Prof Brian Allwood, Associate Professor, Division of Pulmonology, Stellenbosch University, Stellenbosch

As physicians we pride ourselves in using the latest available evidence to objectively assess and treat our patients, to obtain the best possible outcomes.

The prognostic information gained from regular risk assessment provides information about the patient’s disease course and guides individualised treatment decisions



Yet, in doing so, there is risk of neglecting the patient on the other side of the parameters.

Receiving a diagnosis of pulmonary artery hypertension (PAH) can be devastating to patients and families, a frustration that is often compounded by the ubiquitous delays in diagnosis, all the while symptoms progress. Misinformation abounds on the internet and social media platforms, and patients can initially be both fearful and overwhelmed, while at the same time feeling isolated.

It is important for us as clinicians to be aware of our individual patient’s perspective, recognising up to half may be experiencing depression. But the personal impact of PAH extends beyond depression, with 60% reporting a major impact on overall quality of life, and 90% reporting at least some concerns about life-expectancy, while 73% report reductions in household incomes. This impact is not limited to the patients, with 29% of carers also reporting negative effects on their employment. As doctors, we need to take steps to identify each patient’s ‘extra-medical’ needs and take steps to address these. Dr Howard emphasises in the second article, two key steps namely, empowering our patients through providing correct information and shared decision making, and directing our patients towards reputable patient associations and support groups. Each patient has unique expectations of their care, but improvement in overall quality of life and increased life expectancy are valued as ‘most important’ for the majority. Fortunately, the hopelessness of previous generations can now be dispelled. With appropriate assessment and management, improved outcomes are possible for most patients. Better understanding of the pathophysiology of PAH and availability of therapy combinations have driven these advances.

Prof Hoeper, of the Hannover Medical School, Germany, emphasises the importance of regular, objective risk assessments in PAH, highlighting the importance of aiming for low-risk criteria in patients. Large prospective registry data has confirmed that this can now be effectively assessed non-invasively. Two meta-analyses have shown that dual therapy reduces the risk of clinical worsening over mono-therapy by approximately 30%, both overall and in connective tissue disease (CTD) associated PAH. These data are encouraging, and Prof Hoeper explores the use of dual therapy further in his article.

PAH is not an easy burden for patients to carry, and we as clinicians, therefore, need to frequently reassess our patients with PAH to optimise treatment and maximise outcomes, while using these important patient interactions to encourage, educate, understand and assist as best we can with their ‘extra-medical’ needs.


Marius Hoeper, Hannover Medical School, Hannover, Germany

This article is from the abstract: The lung, at the heart of pulmonary arterial hypertension, presented at: Janssen-sponsored Industry Evening Symposium, 30th European Respiratory Society International Congress, 9 September 2020.

The importance of comprehensive, multiparameter risk assessment in the management of PAH has continued to increase over the last decade. The prognostic information gained from regular risk assessment provides information about the patient’s disease course and guides individualised treatment decisions, with the overall goal of keeping the risk of mortality low. There have been numerous methods proposed for assessing risk, including the REVEAL risk score calculator and the risk stratified approach in the ESC/ ERS 2015 Guidelines. The latter approach, developed based on expert opinion and clinical evidence, stratifies patients into categories reflecting low-, intermediate- and high-risk of one-year mortality based on multiple parameters. These parameters address clinical signs of disease progression, functional and exercise capacity, and measures of right ventricular function. It is recommended that patients are assessed at baseline and at regular follow-up intervals, every 3-6 months during the course of therapy, which allows tailored treatment decisions and early intensification of therapy to ensure that each patients gets the best possible outcome.

COMPERA, SPAHR and the French PH registry are three European registries that have recently been used to validate the risk assessment approach proposed in the ESC/ERS 2015 Guidelines. The prognostic relevance of risk stratification in over 3 000 incident patients was examined in these studies. An increased number of low-risk criteria, or a low-risk status, was associated with a significant survival advantage. This was observed at baseline and was even more pronounced at follow-up. Moreover, a non-invasive approach to risk assessment using only World Health Organization functional class (WHO FC), six-minute walking distance (6MWD) and (NTpro-)BNP has shown to be also very effective at baseline and follow-up, and has been validated also in the COMPERA registry. Furthermore, inclusion of immutable risk factors such age, sex and PAH aetiology in REVEAL 2.0 risk assessment has demonstrated prognostic value for long-term survival and can be used to guide the initial treatment decision.

The primary goal of PAH-specific treatment is to achieve and maintain a low-risk status. For those patients who are diagnosed at low- or intermediate-risk of mortality, initial oral combination therapy is strongly recommended by the 6th WSPH. Recent studies provide compelling evidence of improved long-term outcomes with double oral combination compared with monotherapy. For example, intensification to combination with macitentan improves health-related quality of life, exercise capacity and haemodynamics in PAH patients previously treated with phosphodiesterase type 5 inhibitors (PDE-5i). However, for a small subset of patients including those for example with suspicion or high probability of pulmonary veno-occlusive disease or pulmonary capillary haemangiomatosis, monotherapy is still recommended as an initial treatment choice.

In AMBITION, a randomised, controlled, multicentre study, a reduction in the risk of clinical failure was observed for patients receiving initial double combination therapy with an endothelin receptor antagonist (ERA) and a PDE-5i compared with patients receiving mono therapy, even when patients’ symptoms were less severe at baseline (WHO FC II). Moreover, results from the OPTIMA study show that initial combination therapy of macitentan and tadalafil improves the number of low-risk criteria after 16 weeks of treatment while improving haemodynamics and exercise capacity compared to baseline. More recently, data from the randomised controlled study TRITON, evaluating whether initial oral triple was superior to initial oral double combination therapy in treatment-naïve patients, showed improvements in haemodynamics, NT-proBNP and functional capacity in both treatment groups, confirming the importance of combination therapy in PAH.

Although the primary endpoint of the study was not met, the initial triple combination group of macitentan, tadalafil and selexipag showed positive signals towards improved long-term outcomes. These data support what was already observed in the GRIPHON study, showing that the addition of selexipag to patients already treated with a PDE-5i and an ERA reduced the risk of morbidity/ mortality events (by 37% compared to placebo), which seem to be even more pronounced when selexipag was added earlier in the course of the disease. The GRIPHON study, the largest randomised controlled study investigating the effects of selexipag on long-term outcomes in patients with PAH, suggested selexipag-treated patients, when compared to placebo, were more likely to increase their number of low-risk criteria from baseline. In conclusion, the use of initial double combination therapy for most PAH patients is strongly supported by clinical trial data and the recent WSPH 2018 Proceedings. This treatment approach has improved the outcomes of many patients, and escalation of treatment at the first sign of intermediate risk, earlier on in the course of the disease improves outcomes further.

REFERENCES: Allwood B, Hoeper M. in PHocus. Latest developments in the management of Pulmonary Hypertension. Issue 3:2021:3;12.