Now, similarly, the management of pulmonary arterial hypertension (PAH) is evolving to ‘keep the barn door closed’ before the proverbial horse bolts. In the case of PAH, the failing right ventricle would be analogous to the barn door, and keeping it together requires a two-pronged approach: the early diagnosis of PAH and aggressive evidenced-based treatment earlier in the disease course. The latter has thankfully been made possible through the 14 different medications now available for PAH treatment.

*Supplied content

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

Dr Gaine’s article highlights that pulmonary hypertension diagnosis frequently takes more than two years from symptom onset and provides clues to the diagnosis for physicians. Importantly, clinicians need to be aware of the 6th World Symposium on Pulmonary Hypertension’s recommendation to lower the definition of PAH from a mean pulmonary artery pressure (mPAP) of >25mmHg to >20mmHg (with an elevated pulmonary vascular resistance). This important change was driven by right heart catheterisation data obtained from normal subjects and represents the upper limit of the 97.5th percentile. Naturally this is likely to facilitate diagnosis earlier in the disease course, and lowering this threshold now identifies an early-disease population who have subsequently been found to also be at risk of poor outcomes.

Traditionally, the invasive measures of right atrial pressure and cardiac index (and not mPAP as commonly believed) have been the best predictors of outcome. However, robust evidence from registry data now shows the relatively simple assessments of WHO functional class (FC), 6MWD and serum BNP/ NT-proBNP measurement appear adequate in risk stratifying many patients with PAH. Striving for low risk is the new mantra of the PAH community. Thus, assessment of these simple objective measures at baseline and regularly throughout the disease course, will remind clinicians to be vigilant for opportunities to intervene and lower patient’s risk profile wherever possible.

Dual therapy (endothelin receptor antagonist and phosphodiesterase-5 inhibitor) is now considered standard initial care for PAH patients in FC II (mild symptoms with exertion) and FC III (moderate dyspnoea with activities of daily living). But the initiation of the third class of therapy, prostacyclin pathway agents (PPAs), can be complex as they have conventionally been given parenterally. Enter the oral PPAs. But when should they be initiated? Certainly, their use is not advocated for PAH patient in WHO FC I (no symptoms with routine exertion), nor WHO FC IV patients (dyspnoea at rest) whom should be initiated directly onto intravenous PPAs, where available. In terms of the PIXEL consensus statement on the positioning of the oral PPAs in PAH, it is suggested that PAH patients with WHO FC II and adverse haemodynamic parameters, recent hospitalisations or features of RV dysfunction; as well as most WHO FC III patients should be considered for selexipag in addition to dual therapy, but not oral Treprostinil, for which there is little data.

This line of thought has largely been driven by the positive GRIPHON TRIAL of 1156 PAH patients, 98% of whom were in WHO FC II and WHO FC III, with a third already on dual PAH therapy. Yet, repeated risk assessment is advised, and importantly caution should be taken against anecdotal experience, where lack of anticipated symptom improvement combined with well described side-effects profile, may jeopardise the evidence-based longer-term outcomes for the individual patient on selexipag, if therapy is withdrawn prematurely.

PAH management involves complexities in both diagnostic accuracy and therapy selection, but hopefully as improved outcomes become more visible, the paradigm shift of ‘striving for low risk’ will gain further momentum.

Assessing risk to make timely treatment decisions

From: Modern patient management in SSc-PAH – early diagnosis & treatment initiation (Abstracts)

Presented at: Actelion-sponsored Satellite Symposium, 6th Systemic Sclerosis World E-Congress, 13 July 2020.

Prof Sean Gaine, Mater Misericordiae University Hospital, Dublin, Ireland

PAH affects approximately one in 10 patients with systemic sclerosis (SSc) and is responsible for almost 30% of all SSc-related deaths. When compared with patients with idiopathic or other connective tissue disease-associated PAH, patients with SSc- PAH have higher mortality rates despite similar or less severe baseline haemodynamics. SSc-PAH patients can deteriorate rapidly, and disease progression events can occur frequently even in patients with mild or no PAH symptoms at diagnosis.

Following diagnosis of PAH, risk assessment is essential both at baseline and at regular intervals during therapy to determine prognosis and to allow treatment decisions to be tailored to the patients’ status. Several methods of assessing risk have been proposed, including the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) risk calculator and the risk stratification parameters in the ESC/ERS 2015 Guidelines.

The REVEAL risk score calculator factors in modifiable and non-modifiable parameters such as comorbidities, and gender provides a score that can be used to categorise patients as being at low, intermediate or high risk of death. The calculator was recently updated to include new and revised variables including all-cause hospitalisations within the last six months. The REVEAL risk calculator has been validated in several patient populations including in those with SSc-PAH (n=292) enrolled in the PHAROS registry.

The ESC/ERS 2015 Guidelines proposed a set of modifiable invasive and non-invasive parameters to help stratify patients according to low, intermediate or high risk of one-year mortality. Based primarily on clinical evidence and expert opinion, these stratified parameters have since been validated in three European registries (COMPERA, SPAHR and the French Pulmonary Hypertension registry), comprising more than 3 000 incident patients. Results from the French registry showed that the number of low-risk criteria (WHO/ NYHA functional class I–II, 6MWD >440m, right atrial pressure <8mmHg and cardiac index ≥2.5 L·min-1·m-2) at baseline and follow-up accurately determined the risk of death or lung transplantation.

Further analyses also showed that using only non-invasive criteria (WHO/NYHA functional class I– II, 6MWD > 440 m, BNP <50 ng/L−1 or NT-proBNP <300 ng·L−1) were sufficient to discriminate for survival and clinical worsening-free survival in PAH patients (idiopathic, heritable and drug-induced) at baseline and follow-up. In the SPAHR and COMPERA analyses, PAH patients identified as low risk using composite scoring had a better prognosis at baseline and follow-up. Independent of the methods used, these studies highlight the importance of improving to or maintaining a low-risk status for improved prognosis. These methodologies for risk assessment based on the ESC/ERS 2015 Guidelines have also been specifically validated in SSc-PAH patients in two large cohorts including over 600 patients with SSc-PAH24. In both studies, a reduced risk of mortality was significantly associated with a low-risk status at baseline and follow-up.

It is clear from the ongoing research in this area that regardless of which method is used for risk assessment, the most crucial aspect is that a patient’s risk is evaluated at baseline and regularly at follow-up, including in those patients with SSc-PAH. It is essential that the assessment is comprehensive and includes multiple parameters, which when viewed alongside clinical gestalt can give a good estimate of how the patient’s disease will progress, and consequently provide guidance on optimal therapeutic strategies. Each risk assessment method comes with advantages and disadvantages. Ultimately, it is up to the individual physician to decide which method is most suitable for their clinical practice.

Delays in diagnosis adversely impact clinical outcomes and patients often wait too long for a PAH diagnosis. However, advancements in disease management, which include comprehensive risk assessment and combination therapy regimens, have led to encouraging improvements in patient outcomes. Attaining and maintaining a low-risk status in patients is the ultimate treatment goal in PAH.

REFERENCES:

Source: in PHocus: Latest developments in the management of Pulmonary Hypertension. 2021:1;3-4.