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Anticholinergic and sympathomimetic combination therapy of asthma
Anticholinergic and sympathomimetic combination therapy of asthma Anthony Kenneth
S. Rebuck, M.D., F.R.C.P.(C), Michael Gent, M.Sc., and R. Chapman, M.D., F.R.C.P.(C)* Toronto and Hamilton, Ontario, Canada
The role of the anticholinergic drug, ipratropium bromide, in maintenance antiasthmatic therap) kt’a.se,~aluated in a double-blind crossover trial of three bronchodilator regimens: (I) inhaled ipratropium, placebo, and oral oxtriphylline; (2) inhaled fenoterol, placebo, and oral oxtriphylline; and (3) both inhaled ipratropium and fenoterol plus oral oxtriphylline. Twenty-two asthmatics were treated with all three regimens, each for I mo, allocated in random sequence. On the first and last treatment days of each month, spirometric measurements were performed before and 0.5, I, 2, 3, 4, and 6 hr after administration of the test drugs. On the$rst treatment day of each month, all regimens produced significant bronchodilatation at 30 min after dose, an improvement that declined between 3 and 6 hr after dose. After continuous administration for I mo the two combinations employing fenoterol showed a decline in bronchodilator responsiveness from the initial treatment day, measured as the level of response (v,,) or duration of response (FEV,, VC). lpratropium plus oxtriphylline showed no such decline, suggesting the development of tolerance to long-term administration of fenoterol. Overall benejit at the end of 1 mo. measured as the area under the curves of FEVI, VC, or r’,, vs time after dose, was greatest for the triple drug regimen. There were no differences in heart rate, blood pressure response. or side effects among the three treatments. It is concluded that when the anticholinergic drug ipratropium is administered concurrently with an inhaled beta2 agonist and an oral theophylline derivative, increased bronchodilatation occurs with no detectable additional side efiects. (JAUERGY CUNIMMUNOL 71:317, 1983.)
Combination bronchodilator therapy, employing a beta-adrenoreceptor agonist and a theophylline derivative, has been demonstrated to be more effective than treatment with either agent alone for both stable and acutely ill asthmatics.le3 If the combination of two sympathomimetic agents acting via different mechanisms can produce greater bronchodilatation with fewer side effects than either agent used alone, it is possible that the addition of an anticholinergic bronchodilator could further improve treatment resuits. Ipratropium bromide, an N-isopropyl derivative of atropine, is an effective aerosol bronchodilator free of the unwanted systemic side effects of the parent From the Division of Respiratory Medicine, Toronto Western Hospital, University of Toronto, Toronto, and Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada. Received for publication June 24, 1982. Accepted for publication Sept. 24, 1982. Reprint requests to: Dr. A. S. Rebuck, Respiratory Division, Toronto Western Hospital, 399 Bathurst St., Edith Cave11 Wing, Suite 204, Toronto, Ontario, Canada M5T 2S8. *Fellow of the Medical Research Council of Canada.
compound.4 Short-term studies of ipratropium and beta, agonists have shown that the combination of ipratropium with either albuterol or fenoterol produces a greater effect than any of these agents used alone.“, 6 A comparison of ipratropium and oral theophylline used singly and together has demonstrated synergy between the two drugs.7 In a study of the acute effects of bronchodilators in a small group of asthmatics, Wildbolz et al.s found that the combination of ipratropium, orciprenaline, and theophylline produced greater increases in FEV, than either orciprenaline alone or orciprenaline plus theophylline. To date, no study has determined whether ipratropium is a useful addition to a beta agonist plus theophylline in the long-term maintenance therapy of stable asthma. Accordingly, we conducted a long-term double-blind crossover trial that combined the use of these drugs. METHODS Twenty-two stable, ambulatory asthmatics were studied, including nine male and 13 female patients, ages 17 to 75 yr (mean age 46 yr). Additional patient data are given in Table I. All patients met American Thoracic Society criteria for Vol.
71, No.
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318
FEV,: VC: vso:
Forced expiratory volume in 1 second Vital capacity Maximum expiratory flow rate at 50%
ii,,:
vc
Maximum expiratory fow rate at 25%'
I
J. ALLERGY CLIN. iMMUNOC MARCH 1983
Rebuck et al.
vc
I
the diagnosis of asthma!’ and demonstrated bronchodilator responsivenesswith at least a 15% increasein FEV, after a test dose of 400 pg of fenoterol administered by metered aerosol. Subjectswere excluded from the study if they had a history of significant cough and sputum production during clinically stable periods, recent viral respiratory tract infection, or major cardiac, hepatic, renal, or metabolic disease. Patients with glaucoma, prostatic hypertrophy, bladderneck obstruction, or hypersensitivity to atropinic compounds were also excluded. At the time of the study, all patients had been clinically stable for at least I mo. The purpose and nature of the investigation were explained to each participant, and informed written consent was obtained. Three combined regimens were tested in random order, each for 30 days. The drugs and dosages used were as follows: ipratropium bromide, 40 pg four times daily by metered aerosol: fenoterol, 200 pg four times daily by metered aerosol; and oxtriphylline 200 mg orally four times daily. The following combinations were used: (1) ipratropium plus placebo plus oxtriphylline. (2) placebo plus fenoterol plus oxtriphylline, and (3) ipratropium plus fenoterol plus oxtriphylline. Drugs and placebos were administered in a double-blind fashion and the code remained unbroken until all studieswere completed. Concurrent therapy with oral or inhaled steroids was continued, with no change in dosage throughout the study. On day 1 and day 30 of each treatment period, subjects attended the laboratory for spirometric measurementsand clinical assessment.Aerosol bronchodilators were withheld for 8 hr before spirometric measurement, and subjectswere asked to abstain from xanthine-containing beveragesfor 4 hr before baseline testing and for 6 hr after until all measurementswere taken. FEV,, VC, vj,,, v,,, blood pressure, and heart rate were measured immediately before and 0.5, 1, 2, 3, 4, and 6 hr after administration of the appropriate test treatment. Spirometric values were measured on the best of three reproducible maximum expiratory flow volume curves obtained on a Hewlett-Packard 47804A Pulmonary Calculator System (Hewlett-Packard Co., Waltham, Mass.). A 12-lead electrocardiogram was recorded just before and 1 hr after drug administration. Peakflow rates were measured (Mini-Wright peak flow meter; Airmed, London, England) and recorded four times daily by every patient throughout the study. Patient diaries were used to record peak flow; medications used; number, duration, and severity of attacks; and alleged sideeffects of medications. Blood was taken on the first and last day of the study for the
following measurements: hemoglobin, hematocrit,, white blood cell count with differential, platelet count, serum electrolytes, serum glutamic oxaloacetic transaminase, alkaline phosphatase, total bilirubin, totai serum protein and albumin, cholesterol, blood urea nitrogen, creatinine, and uric acid. On thesedays, urine specimenswere collected for microscopic analysis and for measurementof pH” plucose protein, and specific gravity. Statistical analysis was peribrmed wtlth an;ilysIs rll‘ vafiante procedures appropriate to a crossover &sign with before/after assessmentsand with repeated measurements over time: t tests were used when applicable to ictmpnrr differences between two means. RESULTS Four subjects failed to complete the triai, Pattent 2, while taking ipratropium, fenoterol, and urtriphyl-, line, suffered an acute asthmatic attack anJ used un. authorized medications. Patient 10 could not attend the clinic regularly as required by the protocc,i and withdrew from the study (while receiving fenoteroi and oxtriphylline). Patients 11 and 15 withdrew from the study because of alleged side effects, including cough, headache, dizziness, and tremor: one patient was receiving ipratropium, fenoterol, and arrtriphylline, and the other was receiving fenoterol and oxtriphylline. Eight male and IO female patients (mean age 47 yrl completed the study. Mean duration of disease was 24 yr. Spirometric data were incomplete for one of these subjects for one test day so that subsequent statisticaii analysis is based on the remaining 17 patients L Day 1 treatment
responses
All three regimens produced significant increases in FEV,, VC, vs,,, and i’,, at 30 min after administration. This improvement began to decline at 3 hr after treatment and dropped significantly over the next 3 hr. This pattern is illustrated in Fig. 1 for mean increases in FEV,. Similar curves obtained for VC. Qj(,, and ‘\I,, are not shown. There was a significant difference among the three regimens in the level of response as measured by the FEV, and v,, (p < 0.05). By means of the Newman-Keuls multiple comparison proccdure, the three-drug regimen gave a greater FEV, and ir,, acute response than the ipratropium-oxtriphylline regimen (for both variables, p *: 0.05). Other similar comparisons did not reach significance. Day 30 vs day 1 treatment responses-changes wfthin
re&nens
Prebronchodilator values of FEV,, VC. %“,,, and v’,, did not vary significantly between day I and day 30 for any treatment regimen, making it valid to compare initial and final bronchodilator response in terms
Combination
VOLUME 71 NUMBER 3
TABLE
I. Clinical
data for the 22 patients
therapy of asthma
studied* Concurrent
Baseline FEVl (% predicted)
Disease
duration (yr)
Inhaled steroids
therapy
Oral steroids
Sodium cromoglycate
Patient
Sex
1 2 3 4
M F F F
36 18 40 58
46 30 71 33
32 17 37 50
+ + + +
+ + -
+ + -
.-
5 6
F M
46 62
68 56
25 6
+ -
+ +
+
+ .-
7 8 9 10 11 I? 13 14 1s 16 17 18
F F M F M F F M F F M M
46 51 34 31 59 75 60 59 46 60 39 17
48 72 71 46 58 52 47 64 84 29 69 100
41 4 10 27 1 1.5 60 37 15 55 1 IO
+ + + + + + + +
+ + + + +
+ -
+ + + +
+ -
19 20 21 22
F F M M
47 35 32 57
46 91 39 21
14 .75 30 8
-
+ + + +
+ +
Age
(vr)
*Patients 2, IO, 11, and 15 withdrew are not included in the analysis.
319
from the study before
its completion.
of increases over the corresponding baseline. (Analysis of variance procedures applied to actual level of FEV,, VC, V,,, and V,, yielded results similar to those outlined below with increase over the baseline.) Mean increases for FEV, and V5,, are shown graphically for each regimen in Fig. 2. Ipratropium and oxtriphylline. For each of the four variables (FEV,, VC, V,,, and Vz,) the onset of improvement and the duration of improvement were similar for the initial and final days of treatment. The level of improvement tended to be higher on the last day of treatment for each variable, but this improvement in the general level of response did not reach statistical significance for any parameter. Mean increases for both first and last treatment days are shown in Fig. 2, A and B, for FEV, and V,,, respectively . Fenoterol and oxtriphylline. As with ipratropium and oxtriphylline, the regimen of fenoterol plus oxtriphylline showed no change in the pattern of response between first and last treatment days for any variable. However, the observed increases were consistently lower on the last day of treatment for FEV, (Fig. 2, C), V5,, (Fig. 2, D), and V,, (not shown). These differences approached but did not reach statis-
Atow
Incomplete
data were available
tical significance p = 0.10).
-
i .-
for patient h; therefore,
(for FEV,,
his results
p = 0.08; for VjO,
lpratropium, fenoterol, and oxtriphylline. For this regimen a decline in the duration and level of response was evident by the last day of long-term administration. For FEV, (Fig. 2, E) the onset of improvement was similar on the first and last treatment days, and analysis of variance showed that the duration of improvement was much shorter on the latter day (p < 0.01). A similar change in response pattern was found for VC (p < 0.01) (not illustrated). For V,,, (Fig. 2, F) and Vz5 the pattern of response over time was not significantly different between day 1 and day 30, but the level of response was much less on day 30 and this difference was statistically significant for VS0 (p < 0.01).
Overall benefit, regimens
day 30-comparison
among
To determine the relative efficacy of the three regimens after long-term administration a comparison of day 30 responses was made. As can be seen in Fig. 2, the two treatment regimens containing fenoterol showed a more rapid initial response but shorter duration of response than the
320
Rebuck
0.6
J. ALLERGY CLIN. Ik4MUNOL. MARCH 1903
et al.
-
1
2
3
4
5
6
TIMEthours)
FIG. 1. Mean increase in FEV, over 6 hr after treatment subjects (day 1). Bars represent one standard error. line, lpratropium + fenoterol + oxtriphylline; dashed fenoterol + placebo + oxtriphylline; dotted line, tropium + placebo + oxtriphylline.
in 17 So/id line,
ipra-
regimen of ipratropium and oxtriphylline. This difference in the pattern of response among the regimens was statistically significant (p < 0.01) for FEV,, VC, and VsO. Since the onset and duration of improvement varied among the three treatment regimens, an index of overall benefit was sought that would allow valid and informative comparison between regimens. The area under the bronchodilator response curve was used as a useful composite of the magnitude of the response and the duration of that response. These areas for each of the regimens on the initial and final treatment day are represented graphically in Fig. 3. As can be seen, for FEV,, VC, and V,, overall benefit on day 30 was greatest for the triple regimen of ipratropium, fenoterol, and oxtriphylline. By means of the Newman-Keuls multiple comparison procedure, this difference between regimens reached statistical significance for the greater benefit of ipratropium, fenoterol, and oxtriphylline over fenoterol and oxtriphylline in terms of FEV, (p < 0.05). Tolerance
to fenoterol
As outlined above, both regimens containing fenoterol showed a decrease in duration and level of
response for several pulmonary function prarameters between day 1 and day 30 of administration. By comparison, the regimen without fenoterol did not show this effect and in fact overall level of response was generally higher on the last day of treatment (Fig. 2. A and B). This suggested the possibility that toterance tc~ fenoterol had developed during the treatment period To assessthis possibility, overall benefit measured as the area under the curve was again used to comparc regimens. Fig. 3 shows that these areas were all in creased by day 30 of treatment with ipratropium and theophylline. On the other hand. the areas decreased for FEV,, VC, VXo, and VZ, after a period of treatment with fenoterol and oxtriphylline or fenoterol plus ipratropium and oxtriphylline. These reductions in overall benefit were not statistically different be” tween the two fenoterol-containing regimens. When the data for these two regimens were pooled, the reduction in the areas under the curves of FEV, and ii,!“) were statistically significant (p
patient
acceptance
The pattern of blood pressure and heart rate w sponse was not different among treatment regimens OI between initial and final days of treatment. Systolic and diastolic blood pressures declined slightly over each 6 hr period and heart rate declined slightly to ward the midpoint of each 6 hr period, returning to baseline by the end of the period. The battery of biochemical and hematologic laboratory tests failed to detect any toxicity of the three regimens after longterm administration.
VOLUME 71 NUMBER 3
Combination
Ipratropium, Placebo and Oxtriphylline
,::.q::
therapy
Fenoterol, Placebo and Oxtriphylline
of asthma
321
Ipratropium, Fenoterol Oxtriphylline
and
h -1. 02 _ * . .
Ol-
&
~~~~.~
1 06-
:.*. *.
0.5-
***
*.
E *..*
04-
0.6.
..*.-
. ...*
F
-.*.
1
*..* .-.*
03-
. . . . ..!!I
*q
0.2 0.1 A,
1
2
3
4
5
6
1
,
,
,
,
\
2
3
4
5
6
30 DAY
1
30 DAY
1
30 DAY
FIG. 3. Mean (for 17 subjects) of the area under the 6 hr response curves for FEV, (L . hr), VC (L hr), V,, (L hr) as measured on the first set-’ . hr) and V,, (L set-’ and last treatment days with the three regimens. Bars represent one standard error.
TIME (hours) FIG. 2. Mean increases in FEV, and V,, on day 1 (dotted line) and day 30 (solid line) for each treatment regimen (A and B, ipratropium + oxtriphylline; C and D, fenoterol + oxtriphylline; E and F, ipratropium + fenoterol + oxtriphyiline). For each of the fenoterol-containing regimens, day 30 increases were less than day 1 increases (C, 0, E, and F). The greatest mean increases on day 30 for FEV,, VC, and V, were observed with the triple-drug regimen (E and F).
Review of patient diaries showed that there was no significant difference in the number or severity of acute attacks among the three treatments. Compliance assessedby pill count and record of drug taking in the patient diaries was good with all three regimens. The patients’ subjective rating of improvement with each of the regimens was generally favorable and not significantly different among the regimens. Alleged side effects reported by the patients were generally minor, including mild tremor, loss of taste, fatigue, mild cough, and light-headedness. Seven of the 18 study patients complained of one or more of these side effects during the course of the entire study, three after receiving ipratropium plus oxtriphylline, four after receiving fenoterol plus oxtriphylline, and five after receiving ipratropium plus fenoterol plus oxtriphylline. These differences were not statistically significant. DISCUSSION One rationale for using beta agonists and methylxanthines in combination to treat asthma is that they
bronchodilate via different pharmacologic mechanisms, the former by stimulating cyclic AMP production and the latter by inhibiting the degradation of cyclic AMP by phosphodiesterase.10 A similar rationale is applicable to the addition of anticholinergic agents, which produce bronchodilatation via pathways distinct from the sympathomimetics. At the intracellular level, anticholinergic agents diminish cyclic GMP levels, thereby producing bronchial smooth muscle relaxation. (An effect on mast cell cholinergic receptors may also be important in asthma.‘)) At the neuronal level, anticholinergics such as ipratropium inhibit vagal efferent pathways, an important influence given that the vagal tone is the major determinant of resting airway caliber in normal subjects.12 In disease states such as asthma, vagal influences may be particularly important in some individuals, e.g., those with emotionally influenced or triggered asthmatic attacks.13 Not only does the mechanism of action of anticholinergics differ from that of existing antiasthmatic agents but the site of bronchodilator effect appears to differ as well. There is evidence that atropine preferentially dilates proximal airways.14* l5 The development of ipratropium bromide has made available an anticholinergic bronchodilator with a minimum of adverse effects.16 Used alone, it is an effective bronchodilator for patients with asthma or chronic bronchitis.‘? Contrasted with inhaled betaadrenoreceptor agonists, it has a later onset of action
322
Rebuck
J. ALLERGY CLIN. IMMUhKlt. MARCH W3
et al.
but a more prolonged effect.lX In asthma, inhaled ipratropium produces less bronchodilatation than inhaled beta agonists, but in chronic bronchitis the bronchodilatation is equal to or greater than that produced by beta stimu1ation.l” The combination of ipratropium and various beta agonists has generally produced greater bronchodilatation than either agent used alone.” When ipratropium is combined with theophylline, synergy between the two drugs can be demonstrated.’ A steroid-sparing effect of ipratropium has even been suggested.“” Despite these early promising results, the role of ipratropium in antiasthmatic therapy has not been defined, and in particular its place in combination regimens is unclear. Our data show that not only can a combination of ipratropium, fenoterol, and a theophylline derivative produce greater bronchodilatation than that produced by either fenoteroi and theophylline or ipratropium and theophylline by short-term administration (Fig. 1) but also that after long-term administration, the threedrug regimen produces greater overall benefit than either of the two-drug regimens. Previous studies have shown that bronchodilator responsiveness to ipratropium does not decline after long-term administration.” We have shown this to be true for the combination of ipratropium and oxtriphylline. By contrast, both regimens incorporating fenoterol showed a decline in responsiveness after prolonged treatment. Tolerance to long-term beta agonists has been described previously, although several studies have produced discrepant results. 21-23 Certainly, at a cellular level, oral administration of terbutaline for 4 wk is sufficient to produce marked decrease in the density of lymphocyte beta receptors in both normal subjects and in patients with mild asthma.2” A decline in bronchodilator response may accompany this, although the effect may be small and is of unknown clinical significance. Our data suggest at least one reason why not all studies have demonstrated tolerance to longterm beta agonists. The decline in responsiveness that we observed was not only in the level of bronchodilator response but also in the pattern of this response. Studies that examine only the peak levels of bronchodilatation after drug administration may fail to detect changes in duration of effect. Our study has demonstrated that the addition of ipratropium to a beta, agonist and a theophylline derivative can produce measurable improvement in bronchodilatation, with no increase in unwanted side effects. Yet, despite an apparent spirometric benefit associated with the use of ipratropium, we were unable to demonstrate any decrease in the number, severity, or duration of intercurrent acute asthmatic attacks by the addition of ipratropium.
We thank Ms. M. Leslie for her technical assistance. G. M. Worsley, M.D.. and F. Vickerson, Ph.D., for their support and assistance throughnut the study. XXI Mrs. M Sweetman for her assistance in preparation of the manuscript. REFERENCES I
2
7
3 5
6
1.
8. 9.
10. II.
12. 1.3.
13. 15.
16. 17.
18.
19.
20.
Wolfe JD. Tashkin UP. Calvarese H. S~mmi~rrs 2/I. Bran chodilator effects of terbutaline and aminophyliinr alone and in combination in asthmatic patients. N Engl J Med 298:363. 1978 Rossing TH, Fanta CH. McFadden E,R: A ctmtrolled ma1 ut the use of smgle versus combined-drug therapy in the treatment of acute episodes of asthma. Am Rev Kespir Dis 123: 190, 1981. Nassif EG, Weinberger M. Thompson R. Hun&y ti. The value of maintenance theophylline in steroid-dependent dsthma. N Engl J Med 304:71, t 981. Gross NJ: SCH 1000: a new anrichohnerglc bronchadilatol Am Rev Respir Dis 112:823. 1975 Ruffin RE, McIntyre E, Crockett AJ. Zielonka K. .;‘rlpers JH: Combination bronchodilator therapy in asthmil I/ Al.1 EKC~~ CLIN ~MUNOI. 69:60. 1982. Lightbody IM, Ingram CG. Legge JS. Johnst
VOLUME 71 NUMBER 3
21.
Nelson HS, Raine D, Doner HC, Posey WC: Subsensitivity to the bronchodilator action of albuterol produced by chronic administration. Am Rev Respir Dis 116:871, 1977. 22. Plummer AL: Development of drug tolerance to beta-2 adrenergic agents in asthmatics. Chest 73(Suppl.):949, 1978. 23. Peel ET, Gibson GJ: Effects of long-term inhaled salbutamol
Combination
therapy
of asthma
323
therapy on the provocation of asthma by histamine. Am Rev Respir Dis 121:973, 1980. 24. Tashkin DP, Conolly ME, Deutsch RI, Hui KK, Littner M, Scarpace P, Abrass I: Subsensitization of beta-adrenoreceptors in airways and lymphocytes of healthy and asthmatic subjects. Am Rev Respir Dis 125185, 1982.
S. Rebuck, M.D., F.R.C.P.(C), Michael Gent, M.Sc., and R. Chapman, M.D., F.R.C.P.(C)* Toronto and Hamilton, Ontario, Canada
The role of the anticholinergic drug, ipratropium bromide, in maintenance antiasthmatic therap) kt’a.se,~aluated in a double-blind crossover trial of three bronchodilator regimens: (I) inhaled ipratropium, placebo, and oral oxtriphylline; (2) inhaled fenoterol, placebo, and oral oxtriphylline; and (3) both inhaled ipratropium and fenoterol plus oral oxtriphylline. Twenty-two asthmatics were treated with all three regimens, each for I mo, allocated in random sequence. On the first and last treatment days of each month, spirometric measurements were performed before and 0.5, I, 2, 3, 4, and 6 hr after administration of the test drugs. On the$rst treatment day of each month, all regimens produced significant bronchodilatation at 30 min after dose, an improvement that declined between 3 and 6 hr after dose. After continuous administration for I mo the two combinations employing fenoterol showed a decline in bronchodilator responsiveness from the initial treatment day, measured as the level of response (v,,) or duration of response (FEV,, VC). lpratropium plus oxtriphylline showed no such decline, suggesting the development of tolerance to long-term administration of fenoterol. Overall benejit at the end of 1 mo. measured as the area under the curves of FEVI, VC, or r’,, vs time after dose, was greatest for the triple drug regimen. There were no differences in heart rate, blood pressure response. or side effects among the three treatments. It is concluded that when the anticholinergic drug ipratropium is administered concurrently with an inhaled beta2 agonist and an oral theophylline derivative, increased bronchodilatation occurs with no detectable additional side efiects. (JAUERGY CUNIMMUNOL 71:317, 1983.)
Combination bronchodilator therapy, employing a beta-adrenoreceptor agonist and a theophylline derivative, has been demonstrated to be more effective than treatment with either agent alone for both stable and acutely ill asthmatics.le3 If the combination of two sympathomimetic agents acting via different mechanisms can produce greater bronchodilatation with fewer side effects than either agent used alone, it is possible that the addition of an anticholinergic bronchodilator could further improve treatment resuits. Ipratropium bromide, an N-isopropyl derivative of atropine, is an effective aerosol bronchodilator free of the unwanted systemic side effects of the parent From the Division of Respiratory Medicine, Toronto Western Hospital, University of Toronto, Toronto, and Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada. Received for publication June 24, 1982. Accepted for publication Sept. 24, 1982. Reprint requests to: Dr. A. S. Rebuck, Respiratory Division, Toronto Western Hospital, 399 Bathurst St., Edith Cave11 Wing, Suite 204, Toronto, Ontario, Canada M5T 2S8. *Fellow of the Medical Research Council of Canada.
compound.4 Short-term studies of ipratropium and beta, agonists have shown that the combination of ipratropium with either albuterol or fenoterol produces a greater effect than any of these agents used alone.“, 6 A comparison of ipratropium and oral theophylline used singly and together has demonstrated synergy between the two drugs.7 In a study of the acute effects of bronchodilators in a small group of asthmatics, Wildbolz et al.s found that the combination of ipratropium, orciprenaline, and theophylline produced greater increases in FEV, than either orciprenaline alone or orciprenaline plus theophylline. To date, no study has determined whether ipratropium is a useful addition to a beta agonist plus theophylline in the long-term maintenance therapy of stable asthma. Accordingly, we conducted a long-term double-blind crossover trial that combined the use of these drugs. METHODS Twenty-two stable, ambulatory asthmatics were studied, including nine male and 13 female patients, ages 17 to 75 yr (mean age 46 yr). Additional patient data are given in Table I. All patients met American Thoracic Society criteria for Vol.
71, No.
3, pp.
317-323
318
FEV,: VC: vso:
Forced expiratory volume in 1 second Vital capacity Maximum expiratory flow rate at 50%
ii,,:
vc
Maximum expiratory fow rate at 25%'
I
J. ALLERGY CLIN. iMMUNOC MARCH 1983
Rebuck et al.
vc
I
the diagnosis of asthma!’ and demonstrated bronchodilator responsivenesswith at least a 15% increasein FEV, after a test dose of 400 pg of fenoterol administered by metered aerosol. Subjectswere excluded from the study if they had a history of significant cough and sputum production during clinically stable periods, recent viral respiratory tract infection, or major cardiac, hepatic, renal, or metabolic disease. Patients with glaucoma, prostatic hypertrophy, bladderneck obstruction, or hypersensitivity to atropinic compounds were also excluded. At the time of the study, all patients had been clinically stable for at least I mo. The purpose and nature of the investigation were explained to each participant, and informed written consent was obtained. Three combined regimens were tested in random order, each for 30 days. The drugs and dosages used were as follows: ipratropium bromide, 40 pg four times daily by metered aerosol: fenoterol, 200 pg four times daily by metered aerosol; and oxtriphylline 200 mg orally four times daily. The following combinations were used: (1) ipratropium plus placebo plus oxtriphylline. (2) placebo plus fenoterol plus oxtriphylline, and (3) ipratropium plus fenoterol plus oxtriphylline. Drugs and placebos were administered in a double-blind fashion and the code remained unbroken until all studieswere completed. Concurrent therapy with oral or inhaled steroids was continued, with no change in dosage throughout the study. On day 1 and day 30 of each treatment period, subjects attended the laboratory for spirometric measurementsand clinical assessment.Aerosol bronchodilators were withheld for 8 hr before spirometric measurement, and subjectswere asked to abstain from xanthine-containing beveragesfor 4 hr before baseline testing and for 6 hr after until all measurementswere taken. FEV,, VC, vj,,, v,,, blood pressure, and heart rate were measured immediately before and 0.5, 1, 2, 3, 4, and 6 hr after administration of the appropriate test treatment. Spirometric values were measured on the best of three reproducible maximum expiratory flow volume curves obtained on a Hewlett-Packard 47804A Pulmonary Calculator System (Hewlett-Packard Co., Waltham, Mass.). A 12-lead electrocardiogram was recorded just before and 1 hr after drug administration. Peakflow rates were measured (Mini-Wright peak flow meter; Airmed, London, England) and recorded four times daily by every patient throughout the study. Patient diaries were used to record peak flow; medications used; number, duration, and severity of attacks; and alleged sideeffects of medications. Blood was taken on the first and last day of the study for the
following measurements: hemoglobin, hematocrit,, white blood cell count with differential, platelet count, serum electrolytes, serum glutamic oxaloacetic transaminase, alkaline phosphatase, total bilirubin, totai serum protein and albumin, cholesterol, blood urea nitrogen, creatinine, and uric acid. On thesedays, urine specimenswere collected for microscopic analysis and for measurementof pH” plucose protein, and specific gravity. Statistical analysis was peribrmed wtlth an;ilysIs rll‘ vafiante procedures appropriate to a crossover &sign with before/after assessmentsand with repeated measurements over time: t tests were used when applicable to ictmpnrr differences between two means. RESULTS Four subjects failed to complete the triai, Pattent 2, while taking ipratropium, fenoterol, and urtriphyl-, line, suffered an acute asthmatic attack anJ used un. authorized medications. Patient 10 could not attend the clinic regularly as required by the protocc,i and withdrew from the study (while receiving fenoteroi and oxtriphylline). Patients 11 and 15 withdrew from the study because of alleged side effects, including cough, headache, dizziness, and tremor: one patient was receiving ipratropium, fenoterol, and arrtriphylline, and the other was receiving fenoterol and oxtriphylline. Eight male and IO female patients (mean age 47 yrl completed the study. Mean duration of disease was 24 yr. Spirometric data were incomplete for one of these subjects for one test day so that subsequent statisticaii analysis is based on the remaining 17 patients L Day 1 treatment
responses
All three regimens produced significant increases in FEV,, VC, vs,,, and i’,, at 30 min after administration. This improvement began to decline at 3 hr after treatment and dropped significantly over the next 3 hr. This pattern is illustrated in Fig. 1 for mean increases in FEV,. Similar curves obtained for VC. Qj(,, and ‘\I,, are not shown. There was a significant difference among the three regimens in the level of response as measured by the FEV, and v,, (p < 0.05). By means of the Newman-Keuls multiple comparison proccdure, the three-drug regimen gave a greater FEV, and ir,, acute response than the ipratropium-oxtriphylline regimen (for both variables, p *: 0.05). Other similar comparisons did not reach significance. Day 30 vs day 1 treatment responses-changes wfthin
re&nens
Prebronchodilator values of FEV,, VC. %“,,, and v’,, did not vary significantly between day I and day 30 for any treatment regimen, making it valid to compare initial and final bronchodilator response in terms
Combination
VOLUME 71 NUMBER 3
TABLE
I. Clinical
data for the 22 patients
therapy of asthma
studied* Concurrent
Baseline FEVl (% predicted)
Disease
duration (yr)
Inhaled steroids
therapy
Oral steroids
Sodium cromoglycate
Patient
Sex
1 2 3 4
M F F F
36 18 40 58
46 30 71 33
32 17 37 50
+ + + +
+ + -
+ + -
.-
5 6
F M
46 62
68 56
25 6
+ -
+ +
+
+ .-
7 8 9 10 11 I? 13 14 1s 16 17 18
F F M F M F F M F F M M
46 51 34 31 59 75 60 59 46 60 39 17
48 72 71 46 58 52 47 64 84 29 69 100
41 4 10 27 1 1.5 60 37 15 55 1 IO
+ + + + + + + +
+ + + + +
+ -
+ + + +
+ -
19 20 21 22
F F M M
47 35 32 57
46 91 39 21
14 .75 30 8
-
+ + + +
+ +
Age
(vr)
*Patients 2, IO, 11, and 15 withdrew are not included in the analysis.
319
from the study before
its completion.
of increases over the corresponding baseline. (Analysis of variance procedures applied to actual level of FEV,, VC, V,,, and V,, yielded results similar to those outlined below with increase over the baseline.) Mean increases for FEV, and V5,, are shown graphically for each regimen in Fig. 2. Ipratropium and oxtriphylline. For each of the four variables (FEV,, VC, V,,, and Vz,) the onset of improvement and the duration of improvement were similar for the initial and final days of treatment. The level of improvement tended to be higher on the last day of treatment for each variable, but this improvement in the general level of response did not reach statistical significance for any parameter. Mean increases for both first and last treatment days are shown in Fig. 2, A and B, for FEV, and V,,, respectively . Fenoterol and oxtriphylline. As with ipratropium and oxtriphylline, the regimen of fenoterol plus oxtriphylline showed no change in the pattern of response between first and last treatment days for any variable. However, the observed increases were consistently lower on the last day of treatment for FEV, (Fig. 2, C), V5,, (Fig. 2, D), and V,, (not shown). These differences approached but did not reach statis-
Atow
Incomplete
data were available
tical significance p = 0.10).
-
i .-
for patient h; therefore,
(for FEV,,
his results
p = 0.08; for VjO,
lpratropium, fenoterol, and oxtriphylline. For this regimen a decline in the duration and level of response was evident by the last day of long-term administration. For FEV, (Fig. 2, E) the onset of improvement was similar on the first and last treatment days, and analysis of variance showed that the duration of improvement was much shorter on the latter day (p < 0.01). A similar change in response pattern was found for VC (p < 0.01) (not illustrated). For V,,, (Fig. 2, F) and Vz5 the pattern of response over time was not significantly different between day 1 and day 30, but the level of response was much less on day 30 and this difference was statistically significant for VS0 (p < 0.01).
Overall benefit, regimens
day 30-comparison
among
To determine the relative efficacy of the three regimens after long-term administration a comparison of day 30 responses was made. As can be seen in Fig. 2, the two treatment regimens containing fenoterol showed a more rapid initial response but shorter duration of response than the
320
Rebuck
0.6
J. ALLERGY CLIN. Ik4MUNOL. MARCH 1903
et al.
-
1
2
3
4
5
6
TIMEthours)
FIG. 1. Mean increase in FEV, over 6 hr after treatment subjects (day 1). Bars represent one standard error. line, lpratropium + fenoterol + oxtriphylline; dashed fenoterol + placebo + oxtriphylline; dotted line, tropium + placebo + oxtriphylline.
in 17 So/id line,
ipra-
regimen of ipratropium and oxtriphylline. This difference in the pattern of response among the regimens was statistically significant (p < 0.01) for FEV,, VC, and VsO. Since the onset and duration of improvement varied among the three treatment regimens, an index of overall benefit was sought that would allow valid and informative comparison between regimens. The area under the bronchodilator response curve was used as a useful composite of the magnitude of the response and the duration of that response. These areas for each of the regimens on the initial and final treatment day are represented graphically in Fig. 3. As can be seen, for FEV,, VC, and V,, overall benefit on day 30 was greatest for the triple regimen of ipratropium, fenoterol, and oxtriphylline. By means of the Newman-Keuls multiple comparison procedure, this difference between regimens reached statistical significance for the greater benefit of ipratropium, fenoterol, and oxtriphylline over fenoterol and oxtriphylline in terms of FEV, (p < 0.05). Tolerance
to fenoterol
As outlined above, both regimens containing fenoterol showed a decrease in duration and level of
response for several pulmonary function prarameters between day 1 and day 30 of administration. By comparison, the regimen without fenoterol did not show this effect and in fact overall level of response was generally higher on the last day of treatment (Fig. 2. A and B). This suggested the possibility that toterance tc~ fenoterol had developed during the treatment period To assessthis possibility, overall benefit measured as the area under the curve was again used to comparc regimens. Fig. 3 shows that these areas were all in creased by day 30 of treatment with ipratropium and theophylline. On the other hand. the areas decreased for FEV,, VC, VXo, and VZ, after a period of treatment with fenoterol and oxtriphylline or fenoterol plus ipratropium and oxtriphylline. These reductions in overall benefit were not statistically different be” tween the two fenoterol-containing regimens. When the data for these two regimens were pooled, the reduction in the areas under the curves of FEV, and ii,!“) were statistically significant (p
patient
acceptance
The pattern of blood pressure and heart rate w sponse was not different among treatment regimens OI between initial and final days of treatment. Systolic and diastolic blood pressures declined slightly over each 6 hr period and heart rate declined slightly to ward the midpoint of each 6 hr period, returning to baseline by the end of the period. The battery of biochemical and hematologic laboratory tests failed to detect any toxicity of the three regimens after longterm administration.
VOLUME 71 NUMBER 3
Combination
Ipratropium, Placebo and Oxtriphylline
,::.q::
therapy
Fenoterol, Placebo and Oxtriphylline
of asthma
321
Ipratropium, Fenoterol Oxtriphylline
and
h -1. 02 _ * . .
Ol-
&
~~~~.~
1 06-
:.*. *.
0.5-
***
*.
E *..*
04-
0.6.
..*.-
. ...*
F
-.*.
1
*..* .-.*
03-
. . . . ..!!I
*q
0.2 0.1 A,
1
2
3
4
5
6
1
,
,
,
,
\
2
3
4
5
6
30 DAY
1
30 DAY
1
30 DAY
FIG. 3. Mean (for 17 subjects) of the area under the 6 hr response curves for FEV, (L . hr), VC (L hr), V,, (L hr) as measured on the first set-’ . hr) and V,, (L set-’ and last treatment days with the three regimens. Bars represent one standard error.
TIME (hours) FIG. 2. Mean increases in FEV, and V,, on day 1 (dotted line) and day 30 (solid line) for each treatment regimen (A and B, ipratropium + oxtriphylline; C and D, fenoterol + oxtriphylline; E and F, ipratropium + fenoterol + oxtriphyiline). For each of the fenoterol-containing regimens, day 30 increases were less than day 1 increases (C, 0, E, and F). The greatest mean increases on day 30 for FEV,, VC, and V, were observed with the triple-drug regimen (E and F).
Review of patient diaries showed that there was no significant difference in the number or severity of acute attacks among the three treatments. Compliance assessedby pill count and record of drug taking in the patient diaries was good with all three regimens. The patients’ subjective rating of improvement with each of the regimens was generally favorable and not significantly different among the regimens. Alleged side effects reported by the patients were generally minor, including mild tremor, loss of taste, fatigue, mild cough, and light-headedness. Seven of the 18 study patients complained of one or more of these side effects during the course of the entire study, three after receiving ipratropium plus oxtriphylline, four after receiving fenoterol plus oxtriphylline, and five after receiving ipratropium plus fenoterol plus oxtriphylline. These differences were not statistically significant. DISCUSSION One rationale for using beta agonists and methylxanthines in combination to treat asthma is that they
bronchodilate via different pharmacologic mechanisms, the former by stimulating cyclic AMP production and the latter by inhibiting the degradation of cyclic AMP by phosphodiesterase.10 A similar rationale is applicable to the addition of anticholinergic agents, which produce bronchodilatation via pathways distinct from the sympathomimetics. At the intracellular level, anticholinergic agents diminish cyclic GMP levels, thereby producing bronchial smooth muscle relaxation. (An effect on mast cell cholinergic receptors may also be important in asthma.‘)) At the neuronal level, anticholinergics such as ipratropium inhibit vagal efferent pathways, an important influence given that the vagal tone is the major determinant of resting airway caliber in normal subjects.12 In disease states such as asthma, vagal influences may be particularly important in some individuals, e.g., those with emotionally influenced or triggered asthmatic attacks.13 Not only does the mechanism of action of anticholinergics differ from that of existing antiasthmatic agents but the site of bronchodilator effect appears to differ as well. There is evidence that atropine preferentially dilates proximal airways.14* l5 The development of ipratropium bromide has made available an anticholinergic bronchodilator with a minimum of adverse effects.16 Used alone, it is an effective bronchodilator for patients with asthma or chronic bronchitis.‘? Contrasted with inhaled betaadrenoreceptor agonists, it has a later onset of action
322
Rebuck
J. ALLERGY CLIN. IMMUhKlt. MARCH W3
et al.
but a more prolonged effect.lX In asthma, inhaled ipratropium produces less bronchodilatation than inhaled beta agonists, but in chronic bronchitis the bronchodilatation is equal to or greater than that produced by beta stimu1ation.l” The combination of ipratropium and various beta agonists has generally produced greater bronchodilatation than either agent used alone.” When ipratropium is combined with theophylline, synergy between the two drugs can be demonstrated.’ A steroid-sparing effect of ipratropium has even been suggested.“” Despite these early promising results, the role of ipratropium in antiasthmatic therapy has not been defined, and in particular its place in combination regimens is unclear. Our data show that not only can a combination of ipratropium, fenoterol, and a theophylline derivative produce greater bronchodilatation than that produced by either fenoteroi and theophylline or ipratropium and theophylline by short-term administration (Fig. 1) but also that after long-term administration, the threedrug regimen produces greater overall benefit than either of the two-drug regimens. Previous studies have shown that bronchodilator responsiveness to ipratropium does not decline after long-term administration.” We have shown this to be true for the combination of ipratropium and oxtriphylline. By contrast, both regimens incorporating fenoterol showed a decline in responsiveness after prolonged treatment. Tolerance to long-term beta agonists has been described previously, although several studies have produced discrepant results. 21-23 Certainly, at a cellular level, oral administration of terbutaline for 4 wk is sufficient to produce marked decrease in the density of lymphocyte beta receptors in both normal subjects and in patients with mild asthma.2” A decline in bronchodilator response may accompany this, although the effect may be small and is of unknown clinical significance. Our data suggest at least one reason why not all studies have demonstrated tolerance to longterm beta agonists. The decline in responsiveness that we observed was not only in the level of bronchodilator response but also in the pattern of this response. Studies that examine only the peak levels of bronchodilatation after drug administration may fail to detect changes in duration of effect. Our study has demonstrated that the addition of ipratropium to a beta, agonist and a theophylline derivative can produce measurable improvement in bronchodilatation, with no increase in unwanted side effects. Yet, despite an apparent spirometric benefit associated with the use of ipratropium, we were unable to demonstrate any decrease in the number, severity, or duration of intercurrent acute asthmatic attacks by the addition of ipratropium.
We thank Ms. M. Leslie for her technical assistance. G. M. Worsley, M.D.. and F. Vickerson, Ph.D., for their support and assistance throughnut the study. XXI Mrs. M Sweetman for her assistance in preparation of the manuscript. REFERENCES I
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Wolfe JD. Tashkin UP. Calvarese H. S~mmi~rrs 2/I. Bran chodilator effects of terbutaline and aminophyliinr alone and in combination in asthmatic patients. N Engl J Med 298:363. 1978 Rossing TH, Fanta CH. McFadden E,R: A ctmtrolled ma1 ut the use of smgle versus combined-drug therapy in the treatment of acute episodes of asthma. Am Rev Kespir Dis 123: 190, 1981. Nassif EG, Weinberger M. Thompson R. Hun&y ti. The value of maintenance theophylline in steroid-dependent dsthma. N Engl J Med 304:71, t 981. Gross NJ: SCH 1000: a new anrichohnerglc bronchadilatol Am Rev Respir Dis 112:823. 1975 Ruffin RE, McIntyre E, Crockett AJ. Zielonka K. .;‘rlpers JH: Combination bronchodilator therapy in asthmil I/ Al.1 EKC~~ CLIN ~MUNOI. 69:60. 1982. Lightbody IM, Ingram CG. Legge JS. Johnst
VOLUME 71 NUMBER 3
21.
Nelson HS, Raine D, Doner HC, Posey WC: Subsensitivity to the bronchodilator action of albuterol produced by chronic administration. Am Rev Respir Dis 116:871, 1977. 22. Plummer AL: Development of drug tolerance to beta-2 adrenergic agents in asthmatics. Chest 73(Suppl.):949, 1978. 23. Peel ET, Gibson GJ: Effects of long-term inhaled salbutamol
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therapy on the provocation of asthma by histamine. Am Rev Respir Dis 121:973, 1980. 24. Tashkin DP, Conolly ME, Deutsch RI, Hui KK, Littner M, Scarpace P, Abrass I: Subsensitization of beta-adrenoreceptors in airways and lymphocytes of healthy and asthmatic subjects. Am Rev Respir Dis 125185, 1982.