BETA AGONISTS ARE TREATMENT OF CHOICE FOR ACUTE ASTHMA; NHLBI PANEL FAVORS ANTI-INFLAMMATORIES FOR CHRONIC USE: INHALED CORTICOSTEROIDS AND CROMOLYN
Beta-2-adrenergic agonists are "the medication of choice" for acute exacerbations of asthma, but further study of the agents is needed to resolve concerns about chronic use, according to a recently released assessment of treatment regimens for asthma. The treatment recommendations are part of the report of an expert panel convened by the National Heart, Lung & Blood Institute to develop guidelines for diagnosis and management of asthma. The report was released Feb. 5 at a press conference in Bethesda, Maryland. The report is an outgrowth of the National Asthma Education Program established in 1989. Beta-2-adrenergic agonists are part of first-line treatment for all stages of asthma, according to schematics for drug treatment included in the NHLBI report. Inhaled beta agonists (on an "as needed" basis) are recommended for mild asthma; inhaled or oral beta agonists plus an anti-inflammatory agent are suggested for moderate asthma; and beta agonists are included in the treatment of severe asthma with the addition of oral corticosteroids. For management of chronic asthma, the report indicates a shift in preference toward anti-inflammatory drugs: primarily the inhaled corticosteroids (such as AeroBid, Azmacort, Beclovent and Vanceril) and cromolyn sodium (Intal). Declaring that "prevention of exacerbations is an important principle of therapy," the report urges more aggressive asthma treatment with anti-inflammatory medications. "Children and adults who have poor exercise tolerance, recurring symptoms, and frequent nocturnal symptoms -- even patients with mild-to-moderate asthma - - will often benefit," the report finds, "from the regular administration and more aggressive use of anti-asthma medications, especially anti-inflammatory medicine." [EDITORS' NOTE: See box next page for a section on the importance of inflammation treatment from the report's discussion of the management of moderate asthma]. The report notes the increased frequency of inhaled corticosteroid use. "Because of the importance of airway inflammation in the pathogenesis of asthma," the report states, "inhaled corticosteroids are being used more frequently as primary therapy for moderate and severe asthma." The report maintains that the inclusion of inhaled corticosteroids in primary treatment "not only provides symptomatic benefit but also reduces airway hyper- responsiveness." Fisons' cromolyn sodium is described by the report as "the best nonsteroidal anti-inflammatory drug for asthma" and "an important therapeutic approach to the treatment of airway inflammation in asthma." In the discussion of the prophylactic treatment of mild asthma, the report points out a potential advantage of cromolyn over inhaled beta agonists. Beta agonists used prophylactically can mask the effects of antigen exposure in some asthmatics and "may result in a greater likelihood of asthma symptoms occurring about 4-6 hours later." Cromolyn sodium, however, appears to work on the initial antigen exposure and "blocks" the "late reaction to antigen." The strong safety profile of cromolyn sodium is also highlighted. The report notes that the product is "virtually devoid of any side effects." The NHLBI reiteration of the ingredient's safety record may contribute to the growing consensus about the product's safety and potential for a switch from prescription status to OTC. Fisons is not seeking a switch for asthma use but is reportedly pursuing a switch for the nasal/allergic rhinitis form of the product, Nasalcrom. The company began running direct-to-consumer ads for Nasalcrom in May 1989 apparently as a precursor to switching to the OTC market. The expert panel's interest in expanding anti-inflammatory drug treatment of asthma is exemplified in summary materials prepared for the press conference. The chairman of the expert panel, Harvard Medical professor Albert Sheffer, MD, said: "Reducing and hopefully preventing inflammation, not just reversing bronchial constriction, is central to asthma management. This means not only using an inhaled beta-2-agonist, a bronchodilator, to provide immediate symptomatic relief, but also using anti-inflammatory agents, such as cromolyn sodium or inhaled corticosteroids, to reduce inflammation over the long-term." In general, the press release says, "all patients need to have an inhaled beta-2-agonist available for acute asthma episodes; patients who don't respond quickly may also require corticosteroids to help speed recovery." The report emphasized the widespread usefulness of anti-inflammatories: "For patients with moderate to severe asthma, daily treatment with anti-inflammatory agents is required to control symptoms and prevent acute episodes." The movement toward anti-inflammatory use reflected in the NHLBI report mirrors a shift in world trends. Glaxo, a major participant in the asthma market with its albuterol products and corticosteroids, recently indicated that the use of inhaled corticosteroids is a treatment trend developing rapidly in major European markets. Glaxo estimates that based on calculations as of June 1990 inhaled beta agonists represented about 44% of the asthma treatment months worldwide while inhaled steroids were about 12%. Inhaled treatments (beta agonists, and anti-inflammatories) took the lead in worldwide asthma product volume by sales last year, representing about 55% of the world asthma market compared to an even split with oral products in 1989. Similarly, Fisons has experienced substantial growth for its Intal brand of cromolyn sodium in the U.S. The product has reportedly more than doubled in sales over the last three years. Some trade estimates put it at about $ 50 mil. in sales in 1988. Glaxo is the worldwide leader in inhaled corticosteroids with fiscal 1990 sales estimated at $ 450 mil. The chronic use concerns with beta agonists take into account the findings from a New Zealand study of regular vs. on-demand inhaled beta-agonists published in the December 8, 1990 issue of The Lancet. That study (on fenoterol, which is not marketed in the U.S.) attempted to draw a link between the increased long-term use of inhaled beta-agonist treatment of asthma and "the worldwide increase in morbidity from asthma." Although publication of The Lancet study predated the completion of the final draft of the expert panel's report by only a little over a month, the panel's report addresses the conclusions of the study. The panel had originally planned to finish its work by November. It may have delayed its final project to take the New Zealand study into consideration. "A recent report," the NHLBI panel says, "associates the regular use (as opposed to . . . as needed use) of a potent inhaled beta-2-agonist with diminished control of asthma. This study is in contradistinction to the conclusions of previous clinical trials that demonstrated an improvement in asthma symptoms with regularly scheduled treatment with inhaled beta-2- agonist." The NHLBI report notes that "the mechanism of diminished control is unclear" but could be related to rebound airway hyper- responsiveness or increased bronchial secretions. The report urges further clinical studies to evaluate the long-term therapy with inhaled beta-2-agonsts. "Additional placebo-controlled studies are needed," the report says, "on the effects of regular versus intermittent therapy with inhaled beta-2-agonists on asthma symptoms, airway hyper- responsiveness, and asthma mortality." Other research and development projects noted by the expert panel include new anti-inflammatory agents, methotrexate, gold, and longer-acting beta-2-agonists to improve nocturnal treatment. "Longer-acting inhaled beta-2-agonists with action lasting 12- 18 hours are under development," the NHLBI panel noted. "The newer adrenergic agents are more selective for the beta-2 receptor and have a more prolonged duration of action, although they still retain some beta-1 cardiac activity." In December, Glaxo introduced its next generation, long-acting beta-2-agonist Serevent (salmeterol) in the U.K. ("The Pink Sheet," Dec. 10, p. 11). Glaxo claims that the product virtually eliminates nocturnal asthma, and that it has anti-inflammatory properties. Filing of the NDA for the product in the U.S. is planned for the middle of this year ("The Pink Sheet" Oct. 22, p. 3). The report specifically identifies three areas of further research in the anti-inflammatory field: Fisons' nedocromil sodium (Tilade), antihistamines, and Sandoz' ketotifen. The Fisons' product "reduces the acute airway narrowing response to exercise, hyperventilation, mist, and sulfur dioxide." Like cromolyn, the product does not show "any significant adverse effects." Tilade was recommended for approval by an FDA advisory committee in mid-June of last year ("The Pink Sheet" June 18, p. 8). Acknowledging the recent anti-asthma work on antihistamines, the report notes that "some studies show that antihistamines have mild bronchodilator activity. The newer antihistamines also may inhibit mediator release from in vitro cell systems." The "long- held concern" about an adverse drying effect of antihistamines on bronchial mucus is debunked by the report, mimicking a suggested label change by an FDA advisory committee last summer to remove the warning about use of antihistamines in asthma patients. The report notes the use of the oral prophylactic ketotifen in Europe and Japan but points out that the product "has shown limited efficacy in U.S. clinicals." Methotrexate is recommended only for use by very severe asthmatics under treatment by a physician familiar with the product. Controlled clinical trials are necessary to confirm the use of oral gold in severe steroid- dependent asthma patients. Theophylline may have "at least some degree of anti- inflammatory activity," the panel notes. However, it adds that this "is a subject of debate." The sustained release forms of theophylline can be useful in the control of nocturnal asthma. The panel report suggests general monitoring guidelines for theophylline users ("approximately yearly") but notes that the frequency of monitoring is related to "specific clinical situations." Sustained release theophylline is suggested as additional therapy for moderate asthma in adults if symptoms persist after treatment with inhaled beta agonists and anti-inflammatories. The report suggests that immunotherapy be initiated when allergen avoidance is not possible and "appropriate medication fails to control symptoms of allergic asthma." Recent studies, the report observes, "have shown that allergen immunotherapy reduces the late reaction to allergen in the lungs. This suggests that allergen immunotherapy can be employed to prevent the development of allergic inflammation and perhaps the resulting bronchial hyper-responsiveness." The NHLBI expert panel was comprised of 10 professors from teaching hospitals, two doctors affiliated with other hospitals and two federal liaison representatives. Neither of the government employees assigned to the panel were from FDA. The Centers for Disease Control were represented by medical epidemiologist Ruth Etzel, MD/PhD. The National Institute of Allergy & Infectious Diseases was represented by the chairman of the asthma and allergy branch, Lawrence Prograis, MD. AIRWAY INFLAMMATION IN ASTHMA: TREATMENT IMPLICATIONS Excerpted from a section on managing moderate asthma in the Jan. 17 report of the expert panel convened under the auspices of the NHLBI. Increasing evidence suggests that airway inflammation is present in virtually all patients with asthma and that anti- inflammatory therapy should be considered for patients with moderate asthma. Currently, the physician has two choices, cromolyn or inhaled corticosteroids. Experience in Europe and Australia indicates that high-dose, inhaled corticosteroids (e.g., 1,600 mg/day beclomethasone) suppress airway hyperresponsiveness; there is also evidence that similar effects are achieved with smaller doses (400 to 800 mg) in milder cases. Confirmation of these observations is necessary. Nonetheless, the aggressive use of these agents (8-16 puffs per day) may provide improved asthma care with minimal side effects. Cromolyn sodium also has been advocated for anti-inflammatory activity. Cromolyn sodium is virtually devoid of any side effects, but its effectiveness in asthma is less predictable than that of inhaled corticosteroids in all patients treated.
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