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The Controversy Over Long-Acting Beta Agonists: Examining the Evidence

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The Controversy Over Long-Acting Beta Agonists: Examining the Evidence CURRENT DRUG THERAPY DAVID M. LANG, MD* Head, Allergy and Clinical Immunology Section, Department of Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic The controversy over long-acting beta agonists: Examining the evidence ■ ABSTRACT ONCERNS THAT THREE WIDELY prescribed C asthma medications are associated with In the Salmeterol Multicenter Asthma Research Trial an increased risk of asthma-related death led (SMART), patients receiving the long-acting beta agonist to a recommendation by the US Food and salmeterol—particularly African Americans—had a Drug Administration (FDA) on July 13, 2005, statistically significantly higher risk of fatal or potentially fatal that salmeterol (Serevent), formoterol (Foradil), asthma episodes. As a result, medications that contain and the combination agent containing flutica- salmeterol (Serevent, Advair) or formoterol (Foradil) carry a sone propionate and salmeterol (Advair) remain “black box warning.” However, the benefits of these drugs on the market in the United States, but that continue to outweigh the risks, if they are used appropriately. each carry a “black box” warning.1 On November 18, 2005, the FDA fol- ■ KEY POINTS lowed this action with a public health adviso- ry concerning long-acting beta agonists. On Whether the greater risk in African Americans reflects March 2, 2006, it approved new safety label- genetic predisposition, risk associated with long-acting ing for salmeterol and the fluticasone-salme- beta agonist monotherapy, or health maintenance terol combination. Such labeling also applies behaviors cannot be determined definitively at this time. to the recently approved budesonide-for- moterol combination. These decisions were based primarily on Inhaled corticosteroid monotherapy is recommended for data from the Salmeterol Multicenter Asthma patients with mild persistent asthma. Alternatives include Research trial (SMART), in which patients— monotherapy with an antileukotriene, a cromone such as particularly African Americans—who received inhaled cromolyn (Intal) or nedocromil (Tilade), or salmeterol had a statistically significant higher theophylline. risk of fatal or potentially fatal asthma episodes.2 These actions come in a period of height- Salmeterol or formoterol should not be used as monotherapy, ened public concern about adverse effects of but rather added to inhaled corticosteroid therapy for drugs and the notion that some drugs do more patients with moderate or severe persistent asthma. harm than good.3 This concern has been fueled in part by the recent imbroglio over 4 Inform patients about the risks and benefits of long-acting selective cyclooxygenase 2 inhibitors. In this climate, greater scrutiny of possible risks asso- beta agonists, and document the discussion in the medical record. *Dr. Lang has disclosed that he has received honoraria, consulting fees, or other benefits for teaching, speaking, consulting, or conducting research for Patients with asthma require regular ongoing care with the AstraZeneca, Centocor, Critical Therapeutics, Genentech, Novartis, GlaxoSmithKline, MedPointe, Merck, Sanofi-Aventis, and Schering- periodic reexamination and follow-up. Plough/Key corporations. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 11 NOVEMBER 2006 973 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. LONG-ACTING BETA AGONISTS LANG classification or death certification. It was not Asthma deaths in the United States associated closely with a rise in asthma preva- lence, but rather with an increase in case fatal- 2.5 Salmeterol introduced ity. The trend was associated with use of a Salmeterol- fluticasone high-dose aerosol beta agonist, isoprenaline 2.0 introduced forte, which contained a concentration of iso- prenaline several times greater than that in 1.5 the standard isoprenaline inhaler used in other countries where a rise in asthma death 1.0 rates was not observed.6,7 In the 1970s and early 1980s, a second Deaths per 100,000 0.5 epidemic of asthma deaths occurred in New Zealand, and again the trend was associated 0 most closely with an increase in case fatality. 1976 1980 1984 1988 1992 1996 2000 The epidemiologic evidence implicated the use of inhaled fenoterol, a more potent beta FIGURE 1 agonist promoted for more severe asthma, as a DATA FROM THE NATIONAL CENTER FOR HEALTH STATISTICS. major influence,8 although this interpretation has been questioned.9 Contributory roles for ciated with drug treatment can be expected. psychologic comorbidity, patterns of health Another element of the present situation care access and utilization, and socioeconom- is revealed by a Google search for any of the ic factors have also been proposed.9,10 When above three drugs combined with the term fenoterol was withdrawn from the New “asthma”: each generates a link to a “death Zealand market, rates of asthma hospitaliza- injury” or “side effects injury” lawyer. tions and deaths declined.8 This paper reviews recent trends in asth- In contrast, asthma death rates rose more ma deaths in the United States, presents the gradually during the 1970s and 1980s in many Asthma deaths issues considered by the FDA in reaching its countries (including the United States) that plateaued in decision, critically examines the evidence, did not experience the 1960s epidemic. As and offers recommendations for clinicians in asthma deaths increased, so did rates of hospi- the 1990s and managing asthma patients who are already talization and emergency department visits.11 have declined taking or may require long-acting beta ago- It is tempting to attribute the rise in asthma nists. deaths to the undeniable increase in asthma since 1999 prevalence that also occurred.12–14 However, ■ ASTHMA DEATH TRENDS studies using similar methodology indicate no remarkable disparity in prevalence of asthma In recent decades, asthma has become more in children in New Zealand, Australia, and prevalent, more severe, and more deadly. Canada, despite hospitalization and death Between 4,000 and 4,500 people have died rates from asthma that are several times high- from asthma annually in recent years in the er.15–17 United States; in 2003, there were 4,099 US Asthma mortality rates in the United cases with asthma designated as the primary States are highest in African Americans living cause of death. This is unacceptable for a con- in poorer areas of large cities.11,18,19 Race, eth- dition for which there is effective manage- nicity, and poverty appear to contribute inde- ment. pendently to this greater risk.20 Concern about beta agonists was first In the United States, the asthma death raised in the 1960s, when asthma death rates rate rose to a plateau in the mid-1990s, and increased alarmingly in England, Wales, since 1999 has decreased (FIGURE 1).21 It has Scotland, Ireland, New Zealand, Australia, also decreased in New Zealand,6 Australia,22 and Norway—but not in the United States or England and Wales,23 and Israel.24 Canada.5 This trend could not be attributed to As shown in FIGURE 1, the asthma mortality spurious factors such as changes in diagnostic rate in the United States in 1997 and 1998, 974 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 11 NOVEMBER 2006 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. 2.0 per 100,000, was lower than in nedocromil (Tilade) or cromolyn (Intal). 1994–1996, ie, 2.1 per 100,000. In 1999, a Long-acting beta agonists had statistically sig- transition occurred from the ninth version of nificant advantages compared with placebo in the International Classification of Diseases morning peak expiratory flow rate, evening (ICD-9), in which asthma carried the code peak expiratory flow rate, asthma symptoms, 493, to ICD-10, in which asthma is coded J45 use of rescue medication, and quality of life. and J46. For this reason, the decline to 1.7 per The risk of asthma exacerbation was signifi- 100,000 observed in 1999 was initially ques- cantly lower in adults using long-acting beta tioned as spurious; however, further declines agonists in combination with inhaled corti- in 2000, 2001, and 2002 indicate that annual costeroids. rates of asthma deaths in the United States in Several other meta-analyses also found the initial years of the 21st century are declin- significantly lower exacerbation rates with the ing,25 and that the trend is real. combination of an inhaled corticosteroid and In countries where asthma death rates a long-acting beta agonist compared with have stopped increasing, prescriptions for inhaled corticosteroid monotherapy.35–37 A inhaled corticosteroids have increased,5,21–24 prospective economic analysis found combi- implying that more frequent use of inhaled nation therapy to be more cost-effective than corticosteroids by patients with potentially inhaled corticosteroid monotherapy in higher fatal asthma accounts for this new trend. This doses in managing moderate-to-severe persis- explanation has been supported by a number tent asthma.38 Neither cohort studies39–41 nor of studies.26,27 However, the results of case-control studies42–44 have found evidence SMART2 have refocused attention on beta linking long-acting beta agonist exposure to a agonists and the possibility that regular use of risk of fatal or near-fatal asthma. long-acting beta agonists plays a role in some fatal and near-fatal asthma episodes. Combination therapy in moderate persistent asthma ■ EVIDENCE THAT LONG-ACTING In the Oxis and Pulmicort Turbuhaler in the BETA AGONISTS ARE BENEFICIAL Management of Asthma (OPTIMA) trial,30 Asthma death 1,272 patients with moderate persistent asth- rates are In clinical trials,28–33 patients who received ma took the inhaled corticosteroid budes- long-acting beta agonists in combination with onide (Pulmicort) in a low dose (100 µg twice highest in inhaled corticosteroids had fewer symptoms a day) for 4 weeks to demonstrate that this did African (including nocturnal awakening), improved not control their asthma optimally—by defin- lung function, better health-related quality of ition, they had moderate persistent asthma.
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