ERS 2022: NEJM/ERS Joint Session
In this session, the editors of the European Respiratory Journal (ERJ) and the New England Journal of Medicine (NEJM) introduced seminal papers published in the journal in 2022.
Variability in airway inflammation places all patients with asthma at a high risk of symptoms and severe exacerbations. Short-acting ?2-agonists (SABA) address the symptoms but do not address the underlying inflammation. This leaves patients at a high risk of exacerbations. However, the "window of opportunity" still exists to prevent a severe exacerbation if symptoms and inflammation are treated concomitantly as recommended by the Global Initiative for Asthma (GINA) and the National Asthma Education and Prevention Program (NAEPP).
Albuterol-budesonide fixed-dose combination (FDC) rescue therapy was developed to provide rapid relief of asthma symptoms and simultaneously treat inflammation. A multinational, phase 3, double-blinded, randomized, event-driven trial was conducted to evaluate the efficacy and safety of albuterol–budesonide, compared to albuterol alone, as rescue medication in patients with uncontrolled moderate-to-severe asthma who were receiving inhaled glucocorticoid-containing maintenance therapy. The ICS containing maintenance therapy was continued throughout the trial. A total of 3132 patients underwent randomization, among whom 97% were ≥12 years of age. Adults and adolescents (≥12 years of age) were randomly assigned in a 1:1:1 ratio to one of three trial groups: albuterol-budesonide 180/160 ?g, albuterol-budesonide 180/80 ?g, or albuterol 180 ?g. Children 4 to 11 years of age were randomized 1:1 to only albuterol-budesonide 180/80 ?g or albuterol 180 ?g. The primary efficacy end point of the study was the time-to-first event of severe asthma exacerbation. The study's secondary endpoints included annualized severe exacerbation rate, total systemic corticosteroid dose, asthma control questionnaire (ACQ-5) responder analysis at week 24 and asthma quality of life questionnaire (AQLQ+12) responder analysis at week 24. Albuterol-budesonide significantly reduced severe exacerbation risk as compared to albuterol. The risk of severe asthma exacerbation was significantly lower, by 26%, in the higher-dose combination group compared to the albuterol-alone group. Mean total SCS exposure for albuterol-budesonide 180/160 ?g was reduced by 33% and 36% versus albuterol. Albuterol-budesonide is also effective in achieving clinical outcomes related to everyday asthma control and quality of life. Patterns of as-needed use of study medications were similar between treatment groups. In patients with uncontrolled moderate-to-severe asthma who received a variety of inhaled glucocorticoid-containing maintenance therapies, the risk of severe asthma exacerbation was significantly lower with the as-needed use of a fixed dose combination of 180 ?g of albuterol and 160 ?g of budesonide than with as-needed use of albuterol alone. Both doses of albuterol-budesonide had an acceptable safety profile, consistent with the active components, with no safety concerns identified.
Pulmonary arterial hypertension (PAH) is a progressive disease driven by pulmonary vascular remodelling due to an imbalance in anti-proliferative and pro-proliferative signalling pathways, resulting in the hyperproliferation of vessel wall cells. Sotatercept acts as a reverse-remodelling agent proposed to rebalance the anti-proliferative and pro-proliferative signalling. The PULSAR study is a phase 2, multicenter, randomized, placebo-controlled, double-blind study evaluating the safety and efficacy of sotatercept on top of background PAH therapy in World Health Organization functional class (WHO FC) II/III PAH participants. The study's primary efficacy endpoint was changed from baseline to months 18–24 in pulmonary vascular resistance (PVR). Secondary endpoints included a 6-minute walk distance (6MWD) and functional class (FC). Serious treatment-emergent adverse events were reported in 30.8% of the participants; 9.6% reported treatment-emergent adverse events (TEAEs) leading to study discontinuation. No severe TEAEs led to treatment or study discontinuation. In participants who originally received placebo, significant improvements in PVR, 6MWD, WHO FC and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement were achieved at months 18-24 compared with baseline after being randomized to sotatercept. Improvement across all endpoints was maintained in participants with long-term use. About 90% of the participants were classified as WHO FC I or II at 18-24.
Phosphodiesterase 4 (PDE4) inhibition is associated with anti-inflammatory and antifibrotic effects that may benefit patients with idiopathic pulmonary fibrosis (IPF). PED4 inhibitors can potentially reduce inflammation and fibrotic remodelling in pulmonary disease. BI 1015550 is an oral preferential inhibitor of the PDE4B subtype, in patients with IPF, with approximately 10-fold greater selectivity for PDEB4 than PDE4D. In this phase 2, double-blind, placebo-controlled trial, the efficacy and safety of BI 1015550, taken at 18 mg twice daily for 12 weeks, were investigated in patients with IPF. The primary endpoint was the change from baseline in the forced vital capacity (FVC) at 12 weeks. In patients without background antifibrotic use, the median change in the FVC was 5.7 ml in the BI 1015550 group and –81.7 ml in the placebo group. In patients with background antifibrotic use, the median change in the FVC was 2.7 ml in the BI 1015550 group and –59.2 ml in the placebo group. The percentages of patients with serious or severe adverse events were similar in the two trial groups. Compared with placebo, treatment with BI 1015550, either alone or with background use of an antifibrotic agent, prevented a decrease in lung function in patients with IPF and had an acceptable safety and tolerability profile.
Risk stratification has become essential to pulmonary arterial hypertension management (PAH). The 2015 joint pulmonary hypertension (PH) guidelines of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) introduced treatment decisions based on risk stratification. The guidelines proposed a multidimensional risk assessment model based on 14 variables derived from nine assessments. According to this model, the risk is classified into three strata as low, intermediate, or high, with estimated 1-year mortality rates of <5%, 5–10% and >10%, respectively. In patients with PAH, achieving and maintaining a low-risk profile is recommended as a treatment goal. Several registry-based studies have shown that simplified versions of the ESC/ERS tool provided reliable prognoses. From the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), the French database, and the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), WHO functional class (FC), 6-min walk distance (6MWD), and brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) emerged as the strongest predictors of outcomes. However, it was noted in the SPAHR and COMPERA analyses that most patients did not meet the low-risk criteria while receiving PAH treatment. The majority of patients met the intermediate risk criteria.
Hoeper MM et al. analyzed data from COMPERA and calculated the risk at diagnosis and first follow-up based on WHO FC, 6HWD, and BNP/NT-proBNP, using refined cut-off values. The authors hypothesized a subdivision into four risk strata (low, intermediate-low, intermediate-high, and high) based on more specificity within the cut-off levels of 6MWD, WHO FC and BNP/NT-proBNP may improve risk stratification. The study concluded that modified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk as compared to the original three-stratum model. Thus, the four-stratum model may be more useful in clinical practice and as a research tool in clinical trials. The 2022 ESC/ERS PH guidelines have also incorporated the 4-strata risk model in the treatment algorithm. For risk stratification at the time of diagnosis, the three strata model is recommended, taking into account all available data, including hemodynamics. A four-strata model based on WHO FC, 6MWD, and BNP/NT-proBNP are recommended for risk stratification during follow-up, with additional variables considered necessary.
European Respiratory Society (ERS) International Congress 2022, 3rd-6th Sept. 2022, Barcelona
