- Email: [email protected]
High-dose inhaled steroid therapy for asthma
ose inhaled steroid therapy . Toogood, MD, FRCPC, FCCP London, Ontario, Canada only a small minority of patients with asthma have symptoms severe enough to require high-dose inhaled steroid therapy. Because they need more aggressive treatment, this group is disproportionately represented in tertiary care referral centers. Therapeutic effects are dose dependent, and the daily dose of steroid required to normalize pulmonary function far exceeds that for symptom relief. Studies show that, if titrated to minimum dose levels of each the combination of inhaled and oral steroids provides a better balance between antiasthmatic and systemic glucocorticoid activity compared with oral steroid alone. Also, rapidly metabolized inhaled steroids such as budesonide may be associated with a lower risk for the osteoporotic complications seen with long-term oral steroid use. However, high doses of inhaled steroids may lead to adrenocortical suppression and hence estrogen deficiency in postmenopausal women. Morning dosing may mitigate this effect. Oropharyngeal thrush may be prevented by lowering the dose frequency or using a spacer. During prolonged inhaled steroid therapy, patient compliance has proved an important determinant of outcome. (J ALLERGYCLIN IMMUNOL 1989;83:528-36.)
High-dose inhaled steroid therapy is applicable to only a small minority of patients with asthma, but these patients are disproportionately representedin tertiary care referral centers. Becauseof the severity of their asthma,they generally needmore aggressive treatmentthan patients seenin ordinary family practice to achievesatisfactorycontrol of the disease.This may include the use of higher than usual doses of inhaled steroid. The influenceof doseon the effectivenessof inhaled steroid treatment for asthma is illustrated in Fig. 1. Both the benefits and adverseeffects of beclomethasonedipropionate (BDP) are dose dependent.In this study,’ the relationship was approximately linear on log dose. Only a quarter of this group attained a symptom-freestatusat the recommendedstartingdose of 400 pg of BDP/day. The dose required to attain a normal statusin half the patient group (median effective dose)varied dependingon the responseindex measured.By comparing the median effective dose for the different indexesshownin Fig. 1, it is apparent that the per diem dose required to normalize pulmonary function is much higher than what is adequate to relieve symptoms. Normalization of pulmonary function is considereda more efficient goal of longterm asthmatreatmentthan suppressionof symptoms alone. At the end of the study illustrated in Fig. 1, all patientsreceived 1.6 mg of BDP/day plus oral predFrom the University of Western Ontario, and Allergy Clinic, Victoria Hospital, London, Ontario, Canada. Reprint requests: John A. Toogood, MD, Victoria Hospital, Allergy Clinic, 375 South St., London, Ontario, Canada N6A 4G5.
Abbreviations used
BDP: BUD: HPA: MDI:
Beclomethasone dipropionate Budesonide Hypothalamic-pituitary-adrenal Metered-dose inhaler
nisone. Subsequently,these drug doseswere titrated downward to identify the minimum dosesof prednisone and BDP that each individual subject required to avoid asthmaticdisability and to maintain at least half the improvementin airflows that hadaccruedwith the initial high-doseregimen.’ The titrated minimum doserequirementsare shown in Fig. 2. The minimum requirements for BDP varied widely.’ Only four patients were controlled satisfactorily at 400 pg of BDPiday throughout the last 6 monthsof the 18-monthobservationperiod. The median requirement was 1000 kg/day (i.e., half the grouprequireda doseof BDP higherthanthe currently recommendedsafe upper limit of usage). CONCOMITANT ORAL AND INHALED STEROIDS Similarly, the titrated minimum requirementsfor prednisonevaried widely from 0 to 23 mgiday.’ Only six of the 34 patients were able to discontinueprednisoneduring the last 6 monthsof the I$-month dose titration period. An additional nine patientswere able to convert to intermittent prednisoneuse. However, most patientsin this group requiredboth the oral and inhaled steroids to maintain optimal control of the
High-dose
VOiUME 83 NUMBER 2. PART 2
inhaled steroid therapy
FIG. 1. Responses of 34 prednisone-dependent adult asthmatics to BDP. Prednisone dosage was held stable, whereas stepwise BDP increments were added as shown. Mean prednisone dosage = 11.0 mgiday. At each encircled point the mean change from the pre-BDP baseline value was significant (p < 0.05 or better). The BDP dose effective for 50% of the group (ED,,) may be determined by relating the intercepts of the dashed line and each regression line to the abscissa scale. The high incidence of adrenal suppression reflects the group’s past systemic steroid therapy plus the effect of the combined oral and inhaled steroid treatment. (From Jenne JW, Murphy S. Drug therapy for asthma. New York: Marcel Dekker, 1987:719, reprinted by courtesy of Marcel Dekker.)
MINIMUM STEROID
REOUIREHENTS
MEAN, la.8 MG/D MEDIAN 3.2 MG/D
0
200
FIG. 2. Titrated represents one period of dose after weaning, Baskerville JC.
400
600
800
1000
1200
1400
1600
0
IO
20
so
minimum maintenance dose requirements for BDP (MMD-B) f’left). Each dot patient’s average daily usage of BDP during the last 6 months of an 18-month titration and follow-up. Prednisone use by the same patients (‘right), before and to minimum maintenance dosage (MMD-P). (From Toogood JH, Jennings 8, J Asthma 1983;20:51, reprinted by courtesy of Marcel Dekker.)
disease. Because the systemic effects of inhaled and oral steroids are additive, it has been suggested the two drugs should not be used in combination. Our experience does not support that point of view (Table I>. The clinical status of these patients is summarized in the indexes of optimal asthma control listed in Table I, before and after the period of high-dose BDP treat-
ment and prednisone weaning. Favorable results are evidenced by the statistically significant reductions in asthmatic disability, symptom activity, and the numbers of patients receiving high-risk prednisone regimens. Also, some previously hypertensive patients became normotensive-an important change for those individuals because it implies increased longevity. Overall the therapeutic outcome appears clinically
J. ALLERGY
In m’ 3” a-J Ea .-
2ii 2
BUDESONIDE
CLIN. IM~~U~OL. FEBRUARY ?Y80
~~ED~ISONE
\
\
lo(n=34) 0
A .6
1.2
\ a.7
2.4
17.5
35
Daily Dose Steroid (mg) FIG. 3. Incidence of disabling asthma relapses during a double-blind crossover comparison of budesonide (inhaled four times daily) vs prednisone (single morning oral dose). All patients took three graduated doses of each drug for 2 weeks. Group mean dosages are shown. The actual dosages prescribed varied with the patient’s estimated asthma severity. (From Jenne JW, Murphy S. Drug therapy for asthma. New York: Marcel Dekker, 1987:719, reprinted by courtesy of Marcel Dekker.)
TABLE I. Patients with QAC
Net gain in OAC
(B-4 Criteria for OAC
(N =B34)
(N A,*34,
% of group
13 0 4 0 17 24
22 7 18 11 34 32
+26 i-21 +41 f32 +50 $23
17
16
-3
0.90
11 20
20 25
+26
0.10
-I- 1.5
0.40
Peak flows 270% PN Zero attack frequency Zero disability Zero prednisone Off d&y prednisone Off high-risk dosageprednisone(> 15 mg/dl) Normal AM serum cortisol (310 kg/dl) Normotensive Systolic Cl40 mm Hg Diastolic s9.5 mm Rg
Before and after ratings based on same number of data points per patient: four visits before BDP year and four visits after more than 1 year of treatment when inhaled and oral steroids had been weaned to lowest doses possible. OAC, optimal asthma control; B, before; A, after; PN, predicted normal. *After > I-year follow-up. iFrom x2. From Toogood JH, Jennings B, Baskerville JC. Bronchial asthma: mechanisms and therapeutics. 2nd ed. Boston: Little, Brown and Co, 1985:698.
valuable despite the fact that most patients in the group found it necessary to continue oral prednisone in addition to the inhaled steroid and that the regimen perpetuated (but did not worsen) the functional hypothalmic-pituitary-adrenal (HPA)-axis suppression, which dated from their previous prednisone treatment. These data provide a rationale for the combination of inhaled plus oral steroid therapy whenever it is clinically necessary. Provided the doses of each drug
are titrated to minimum effective levels, a more advantageous balance between antiasthmatic and systemic glucocorticoid activity may be attained with the combination than with oral prednisone alone. The need for such combined therapy reflects the fact that the inhaled steroid formulations currently marketed in the United States are too dilute to meet the needs of patients with severe asthma. If more concentrated formulations were clinically available, one might reasonably assume that more patients with
High-dose
VCJLUWiE83
NUMBER
inhaled steroid therapy
2, PART 2
persistingprednisonedependencycould be converted to inhaled steroid therapy alone. The basis for this assumptionis illustrated in Fig. 3. The data derive from a double-blind, crossover comparison of oral rednisone versus the inhaled steroid, budesonide UD).3 BUD is a topically active steroid with about twice the anti-inflammatory potency of BDP and half its systemic glucocorticoid activity after absorption.4 The data show that provided a sufficiently large dose is given, either an inhaled or oral steroid may be equally effective. Under the conditions of this study, the dose necessaryto completely inhibit disabling asthmarelapseswas about 50 mg of prednisone/day or 2 mg of BUD/day. This level of BUD dosageis high enough to show measurablesystemic glucocorticoid activity in most patients. This raisesthe question, is the systemicactivity of high-doseBUD greater or less than what would occur if the therapeuticalternative, that is, prednisone, is used at doses that achievean equivalent level of antiasthmaticresponse in the samepatients?This questionwas addressedby determining the bioequivalent doses of these two drugs over a wide range of dosage. Pairs of dose equivalentswere usedto constructthe graphic plot in Fig. 4.
ELATIONSHIP BETWEEN BUD AND PREDNISONE The relationshipsbetweenthe indexesof antiasthmatic systemic activity that are apparent in Fig. 4 indicate that at any particular doselevel of BUD (inhaled four times a day), regardlessof whetherit manifests measurablesystemicglucocorticoid activity, the latter is less than that of oral prednisone(once daily, morning dosage)when the two drugs are given at the dosesnecessaryto achievethe same level of asthma control in the samepatients. In a separatestudy of similar design, inhaled BUD was compared with alternate-morning oral prednisane.’ After switching from the baselineregimen of P plus prednisoneto BUD alone, forced expiratory volume in 1 second improved without an accompanying improvementin symptomstatus(becausesymptoms were under almost optimal control at baseline time). On the other hand, after switching to prednisone, both airflows and asthmasymptomsdeteriorated in thesepatients, and it proved impossible to subsequently recoup the loss despite doubling then quadrupling the alternate-morningprednisonedose. The greater efficacy of the BUD was statistically significant for all indexesmeasured. The systemicglucocorticoid activity of the two steroid regimensmeasuredin the 8:00 AM serumcortisol level did not differ significantly from one anotheror from baselinevaluesexceptin the caseof the highest
DOSE EQUIVALENTS
- DEP GROUP
h-17)
50s
40-c
G 2 g 20.0 P s ; 10.0 OJ H 4 5.0
2.5
0.25
0.5
1.0
2.0
4.0
8.0
Log dose Budesonrde (rw$dJ
FIG. 4. Relative antiasthmatic and systemic ~~u~o~o~~coid potencies of budesonide (inhaled four times daily) and oral prednisone (single morning daily dose), determined from a double-blind, crossover, graded-dose comparison of the 2 drugs in 17 prednisone dependent adults.‘3 The regressions were derived from the observed effects of each drug on indexes of systemic glucocorticoid activity or antiasthmatic response. MLPF, mean of the lower peak expiratory flow rate value measured twice daily during the second week of each 14 day treatment period; FEY,, volume expired in first second of forced vital capacity; MSA, mean severity of asthma rated by patient on a visual analog scale; FA, frequency of asthma attacks per week during second week of treatment period. Serum cortisol (SC) and blood eosinophil count (%X) measured at 8:00 AM. The medians of the four asthma response indexes (0 ) and two systemic activity indexes (01 indicate ? .O mg prednisoneiday exhibiting an antiasthmatic effect equivalent to -47 mg prednisonelday, along with a systemic effect equivalent to -5.5 mg prednisoneiday (r~~~t-~a~d vertical axis).
doseof BUD; 3.2 mg of BUD/day sig~~fic~t~y suppressedendogenouscortisol production5 lem could probably be circumventedby res the high-doseinhaled steroidtherapy so doseis given entirely in the morning, as was done in the study illustrated in Fig. 5. In the latter study, morning dosing eliminated the drop in endogenouscortisol output that occursi is administeredat high dosagediumally.6 I-IO morning dosing appeared somewhat less effective ts and (p = 0.12) than diurnal dosing in these eosindid not sparedose-dependent,steroid-in openia(Fig. 5). Thus it is uncertainwhetheravowing dosing would achievea clinically useful reduction in the risk of adverseeffectsof high-doseinh therapy on target tissuesother than the W
J. ALLERGY CLIN. IMMU!KX. FEBRUARY 1989 aEOS LmLPF* P FROM ANOVA
DOSE:
xii?
SCHEDULING:
.17 .61
DOSE X SCHEDULING:
31 .12
.50
nx ,000
.66 ,03
25
AEOS INCREASING
SYSTEMIC
EFFECT
FIG. 5. Effects of diurnal (A) vs morning dose (01 scheduling of BUD therapy on the systemic activity of BUD at 0.4, 0.8, and 1.6 mg/day dosage in the same patients6 Group means are shown. Systemic glucocorticoid effects, measured by blood eosinopenia (aEOS), and the drop in the serum cortisol level at 8:00 AM (ASC),are plotted against the dose-dependent antiasthmatic response, MLPF, (i.e., the change in the mean of the lower of two daily measurements of peak expiratoryflow rate during the second week of each treatment period). Thep values from analysis of variance indicate significant effects of budesonide dose on all three responses (p = 0.001 or better), and also a significant deviation from linearity for ASC (p = 0.03) when the BUD dose was increased above 0.8 mg/day.
TABLE lil. Effect of dosing frequency
on the incidence of thrush during inhaled BUD treatment; in a balanced crossover, two groups of asthmatic patients took the same aily doses of inhaled BUD for 16 weeks, ice or four times daily”’ Nystatin
doiesl2
wk (Mean f SD)
BUD dose frequency
Prednisone users (N = 19)
No prednisone (N = 15)
4X daily 2X daily p (From paired t) Patientswith thrush
0.965 k 4.58 0.070 Ifr 0.41 co.05 5/19
0.166 -e 1.58 0 l/15
FromJenneJW,MurphyS. Drug therapyfor asthma.NewYork: Marcel Decker, 1987:719,reprintedby courtesyof Marcel Dekker.
OTENTlAL ADVERSE EFFECTS ND COMPLlCATlONS The potential for adverse effects on bone is important in any considerationof the feasibility versus safety of high-doseinhaled steroid treatmentbecause
osteoporotic complications are one of the most serious complicationsthat occur during long-term oral steroiduse. There arevery few dataasyet to quantify this particular risk potential of high-doseinhale roid therapy. In one pilot study, no were treated with low- and high-dose weeks.‘,8The high doseclearly suppre function but did not inhibit calcium absorptionfrom the gut, increaseurinary calcium loss, or evoke secondary hyperparathyroidismor a rise in. the serum level of 1,25 dihydroxyvitamin D. This suggeststhat rapidly metabolized inhaled steroids such as might have significantly less risk potential for bone complicationsthan oral prednisone,evenif high doses of the inhaled drug are used. However, more studies are neededto clarify theseissues. Inhaled steroid doseshigh enoughto suppressthe 8:00 AM serum cortisol level also suppress the adrenocortical production of androstenedioneand dihydroepiandrosterone.’These androgensconstitute the substrateon which postmenopausalwomen are entirely dependentfor their supply of estrogen.Because estrogendeficiency is known to be a major risk determinant of osteoporosisand fracture, postmenopausalwomen, if given high-doseinhaledsteroidther-
High-dose
VOLUME 83 NUMBER 2, PART 2
inhaled steroid therapy
/
2 PUFFS / DO /
17 PUFFS / DOSE
I I
I
I
2
4
8
8
I
15
32
LOG PUFFS / DOSE BUDESONIDE
FIG. 6. Antiasthmatic efficacy of inhaled BUD given at different dosing frequencies using the same per diem dosages, 0.4 (o), 0.8 (m), and 1.6 (A,) mg.6 Every patient took each dose and frequency combination for 2 weeks. Group means are shown. Upper regression line shows the results with four times daily inhalation of a 50 pgipuff formulation. Lowerregression line shows the results with twice daily inhalation of a 200 pg/puff formulation. The p values from analysis of variance quantify the significance of the effects of dose/day and dosing frequency on the peak expiratory flow rate response to BUD. (Adapted from Toogood JH. Lancet 198~;2:79~.~
apy for asthma, should also receive an estrogen supplement unless a positive contraindication to estrogen therapy exists.’ A complication of high-dose inhaled steroid therapy that is of more immediate concern is oropharyngeal thrush. As shown in Fig. 1, the incidence of thrush rises as the daily dose is increased. This development may be circumvented by adjusting the dose schedule. Table II shows the incidence of oral thrush in prednisone-dependent and nondependent asthma patients, who inhaled BUD four times or twice daily, at the same per diem doses.” Clinically overt thrush was virtually confined to the prednisone users during the periods in which they took BUD four times a day. Thus, reducing the dose frequency of an inhaled steroid to twice daily (keeping the same total dosage per day) may be tactically useful in subjects who are known to be prone to recurrent thrush, particularly in circumstances that have been found to increase the likelihood of thrush, for example, when patients using a combined prednisone plus inhaled steroid regimen are given an antibiotic for infection.” The penicillins in particular stimulate Candidu overgrowth. The reduced dose frequency should be used temporarily rather than indefinitely for reasons that are illustrated in Fig. 4.
FIG. 7. Effect of differences in asthma activity at baseline time on the relationship of the dosing frequency of budesonide to the drug’s antiasthmatic potency.6 Group means linked by lines were referenced to the same baseline. The split in the lines emphasizes that these were intergroup comparisons. (From Toogood JH, Baskervilie JC, Jennings B, Lefcoe NM, Johansson S-A. J ALLERGVCLIN IMMUNOL 1982;70:288.)
J. ALLERGY
EFFECT
%a
OF
CONE
-100
SPACER ON BUDESONIDE OROPHARYNX AND LUNG
-60
-20
20
60
(n
100
DEPOSITION = 35)
140
CLiK IMMUNOL. FEBRUARY 1989
IN
180
FIG. 8. Effects of a 750 ml spacer on BUD deposition relative to the conventional MDI. inhaling BUD via the spacer reduced the oropharyngeal deposition of the drug by 94%, as reflected by change in oropharyngeal Candida colony counts, while doubling its delivery to the airways as shown by the airflow.‘* PER?, peak expiratory flow rate; FEV,.,, forced expiratory volume in 1 forced expiratory flow in the mid-portion of vital capacity; ANCOVA, analysis second; FEF257Pb, of covariance. (From Jenne JW, Murphy S. Drug therapy for asthma. ‘New York: Marcel Dekker, 1987:719, reprinted by courtesy of Marcel Dekker.)
20
15 CONE 580 !O
05
POTENCY RATIOS VS ACTUATOR 0
TUBE 1.96 CONE 2.33
/ - 05
/
DOSE P FROM .ooo ANCOVA I
DEV
DOSE X DEV .77
.;;P
- IC
400
800
1600
FIG. 9. Group mean responses to low- and high-dose BUD inhaled via an MDI, that is, actuator (01, Cone (a), or tube (A.) spacer.” The p values from analysis of covariance quantify the statistical significance of the effects of the drug dose and the inhalation device (DE\/) on the FEVI,, response. (From Toogood JH. Determinants of deposition of inhaled particles. Inhaled corticosteroids in the treatment of asthma. Helsinki: Julk Aisija : Suomen Oy, 1983:35.)
EFFECTIVENESS OF VARIOUS DOSE FREQUENCIES The efficacy of twice daily versus four times daily dosing of BUD was compared over a series of graded doses with standard and concentrated formulations. 6
Under the conditions of the study, it proved necessary to give about 17 puffs twice daily of the concentrated formulation to achieve an antiasthmatic effect equivalent to two puffs of 50 Kg per puff formulation given four times per day. *I This is impractical; it inflates the
High-dose
VOLUME a3 NUM’dER 2, PART 2
inhaled steroi
NDER- AND OVER-UTILIZATION OF THE TEST DRUG RELATED TO DISEASE ACTWW
Non-DEP 0
2
4
6
8
10
Increasing symptoms (asthma attacks group mean per week)
480
440
400
360
-.8@
320
(1)
.OP j 280
Increasing airway obstruction (weekly mean of daily PEFRI
FIG. 10. Influence of changes in asthma severity on patient use of an inhaled steroid during a double-blind trial of BUD in 14 prednisone-dependent (0) and 17 nondependent (A) asthmatic sdults.5.‘5 Use was measured objectively from the drug canister weights at each visit. Group means shown. The r is Pearson correlation coefficient. The p values indicate significant correiations between changes in symptom frequency and peak expiratory flow rate and use of the inhaled steroid.
It also diminishes the benefit-tocost or^ treatment. risk ratio becausethe dose required to achieve an equivalent antiasthmatic effect rises from low- and nontoxic levels to high and potentially toxic levels. In practical terms the data demonstratethat to maximize the antiasthmaticpotency of inhaled BUD in clinical practice, it is more feasibleand lesscostly to increase dosesper day rather than puffs per dose. In the study from which the data in Fig. 6 are derived, two versusfour times daily dosing was compared twice in each patient-on one occasionwhen the patients’ asthma was unstable and poorly controlled and subsequentlywhen the asthmawas well controlled. All the difference shown in Fig. 6 stems from the first comparison.6Whenthe asthmawas well controlled at baseline time, there was no difference in efficacy between the two regimens. On the other hand, when the asthmawas unstable,four times daily dosing proved more effective than twice daily treatment {Fig. 7). How one choosesto translate these experimental observationsinto clinical tactics is essentiallya judgment call. It would appearreasonablethat four times daily dosing continues to be the standard recommended regimen as opposedto less frequent dosing given the following: (1) The clinical courseof chronic asthmais characteristically variable; (2) it is impossible to predict accuratelywhen the next clinical relapsewill occur in an individual patient; and (3) these datashow that whetherthe asthmaentersa sufficiently unstablephase, dose frequency will becomea major response-limitingfactor that cannotbe offset evenby
large increasesin the daily dose or the ~~rnb~r of puffs per day. This type of data is presentlyavailable only for budesonide;however,the principle probably applies to most if not all the other inhaled steroids that are currently used to treat asthma. Rather than reducing the dose frequency, a better solution to the problem of oropb~~ge~ complications with high-dose inhaled steroid treatment is to administerthe drug via a spacerfitted to the metereddoseinhaler (MDI). This carries less corollary risk of reducingefficacy. Indeed,asshownin Fig. 8, inhaling the drug via a large volume (750 ml) spacerrather than directly from the MD1 not only can reduce the oropharyngealdepositionof the drug (by 90% in this study), but can increaseits intrap~lmQ~a~delivery.I2 The practical value of the spaceris illustrated in Fig. 9. In theseadult asthmatics,who had beenpretrained to ensuremaximum efficiency of their inhalationtechnique with the MDI, adding the spacerto the MDI doubled intrapulmonary drug deposition and the benefit-to-costratio of the treatment.12 PATIENT COMPLIANCE: A IMPORTANT D THERAPEUTIC Patient compliance with inhaled steroid regimens varieswith symptomactivity. Fig. 10 shows datafrom two groupsof adult asthmaticpatients,who had been recruitedto participatein a clinical trial of budesonide. They were pretrained in the desired treatment proceduresand then monitoredclosely to maximize their compliance with all aspectsof the study protocol,
Toogood including e use of the test drug. Use of the latter was measured objectively by weighing the drug canisters at each visit. As shown in Fig. 10, use fell when the asthma improved with treatment and vice versa. This relationship was statistically significant in both patient groups. We have observed this relationship in three different studies of BUD or BDP.13 Inspection of the individual patient data that make up the group means shown in Fig. 10 revealed that some individuals had used only about 60% of the dose prescribed, whereas others had taken as much as 1.50%,depending on differences in the level of asthma control at different times in the study. These extremes of variability in drug use may be assumed to be much wider in ordinary clinical practice than the variability observed in these supervised clinical trials in patients preselected to exclude those the investigators judged likely to be poorly compliant. Patient compliance is also an important determinant of the long-term outcome of inhaled steroid therapy. In the study illustrated in Fig. 2, we quantified the success of the BDP treatment in terms of the amount of prednisone each patient still required after more than a one-year trial with BDP therapy.* Although all patients were treated the same way, the success of the prednisone weaning varied widely among the group. Compliance, which was rated indirectly by a global score of patient “reliability,” emerged as the strongest single correlate of the success of prednisone weaning uring high-dose BDP therapy. Less reliable patients required relatively more prednisone presumably because they are as unreliable in taking the BDP as with their other drugs. The reliability factor proved to be more important to outcome than age, the type of asthma, that is, atopic versus nonatopic, or the degree of ventilatory impairment at induction into the program. l4 In summary, the therapeutic effects of inhaled steroid drugs are dose dependent, and patients with severe asthma require relatively high doses to achieve optimal control of the disease. If enough drug is given, inhaled steroids may be equally as effective as oral steroids. Regardless of the presence or absence of demonstrable systemic glucocorticoid activity, inhaled BUD (and probably some other inhaled steroids) shows less systemic activity than the dose of oral prednisone needed to achieve the same level of asthma control in the same patient. A morning-dose schedule can mitigate the HPA-axis suppression induced by high-dose inhaled steroid therapy. Administering the inhaled steroid via a spacer reduces the oropharyngeal complications that otherwise inevitably occur when
J, ALLERGY
CLIP& IMIMUNOL. FEBRUARY 1969
the dose is raised to high levels. Also, if correctIy used, a spacer can increase intrapulmonary drug delivery, antiasthmatic efficacy, and the benefit-to-cost ratio. Patient compliance is the most impo t determinant of therapeutic outcome during long-term inhaled steroid therapy. REFERENCES 1. Toogood JH, Lefcoe NM, Jennings B, Errington N, Baksh L, Chuang L. A graded dose assessment of the efficacy of beclomethasone dipropionate aerosol for severe chronic asthma J ALLERGYCLIN IMMIJNOL1977;59:298-308. 2. Toogood JH, Lefcoe NM, Haines DSM, et al. Minimum dose requirements of steroid-dependent asthmatic patients for aerosol beclomethasone and oral prednisone. J ALLERGY CLINIMMUNOL1978;61:355-64. 3. Toogood JH, Jennings B, Johansson S-A. A role for concentrated formulations of inhaled steroid in severeasthmatics [Abstract]. Ann Allergy 1985;55:257. 4. Johansson S-A, Anderson RB, Brattsand R, Gruvstad E, Hedner P. Topical and systemic glucocorticoid potencies of budesonide and beclomethasone dipropionate in man. Em J Respir Dis 1982;63(suppl):74-82. 5. Toogood JH, Jennings B, Baskerville J, Lefcoe N, Johansson S-A. Bioequivalent doses of inhaled vs. oral steroids for severe asthma [Abstract]. Chest 1983;84:349. 6. Toogood JH, Baskerville JC, Jennings B: Lefcoe NM, Johansson S-A. Influence of dosing frequency and schedule on the response of chronic asthmatics to the aerosol steroid, budesonide. J ALLERGYCLINIMMUNOL1982;70:288-98. 7. Toogood JH, Nadeau J, Crilly R. Effect of the ~tiastbm~tic aerosolized steroid budesonide (BUD) on calcium (Ca) and phosphate (PO3 metabolism [Abstract]. Clin Invest Med 1985;8:A42. 8. Toogood JH, Crilly RG, Jones 6, Nadeau J, Weiis GA. Effect of high dose inhaled budesonide on calcium and phosphate metabolism and the risk of osteoporosis. Am Rev Respir Dis 1988;138:57-61. 9. Nadeau J, Toogood JH, Crilly RG, Wells GA Suppression of androgen production by the antiasthmatic inhaled steroid, budesonide (BUD) [Abstract]. J ALLERGYCLINIMMLXOL1986; 77: 150. 10. Toogood JH, Jennings B, Baskerville J, Anderson J, Johansson S-A. Dosing regimen of budesonide and occurrence of oropharyngeal complications. Eur J Respir Dis 1984;65:33-44. 11. Toogood JH. Concentrated aerosol formulations in asthma. Lancet 1983;2:790-1. 12. Toogood JH, Baskerville J, Jennings B, Lefcoe NM, Johansson S-A. Use of spacers to facilitate inhaled corticosteroid treatment of asthma. Am Rev Respir Dis 1984;129:723-9. 13. Toogood JH, Baskerville .I. Patient compliance during inhaled steroid therapy [Abstract]. J ALLERGVCLDJIMMUNOL 1987; 79: 144. 14. Toogood JH, Jennings B, Baskerville 5. Aerosol corticosteroids. In: Weiss EB, Stein MS, Segal M, eds. Bronchial Asthma: Mechanisms and Therapeutics. 2nd ed. Boston: Little, Brown & Company, 1985:698-713. 15. Toogood JH, Jennings B, Baskerville J, Lefcoe N. Comparison of alternate-morning prednisone vs. inhaled steroid for asthma [Abstract]. Ann R Coil Phys Surg (Can) 1983;16:308.
High-dose inhaled steroid therapy is applicable to only a small minority of patients with asthma, but these patients are disproportionately representedin tertiary care referral centers. Becauseof the severity of their asthma,they generally needmore aggressive treatmentthan patients seenin ordinary family practice to achievesatisfactorycontrol of the disease.This may include the use of higher than usual doses of inhaled steroid. The influenceof doseon the effectivenessof inhaled steroid treatment for asthma is illustrated in Fig. 1. Both the benefits and adverseeffects of beclomethasonedipropionate (BDP) are dose dependent.In this study,’ the relationship was approximately linear on log dose. Only a quarter of this group attained a symptom-freestatusat the recommendedstartingdose of 400 pg of BDP/day. The dose required to attain a normal statusin half the patient group (median effective dose)varied dependingon the responseindex measured.By comparing the median effective dose for the different indexesshownin Fig. 1, it is apparent that the per diem dose required to normalize pulmonary function is much higher than what is adequate to relieve symptoms. Normalization of pulmonary function is considereda more efficient goal of longterm asthmatreatmentthan suppressionof symptoms alone. At the end of the study illustrated in Fig. 1, all patientsreceived 1.6 mg of BDP/day plus oral predFrom the University of Western Ontario, and Allergy Clinic, Victoria Hospital, London, Ontario, Canada. Reprint requests: John A. Toogood, MD, Victoria Hospital, Allergy Clinic, 375 South St., London, Ontario, Canada N6A 4G5.
Abbreviations used
BDP: BUD: HPA: MDI:
Beclomethasone dipropionate Budesonide Hypothalamic-pituitary-adrenal Metered-dose inhaler
nisone. Subsequently,these drug doseswere titrated downward to identify the minimum dosesof prednisone and BDP that each individual subject required to avoid asthmaticdisability and to maintain at least half the improvementin airflows that hadaccruedwith the initial high-doseregimen.’ The titrated minimum doserequirementsare shown in Fig. 2. The minimum requirements for BDP varied widely.’ Only four patients were controlled satisfactorily at 400 pg of BDPiday throughout the last 6 monthsof the 18-monthobservationperiod. The median requirement was 1000 kg/day (i.e., half the grouprequireda doseof BDP higherthanthe currently recommendedsafe upper limit of usage). CONCOMITANT ORAL AND INHALED STEROIDS Similarly, the titrated minimum requirementsfor prednisonevaried widely from 0 to 23 mgiday.’ Only six of the 34 patients were able to discontinueprednisoneduring the last 6 monthsof the I$-month dose titration period. An additional nine patientswere able to convert to intermittent prednisoneuse. However, most patientsin this group requiredboth the oral and inhaled steroids to maintain optimal control of the
High-dose
VOiUME 83 NUMBER 2. PART 2
inhaled steroid therapy
FIG. 1. Responses of 34 prednisone-dependent adult asthmatics to BDP. Prednisone dosage was held stable, whereas stepwise BDP increments were added as shown. Mean prednisone dosage = 11.0 mgiday. At each encircled point the mean change from the pre-BDP baseline value was significant (p < 0.05 or better). The BDP dose effective for 50% of the group (ED,,) may be determined by relating the intercepts of the dashed line and each regression line to the abscissa scale. The high incidence of adrenal suppression reflects the group’s past systemic steroid therapy plus the effect of the combined oral and inhaled steroid treatment. (From Jenne JW, Murphy S. Drug therapy for asthma. New York: Marcel Dekker, 1987:719, reprinted by courtesy of Marcel Dekker.)
MINIMUM STEROID
REOUIREHENTS
MEAN, la.8 MG/D MEDIAN 3.2 MG/D
0
200
FIG. 2. Titrated represents one period of dose after weaning, Baskerville JC.
400
600
800
1000
1200
1400
1600
0
IO
20
so
minimum maintenance dose requirements for BDP (MMD-B) f’left). Each dot patient’s average daily usage of BDP during the last 6 months of an 18-month titration and follow-up. Prednisone use by the same patients (‘right), before and to minimum maintenance dosage (MMD-P). (From Toogood JH, Jennings 8, J Asthma 1983;20:51, reprinted by courtesy of Marcel Dekker.)
disease. Because the systemic effects of inhaled and oral steroids are additive, it has been suggested the two drugs should not be used in combination. Our experience does not support that point of view (Table I>. The clinical status of these patients is summarized in the indexes of optimal asthma control listed in Table I, before and after the period of high-dose BDP treat-
ment and prednisone weaning. Favorable results are evidenced by the statistically significant reductions in asthmatic disability, symptom activity, and the numbers of patients receiving high-risk prednisone regimens. Also, some previously hypertensive patients became normotensive-an important change for those individuals because it implies increased longevity. Overall the therapeutic outcome appears clinically
J. ALLERGY
In m’ 3” a-J Ea .-
2ii 2
BUDESONIDE
CLIN. IM~~U~OL. FEBRUARY ?Y80
~~ED~ISONE
\
\
lo(n=34) 0
A .6
1.2
\ a.7
2.4
17.5
35
Daily Dose Steroid (mg) FIG. 3. Incidence of disabling asthma relapses during a double-blind crossover comparison of budesonide (inhaled four times daily) vs prednisone (single morning oral dose). All patients took three graduated doses of each drug for 2 weeks. Group mean dosages are shown. The actual dosages prescribed varied with the patient’s estimated asthma severity. (From Jenne JW, Murphy S. Drug therapy for asthma. New York: Marcel Dekker, 1987:719, reprinted by courtesy of Marcel Dekker.)
TABLE I. Patients with QAC
Net gain in OAC
(B-4 Criteria for OAC
(N =B34)
(N A,*34,
% of group
13 0 4 0 17 24
22 7 18 11 34 32
+26 i-21 +41 f32 +50 $23
17
16
-3
0.90
11 20
20 25
+26
0.10
-I- 1.5
0.40
Peak flows 270% PN Zero attack frequency Zero disability Zero prednisone Off d&y prednisone Off high-risk dosageprednisone(> 15 mg/dl) Normal AM serum cortisol (310 kg/dl) Normotensive Systolic Cl40 mm Hg Diastolic s9.5 mm Rg
Before and after ratings based on same number of data points per patient: four visits before BDP year and four visits after more than 1 year of treatment when inhaled and oral steroids had been weaned to lowest doses possible. OAC, optimal asthma control; B, before; A, after; PN, predicted normal. *After > I-year follow-up. iFrom x2. From Toogood JH, Jennings B, Baskerville JC. Bronchial asthma: mechanisms and therapeutics. 2nd ed. Boston: Little, Brown and Co, 1985:698.
valuable despite the fact that most patients in the group found it necessary to continue oral prednisone in addition to the inhaled steroid and that the regimen perpetuated (but did not worsen) the functional hypothalmic-pituitary-adrenal (HPA)-axis suppression, which dated from their previous prednisone treatment. These data provide a rationale for the combination of inhaled plus oral steroid therapy whenever it is clinically necessary. Provided the doses of each drug
are titrated to minimum effective levels, a more advantageous balance between antiasthmatic and systemic glucocorticoid activity may be attained with the combination than with oral prednisone alone. The need for such combined therapy reflects the fact that the inhaled steroid formulations currently marketed in the United States are too dilute to meet the needs of patients with severe asthma. If more concentrated formulations were clinically available, one might reasonably assume that more patients with
High-dose
VCJLUWiE83
NUMBER
inhaled steroid therapy
2, PART 2
persistingprednisonedependencycould be converted to inhaled steroid therapy alone. The basis for this assumptionis illustrated in Fig. 3. The data derive from a double-blind, crossover comparison of oral rednisone versus the inhaled steroid, budesonide UD).3 BUD is a topically active steroid with about twice the anti-inflammatory potency of BDP and half its systemic glucocorticoid activity after absorption.4 The data show that provided a sufficiently large dose is given, either an inhaled or oral steroid may be equally effective. Under the conditions of this study, the dose necessaryto completely inhibit disabling asthmarelapseswas about 50 mg of prednisone/day or 2 mg of BUD/day. This level of BUD dosageis high enough to show measurablesystemic glucocorticoid activity in most patients. This raisesthe question, is the systemicactivity of high-doseBUD greater or less than what would occur if the therapeuticalternative, that is, prednisone, is used at doses that achievean equivalent level of antiasthmaticresponse in the samepatients?This questionwas addressedby determining the bioequivalent doses of these two drugs over a wide range of dosage. Pairs of dose equivalentswere usedto constructthe graphic plot in Fig. 4.
ELATIONSHIP BETWEEN BUD AND PREDNISONE The relationshipsbetweenthe indexesof antiasthmatic systemic activity that are apparent in Fig. 4 indicate that at any particular doselevel of BUD (inhaled four times a day), regardlessof whetherit manifests measurablesystemicglucocorticoid activity, the latter is less than that of oral prednisone(once daily, morning dosage)when the two drugs are given at the dosesnecessaryto achievethe same level of asthma control in the samepatients. In a separatestudy of similar design, inhaled BUD was compared with alternate-morning oral prednisane.’ After switching from the baselineregimen of P plus prednisoneto BUD alone, forced expiratory volume in 1 second improved without an accompanying improvementin symptomstatus(becausesymptoms were under almost optimal control at baseline time). On the other hand, after switching to prednisone, both airflows and asthmasymptomsdeteriorated in thesepatients, and it proved impossible to subsequently recoup the loss despite doubling then quadrupling the alternate-morningprednisonedose. The greater efficacy of the BUD was statistically significant for all indexesmeasured. The systemicglucocorticoid activity of the two steroid regimensmeasuredin the 8:00 AM serumcortisol level did not differ significantly from one anotheror from baselinevaluesexceptin the caseof the highest
DOSE EQUIVALENTS
- DEP GROUP
h-17)
50s
40-c
G 2 g 20.0 P s ; 10.0 OJ H 4 5.0
2.5
0.25
0.5
1.0
2.0
4.0
8.0
Log dose Budesonrde (rw$dJ
FIG. 4. Relative antiasthmatic and systemic ~~u~o~o~~coid potencies of budesonide (inhaled four times daily) and oral prednisone (single morning daily dose), determined from a double-blind, crossover, graded-dose comparison of the 2 drugs in 17 prednisone dependent adults.‘3 The regressions were derived from the observed effects of each drug on indexes of systemic glucocorticoid activity or antiasthmatic response. MLPF, mean of the lower peak expiratory flow rate value measured twice daily during the second week of each 14 day treatment period; FEY,, volume expired in first second of forced vital capacity; MSA, mean severity of asthma rated by patient on a visual analog scale; FA, frequency of asthma attacks per week during second week of treatment period. Serum cortisol (SC) and blood eosinophil count (%X) measured at 8:00 AM. The medians of the four asthma response indexes (0 ) and two systemic activity indexes (01 indicate ? .O mg prednisoneiday exhibiting an antiasthmatic effect equivalent to -47 mg prednisonelday, along with a systemic effect equivalent to -5.5 mg prednisoneiday (r~~~t-~a~d vertical axis).
doseof BUD; 3.2 mg of BUD/day sig~~fic~t~y suppressedendogenouscortisol production5 lem could probably be circumventedby res the high-doseinhaled steroidtherapy so doseis given entirely in the morning, as was done in the study illustrated in Fig. 5. In the latter study, morning dosing eliminated the drop in endogenouscortisol output that occursi is administeredat high dosagediumally.6 I-IO morning dosing appeared somewhat less effective ts and (p = 0.12) than diurnal dosing in these eosindid not sparedose-dependent,steroid-in openia(Fig. 5). Thus it is uncertainwhetheravowing dosing would achievea clinically useful reduction in the risk of adverseeffectsof high-doseinh therapy on target tissuesother than the W
J. ALLERGY CLIN. IMMU!KX. FEBRUARY 1989 aEOS LmLPF* P FROM ANOVA
DOSE:
xii?
SCHEDULING:
.17 .61
DOSE X SCHEDULING:
31 .12
.50
nx ,000
.66 ,03
25
AEOS INCREASING
SYSTEMIC
EFFECT
FIG. 5. Effects of diurnal (A) vs morning dose (01 scheduling of BUD therapy on the systemic activity of BUD at 0.4, 0.8, and 1.6 mg/day dosage in the same patients6 Group means are shown. Systemic glucocorticoid effects, measured by blood eosinopenia (aEOS), and the drop in the serum cortisol level at 8:00 AM (ASC),are plotted against the dose-dependent antiasthmatic response, MLPF, (i.e., the change in the mean of the lower of two daily measurements of peak expiratoryflow rate during the second week of each treatment period). Thep values from analysis of variance indicate significant effects of budesonide dose on all three responses (p = 0.001 or better), and also a significant deviation from linearity for ASC (p = 0.03) when the BUD dose was increased above 0.8 mg/day.
TABLE lil. Effect of dosing frequency
on the incidence of thrush during inhaled BUD treatment; in a balanced crossover, two groups of asthmatic patients took the same aily doses of inhaled BUD for 16 weeks, ice or four times daily”’ Nystatin
doiesl2
wk (Mean f SD)
BUD dose frequency
Prednisone users (N = 19)
No prednisone (N = 15)
4X daily 2X daily p (From paired t) Patientswith thrush
0.965 k 4.58 0.070 Ifr 0.41 co.05 5/19
0.166 -e 1.58 0 l/15
FromJenneJW,MurphyS. Drug therapyfor asthma.NewYork: Marcel Decker, 1987:719,reprintedby courtesyof Marcel Dekker.
OTENTlAL ADVERSE EFFECTS ND COMPLlCATlONS The potential for adverse effects on bone is important in any considerationof the feasibility versus safety of high-doseinhaled steroid treatmentbecause
osteoporotic complications are one of the most serious complicationsthat occur during long-term oral steroiduse. There arevery few dataasyet to quantify this particular risk potential of high-doseinhale roid therapy. In one pilot study, no were treated with low- and high-dose weeks.‘,8The high doseclearly suppre function but did not inhibit calcium absorptionfrom the gut, increaseurinary calcium loss, or evoke secondary hyperparathyroidismor a rise in. the serum level of 1,25 dihydroxyvitamin D. This suggeststhat rapidly metabolized inhaled steroids such as might have significantly less risk potential for bone complicationsthan oral prednisone,evenif high doses of the inhaled drug are used. However, more studies are neededto clarify theseissues. Inhaled steroid doseshigh enoughto suppressthe 8:00 AM serum cortisol level also suppress the adrenocortical production of androstenedioneand dihydroepiandrosterone.’These androgensconstitute the substrateon which postmenopausalwomen are entirely dependentfor their supply of estrogen.Because estrogendeficiency is known to be a major risk determinant of osteoporosisand fracture, postmenopausalwomen, if given high-doseinhaledsteroidther-
High-dose
VOLUME 83 NUMBER 2, PART 2
inhaled steroid therapy
/
2 PUFFS / DO /
17 PUFFS / DOSE
I I
I
I
2
4
8
8
I
15
32
LOG PUFFS / DOSE BUDESONIDE
FIG. 6. Antiasthmatic efficacy of inhaled BUD given at different dosing frequencies using the same per diem dosages, 0.4 (o), 0.8 (m), and 1.6 (A,) mg.6 Every patient took each dose and frequency combination for 2 weeks. Group means are shown. Upper regression line shows the results with four times daily inhalation of a 50 pgipuff formulation. Lowerregression line shows the results with twice daily inhalation of a 200 pg/puff formulation. The p values from analysis of variance quantify the significance of the effects of dose/day and dosing frequency on the peak expiratory flow rate response to BUD. (Adapted from Toogood JH. Lancet 198~;2:79~.~
apy for asthma, should also receive an estrogen supplement unless a positive contraindication to estrogen therapy exists.’ A complication of high-dose inhaled steroid therapy that is of more immediate concern is oropharyngeal thrush. As shown in Fig. 1, the incidence of thrush rises as the daily dose is increased. This development may be circumvented by adjusting the dose schedule. Table II shows the incidence of oral thrush in prednisone-dependent and nondependent asthma patients, who inhaled BUD four times or twice daily, at the same per diem doses.” Clinically overt thrush was virtually confined to the prednisone users during the periods in which they took BUD four times a day. Thus, reducing the dose frequency of an inhaled steroid to twice daily (keeping the same total dosage per day) may be tactically useful in subjects who are known to be prone to recurrent thrush, particularly in circumstances that have been found to increase the likelihood of thrush, for example, when patients using a combined prednisone plus inhaled steroid regimen are given an antibiotic for infection.” The penicillins in particular stimulate Candidu overgrowth. The reduced dose frequency should be used temporarily rather than indefinitely for reasons that are illustrated in Fig. 4.
FIG. 7. Effect of differences in asthma activity at baseline time on the relationship of the dosing frequency of budesonide to the drug’s antiasthmatic potency.6 Group means linked by lines were referenced to the same baseline. The split in the lines emphasizes that these were intergroup comparisons. (From Toogood JH, Baskervilie JC, Jennings B, Lefcoe NM, Johansson S-A. J ALLERGVCLIN IMMUNOL 1982;70:288.)
J. ALLERGY
EFFECT
%a
OF
CONE
-100
SPACER ON BUDESONIDE OROPHARYNX AND LUNG
-60
-20
20
60
(n
100
DEPOSITION = 35)
140
CLiK IMMUNOL. FEBRUARY 1989
IN
180
FIG. 8. Effects of a 750 ml spacer on BUD deposition relative to the conventional MDI. inhaling BUD via the spacer reduced the oropharyngeal deposition of the drug by 94%, as reflected by change in oropharyngeal Candida colony counts, while doubling its delivery to the airways as shown by the airflow.‘* PER?, peak expiratory flow rate; FEV,.,, forced expiratory volume in 1 forced expiratory flow in the mid-portion of vital capacity; ANCOVA, analysis second; FEF257Pb, of covariance. (From Jenne JW, Murphy S. Drug therapy for asthma. ‘New York: Marcel Dekker, 1987:719, reprinted by courtesy of Marcel Dekker.)
20
15 CONE 580 !O
05
POTENCY RATIOS VS ACTUATOR 0
TUBE 1.96 CONE 2.33
/ - 05
/
DOSE P FROM .ooo ANCOVA I
DEV
DOSE X DEV .77
.;;P
- IC
400
800
1600
FIG. 9. Group mean responses to low- and high-dose BUD inhaled via an MDI, that is, actuator (01, Cone (a), or tube (A.) spacer.” The p values from analysis of covariance quantify the statistical significance of the effects of the drug dose and the inhalation device (DE\/) on the FEVI,, response. (From Toogood JH. Determinants of deposition of inhaled particles. Inhaled corticosteroids in the treatment of asthma. Helsinki: Julk Aisija : Suomen Oy, 1983:35.)
EFFECTIVENESS OF VARIOUS DOSE FREQUENCIES The efficacy of twice daily versus four times daily dosing of BUD was compared over a series of graded doses with standard and concentrated formulations. 6
Under the conditions of the study, it proved necessary to give about 17 puffs twice daily of the concentrated formulation to achieve an antiasthmatic effect equivalent to two puffs of 50 Kg per puff formulation given four times per day. *I This is impractical; it inflates the
High-dose
VOLUME a3 NUM’dER 2, PART 2
inhaled steroi
NDER- AND OVER-UTILIZATION OF THE TEST DRUG RELATED TO DISEASE ACTWW
Non-DEP 0
2
4
6
8
10
Increasing symptoms (asthma attacks group mean per week)
480
440
400
360
-.8@
320
(1)
.OP j 280
Increasing airway obstruction (weekly mean of daily PEFRI
FIG. 10. Influence of changes in asthma severity on patient use of an inhaled steroid during a double-blind trial of BUD in 14 prednisone-dependent (0) and 17 nondependent (A) asthmatic sdults.5.‘5 Use was measured objectively from the drug canister weights at each visit. Group means shown. The r is Pearson correlation coefficient. The p values indicate significant correiations between changes in symptom frequency and peak expiratory flow rate and use of the inhaled steroid.
It also diminishes the benefit-tocost or^ treatment. risk ratio becausethe dose required to achieve an equivalent antiasthmatic effect rises from low- and nontoxic levels to high and potentially toxic levels. In practical terms the data demonstratethat to maximize the antiasthmaticpotency of inhaled BUD in clinical practice, it is more feasibleand lesscostly to increase dosesper day rather than puffs per dose. In the study from which the data in Fig. 6 are derived, two versusfour times daily dosing was compared twice in each patient-on one occasionwhen the patients’ asthma was unstable and poorly controlled and subsequentlywhen the asthmawas well controlled. All the difference shown in Fig. 6 stems from the first comparison.6Whenthe asthmawas well controlled at baseline time, there was no difference in efficacy between the two regimens. On the other hand, when the asthmawas unstable,four times daily dosing proved more effective than twice daily treatment {Fig. 7). How one choosesto translate these experimental observationsinto clinical tactics is essentiallya judgment call. It would appearreasonablethat four times daily dosing continues to be the standard recommended regimen as opposedto less frequent dosing given the following: (1) The clinical courseof chronic asthmais characteristically variable; (2) it is impossible to predict accuratelywhen the next clinical relapsewill occur in an individual patient; and (3) these datashow that whetherthe asthmaentersa sufficiently unstablephase, dose frequency will becomea major response-limitingfactor that cannotbe offset evenby
large increasesin the daily dose or the ~~rnb~r of puffs per day. This type of data is presentlyavailable only for budesonide;however,the principle probably applies to most if not all the other inhaled steroids that are currently used to treat asthma. Rather than reducing the dose frequency, a better solution to the problem of oropb~~ge~ complications with high-dose inhaled steroid treatment is to administerthe drug via a spacerfitted to the metereddoseinhaler (MDI). This carries less corollary risk of reducingefficacy. Indeed,asshownin Fig. 8, inhaling the drug via a large volume (750 ml) spacerrather than directly from the MD1 not only can reduce the oropharyngealdepositionof the drug (by 90% in this study), but can increaseits intrap~lmQ~a~delivery.I2 The practical value of the spaceris illustrated in Fig. 9. In theseadult asthmatics,who had beenpretrained to ensuremaximum efficiency of their inhalationtechnique with the MDI, adding the spacerto the MDI doubled intrapulmonary drug deposition and the benefit-to-costratio of the treatment.12 PATIENT COMPLIANCE: A IMPORTANT D THERAPEUTIC Patient compliance with inhaled steroid regimens varieswith symptomactivity. Fig. 10 shows datafrom two groupsof adult asthmaticpatients,who had been recruitedto participatein a clinical trial of budesonide. They were pretrained in the desired treatment proceduresand then monitoredclosely to maximize their compliance with all aspectsof the study protocol,
Toogood including e use of the test drug. Use of the latter was measured objectively by weighing the drug canisters at each visit. As shown in Fig. 10, use fell when the asthma improved with treatment and vice versa. This relationship was statistically significant in both patient groups. We have observed this relationship in three different studies of BUD or BDP.13 Inspection of the individual patient data that make up the group means shown in Fig. 10 revealed that some individuals had used only about 60% of the dose prescribed, whereas others had taken as much as 1.50%,depending on differences in the level of asthma control at different times in the study. These extremes of variability in drug use may be assumed to be much wider in ordinary clinical practice than the variability observed in these supervised clinical trials in patients preselected to exclude those the investigators judged likely to be poorly compliant. Patient compliance is also an important determinant of the long-term outcome of inhaled steroid therapy. In the study illustrated in Fig. 2, we quantified the success of the BDP treatment in terms of the amount of prednisone each patient still required after more than a one-year trial with BDP therapy.* Although all patients were treated the same way, the success of the prednisone weaning varied widely among the group. Compliance, which was rated indirectly by a global score of patient “reliability,” emerged as the strongest single correlate of the success of prednisone weaning uring high-dose BDP therapy. Less reliable patients required relatively more prednisone presumably because they are as unreliable in taking the BDP as with their other drugs. The reliability factor proved to be more important to outcome than age, the type of asthma, that is, atopic versus nonatopic, or the degree of ventilatory impairment at induction into the program. l4 In summary, the therapeutic effects of inhaled steroid drugs are dose dependent, and patients with severe asthma require relatively high doses to achieve optimal control of the disease. If enough drug is given, inhaled steroids may be equally as effective as oral steroids. Regardless of the presence or absence of demonstrable systemic glucocorticoid activity, inhaled BUD (and probably some other inhaled steroids) shows less systemic activity than the dose of oral prednisone needed to achieve the same level of asthma control in the same patient. A morning-dose schedule can mitigate the HPA-axis suppression induced by high-dose inhaled steroid therapy. Administering the inhaled steroid via a spacer reduces the oropharyngeal complications that otherwise inevitably occur when
J, ALLERGY
CLIP& IMIMUNOL. FEBRUARY 1969
the dose is raised to high levels. Also, if correctIy used, a spacer can increase intrapulmonary drug delivery, antiasthmatic efficacy, and the benefit-to-cost ratio. Patient compliance is the most impo t determinant of therapeutic outcome during long-term inhaled steroid therapy. REFERENCES 1. Toogood JH, Lefcoe NM, Jennings B, Errington N, Baksh L, Chuang L. A graded dose assessment of the efficacy of beclomethasone dipropionate aerosol for severe chronic asthma J ALLERGYCLIN IMMIJNOL1977;59:298-308. 2. Toogood JH, Lefcoe NM, Haines DSM, et al. Minimum dose requirements of steroid-dependent asthmatic patients for aerosol beclomethasone and oral prednisone. J ALLERGY CLINIMMUNOL1978;61:355-64. 3. Toogood JH, Jennings B, Johansson S-A. A role for concentrated formulations of inhaled steroid in severeasthmatics [Abstract]. Ann Allergy 1985;55:257. 4. Johansson S-A, Anderson RB, Brattsand R, Gruvstad E, Hedner P. Topical and systemic glucocorticoid potencies of budesonide and beclomethasone dipropionate in man. Em J Respir Dis 1982;63(suppl):74-82. 5. Toogood JH, Jennings B, Baskerville J, Lefcoe N, Johansson S-A. Bioequivalent doses of inhaled vs. oral steroids for severe asthma [Abstract]. Chest 1983;84:349. 6. Toogood JH, Baskerville JC, Jennings B: Lefcoe NM, Johansson S-A. Influence of dosing frequency and schedule on the response of chronic asthmatics to the aerosol steroid, budesonide. J ALLERGYCLINIMMUNOL1982;70:288-98. 7. Toogood JH, Nadeau J, Crilly R. Effect of the ~tiastbm~tic aerosolized steroid budesonide (BUD) on calcium (Ca) and phosphate (PO3 metabolism [Abstract]. Clin Invest Med 1985;8:A42. 8. Toogood JH, Crilly RG, Jones 6, Nadeau J, Weiis GA. Effect of high dose inhaled budesonide on calcium and phosphate metabolism and the risk of osteoporosis. Am Rev Respir Dis 1988;138:57-61. 9. Nadeau J, Toogood JH, Crilly RG, Wells GA Suppression of androgen production by the antiasthmatic inhaled steroid, budesonide (BUD) [Abstract]. J ALLERGYCLINIMMLXOL1986; 77: 150. 10. Toogood JH, Jennings B, Baskerville J, Anderson J, Johansson S-A. Dosing regimen of budesonide and occurrence of oropharyngeal complications. Eur J Respir Dis 1984;65:33-44. 11. Toogood JH. Concentrated aerosol formulations in asthma. Lancet 1983;2:790-1. 12. Toogood JH, Baskerville J, Jennings B, Lefcoe NM, Johansson S-A. Use of spacers to facilitate inhaled corticosteroid treatment of asthma. Am Rev Respir Dis 1984;129:723-9. 13. Toogood JH, Baskerville .I. Patient compliance during inhaled steroid therapy [Abstract]. J ALLERGVCLDJIMMUNOL 1987; 79: 144. 14. Toogood JH, Jennings B, Baskerville 5. Aerosol corticosteroids. In: Weiss EB, Stein MS, Segal M, eds. Bronchial Asthma: Mechanisms and Therapeutics. 2nd ed. Boston: Little, Brown & Company, 1985:698-713. 15. Toogood JH, Jennings B, Baskerville J, Lefcoe N. Comparison of alternate-morning prednisone vs. inhaled steroid for asthma [Abstract]. Ann R Coil Phys Surg (Can) 1983;16:308.