In updated guidelines released in May, the U.S. Preventive Services Task Force (USPSTF) continued to recommend against routine screening for chronic obstructive pulmonary disease (COPD) in asymptomatic adults, and pivotal new research showed no benefit with bronchodilator treatment for symptomatic smokers and former smokers without evidence of airflow limitation on spirometry.
These were among the highlights in COPD research this year, along with very early real-world data on newly available fixed-dose triple therapies, and heightened concerns about inequities associated with race-adjusted spirometry equations.
Still No Benefit to Random Screening
The updated evidence report and systematic review that accompanied the USPSTF recommendation statement found no benefit to routine screening among adults without symptoms associated with COPD, which was the same conclusion that the Task Force came to in their guidelines from 2016.
Research published since 2016 continued to show that COPD treatment effectiveness was largely limited to patients with spirometry-confirmed moderate airflow obstruction.
Respiratory medicine specialist Don Sin, MD, MPH, of the University of British Columbia in Vancouver, said spirometry remains the gold standard for diagnosing COPD, and it should be widely used by clinicians for case finding in at-risk patients.
"Spirometry is relatively cheap and accessible, and if a physician sees a smoker in the office, that patient should have spirometry," he told MedPage Today. "The problem is that by the time lung function decline is evident on spirometry, the patient has probably lost about 40% or 50% of their airways."
Identifying patients earlier in the course of their disease using tools that are more sensitive than spirometry represents the next evolution in COPD diagnostics, Sin said, who predicted that advances in imaging and/or oscillometry testing will make this evolution possible in the next 5 to 6 years.
"There are a lot of promising technologies, but none of them are quite ready for prime time," he noted.
RETHINCing Bronchodilator Therapy When FEV1 Is Normal
The empiric treatment of smokers and former smokers with COPD symptoms but normal lung function gained traction with the publication of the observational SPIROMICS study in 2016.
In this study, about half of participants with a history of smoking but normal forced expiratory volume in 1 second (FEV1) on spirometry had respiratory symptoms such as chronic cough and sputum production. Despite showing no evidence of airway obstruction, these people had a much higher risk for hospitalization and COPD exacerbations compared with asymptomatic smokers and former smokers.
In the RETHINC trial, 535 participants with COPD symptoms, a ≥10 pack-year smoking history, and preserved lung function were randomized to treatment with the inhaled long-acting bronchodilator (LABA) indacaterol plus the long-acting muscarinic antagonist (LAMA) glycopyrrolate or placebo twice daily for 12 weeks.
Use of the combination therapy was not associated with a significant reduction in symptoms or a reduction in treatment failure compared with placebo. FEV1 increased by approximately 40 mL in the active treatment group, which was much lower than the approximately 200-mL increase reported back in 2015 among patients with spirometry-confirmed COPD.
"The most important takeaway message from RETHINC is that clinicians can't just rely on symptoms to guide therapeutic choice for bronchodilators in smokers. It is imperative that smokers be diagnosed with spirometry," Sin said. "If they don't have significant airway obstruction, bronchodilators won't work because there is nothing to bronchodilate."
Fixed-Dose Triple Therapy Gets Real
In clinical trials, fixed-dose, inhaled, triple therapies that combine dual bronchodilator therapy with an inhaled corticosteroid (ICS) were shown to reduce both COPD exacerbations and mortality compared with dual therapies. But it remains to be seen if triple therapy proves as effective in real-world use.
The FDA has approved two single-inhaler, fixed-dose triple drug treatments as maintenance COPD therapies: budesonide/glycopyrrolate/formoterol fumarate (Breztri Aerosphere) and fluticasone/umeclidinium/vilanterol (Trelegy Ellipta).
In a 2019 systematic review of six clinical trials, triple therapy reduced the annual rate of moderate or severe exacerbations by 15% to 52% compared with a LAMA/LABA, 15% to 35% compared with a LABA/ICS, and 20% compared with a LAMA alone.
The benefits appeared to be greatest in patients with elevated eosinophil counts and those with frequent exacerbations, but triple therapy was also associated with a greater risk for pneumonia in the largest of the trials.
Findings from a real-world study from Germany, presented at the American Thoracic Society annual meeting in May, suggested that stepping down from triple therapy to a LABA/LAMA combination may improve patient outcomes.
Among patients who had been receiving triple therapy for at least 6 months, clinician-recommended withdrawal of ICS while continuing on a LABA/LAMA was associated with better outcomes over the course of a year, including fewer exacerbations and fewer serious and non-serious adverse events.
Researchers concluded that the findings showed two things: that removing ICS from COPD maintenance may benefit patients and that physicians are able to identify patients likely to benefit from this strategy.
Pulmonary Hypertension Common in COPD
Pulmonary hypertension (PH) is an increasingly recognized comorbidity in COPD and is associated with poorer quality of life and increased mortality.
In a recent study involving 100 patients with spirometry-confirmed COPD, 40% of all patients and 51.5% of patients with severe COPD had PH.
In a retrospective analysis, researchers examined which noninvasive diagnostic tools and patient characteristics best identify severe PH in COPD patients. They determined that the combination of an echocardiographic systolic pulmonary arterial pressure of ≥56 mm Hg, N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels of ≥650 pg/mL, and a main pulmonary artery (PA) to ascending aorta (Ao) diameter ratio on chest CT scan of ≥0.93 "predicted severe PH with high positive and negative predictive values."
Over a median follow-up of 3.7 years, 50.7% of patients included in the analysis died. Both airflow limitation (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 1-2 vs stage 3: HR 1.56, 95% CI 0.90-2.71; GOLD stages 1-2 vs stage 4: HR 3.45, 95% CI 1.75-6.79) and PH severity were independently associated with survival.
"Our data indicate that echocardiography is an important noninvasive diagnostic tool for detecting severe PH in COPD, but the diagnostic accuracy could be improved markedly when it was complemented by NT-proBNP level and the PA to Ao diameter ratio," the researchers concluded.
Finally, a systematic review published this year examined current treatment options for PH in patients with COPD, finding that supplemental long-term oxygen therapy mildly reduced mean pulmonary artery pressure, slowed progression of PH, and reduced mortality, and phosphodiesterase (PDE) type 5 inhibitors significantly improved systolic pulmonary artery pressure, but had inconsistent clinical benefits.
Nebulized Therapy Trials Continue to Show Promise
In October, more positive findings from the phase III ENHANCE-2 trial of ensifentrine, a first-in-class dual inhibitor of the enzymes PDE 3 and 4, were reported.
In early studies in COPD, treatment with the inhaled drug as a monotherapy or added to maintenance bronchodilator therapy was shown to elicit clinically meaningful improvements in lung function, symptoms, and quality of life.
In the overall ENHANCE-2 study population, treatment with ensifentrine was associated with a 42% reduction in the rate of COPD exacerbations over 24 weeks compared with placebo, according to Verona Pharma, which is developing the drug.
In the newly reported subgroup analysis, treatment with ensifentrine was associated with a 56% reduction in the rate of exacerbations over 24 weeks in current smokers, a 43% reduction in patients with blood eosinophil counts greater than 150 cells/μL, and a 44% reduction in patients currently on ICS therapy.
Clinical trials involving another inhaled PDE-4 inhibitor, CHF6001, are also currently underway.
Sin told MedPage Today that the nebulized PDE-4 inhibitors and P2X3 receptor antagonists for treatment of chronic cough represent exciting novel treatments for COPD.
Findings from the phase III COUGH-1 and COUGH-2 trials reported in March showed that the oral P2X3 receptor antagonist gefapixant was effective for reducing cough in patients with refractory chronic cough and unexplained chronic cough, respectively.
"Cough and sputum production are major concerns among patients with COPD, and these symptoms are not well-treated with existing COPD treatments," Sin said. "Having a drug that can reduce these symptoms would really improve patient quality of life."
Are Race-Based Lung Function Equations Harming Black Patients?
A study published late last year brought renewed attention to potential harms associated with race-based equations for the evaluation of lung disease.
When Aaron Baugh, MD, of the University of California San Francisco, and colleagues compared a race-based formula with adjusted values for Black participants versus a universal formula for assessing lung function, as measured by FEV1, they found significantly better lung function scores in Black participants when the race-adjusted values were used, with an average FEV1 score of 76.2% among Black patients and 71.3% among white patients.
Using a universal formula for both Black and white participants, the average FEV1 score was 77.4% for white patients and 69.4% for Black patients, indicating more serious disease in Black participants than the race-based formula suggested.
An analysis from the MESA Lung Study by the research team also showed that the use of race-adjusted spirometry values had no benefit in that cohort.
In an interview with MedPage Today, Baugh said that while there is growing awareness of potential structural racism in healthcare, there has not been enough movement in addressing the issue of potential inequities involving race-adjusted spirometry values.
He noted that the finding of worse lung function in Black patients when a race-neutral FEV1 formula was used suggests that long-recognized racial differences may not be biological.
"Our findings suggest that these are not natural biological differences, but are more likely to result from social and environmental differences," Baugh said.
Disclosures
Sin and Baugh reported no relevant disclosures.