Randomized Controlled Trial

.2022 Apr 21;386(16):1505-1518.

doi: 10.1056/NEJMoa2118813. Epub 2022 Feb 26.

Reliever-Triggered Inhaled Glucocorticoid in Black and Latinx Adults with Asthma

Elliot Israel¹, Juan-Carlos Cardet¹, Jennifer K Carroll¹, Anne L Fuhlbrigge¹, Lilin She¹, Frank W Rockhold¹, Nancy E Maher¹, Maureen Fagan¹, Victoria E Forth¹, Barbara P Yawn¹, Paulina Arias Hernandez¹, Jean M Kruse¹, Brian K Manning¹, Jacqueline Rodriguez-Louis¹, Joel B Shields¹, Brianna Ericson¹, Alex D Colon-Moya¹, Suzanne Madison¹, Tamera Coyne-Beasley¹, Gretchen M Hammer¹, Barbara M Kaplan¹, Cynthia S Rand¹, Janet Robles¹, Opal Thompson¹, Michael E Wechsler¹, Juan P Wisnivesky¹, M Diane McKee¹, Sunit P Jariwala¹, Elina Jerschow¹, Paula J Busse¹, David C Kaelber¹, Sylvette Nazario¹, Michelle L Hernandez¹, Andrea J Apter¹, Ku-Lang Chang¹, Victor Pinto-Plata¹, Paul M Stranges¹, Laura P Hurley¹, Jennifer Trevor¹, Thomas B Casale¹, Geoffrey Chupp¹, Isaretta L Riley¹, Kartik Shenoy¹, Magdalena Pasarica¹, Rafael A Calderon-Candelario¹, Hazel Tapp¹, Ahmet Baydur¹, Wilson D Pace¹

Affiliations

Affiliation

¹ From the Divisions of Pulmonary and Critical Care Medicine and Allergy and Immunology, Brigham and Women's Hospital, Harvard Medical School (E.I., N.E.M., V.E.F., P.A.H., J.M.K., J.R.L., B.E.), and patient partner (O.T.), Boston, and the Lahey Hospital and Medical Center, Burlington (V.P.P.) - all in Massachusetts; the Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa (J.-C.C., T.B.C.), the Department of Nursing, University of Miami Health System (M.F.), and Miller School of Medicine, University of Miami (R.A.C.C.), Miami, the Department of Community Health and Family Medicine, University of Florida College of Medicine, Gainesville (K.L.C.), and the University of Central Florida College of Medicine, Orlando (M.P.) - all in Florida; the Department of Family Medicine (J.K.C., W.D.P.) and the Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine (A.L.F.), University of Colorado, Aurora, the Public Leadership Group (G.M.H.), the Department of Medicine, National Jewish Health (M.E.W.), and the Denver Health and Hospital Authority (L.P.H.), Denver - all in Colorado; the American Academy of Family Physicians National Research Network, Leawood, KS (J.K.C., B.K.M., J.B.S.); Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (L.S., F.W.R.); the Department of Family and Community Health, University of Minnesota, Minneapolis (B.P.Y.), and patient partner, St. Paul (S.M.) - both in Minnesota; patient partner, South Jordan, UT (A.D.C.M.); the Division of Adolescent Medicine (T.C.B.) and the Lung Health Center, Department of Medicine, University of Alabama, Birmingham (J.T.); the American Lung Association, Washington, DC (B.M.K.); the Department of Medicine, Johns Hopkins School of Medicine, Baltimore (C.S.R.); patient partner (J.R.), the Divisions of General Internal Medicine and Pulmonary and Critical Care Medicine (J.P.W.) and Clinical Immunology and Allergy (P.J.B.), Icahn School of Medicine at Mount Sinai, and Montefiore Medical Center, (E.J.), Albert Einstein College of Medicine (M.D.M., S.P.J.) - all in New York; the Center for Clinical Informatics Research and Education, the MetroHealth System, and the Departments of Internal Medicine, Pediatrics, and Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland (D.C.K.); the Department of Internal Medicine, Section of Allergy and Immunology, University of Puerto Rico, San Juan (S.N.); the Division of Allergy and Immunology, University of North Carolina School of Medicine, Chapel Hill (M.L.H.), the Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University School of Medicine, Durham (I.L.R.), and the Department of Family Medicine, Atrium Health, Charlotte (H.T.) - all in North Carolina; the Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania (A.J.A.), and the Temple Lung Center, Lewis Katz School of Medicine at Temple University (K.S.) - both in Philadelphia; the University of Illinois at Chicago College of Pharmacy, Chicago (P.M.S.); the Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, CT (G.C.); and the Division of Pulmonary, Critical Care, and Sleep Medicine, Keck School of Medicine, University of Southern California, Los Angeles (A.B.).

PMID:35213105
PMCID: PMC10367430
DOI: 10.1056/NEJMoa2118813

Randomized Controlled Trial

Reliever-Triggered Inhaled Glucocorticoid in Black and Latinx Adults with Asthma

Elliot Israel et al. N Engl J Med.2022.

.2022 Apr 21;386(16):1505-1518.

doi: 10.1056/NEJMoa2118813. Epub 2022 Feb 26.

Authors

Affiliation

¹ From the Divisions of Pulmonary and Critical Care Medicine and Allergy and Immunology, Brigham and Women's Hospital, Harvard Medical School (E.I., N.E.M., V.E.F., P.A.H., J.M.K., J.R.L., B.E.), and patient partner (O.T.), Boston, and the Lahey Hospital and Medical Center, Burlington (V.P.P.) - all in Massachusetts; the Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa (J.-C.C., T.B.C.), the Department of Nursing, University of Miami Health System (M.F.), and Miller School of Medicine, University of Miami (R.A.C.C.), Miami, the Department of Community Health and Family Medicine, University of Florida College of Medicine, Gainesville (K.L.C.), and the University of Central Florida College of Medicine, Orlando (M.P.) - all in Florida; the Department of Family Medicine (J.K.C., W.D.P.) and the Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine (A.L.F.), University of Colorado, Aurora, the Public Leadership Group (G.M.H.), the Department of Medicine, National Jewish Health (M.E.W.), and the Denver Health and Hospital Authority (L.P.H.), Denver - all in Colorado; the American Academy of Family Physicians National Research Network, Leawood, KS (J.K.C., B.K.M., J.B.S.); Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (L.S., F.W.R.); the Department of Family and Community Health, University of Minnesota, Minneapolis (B.P.Y.), and patient partner, St. Paul (S.M.) - both in Minnesota; patient partner, South Jordan, UT (A.D.C.M.); the Division of Adolescent Medicine (T.C.B.) and the Lung Health Center, Department of Medicine, University of Alabama, Birmingham (J.T.); the American Lung Association, Washington, DC (B.M.K.); the Department of Medicine, Johns Hopkins School of Medicine, Baltimore (C.S.R.); patient partner (J.R.), the Divisions of General Internal Medicine and Pulmonary and Critical Care Medicine (J.P.W.) and Clinical Immunology and Allergy (P.J.B.), Icahn School of Medicine at Mount Sinai, and Montefiore Medical Center, (E.J.), Albert Einstein College of Medicine (M.D.M., S.P.J.) - all in New York; the Center for Clinical Informatics Research and Education, the MetroHealth System, and the Departments of Internal Medicine, Pediatrics, and Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland (D.C.K.); the Department of Internal Medicine, Section of Allergy and Immunology, University of Puerto Rico, San Juan (S.N.); the Division of Allergy and Immunology, University of North Carolina School of Medicine, Chapel Hill (M.L.H.), the Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University School of Medicine, Durham (I.L.R.), and the Department of Family Medicine, Atrium Health, Charlotte (H.T.) - all in North Carolina; the Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania (A.J.A.), and the Temple Lung Center, Lewis Katz School of Medicine at Temple University (K.S.) - both in Philadelphia; the University of Illinois at Chicago College of Pharmacy, Chicago (P.M.S.); the Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, CT (G.C.); and the Division of Pulmonary, Critical Care, and Sleep Medicine, Keck School of Medicine, University of Southern California, Los Angeles (A.B.).

PMID:35213105
PMCID: PMC10367430
DOI: 10.1056/NEJMoa2118813

Abstract

Background: Black and Latinx patients bear a disproportionate burden of asthma. Efforts to reduce the disproportionate morbidity have been mostly unsuccessful, and guideline recommendations have not been based on studies in these populations.

Methods: In this pragmatic, open-label trial, we randomly assigned Black and Latinx adults with moderate-to-severe asthma to use a patient-activated, reliever-triggered inhaled glucocorticoid strategy (beclomethasone dipropionate, 80 μg) plus usual care (intervention) or to continue usual care. Participants had one instructional visit followed by 15 monthly questionnaires. The primary end point was the annualized rate of severe asthma exacerbations. Secondary end points included monthly asthma control as measured with the Asthma Control Test (ACT; range, 5 [poor] to 25 [complete control]), quality of life as measured with the Asthma Symptom Utility Index (ASUI; range, 0 to 1, with lower scores indicating greater impairment), and participant-reported missed days of work, school, or usual activities. Safety was also assessed.

Results: Of 1201 adults (603 Black and 598 Latinx), 600 were assigned to the intervention group and 601 to the usual-care group. The annualized rate of severe asthma exacerbations was 0.69 (95% confidence interval [CI], 0.61 to 0.78) in the intervention group and 0.82 (95% CI, 0.73 to 0.92) in the usual-care group (hazard ratio, 0.85; 95% CI, 0.72 to 0.999; P = 0.048). ACT scores increased by 3.4 points (95% CI, 3.1 to 3.6) in the intervention group and by 2.5 points (95% CI, 2.3 to 2.8) in the usual-care group (difference, 0.9; 95% CI, 0.5 to 1.2); ASUI scores increased by 0.12 points (95% CI, 0.11 to 0.13) and 0.08 points (95% CI, 0.07 to 0.09), respectively (difference, 0.04; 95% CI, 0.02 to 0.05). The annualized rate of missed days was 13.4 in the intervention group and 16.8 in the usual-care group (rate ratio, 0.80; 95% CI, 0.67 to 0.95). Serious adverse events occurred in 12.2% of the participants, with an even distribution between the groups.

Conclusions: Among Black and Latinx adults with moderate-to-severe asthma, provision of an inhaled glucocorticoid and one-time instruction on its use, added to usual care, led to a lower rate of severe asthma exacerbations. (Funded by the Patient-Centered Outcomes Research Institute and others; PREPARE ClinicalTrials.gov number,NCT02995733.).

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Figures

**Figure 1.. Mean Cumulative Number of Severe Asthma Exacerbations per Participant over Time, with Adjusted Hazard Ratio.**
Shown are the mean cumulative numbers of severe asthma exacerbations per participant over time. Participants in the intervention group received patient-activated, reliever-triggered inhaled glucocorticoid in addition to usual care. Differences in treatment-group hazards were compared with the use of the Andersen–Gill model with adjustment for prespecified covariates.

**Figure 2.. Mean Changes from Baseline in Asthma-Related Scores.**
The least-squares mean differences between treatment groups in the changes from baseline in asthma-related scores were calculated with the use of a mixed model. The Asthma Control Test (Panel A) is a participant-administered tool for assessing the level of asthma control. Total scores range from 5 to 25, with a score of 20 to 25 indicating well-controlled asthma, a score of 16 to 19 indicating asthma that was not well controlled, and a score of 5 to 15 indicating very poorly controlled asthma; the minimal clinically important difference is 3 points. The Asthma Symptom Utility Index (Panel B) is a participant-administered tool for assessing preference-based quality of life. The summary score is on a continuous scale, ranging from 0 (worst possible symptoms) to 1 (no symptoms); the minimal clinically important difference is 0.09. I bars indicate 95% confidence intervals. The widths of the confidence intervals have not been adjusted for multiplicity and cannot be used to infer treatment effects.

**Figure 3. Subgroup Analyses of Severe Asthma Exacerbation Outcome.**
The forest plot shows the risk of severe asthma exacerbations in selected prespecified subgroups. The widths of the confidence intervals have not been adjusted for multiplicity and cannot be used to infer treatment effects. Race was reported by the participant; those who identified as both Black and Latinx were classified as Latinx. Nonsmokers were those who had not smoked within the previous year and had smoked less than 10 pack-years. The participant’s attitude toward asthma medications was assessed with the Beliefs about Medicines Questionnaire; the “accepting” category indicates that the participant believed the therapy was of high necessity and low concern. Depressive status was assessed with the Patient Health Questionnaire–2; scores range from 0 to 6, with a score of 3 or higher indicating depression. The Brief Health Literacy Scale measures participant-reported health literacy and consists of three items. If a participant’s response on any item indicated low or marginal health literacy, the participant was considered to have low or marginal health literacy; otherwise, health literacy was considered to be high. The body-mass index is the weight in kilograms divided by the square of the height in meters. Participant-reported medication adherence was assessed with the Medication Adherence Report Scale–5 by the calculation of the mean score over the five items. Mean scores range from 1 to 5, with higher scores indicating better adherence. FeNO denotes fraction of exhaled nitric oxide, LABA long-actingβ₂-agonist, and ppb parts per billion.

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Comment in

Breaking the Skin Color Barriers for Asthma Medications - It's Not Black, Brown, or White.
Bryant-Stephens T.Bryant-Stephens T.N Engl J Med. 2022 Apr 21;386(16):1574-1575. doi: 10.1056/NEJMe2201666.N Engl J Med. 2022.PMID:35443113No abstract available.
In Black and Latinx patients, as-needed inhaled glucocorticoids reduced asthma exacerbations at 15 mo.
Stanbrook MB.Stanbrook MB.Ann Intern Med. 2022 Jun;175(6):JC68. doi: 10.7326/J22-0040. Epub 2022 Jun 7.Ann Intern Med. 2022.PMID:35667061
The time to PREPARE is over; the time to improve diversity in asthma studies is now.
Williams LK.Williams LK.J Allergy Clin Immunol. 2022 Nov;150(5):1057-1058. doi: 10.1016/j.jaci.2022.09.014. Epub 2022 Sep 22.J Allergy Clin Immunol. 2022.PMID:36154847Free PMC article.No abstract available.

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Reliever-Triggered Inhaled Glucocorticoid in Black and Latinx Adults with Asthma

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Reliever-Triggered Inhaled Glucocorticoid in Black and Latinx Adults with Asthma

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