asthma exacerbations

Mepolizumab associated with fewer asthma exacerbations, lower costs in Medicare population

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Mepolizumab use was associated with fewer exacerbations, reduced oral corticosteroid use and lower costs among patients with asthma on Medicaid, according to a study published in The Journal of Allergy and Clinical Immunology: In Practice.

But because this population comprises individuals aged 65 years and older as well as younger individuals with long-term disabilities, these findings may not be generalizable to the full U.S. population, Sanjay Sethi, MD, professor and chief of pulmonary, critical care and sleep medicine at Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, and colleagues wrote.

Cost redctions among patients on Medicare with mepolizumab include $888 in total costs, $275 in pharmacy costs and $341 in outpatient costs.
Data were derived from Sethi S, et al. J Allergy Clin Immunol Pract. 2022;doi:10.1016/j.jaip.2022.10.021.

Sanjay Sethi

“Most trial and real-world data on the impact of the use of drugs such as mepolizumab (Nucala, GSK) in patients with asthma is from young individuals,” Sethi, who is also vice president of health sciences at Jacobs School of Medicine and Biomedical Sciences, told Healio. “Asthma may differ in its manifestations and response to therapies in elderly individuals, which prompted this study.”

The researchers examined data from 1,278 patients (64.3% women; mean age, 67.9 years) with one or more prescription or administration claims for mepolizumab for asthma between Jan. 1 and Dec. 31, 2017, in the CMS fee-for-services Medicare datasets.

The baseline period spanned the 12 months before the index date, and the follow-up period spanned the following 12 months.

Compared with the baseline period, there was a 27% relative reduction in the proportion of patients who experienced an asthma exacerbation during the follow-up period, which met statistical significance (P < .0001), as well as a 36% relative reduction in the mean number of exacerbations leading to hospitalization per patient per year (P = .0164).

The number of patients with an exacerbation who needed hospitalization also fell from 99 (8%) to 60 (5%) from baseline to the follow-up, for a relative reduction of 40% (P = .0014).

The proportion of patients with one claim or more for all non-mepolizumab asthma treatments additionally fell. Comparing the follow-up to the baseline period, significantly fewer patients had one or more claim for:

  • single-agent inhaled corticosteroids (62% vs. 66%; P = .03);
  • short-acting beta 2 agonists (76% vs. 85%; P < .0001);
  • short-acting muscarinic agonists (22% vs. 28%; P = .003);
  • long-acting muscarinic agonists (33% vs. 41%; P < .0001); and
  • leukotriene receptor antagonists (64% vs. 71%; P < .001).

The researchers also noted a significant 16% relative reduction in the proportion of patients with any oral corticosteroid (OCS) use from the baseline to the follow-up period (P < .0001) along with a 35% relative reduction in the mean number of OCS claims (P < .001).

Total costs fell from baseline to follow-up by $888 (P = .0002), as did pharmacy costs ($275; P < .0001), outpatient costs ($341; P = .0033) and other costs including skilled nursing facilities, home health agencies and hospice ($51; P = .0011). Inpatient costs fell by $219, but this did not reach statistical significance.

Further, the proportion and mean number of exacerbations and exacerbations leading to hospitalizations significantly fell from baseline to follow-up specifically for the 76% of the population who were aged 65 years or older, the researchers continued.

“The response rate in this elderly population to mepolizumab, measured in terms of reduction in exacerbations, hospitalizations and OCS use, were all of a magnitude larger than we had expected,” Sethi said. “Elderly patients with asthma have more fixed airway disease, comorbid COPD and other chronic conditions that could blunt the response to biologics.”

Based on these real-world findings, the researchers concluded that mepolizumab treatment was likely to result in fewer exacerbations, reductions in use of OCS, and reductions in health care costs related to exacerbations.

“These findings would suggest that in the appropriate patient with severe uncontrolled asthma, biologics such as mepolizumab should be considered irrespective of the patient’s age and comorbidities,” Sethi said.

However, Sethi cautioned that all such database real-world studies demonstrate association, not causation.

“A randomized placebo-controlled trial in an elderly severe uncontrolled asthma population that confirms and extends the findings of this study would be the next logical step,” he said.

IV magnesium fails to decrease asthma exacerbation severity in children

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IV magnesium for children with moderate-to-severe asthma exacerbations was associated with increased exacerbation severity and risk for hospitalization without any acceleration in resolution, according to observational study results.

National Heart, Lung, and Blood Institute expert guidelines recommend considering IV magnesium (IV-Mg) for children with moderate-to-severe asthma exacerbations who don’t completely respond to systemic corticosteroid (CCS) and inhaled albuterol, Donald H. Arnold, MD, MPH, professor of pediatrics and director of pediatric emergency medicine research at Monroe Carell Jr. Children’s Hospital at Vanderbilt, and colleagues wrote, adding, however, that a Cochrane systematic review of randomized trials showed varying study results among children treated with IV-Mg

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Donald H. Arnold

“Moreover, recent studies showed that IV-Mg is typically administered late in the ED course, and most children are hospitalized after receiving IV-Mg,” they added. “Yet despite limited evidence for the safety and efficacy of IV-Mg in children, the use of IV-Mg increased in the United States over the past decade.”

Thus, Arnold and colleagues conducted a secondary analysis of a prospective, observational cohort to evaluate whether IV-Mg administered early in the ED decreased exacerbation severity, hospitalizations and time to spacing of inhaled albuterol to 4 hours or more.

The analysis included data from 933 children aged 5 to 17 years with acute moderate or severe asthma exacerbations in an urban tertiary children’s hospital ED between April 2008 and February 2013.

Exacerbations included cough, dyspnea, wheezing and/or chest pain as well as the need for CCS and inhaled albuterol treatments as determined by the clinical team and the Acute Asthma Intensity Research Score (AAIRS), a 0- to 16-point scale, with 16 indicating the most severe cases.

The researchers measured and recorded relevant variables before treatment and 2 and 4 hours after administration of CCS, if the participant was still in the ED. Clinicians considered use of 75 mg/kg IV-Mg if the patient showed insufficient response to CCS and inhaled albuterol after 20 minutes.

A change in AAIRS after 2 hours of ED-administered treatment served as the primary outcome.

According to the study, 301 of the participants (median age, 8.1 years; 57% Black; 67% boys) had an AAIRS of 7 or greater before treatment and were still in the ED 2 hours after treatment began. Of them, 84 (28%) received IV magnesium (IV-Mg) treatment.

IV-Mg treatment appeared associated with a 2-hour increase in AAIRS score based on the study’s propensity score (PS)-adjusted multivariable regression model ( coefficient = 0.98; 95% CI, 0.2-1.77), which denoted increased exacerbations.

Also, patients who received IV-Mg during the first 2 hours of treatment had a 5.8-fold (95% CI, 2.8-11.9) greater odds of hospitalization in the PS-adjusted multivariable regression model. In the inverse probability of treatment weighting multivariable regression model, the odds were 6.8 times greater (95% CI, 3.6-12.9).

There also was no difference in time to albuterol of every 4 hours or more among hospitalized patients (HR = 1.2; 95% CI, 0.8-1.8) in the PS covariate-adjusted Cox proportional hazards model, indicating that IV-Mg did not accelerate exacerbation resolution.

Further, the researchers found an association between IV-Mg treatment and an approximately one-point increase in exacerbation severity on the validated AAIRS. Typically, a decrease of two or more points is clinically meaningful for decisions to deescalate treatment.

The researchers called this one-point increase in clinical severity cause for concern that IV-Mg treatment may be deleterious for children who are experiencing moderate-to-severe asthma exacerbations.

“Although IV-Mg is generally safe and well-tolerated, the results of this observational study of real-world use of IV-Mg indicate that it is associated with increased exacerbation severity and hospitalizations and does not accelerate clinical improvement in hospitalized patients,” they wrote. “In the absence of a randomized controlled trial powered to examine important outcomes, there is insufficient evidence to support the use of IV-Mg for moderate and severe acute asthma exacerbations in children.”

References:

PERSPECTIVE

 Jennifer Namazy, MD)

Jennifer Namazy, MD

For years, magnesium sulfate has been used in the care of acute asthma exacerbations among both children and adults. As an inexpensive treatment available in most hospitals, it is thought to have minimal adverse effects. It is the recommended treatment for children aged older than 4 years who present with severe asthma exacerbations. In fact, a meta-analysis of five studies found that treatment with magnesium sulfate was effective in preventing hospitalizations in children with acute asthma.

The study by Arnold and colleagues is significant, then, because it suggests further studies should assess the safety and efficacy of this treatment in both adults and children. This therapy did not lead to a reduction in rescue medication and was associated with an increased risk for severe exacerbation. The fact that it did not reduce the need of rescue medication is counterintuitive to why we use magnesium sulfate in the first place, which is because it leads to relaxation of bronchial smooth muscle.

Studies have been conflicting in this area. Another randomized trial comparing magnesium sulfate with placebo in children who were wheezing and unresponsive to bronchodilators found no difference between the two groups in reduction of respiratory distress. I agree with Arnold and colleagues that its relative safety and tolerability should not alone advocate its use.

Further studies are needed to assess its efficacy in reductions of moderate-to-severe asthma exacerbations. A large randomized controlled trial comparing magnesium sulfate with placebo looking at outcomes such as symptom improvement, lung function improvement, exacerbation reduction and hospitalizations is warranted.Jennifer Namazy, MDScripps Clinic Medical Group

Dupilumab improves lung function, eases asthma exacerbations

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 Use of dupilumab every 2 weeks as add-on therapy in patients with uncontrolled persistent asthma on ICS+LABA significantly improved lung function and reduced rates of severe asthma exacerbations regardless of atopic history, according to a study presented at the European Academy of Allergy and Clinical Immunology (EAACI) Congress 2016 held recently in Vienna, Austria.

Researchers conducted a multinational, double-blind, placebo-controlled pivotal phase 2b dose-ranging study to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma. They randomized 769 patients to 24 weeks add-on therapy with dupilumab 200 or 300 mg every 2 or 4 weeks (n=611), or to placebo (n=158). Patients with atopy were defined as those with ≥2 positive aeroallergen-specific IgE antibodies at baseline. [EAACI 2016, abstract 609]

For patients with or without atopy, researchers estimated least-square mean change from baseline in lung function at week 12 and adjusted annualized rate of severe exacerbations in the 24-week treatment period. Safety was evaluated based on adverse event reports and laboratory assessments.

At week 12, lung function was significantly improved in patients with or without atopy (p<0.05 for both doses vs placebo). The severe exacerbation rate was reduced in patients with atopy for both doses versus placebo (−59.1 to −77.5 percent; p<0.05). In patients without atopy, improvements similar (or better) to those in patients with atopy were seen for both doses versus placebo (−59.5 to −91.6 percent), but reached statistical significance for the 200 mg dose only (p=0.0029).

The overall incidence of adverse events was similar across treatment groups (dupilumab, 78 to 80 percent; placebo, 75 percent). The most common adverse events in dupilumab-treated patients compared with placebo were upper respiratory tract infection (13 to 15 vs 18 percent) and injection-site erythema (14 to 22 vs 8 percent).

Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that inhibits interleukin-4 and interleukin-13 signalling, which are key drivers of type-2-mediated inflammation. Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist require additional treatment options as add-on therapy. [Lancet2016;doi:10.1016/S0140-6736(16)30307-5]

A previous trial showed that in patients with difficult-to-control asthma, dupilumab can significantly decrease asthma exacerbations and improve respiratory symptoms and lung function. These effects were paralleled by significant reductions in T-helper 2-associated inflammatory biomarkers. However, further larger and longer trials are required to extend and validate these preliminary results, and to carefully study the safety and tolerability profile of dupilumab.