The utility of peak flow, symptom scores, and beta-agonist use as outcome measures in asthma clinical research.

STUDY OBJECTIVES: Several methods of utilizing peak expiratory flow (PEF) and other markers of disease activity have been suggested as useful in the management of asthma. It remains unclear, however, as to which surrogate markers of disease status are discriminative indicators of treatment failure, suitable for use in clinical trials. DESIGN: We analyzed the operating characteristics of 66 surrogate markers of treatment failure using a receiver operating characteristic (ROC) curve analysis. PARTICIPANTS: Information regarding FEV(1), symptoms, beta(2)-agonist use, and PEF was available from 313 subjects previously enrolled in two Asthma Clinical Research Network trials, in which 71 treatment failures occurred (defined by a 20% fall in FEV(1) from baseline). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: None of the measures had an acceptable ability to discriminate subjects with a > or % fall in FEV(1) from those without, regardless of the duration of the period of analysis or the criteria for test positivity employed. Areas under the ROC curves generated ranged from 0.51 to 0.79, but none were statistically superior. Sensitivity and specificity combinations were generally poor at all cutoff values; true-positive rates could not be raised without unacceptably elevating false-positive rates concurrently. CONCLUSIONS: Studies that seek to detect treatment failure defined by a significant fall in FEV(1) should not use such individual surrogate measures to estimate disease severity.

Occupational radiation exposure to interventional radiologists: a prospective study.

This study investigates the occupational radiation dose to interventional radiologists and the operator-controlled factors that may affect dose. Thirty interventional radiologists wore radiation badges over and under lead aprons for 2 months and answered a questionnaire. The relationships between dose and caseload, case mix, experience, optional fluoroscopy features, lead apron type, and additional lead shielding were evaluated. Mean projected yearly dose (PYD) over lead was 49.1 mSv (1 mSv = 100 mrem) but was 66.6 mSv for persons performing 1,000 or more cases per year (P = .027). Mean PYD under lead was 0.9 mSv but was 1.3 mSv for persons with 0.5-mm lead coverage and 0.4 mSv for those with 1.0-mm lead coverage (P = .002). No other significant correlation was found. Conclusions are that caseload and apron thickness are the primary determinants of total body dose, that over-lead dose is high enough to warrant additional lead shielding for the head and neck, and that a double-thickness apron lowers under-lead dose by two-thirds. The large difference between under-lead and over-lead doses suggests that use of a collar badge alone for monitoring purposes is not predictive of total-body effective dose for this group of radiation workers.

Transient effects in the Cox proportional hazards regression model.

We consider a model for mortality rates that includes both the long and short term effects of switching from an initial to a second state, for example, when patients receive an initial treatment and then switch to a second treatment. We include transient effects associated with the switch in the model through the use of time-dependent covariates. One can choose the form of the time-dependent covariate to correspond with a variety of possible transition patterns. We use an exponential decay model to compare the survival experience of transplant versus dialysis treatment of end stage renal disease (ESRD) patients from the Michigan Kidney Registry (MKR). This model involves a hazard function that has an initial effect in mortality at the time of transplant, expected to be higher, followed by a smooth exponential decay to a long term effect, expected to be lower than the risk for those remaining on dialysis. Cox and Oakes used this model to analyse the Stanford Heart Transplant data. The model implicitly suggests there is a time at which the hazard curves (and survival curves) for the treatment groups cross. Those crossing times are useful in advising patients who have the option of receiving a transplant. We describe methods for obtaining estimates of the crossing times and their associated variances, and then apply them in analysing the MKR data.

Extension of the Carter-Yang polynomial growth curve model to allow unique times of measurement for subjects.

A PC program extending the procedure due to Carter and Yang (Commun Stat: Theory Methods, 8 (1986) 2507-2526) to allow unique times of measurement for subjects is described, illustrated and made available. Given longitudinal observations on each of N subjects comprising a single group, this program determines the lowest degree polynomial in time adequate to fit the average growth curve (AGC); estimates this curve and provides confidence bands for the AGC, and confidence intervals for the corresponding polynomial regression coefficients; and so-called prediction intervals which, with a given level of confidence, will contain the growth curve of a 'new' subject from the same population of which the N subjects constitute a random sample. Two kinds of missing data are accommodated. First, in the context of studies planned so that subjects will be measured at identical times and, second, in unstructured studies where subjects may present with their own, unique times of measurement.

Comparison of survival probabilities for dialysis patients vs cadaveric renal transplant recipients.

OBJECTIVE: To compare mortality risk among cadaveric renal transplant recipients vs transplant candidates on dialysis in the cyclosporine era. SETTING: Patient mortality risk was analyzed by treatment modality for a completed statewide patient population. PATIENTS: All Michigan residents younger than age 65 years who started endstage renal disease (ESRD) therapy between January 1, 1984, and December 31, 1989, were included. Patients were followed up from ESRD onset (n = 5020), to wait-listing for renal transplant (n = 1569), to receiving a cadaveric first transplant (n = 799), and to December 31, 1989. MAIN OUTCOME MEASURE: Mortality rates. RESULTS: Using a time-dependent variable based on the waiting time from date of wait-listing to transplantation and adjusting for age, sex, race, and primary cause of ESRD, the relative risk (RR) of dying was increased early after transplantation and then decreased to a beneficial long-term effect, given survival to 365 days after transplantation (RR, 0.36; P < .001). This lower long-term risk was most pronounced (RR, 0.25) among diabetic transplant recipients compared with diabetic wait-listed dialysis patients (P < .001) and not observed among patients with glomerulonephritis as cause of ESRD (P > .05). Overall, the estimated times from transplantation to equal mortality risk was 117 +/- 28 days and to equal cumulative mortality was 325 +/- 91 days. CONCLUSIONS: The overall mortality risk following renal transplantation was initially increased, but there was a long-term survival benefit compared with similar patients on dialysis. These analyses allow improved description of comparative mortality risks for dialysis and transplant patients and allow advising patients regarding comparative survival outcomes.

Hospitalization among United States dialysis patients: hemodialysis versus peritoneal dialysis.

Measurements of hospitalization in the dialysis population are important because they provide insight into the morbidity and the cost of treatment among dialysis patients. Prior comparisons of hospitalization for different dialysis modalities have had conflicting results. This study was designed to compare hospitalization for patients treated with peritoneal dialysis (PD) versus hemodialysis (HD) using the data from the U.S. Renal Data System 1993 Annual Data Report. The study population included all Medicare dialysis patients prevalent on January 1, 1988 through 1990. Patients were monitored to transplantation, death, or end of the calendar year for a total of 189,654 patient years. Hospital admission rates were computed from the total number of hospital admissions during the year divided by the total number of patient years at risk. Patients were classified by treatment modality (PD, HD), cause of ESRD (diabetes as a cause of ESRD versus all other causes), age (0 to 19, 20 to 44, 45 to 65, +65), and race (black, white). Rate ratios (RR:PD/HD) for hospital admissions per year at risk were estimated, while adjusting for the other factors with Poison regression. On average, hospital admission rates per patient year at risk for dialysis patients treated with PD were 14% higher than for those treated with HD (RR = 1.14; 95% confidence interval (Cl), 1.13 to 1.15) when adjusting for race, age, gender, and cause of ESRD. The excess in the overall adjusted admission rates in PD patients compared with HD patients was higher for black than for white patients (RR:PD/HD = 1.22 versus RR = 1.11; 95% Cl, 1.10 to 1.13).(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of mortality between patients treated with hemodialysis and peritoneal dialysis.

Patients with ESRD treated with dialysis have a high mortality rate. Controversy exists as to whether this high mortality rate is affected by modality choice. The purpose of this epidemiologic study was to compare mortality in prevalent hemodialysis-treated (HD) and peritoneal dialysis-treated (PD) patients in a large national sample, adjusting for demographic characteristics. Data were obtained from the U.S. Renal Data System for patients prevalent on January 1 of the years 1987, 1988, and 1989, each with 1 yr of follow-up. Patients were censored at transplantation. Death rates per 100 patient years were compared between HD and PD, adjusting for age, race, gender, cause of ESRD (diabetes versus nondiabetes) and < 1 yr or > 1 yr of prior ESRD, by the use of Poisson regression. There were 42,372 deaths occurring over 170,700 patient years at risk. On average, prevalent patients treated with PD had a 19% higher adjusted mortality risk (relative risk (RR) = 1.19; P < 0.001) than did those treated with HD. This risk was found to be insignificant (P > 0.05) and small for ages < 55 and increasingly large and significant for ages > 55 yr. It was accentuated in diabetics (RR = 1.38; P < 0.001) but was also present in nondiabetics (RR = 1.11; P < 0.001). Although present in both males and females, this risk was accentuated in females (RR = 1.30 versus 1.11; both P < 0.001). In this national study of prevalent U.S. dialysis patients, treatment assignment to PD was associated with a 19% higher all-cause mortality rate than HD.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of cause of death between patients treated with hemodialysis and peritoneal dialysis.

Mortality rates associated with peritoneal dialysis (PD) have been found to be higher than those associated with hemodialysis (HD) among prevalent U.S. patients over the age of 55 in the preceding study. Given the substantial technical differences between PD and HD, causes of death might also be expected to differ between these dialytic modalities. In order to help elucidate the relative contributions of these technical differences and to further the understanding of the excess mortality observed among PD-treated dialysis patients, this epidemiologic study compared cause of death in prevalent HD- and PD-treated patients in a large national sample, adjusting for demographic characteristics. Data for patients prevalent on January 1 of the years 1987, 1988, and 1989, each with 1 yr of follow-up, were obtained from the U.S. Renal Data System. Patients were censored at transplantation. Death rates per 100 patient years for seven cause-of-death categories were compared between HD and PD, adjusting for age, race, gender, cause of ESRD (diabetes versus nondiabetes), and < 1 yr or > 1 yr of prior ESRD, by use of the Poisson regression. There were 42,372 deaths occurring over 170,700 patient years at risk. There was a significantly increased mortality risk for PD compared with HD for all cause-of-death categories, except malignancy, for which there was a higher mortality risk for HD. The excess all-cause mortality observed in PD-treated patients can be accounted for, in decreasing order, by infection (35%), acute myocardial infarction (24%), other cardiac causes (16%), cerebrovascular disease (8%), withdrawal (8%), and malignancy (-6%).(ABSTRACT TRUNCATED AT 250 WORDS)

Causes of death in dialysis patients: racial and gender differences.

The risk of death in the dialysis population is high and has previously been shown to be accentuated in male (versus female) and white (versus black) subgroups. To better understand the difference in mortality among these subgroups, the causes of death between males and females as well as between whites and blacks adjusting for age, cause of ESRD (diabetic versus nondiabetic), dialysis modality, and time on dialysis (< 1 yr versus > 1 yr) were compared, with national data obtained from the U.S. Renal Data System. A total of 42,372 deaths occurring over 170,700 patient years at risk were analyzed. Males had a 22% higher risk of death than females (P < 0.001), attributable to a higher risk of death due to acute myocardial infarction (relative death rate ratio (RR) = 1.48; P = 0.001), all other cardiac causes (RR = 1.3; P = 0.001), and malignancy (RR = 1.59; P < 0.001). Whites had a 29% higher risk of death than blacks (P < 0.001), accounted for by an increased risk of death due to acute myocardial infarction (RR = 1.34), all other cardiac causes (RR = 1.30), withdrawal from dialysis (RR = 2.72) (all P < 0.001), and infection (RR = 1.09; P = 0.005). This analysis expands the knowledge and understanding of the excess mortality seen in male and white subgroups, which is a necessary step in designing strategies to reduce the high mortality in dialysis patients.

Association of gender and access to cadaveric renal transplantation.

Previous studies have revealed that females are less likely than males to receive a renal transplant, the most successful form of treatment of end-stage renal disease (ESRD). The purpose of this study was to determine whether the barrier is to inclusion on the transplant waiting list or to transplantation after being placed on the transplant waiting list. An existing data set was used that included data from the Michigan Kidney Registry, supplemented with data received from the Organ Procurement Agency of Michigan. White and black patients less than 65 years of age and starting ESRD treatment between January 1, 1984, and December 31, 1989, were included. Cox proportional hazards models were used to determine the effect of gender on (1) time to transplantation among all ESRD patients, (2) time from diagnosis of ESRD to inclusion on the transplant waiting list among all ESRD patients, and (3) time from inclusion on the waiting list to transplantation among those patients on the waiting list. Patients were censored at the time of living-related transplantation or death, and were monitored until December 31, 1989. In all, 5,026 incident ESRD patients were included in the study (44.3% female). Of these, 1,626 patients were included on the waiting list (40.1% female); 823 of these received a transplant (37.7% female). Adjusting for age, race, and diagnosis, females were 25% less likely to receive a cadaveric transplant than males (female to male relative rate ratio [RR], 0.75; P < 0.001). Females with ESRD aged 46 to 55 years and 56 to 65 years were 33% (RR, 0.67; P < 0.001) and 29% (RR, 0.71; P < 0.05) less likely to be included on the transplant waiting list, respectively, than their male counterparts. There was no difference in the rate of wait list inclusion among ESRD patients younger than 46 years. Females with ESRD who were included on the transplant waiting list were 26% (RR, 0.74; P < 0.001) less likely to receive a transplant than males on the waiting list. These results indicate that females are both less likely to be on the transplant waiting list (ages over 45 years) and, once on the list, less likely to receive a transplant (all ages) than males. Further study is necessary to determine the factors contributing to these important barriers to transplantation among females with ESRD.

Summarizing methacholine challenges in clinical research.

In clinical trials in asthma, airway reactivity is commonly assessed by performing a methacholine challenge. Airway reactivity is thought to vary in proportion to asthma severity, and methacholine causes the airways of asthma subjects to constrict, thus lowering forced expiratory volume in 1 second (FEV(1)). A dose-response curve is obtained for each subject who meets standardized eligibility requirements to proceed with a methacholine challenge. When data from a methacholine challenge are used as an outcome variable in analysis, a univariate measure called the PC(20), the concentration of methacholine needed to produce a 20% fall in FEV(1) from baseline, is typically used to summarize the dose-response curve. Questions that arise regarding data generated from the methacholine challenge include: how to express data that do not yield a PC(20) value; whether PC(20) actually represents the best way to capture airway activity as expressed in a methacholine challenge; and whether the baseline FEV(1) is defined appropriately in calculation of PC(20). The impact of these issues on the statistical analysis of methacholine challenge data is described in this article. Some adjustments to the usual estimates of PC(20) and parametric modeling of the entire dose-response curve are proposed as alternatives that address some of the shortcomings of PC(20).

Relative impact of donor type on renal allograft survival in black and white recipients.

Renal allograft survival of organs from living-related donors (LRDs) is superior to that of organs from cadaveric donors (CAD). Allograft survival rates are lower in black recipients of both CAD and LRD transplants compared with recipients of other races. It is not known whether the superior donor effect of LRD varies between races. We investigated the graft survival outcome of first renal transplants performed in the United States in 1986 and 1989 to determine whether the donor effect differs between black and white recipients. A measurement of "donor type effect" is introduced. There were 7,002 and 7,307 first renal transplants in 1986 and 1989, respectively, for which allograft survival data were available from the United States Renal Data Systems. Both black and white recipients showed a greater than 50% reduction in the risk of allograft loss at all the points studied up to 5 years posttransplant when LRD was chosen over CAD transplantation. A measurement of donor type effect indicates that graft loss is reduced by 7 to 21 percentage points at 1 and 5 years posttransplant. The donor type effect is proportionally equal in both races. Therefore, kidney donation from living relatives as a first transplant should be encouraged for all medically suitable end-stage renal disease patients as a means of improving outcome and reducing CAD transplantation waiting time for patients in whom LRD transplants cannot be performed.

Comparative mortality risks of chronic dialysis and cadaveric transplantation in black end-stage renal disease patients.

In view of the relatively low mortality risk on dialysis and the high risk of allograft loss among black compared with white end-stage renal disease (ESRD) patients, we studied the relative mortality risks of all black renal transplant candidates in Michigan from 1984 to 1989. There were 770 black ESRD patients followed from wait-listing for cadaveric (CAD) kidney transplantation until the time of transplantation, death, or December 31, 1989. The time on dialysis prior to wait-listing exceeded 1 year in 24% of these patients. Black diabetic patients on the waiting list have more than twofold relative mortality risk (RR) compared with nondiabetic individuals (RR = 2.73, P < 0.001) while the RR by diabetes status among CAD transplant recipients was small. Overall, CAD transplantation was associated with elevated risk of mortality in the first month posttransplantation (RR = 3.39, P < 0.03). Cadaveric donor transplant and wait-listed dialysis patients have equal death rates 112 days after transplantation. Thereafter, death rates were lower for transplant recipients compared with transplant candidates on dialysis. One year after transplantation, CAD transplant recipients on the average have approximately half the risk of death compared with dialysis patients who remain on the waiting list (RR = 0.49, P < 0.03). The cumulative survival probabilities are superior in transplant recipients just beyond 1 year after transplantation. Therefore, CAD transplantation in black ESRD patients is associated with a high risk of mortality in the early period after transplantation. Beyond 1 year, black transplant recipients have a substantial survival advantage over corresponding dialysis patients on the waiting list.

Gender discrepancies in living related renal transplant donors and recipients.

Renal transplantation is the most successful treatment strategy for patients with ESRD to improve survival and quality of life. The study presented here examines the relationship of gender and living related (LR) transplantation donor and recipient rates in the United States. National data from the United States Renal Data System (USRDS) were used for this study. All LR transplants occurring between 1991 and 1993 among blacks and whites were included (N = 6193). Transplantation and donation rates for men and women were calculated. Poisson regression was used to calculate female/male transplantation and donation rate ratios. Overall, women were 10% less likely to receive a LR transplant than men (rate ratio [RR] = 0.90, P < 0.001). This gender difference increased over time from 1991 (Female/Male RR = 0.95, P = not significant [NS]) to 1993 (RR = 0.85, P < 0.001). In contrast, women were significantly more likely to donate a kidney than men (RR = 1.28, P < 0.001 and RR = 1.29, P < 0.001 among whites and blacks, respectively). Analyses by age subgroups revealed that only among ESRD patients aged 20 to 44 yr was the likelihood of receiving a LR kidney transplant equal for men and women. Higher donation rates among women compared with men were observed in all donor age and race subgroups except young blacks (aged 0 to 19 yr). Recipient gender appeared to influence donation rates. The female-to-male relative donation rates were higher when donations were to female, compared with male, recipients. This study of national data suggests an imbalance in LR donation and transplantation between men and women. Women are more likely to donate a kidney but are less likely to receive a LR transplant than men. Several potential explanatory factors are explored. These findings suggest a need for the development of gender-appropriate interventions to encourage donation among men and LR transplantation among women, to ultimately facilitate greater use of this ESRD treatment modality.

Bone status among postmenopausal women with different habitual caffeine intakes: a longitudinal investigation.

OBJECTIVE: Caffeine consumption has been proposed as a risk factor for bone loss in postmenopausal women. Past epidemiologic studies on caffeine and bone have been confounded by covariates including cigarette and alcohol use, differing levels of physical activity and hormone replacement therapy. The purpose of the study was to use a longitudinal design to determine the relationship between habitual dietary caffeine intake and postmenopausal bone status. METHODS: Data were collected at two time points separated by two years; 138 women with little or no exposure to tobacco or to drugs known to affect bone status were seen at Visit 1, and 112 returned for Visit 2. Ninety-two of these subjects had received no drugs known to affect bone status over the two-year interval and were kept in the sample. Nutrient and caffeine intake were assessed from three-day diet records. Bone measurements were made by dual energy x-ray absorptiometry (DXA). RESULTS: Correlation analyses indicated no association between dietary caffeine intake and total body or femoral neck bone density or bone mass. Similarly, no associations were found between caffeine consumption and longitudinal changes in total body or femoral neck bone measurements. These results held true both with and without statistical adjustment for calcium intake. CONCLUSIONS: This study does not support the idea that caffeine is a risk factor for bone loss in healthy postmenopausal women.

Socioeconomic status and end-stage renal disease in the United States.

The incidence of treated end-stage renal disease (ESRD) varies markedly according to age, race, sex, and geographic characteristics of the population. We asked whether some of the variability in the incidence of treated ESRD (t-ESRD) was associated with differences in socioeconomic status and whether socioeconomic status could explain some of the effects of race on t-ESRD incidence. Demographic characteristics of incident cases of t-ESRD from the years 1983 to 1988 were obtained from the U.S. Renal Data System, which registers most treated cases of ESRD. The average race specific, per capita income of the county of residence, as determined from the Bureau of Health Professions Area Resource File, was used as a surrogate measure of socioeconomic status. the incidence of t-ESRD for individuals < 60 years of age was modeled as a log-linear function of socioeconomic and demographic factors, including age, sex, the urban fraction of the county of residence, and the census geographic region. For both Whites and Blacks, the incidence of t-ESRD was higher for males and older age groups, as expected. In general, the incidence of t-ESRD was inversely related to income level. For Whites, the relative risk was 1.21 for income of $0 to 10.000, 1.11 for $10,000 to 15,000, 1.00 for $15,000 to 20,000 (reference), 0.89 for $20,000 to 25,000, and 0.77 for income > $25,000. For Blacks, the relative risk was 1.10 for income of $0 to 10,000, 1.20 for $10,000 to 15,000, 1.00 for $15,000 to 20,000 (reference), 0.81 for $20,000 to 25,000, and 0.69 for income > $25,000.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of topical nasal azelastine on the symptoms of rhinitis, sleep, and daytime somnolence in perennial allergic rhinitis.

BACKGROUND: Recent data suggested that daytime somnolence in patients with allergic rhinitis was secondary to disrupted sleep caused by nasal congestion. Medications, which decreased congestion, would be expected to improve sleep and daytime somnolence. Previously, we demonstrated that nasal steroids improved all three symptoms. The effect of topical nasal antihistamines on these symptoms has yet to be studied. OBJECTIVE: The objective of this 8-week, double-blind, placebo-controlled study was to determine whether topical nasal azelastine was effective at decreasing congestion, daytime somnolence, and improving sleep. METHODS: We recruited 24 subjects with perennial allergic rhinitis and randomized them in a double-blinded, crossover fashion, to receive placebo or azelastine two sprays BID, using Balaam's design. Questionnaires, daily diary, and Epworth Sleepiness Scale were used as tools. The last 2 weeks of each 4-week treatment period were summarized, scored, and compared by PROC MIXED in SAS. RESULTS: The analysis of the Rhinitis Severity Score showed significant improvement only of rhinorrhea in the azelastine group (P = .03). The symptom severity of nasal congestion and daytime somnolence was not significantly different between placebo and azelastine. Subjects considered azelastine effective at improving their sleep (P = .04), but daytime somnolence (P = .06) and congestion (P = .09) were not statistically improved. CONCLUSION: Azelastine is effective in reducing rhinorrhea and improving sleep quality. We were unable to demonstrate that azelastine can significantly reduce the severity of congestion or daytime somnolence.

Inferior outcome of two-haplotype matched renal transplants in blacks: role of early rejection.

Acute rejection in the early post-transplant period is a major determinant of long-term outcome. A cohort analysis was performed to evaluate the race-specific incidence rates of early acute rejection episodes (AR) and delayed graft function (DGF) in Americans of African (blacks) and European (whites) descent (N = 2565) who received a 2-HM living-related donor (LRD) first kidney transplant between 1984 and 1992. After adjusting for center and recipient characteristics, blacks had a higher incidence of AR during the initial transplant hospitalization (blacks 13.2% vs. whites 7.4%, OR = 1.64, P = 0.02). DGF also occurred more frequently in blacks (unadjusted OR = 1.58, P = 0.07). Blacks with AR had significantly worse Cox-adjusted five year graft survival than similarly affected whites (blacks 50% vs. whites 76%, P < 0.01). We conclude that failure to take immunosuppressive medications cannot be implicated as a cause of the higher incidence of AR during the initial transplant hospitalization in black kidney transplant recipients. The excess risk of AR in blacks may reflect previously reported intrinsic differences in immune responsiveness and/or pharmacokinetics of immunosuppressive agents. The profound deleterious effect of AR appears to be largely responsible for the accelerated rate of late graft loss in African Americans.

An evaluation of colchicine as an alternative to inhaled corticosteriods in moderate asthma. National Heart, Lung, and Blood Institute's Asthma Clinical Research Network.

Colchicine demonstrates an array of anti-inflammatory properties of potential relevance to asthma. However, the efficacy of colchicine as an alternative to inhaled corticosteroid therapy for asthma is unknown. Five centers participated in a controlled trial testing the hypothesis that in patients with moderate asthma needing inhaled corticosteroids for control, colchicine provides therapeutic benefit as measured by maintenance of control when inhaled steroids are discontinued. Subjects were stabilized on triamcinolane acetonide (800 microg daily) and then enrolled in a 2-wk run-in during which all subjects took both colchicine (0.6 mg/twice a day) and triamcinolone. At the end of the run-in, all subjects discontinued triamcinolone and were randomized to continued colchicine (n = 35) or placebo (n = 36) for a 6-wk double-blind treatment period. The treatment groups were similar in terms of disease severity. After corticosteroid withdrawal, 60% of colchicine-treated and 56% of placebo-treated subjects were considered treatment failures as defined by preset criteria. No significant difference in survival curves was found between treatment groups (log rank = 0.38). Other measures, including changes in FEV1, peak expiratory flow, symptoms, rescue albuterol use, and quality of life scores, also did not differ between groups. Of note, subjects failing treatment had significantly greater methacholine responsiveness at baseline than did survivors (PC20, 0.81+/-1.38 versus 2.11+/-2.74 mg/ml; p = 0.01). An analysis of treatment failures suggested that the criteria selected for failure reflected a clinically meaningful but safe level of deterioration. We conclude that colchicine is no better than placebo as an alternative to inhaled corticosteroids in patients with moderate asthma. Additionally, we conclude that the use of treatment failure as the primary outcome variable in an asthma clinical trial where treatment is withdrawn is feasible and safe under carefully monitored conditions.

Safety and reproducibility of sputum induction in asthmatic subjects in a multicenter study.

The safety of sputum induction and the reproducibility of measurements in induced sputum in multicenter studies is unknown. We examined the safety of sputum induction in a two-visit, six-center study in 79 subjects with moderate to severe asthma (mean +/- SD FEV(1) 71 +/- 12% predicted, 67% taking inhaled corticosteroids). In addition, we compared the reproducibility of markers of inflammation in induced sputum with the reproducibility of the FEV(1) and the methacholine PC(20). The FEV(1) decreased > or = 20% from the postbronchodilator baseline in 14% of all subjects and in 25% of subjects whose initial prebronchodilator baseline was 40 to 60% of predicted. All subjects responded promptly to additional albuterol treatment, and no subject developed refractory bronchoconstriction requiring treatment other than reversal of bronchospasm in the study laboratory. The reproducibility of measurements of the eosinophil percentage, eosinophil cationic protein, tryptase, and methacholine PC(20) were similar (concordance correlation coefficients of 0.74, 0.81, 0.79, and 0.74, respectively), without any significant among-center effect. We conclude that sputum induction can be performed safely in subjects with moderate to severe asthma in multicenter clinical trials when carried out under carefully monitored conditions. Importantly, we demonstrate that measurement of markers of inflammation in induced sputum is as reproducible as methacholine PC(20) and should prove useful in the assessment of airway inflammation in multicenter clinical trials.