case of a patient diagnosed with Eisenmenger syndrome due to a large patent ductus arteriosus and discusses optimal diagnosis and treatment options based on available evidence and expert consensus.

The reviews in this issue of the European Respiratory Review highlight the continued evolution of the PAH field. Within the next few years drugs will be available that have a demonstrated effect on the clinically relevant outcomes of morbidity and mortality, with new pathways emerging as potential targets for continuing pre-clinical research. Such progress must continue if PAH is to eventually become a curable disease.

• Received September 17, 2013.
• Accepted September 17, 2013.

• ©ERS 2013