Speaker: Olivier Sitbon
The task force on treatment algorithm has presented its findings, focusing on the evolution of treatment approaches for pulmonary arterial hypertension (PAH). Initially, treatment algorithms were primarily based on functional class assessments which was very subjective. However, algorithms became more complex with the advent of drug classes like endothelin receptor antagonists (ERAs) and phosphodiesterase-5 (PDE5) inhibitors. Since 2015, a paradigm shift has occurred, by algorithms emphasizing on risk assessment over the functional class to determine right treatment for the right patient. The goal of the new algorithm is to simplify the existing algorithm while ensuring optimal patient care.
The first step after diagnosing PAH involves assessing vasoreactivity to identify patients who may benefit from calcium channel blockers. A positive vasoreactivity test is defined as a decrease in mean pulmonary artery pressure (mPAP) by >10 mmHg to <40 mmHg without a change in cardiac output or index. Recent studies suggest that a significant proportion of patients who respond acutely to calcium channel blockers may also exhibit long-term benefits. Therefore, in the new algorithm, vasoreactivity testing is a crucial initial step. Patients who demonstrate a positive response may be treated with calcium channel blockers to achieve low-risk status and near-normal hemodynamics.
For the non-responders, the treatment of PAH has evolved to target four pathways, including the traditional nitric oxide pathway, endothelin pathway, prostacyclin pathway, and the newer, transforming growth factor-beta (TGF-beta) pathway. The 2022 European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines considered comorbidity as a primary determinant in deciding the treatment approach, while the newer algorithm is shifted to a more patient centric approach. While comorbidities remain important considerations, the severity of PAH and the patient's overall condition should guide the selection of therapy. Considering the number and individual weight of comorbidities, a personalized approach should be adapted to optimize treatment outcomes. Monotherapy may not be sufficient for all patients with comorbidities, particularly those with severe PAH.
The initial step after diagnosing PAH involves a comprehensive risk assessment outlined in the ESC/ERS guidelines. The three strata risk assessment categorizes patients into three of the following risk status: low, intermediate, and high. Several other methods, including the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) risk score, can also be employed to determine risk status. The new algorithm proposes a revised approach by modifying the risk stratification into a binary approach: high risk versus not high risk. This shift was motivated by need of identifying patients who would benefit most from triple combination therapy which includes parenteral prostacyclins. In the previous treatment algorithm, for both patients with low and intermediate risk, oral dual combination therapy was the recommended treatment. Recent studies including of macitentan and tadalafil have demonstrated the superiority of dual combination therapy over monotherapy in these subsets of patients. Conversely, based on registry and observational studies, patients with high risk, typically treated with triple combination therapy, have demonstrated improved survival. However, the decision to initiate triple combination therapy may also extend beyond the high-risk category. Some patients with intermediate risk, particularly those with severe hemodynamics or impaired right ventricular function, may also be considered for this treatment approach. Age, patient preference, and other clinical variables influence this decision.
Reassessing the patient's condition is crucial after three to four months and should be repeated regularly. At follow up, the primary goal of treatment is to achieve a low-risk status, which is assessed by evaluating functional class, 6 minute walk test, and brain natriuretic peptide (BNP) levels. Hemodynamics and echocardiography may also be considered in certain situations. The four risk stratification outlined in the ESC/ERS guidelines is generally effective for risk determination for intermediate risk patients. However, addition of hemodynamics in this can provide additional insights for these patients. A recent study by Athénaïs Boucly and the French group demonstrated the value of hemodynamics in refining risk assessment in these patients.
The primary goal of treatment at follow-up for PAH patients is to achieve and maintain a low-risk profile. This aligns with the recommendations outlined in the 2022 ESC/ERS guidelines. For patients at an intermediate-low risk, the new treatment algorithm suggests adding an oral or inhaled prostacyclin pathway agent. The data from the GRIPHON, TRIUMPH, and FREEDOM-EV studies support this recommendation. Alternatively, switching from phosphodiesterase type 5 (PDE5) inhibitors to soluble guanylate cyclase (sGC) stimulators can be considered, with evidence shown in the REPLACE study. For patients at an intermediate-high or high risk, the recommended initial treatment is the addition of intravenous (i.v) or subcutaneous (s.c) epoprostenol. While studies have demonstrated that the proportion of patients achieving a low-risk status with this sequential combination approach is not consistently high, it remains a viable option. Another emerging treatment approach is the addition of an activin signaling inhibitor, which a new treatment, currently available in the United States and is expected to be approved in Europe soon. The STELLAR study, which included over 300 patients with stable background PAH therapy including monotherapy, dual combination and triple combination therapy, demonstrated efficacy with addition of activin signaling inhibitor even as the third or fourth drug. The primary endpoint of the study was a change in six-minute walk distance, which showed a significant improvement of approximately 40 meters compared to placebo. Secondary endpoints, such as multi-component clinical improvement, pulmonary vascular resistance, functional class and especially right ventricular function, had markedly positive improvements.
Lung transplantation may be indicated at each step, at baseline, and during follow-up. The consensus statement by the Task Force on Lung Transplantation decided on 3 main indications for lung transplantation: transplant referrals should be considered for select high-risk patients at the time of diagnosis, for intermediate-high-risk and high-risk patients at the first or subsequent follow-up and for patients with persistent intermediate-high or high-risk stratification while on maximal therapy, which is likely 4 drugs.
The pipeline for PAH is rich with potential therapeutic targets. While the task force did not extensively discuss this topic, it was noted that the platelet-derived growth factor (PDGF) inhibition pathway is a promising area of focus. Seralutinib, a tyrosine kinase inhibitor administered via inhalation, has shown potential to improve hemodynamics in patients with severe PAH, as demonstrated in the Phase II TORREY trial. Beyond the traditional pathways targeting endothelial dysfunction, other avenues under investigation include the bone morphogenetic protein/transforming growth factor beta (BMP/TGF-beta) pathway, PDGF inhibition, anti-inflammatory and immunomodulatory therapies, hormonal pathways, metabolism, epigenetic alterations, pathways targeting the sympathetic nervous system, extracellular matrix, and cell-based therapies. These investigational pathways include numerous potential drugs which seem promising in this evolving landscape of PAH treatment.
European Respiratory Society Congress (ERS) 2024, 7–11 September, Vienna, Austria.
