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Changes in Asthma Maintenance Therapy Prescribing Patterns Following the 2006 Long-acting β-Agonist FDA Drug Warning

      Abstract

      Purpose

      The US Food and Drug Administration issued a boxed warning on all products containing a long-acting β-agonist (LABA) in March 2006, after the findings from a trial suggested an increased risk for death in patients treated with salmeterol monotherapy. Almost nothing is known about the impact of this warning on LABA prescribing patterns or on clinicians’ approaches to asthma maintenance therapy.

      Methods

      A cohort of asthmatic adults on LABA therapy was retrospectively identified from a Baltimore-area Medicaid data warehouse. Pharmacy claims were used for determining the utilization rates of all asthma maintenance medications. Rates from the 6-month period before the warning (September 1, 2005, to February 28, 2006) were compared with rates from a similar 6-month period 1 year afterward (September 1, 2006, to February 28, 2007). The demographic characteristics of patients who continued LABA use were compared with those of discontinuers. In LABA discontinuers, utilization of alternative maintenance drugs was assessed.

      Findings

      In this cohort of 455 asthmatic patients, LABAs were prescribed only in combination with inhaled corticosteroids. Following the warning, 53% of patients discontinued LABA use, and the mean number of LABA prescription fills per patient decreased from 2.6 to 1.8 (P < 0.0001). Concurrently, the use of inhaled corticosteroids increased from 0.3 to 0.8 fills per patient (P < 0.0001). LABA continuers were younger (P = 0.0005), more likely to be black (P = 0.0079), and more consistent with LABA fills prewarning (P < 0.0001). Of the 243 LABA discontinuers, 155 were placed on no alternative maintenance therapy.

      Implications

      The management of asthma changed significantly after the LABA warning. The use of LABAs combined with inhaled corticosteroids plummeted, while the use of inhaled corticosteroid monotherapy increased. More than half of patients who discontinued LABAs were not placed on alternative maintenance therapy.

      Key words

      Introduction

      The US Food and Drug Administration (FDA) issued a boxed warning for all products containing a long-acting beta-agonist (LABA) in March 2006, after SMART (the Salmeterol Multicenter Asthma Research Trial) raised concerns about the tolerability of the LABA salmeterol.

      Post Market Drug Safety Information for Patients and Providers: Advair Diskus, Advair HFA, Brovana, Foradil, Perforomist, Serevent Diskus, and Symbicort Information (Long Acting Beta Agonists). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm108111.htm. Accessed August 26, 2016.

      • Nelson H.S.
      • Weiss S.T.
      • Bleecker E.R.
      • et al.
      The salmeterol multicenter asthma research trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol.
      SMART, in 26,355 patients with asthma, reported 13 asthma-related deaths and 37 life-threatening experiences in a salmeterol-treated group compared with 3 and 22, respectively, in a placebo group.
      • Nelson H.S.
      • Weiss S.T.
      • Bleecker E.R.
      • et al.
      The salmeterol multicenter asthma research trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol.
      Although concerns about design and analysis caused some to question the validity and generalizability of the conclusions drawn from SMART, the findings from that study seemed to support the results from the Serevent National Surveillance trial, which also suggested a potential for increased mortality from LABA monotherapy use.
      • Castle W.
      • Fuller R.
      • Hall J.
      • Palmer J.
      Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment.
      • Lurie P.
      • Wolfe S.M.
      Misleading data analyses in salmeterol (SMART) study.
      There is consistent evidence, however, that compared to inhaled corticosteroid monotherapy, LABA combination therapy reduces asthma symptoms and exacerbations while improving asthma control, lung function, and health-related quality of life.
      • Greening A.P.
      • Ind P.W.
      • Northfield M.
      • Shaw G.
      for Allen & Hanburys Limited UK Study Group
      Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid.
      • Salvi S.
      Effect of inhaled formoterol and budesonide on exacerbations of asthma.
      • Shrewsbury S.
      • Pyke S.
      • Britton M.
      Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA).
      • FitzGerald J.M.
      Effect of inhaled formoterol and budesonide on exacerbations of asthma.
      • Sin D.D.
      • Man J.
      • Sharpe H.
      • et al.
      Pharmacological management to reduce exacerbations in adults with asthma: a systematic review and meta-analysis.
      Thus, the significance of the findings from SMART in patients stable on combination therapy is subtle, and clinicians and patients had to weigh the therapeutic benefits of the medication class with its potential for risk - a challenge for even experienced prescribers and sophisticated health care consumers.
      • Lang D.M.
      • Davis R.S.
      The long-acting beta-agonist controversy: a clinical dilemma.
      The FDA is responsible for ensuring the safety of prescription drugs. Inherent in this mission is the duty to inform the public and providers about updated drug safety information. The purpose of risk communication is to minimize harm. However, risk communication is a complex science, and the impact of safety alerts on physicians’ prescribing patterns and on health outcomes can be unpredictable.
      • Dusetzina S.B.
      • Higashi A.S.
      • Dorsey E.R.
      • et al.
      Impact of FDA drug risk communications on health care utilization and health behaviors: a systematic review.
      How best to inform both the medical and lay populations about rare but severe risks of commonly prescribed medications remains a delicate challenge informed by only limited data.
      • Dusetzina S.B.
      • Higashi A.S.
      • Dorsey E.R.
      • et al.
      Impact of FDA drug risk communications on health care utilization and health behaviors: a systematic review.
      Little is known about how the FDA boxed warning for LABA-containing products has affected physicians’ prescribing patterns and patients’ utilization of these products, or asthma control in general.
      • Dusetzina S.B.
      • Higashi A.S.
      • Dorsey E.R.
      • et al.
      Impact of FDA drug risk communications on health care utilization and health behaviors: a systematic review.
      • Stockl K.M.
      • Le L.
      • Harada A.S.
      • Zhang S.
      Use of controller medications in patients initiated on a long-acting beta2-adrenergic agonist before and after safety alerts.
      This study sought to evaluate how prescribing asthma maintenance has changed following the release of the FDA’s LABA risk communication.

      Materials and Methods

      Study Design and Sample

      The study protocol was approved by the institutional review board at the Medstar Health Research Institute (Hyattsville, MD). This retrospective cohort study utilized data extracted from the warehouse of Medstar Family Choice, a Medicaid managed care organization in the greater Baltimore area, Maryland. The cohort comprised all patients over the age of 18 years with a diagnosis of asthma and who had a prescription for any LABA-containing product filled at least twice in the 6 months prior to the March 2006 boxed warning. In addition to the demographic variables of age, race, and sex, pharmacies’ fills of prescriptions for all respiratory maintenance medications were identified and trended for the period of September 2005 to February 2007. Asthma maintenance medications commercially available during that time period included the 2 LABA-containing products salmeterol
      Trademarks: Serevent (GlaxoSmithKline, Research Triangle Park, NC)
      and fluticasone/salmeterol,
      Advair (GlaxoSmithKline)
      the inhaled corticosteroids budesonide
      Pulmicort (AstraZeneca, Wilmington, DE)
      and fluticasone,
      Flovent (GlaxoSmithKline)
      as well as the mast cell stabilizers montelukast
      Singulair (Merck Sharp & Dohme, Whitehouse Station, NJ)
      and theophylline.
      The pharmacy benefits for this Medicaid managed care organization did not change over the study period. Budesonide/formoterol
      Symbicort (AstraZeneca)
      and formoterol
      Perforomist (Mylan Specialty LP, Canonsburg, PA)
      became available later in 2006, but neither was available to this cohort of Medicaid patients.

      Statistical Analysis

      The mean numbers of prescriptions for LABAs, inhaled corticosteroids, and mast cell stabilizers per patient were identified for the time period of September 1, 2005, to February 29, 2006 (the 6 months prior to the March 2006 FDA warning) and for a similar time period 12 months later, September 1, 2006, to February 29, 2007. The same fall/winter time period was chosen to adjust for any seasonal variation in asthma medication use. These variations were compared using a generalized linear mixed model with a Poisson distribution and log link function. The model included a 2-level fixed effect for time (pre/post), and a patient-level random effect to account for dependence over time within patients. The use of a LABA-containing product in the final 6 months of the study period was examined for associations with the categorical patient characteristics of sex and race using χ2 tests and with the continuous patient characteristic of age using 2-sample equal-variance t tests and logistic regression. In patients who did not have a prescription for a LABA-containing product filled following the warning, the rates of use of alternative therapies were summarized. The GLIMMIX, FREQ, and TTEST procedures from SAS software version 9.4 (Cary, NC) were used for all data summaries and analyses.

      Results

      In this cohort, no salmeterol was prescribed. The only LABA-containing medication used was the combination product fluticasone/salmeterol. A total of 455 patients who met specified criteria over an 18 month period - 6 months before the warning and 12 months thereafter were identified and included in the study.
      Of the 455 patients who had at least 2 prescriptions for a LABA-containing product filled in the 6 months prior to the warning, 212 (47%) had a prescription for a LABA-containing product filled in the similar 6-month period 1 year later. Furthermore, on comparison of data from the 6 months prior to the warning to those from the same 6-month period 1 year later, the mean number of LABA-containing product prescription fills per patient decreased significantly, from 2.6 to 1.8 (P < 0.0001). Over that same time period, the use of inhaled corticosteroid monotherapy almost tripled, from a mean of 0.3 to 0.8 fills per patient (P < 0.0001). Utilization of mast cell stabilizers did not change (Table I). There were significant variances in race and age between the patients who continued to use LABA products after the warning compared with those who discontinued the medication (Table II). Patients who continued on LABA products were significantly older than their counterparts who discontinued LABA use (P = 0.0005); they were also more likely to be black (P = 0.0079) and were less likely to have race listed as "unknown." As seen in Table II, LABA continuers had also been more consistent in having their prescriptions filled prior to the warning (P < 0.0001). The difference in sex between the 2 subgroups was not significant (Table II). Of the 243 patients who discontinued LABA use following the warning, 88 were placed on new maintenance medications while 155 were placed on no alternative preventive agent (Table III).
      Table INumber of prescriptions filled per patient before (pre) and after (post) the FDA LABA warning.
      Drug ClassPrescriptions Filled, Mean (95% CI)P
      LABAs<0.0001
       Pre (n = 455)2.6 (2.4–2.8)
       Post (n = 212)1.8 (1.7–2.0)
      Inhaled corticosteroids<0.0001
       Pre (n = 59)0.3 (0.2–0.4)
       Post (n = 110)0.8 (0.6–1.0)
      Mast cell stabilizers0.86
       Pre (n = 130)1.1 (0.9–1.3)
       Post (n = 110)1.1 (0.9–1.4)
      FDA = US Food and Drug Administration; LABA = long-acting β-agonists.
      Table IIDemographic characteristics and numbers of LABAs used in LABA continuers and discontinuers (N = 455).
      Some percentages may not total 100 due to rounding error.
      ParameterLABA Continuers (n = 212)LABA Discontinuers (n = 243)P
      Sex, no. (%)NS
       Female141 (66)152 (63%)
       Male71 (34)91 (37%)
      Age, mean (95% CI)33.4 (30.9, 36.0)27.2 (24.9, 29.5)0.0005
      Race, no. (%)0.0079
       Black118 (56)114 (47)
       White84 (40)94 (39)
       Hispanic2 (1)4 (2)
       Asian1 (<1)5 (2%)
       Unknown7 (3)26 (10)
      LABA prescriptions filled per patient per month before FDA LABA warning, mean (95% CI)2.84 (2.58–3.11)1.66 (1.81–2.23)<0.0001
      FDA = US Food and Drug Administration; LABA = long-acting β-agonist.
      low asterisk Some percentages may not total 100 due to rounding error.
      Table IIIMaintenance therapies used by LABA discontinuers (n = 243).
      Drug classNo. (%) of Patients
      Inhaled corticosteroids51 (21)
      Mast cell stabilizers37 (15)
      No maintenance medication155 (63)

      Discussion

      Almost nothing is known about the impact of the FDA risk communication about LABA-containing products on the approaches to asthma maintenance therapy. Although the present study was very limited in scope, it does begin to inform how prescribing changed following the warning.
      We acknowledge the following limitations. This study was retrospective and restricted to a Medicaid population. We were unable to query for severity of disease or meaningful clinical outcomes. It should also be noted that although our query surrounded the highly publicized March 2006 FDA boxed warning, an earlier warning had been released in July 2005, and practice could have already begun to change before the initiation of the present study. Furthermore, although we observed significantly different distributions of race between the LABA continuers and discontinuers, this result was almost certainly affected by a substantial amount of patients with "unknown" recorded race. Pharmacy claims are of course also only a marker for physician practices as an unknown number of patients do not consistently fill the prescriptions they have received.
      Notwithstanding, in this limited population, the results suggest that a marked and significant change in the management of asthma followed the FDA risk communication. The use of a LABA in combination with an inhaled corticosteroid (fluticasone/salmeterol) plummeted while the use of inhaled corticosteroid monotherapy dramatically increased. While this study could not identify proportion of patients who purposefully stopped their medication due to the risk communication, LABA discontinuers were younger and had been less consistent with their use of maintenance therapy even prior to the warning. It is certainly plausible that discontinuers of LABA medication had less severe disease. That said, it is noteworthy that more than half of the patients deemed ill enough to merit dual maintenance therapy prior to the release of the warning, and who discontinued their medication use thereafter, were not placed on an alternative preventive regimen. A more comprehensive study of not only changes in prescribing but also asthma control and pulmonary outcomes surrounding the warning would help to inform future risk communications.

      Conclusions

      The management of asthma changed significantly after the FDA issued the LABA warning. The use of LABAs combined with inhaled corticosteroids plummeted, while the use of inhaled corticosteroid monotherapy increased. More than half of patients who discontinued LABAs were not placed on alternative maintenance therapy.

      Conflicts of Interest

      The authors have indicated that they have no conflicts of interest with regard to the content of this article. The authors have received no support from industry or organizations that may have influenced this work, or the decision to submit this manuscript for publication.

      Acknowledgments

      This study (MR, JW, SK) was funded in part by a resident research grant from the American Academy of Family Practice Foundation.

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