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The importance of “effect size” in studies of allergic rhinitis
J ALLERGY CLIN IMMUNOL VOLUME 109, NUMBER 1
8110 II,I U
Nasal Blockage in Allergic RhinitisPatientsTreatedWith a Nasal Steroid, Aatileukotriene or CombinedAatileukotriene+Antihistamine Teet Pullerits*, Lea Praks§, Jan L6tvall* *Lung Pharmacology Group,
Gothenburg, Sweden §University Lung Clinic, Tartu, Estonia Nasal blockage is one of the most bothersome symptoms in allergic rhinitis patients. Intranasal administration of leukotrienes is known to primarily cause nasal blockage with little effect on other rhinitis symptoms. It has therefore been suggested that treatment with antileukotrienes might have beneficial anti-blockage effect in allergic rhinitis patients. We evaluated how treatment with antileukotriene alone or in combination with antihistamine affects nasal blockage compared to the treatment with a nasal steroid. In a double-blind, double-dummy, placebo-controlled study, 62 patients with grass-pollen induced allergic rhinitis were randomized to receive nasal steroid (fluticasone propionate; FP, 200 ktg/day), oral antileukotriene montelukast (10 rag/day), combination of montelukast + the antihistamine loratadine (10 mg/day), or placebo. Treatment started two weeks prior to the expected beginning of the grass-pollen season and lasted for 50 days. Patients recorded their nasal blockage symptoms as well as symptoms for nasal itch, rhinorrhea and sneezing separately for day- and night-time on a scale from 0 to 4. At 5 clinic visits before, during, and after the treatment, peak nasal inspiratory flow (PNIF) was measured using "InCheck" PNIF meter. Interestingly, compared to treatment with montelukast, FP provided significantly better relief for nasal blockage (p=0.025 for day-time and 0.04 for night-time blockage), but not for other rhinitls subsymptoms. This despite the fact that the study was not powered to detect differences for each individual subsymptom. No statistically significant differences were found in PNIF measurements at any of the clinic visits, implying that PNIF measurement on random basis is of limited use for assessment of dynamics of nasal blockage. We conclude that treatment with nasal fluticasone propionate is more effective than treatment with montelukast for relief of nasal blockage in allergic rhinitis patients during a pollen season.
8 n t [ ~ A Comparative Study of Fluticasone Propionate Nasal Spray l ~ J r and the Combination of Loratadine and Montelukast in the Treatment of Seasonal Allergic Rhinitis Marcy Detineo, Fuad M Baroody, Virginia Votypka, Lauran Haney, Robert M Naclerio Section of Otolaryngology-Head and Neck Surgery, The Pritzker School of Medicine, The University of Chicago, Chicago, IL Fluticasone propionate nasal spray (FPNS) is an effective treatment for seasonal allergic rhinitis (SAR). Recently, the use of a combination of loratadine and montelukast (L+M) has been shown to be effective for the treatment of SAR. The purpose of our study was to compare the efficacy of FPNS and L+M in the treatment of seasonal ragweed allergic rhinitis. We performed a randomized, double blind, parallel, double-dummy study during the 2000 fall ragweed season in Chicago. Subjects with symptoms of ragweed allergy and a positive skin prick test were randomized to receive either FPNS 100 ~tg in each nostril and a placebo pill once daily (n=29) or loratadine l0 mg and montelukast 10 mg orally and a placebo spray once daily (n=31) in the evening for 2 weeks. Subjects were evaluated at entry and at the end of treatment. Outcome measures were RhinoconjunctivitisQuality-of-Life-Questionnaire (RQLQ), daily nasal symptom scores, and the number of eosinophils and levels of eosinophil cationic protein (ECP) in nasal lavage. Compared to the first evaluation before starting active treatment, overall and individual domain scores of the RQLQ at the end of treatment were all reduced by both FPNS and L+M (p<0.01). These changes were all clinically meaningful with a change in the score of >0.5. Overall
Abstracts
S265
RQLQ scores were reduced from 2.8+0.2 (mean±sem) tol.4±0.2 with FPNS, and from 2.6_+0.2 (mean_+sem) to 1.7_+0.2 with L+M (p<0.01). When changes from baseline were compared between the 2 active treatments, there was a significantly higher reduction in the nasal symptom domain score by FPNS compared to L+M (-1.7_+0.3 vs -0.9_+0.3, mean_+sem, p<0.05) with the other domains being equivalent between the 2 treatments. Daily total nasal symptom scores were numerically less in subjects receiving FPNS, although the difference was not statistically significant (median scores 4.5 and 6.0 for FPNS and L+M, respectively). An anti-inflammatory effect of FPNS was demonstrated by a significant reduction in eosinophil numbers and ECP levels in nasal lavage (p<0.05), whereas treatment with L+M had no effect. Our data suggest that FPNS provides greater efficacy in treating ragweed SAR than the combination of L+M; however, a larger group of subjects would be needed to support this impression. Supported by a grant from GlaxoSmithKline and grant AI45583 from the NIH.
10The Importance of "Effect Size" in Studies of Allergic Rhinitis David Stempel*, Richard Stanford§ *Virginia Mason Medical Center, Seattle, WA §GlaxoSmithKline, Research Triangle Park, NC Allergic rhinitis is a high prevalence and high cost illness. Treatment options include non-sedating antihistamines (NSA) and intranasal corticosteroids (INCS) and more recently leukotriene receptor antagonists (LTRA). In determining the clinical benefits of a therapy the most important variable is the "effect size." Large sample sizes can be used to generate statistical significance in cases where the effect size is small for a common outcome and produce statistically significant results in the absence of clinical significance. The objective of this study was to compare the effect size of these three rhinitis treatments. A Medline search of published comparative studies of, NSA, INCS and LTRA was conducted and an evidence table was constructed to compare the identified studies. Studies were included for review if they were randomized, double blind, compared at least two active treatments, and reported numerical data of total nasal symptom scores as a primary outcome, Combination therapy was not included. In the 13 studies reviewed, the effect size difference significantly favored INCS versus NSA with a range of mean difference being 22% - 143%. (Consider that in the some of the NSA trials, placebo nasal spray demonstrated a clinical effect greater than oral placebo). Two studies compared 1NCS to LTRA; the effect size difference favored the INCS, (range 110% - 115%). One study comparing NSA to LTRA, no difference in effect size was detected with only a 4-5% difference from placebo. Although the studies are diverse the findings are consistent that large effect sizes are noted with INCS with clinically smaller effect size with NSA and LTRA. Caution needs to be employed when interpreting statistical significance of studies that have small effect size and large sample size. In the study by Pullerits (AJRCCM 1999;159:1814) there is a large effect size for symptom scores with BDP. There is statistical significance even with a small sample size (n= 11). In contrast, Meltzer (JAC12000; 105:917) demonstrated no statistical differences with sample sizes of 90-95 because of the small effect size with NSA and LTRA. In conclusion, when assessing statistical significance the magnitude of the effect size and sample Size need to be considered when determining clinical significance. Effect Size Comparison
Comparison INCS vs. NSA INCS vs. LTRA NSA vs. LTRA
Number of Studies
Effectsize difference (range)
10 2 1
22% - 143% 110% - 115% 5%
8110 II,I U
Nasal Blockage in Allergic RhinitisPatientsTreatedWith a Nasal Steroid, Aatileukotriene or CombinedAatileukotriene+Antihistamine Teet Pullerits*, Lea Praks§, Jan L6tvall* *Lung Pharmacology Group,
Gothenburg, Sweden §University Lung Clinic, Tartu, Estonia Nasal blockage is one of the most bothersome symptoms in allergic rhinitis patients. Intranasal administration of leukotrienes is known to primarily cause nasal blockage with little effect on other rhinitis symptoms. It has therefore been suggested that treatment with antileukotrienes might have beneficial anti-blockage effect in allergic rhinitis patients. We evaluated how treatment with antileukotriene alone or in combination with antihistamine affects nasal blockage compared to the treatment with a nasal steroid. In a double-blind, double-dummy, placebo-controlled study, 62 patients with grass-pollen induced allergic rhinitis were randomized to receive nasal steroid (fluticasone propionate; FP, 200 ktg/day), oral antileukotriene montelukast (10 rag/day), combination of montelukast + the antihistamine loratadine (10 mg/day), or placebo. Treatment started two weeks prior to the expected beginning of the grass-pollen season and lasted for 50 days. Patients recorded their nasal blockage symptoms as well as symptoms for nasal itch, rhinorrhea and sneezing separately for day- and night-time on a scale from 0 to 4. At 5 clinic visits before, during, and after the treatment, peak nasal inspiratory flow (PNIF) was measured using "InCheck" PNIF meter. Interestingly, compared to treatment with montelukast, FP provided significantly better relief for nasal blockage (p=0.025 for day-time and 0.04 for night-time blockage), but not for other rhinitls subsymptoms. This despite the fact that the study was not powered to detect differences for each individual subsymptom. No statistically significant differences were found in PNIF measurements at any of the clinic visits, implying that PNIF measurement on random basis is of limited use for assessment of dynamics of nasal blockage. We conclude that treatment with nasal fluticasone propionate is more effective than treatment with montelukast for relief of nasal blockage in allergic rhinitis patients during a pollen season.
8 n t [ ~ A Comparative Study of Fluticasone Propionate Nasal Spray l ~ J r and the Combination of Loratadine and Montelukast in the Treatment of Seasonal Allergic Rhinitis Marcy Detineo, Fuad M Baroody, Virginia Votypka, Lauran Haney, Robert M Naclerio Section of Otolaryngology-Head and Neck Surgery, The Pritzker School of Medicine, The University of Chicago, Chicago, IL Fluticasone propionate nasal spray (FPNS) is an effective treatment for seasonal allergic rhinitis (SAR). Recently, the use of a combination of loratadine and montelukast (L+M) has been shown to be effective for the treatment of SAR. The purpose of our study was to compare the efficacy of FPNS and L+M in the treatment of seasonal ragweed allergic rhinitis. We performed a randomized, double blind, parallel, double-dummy study during the 2000 fall ragweed season in Chicago. Subjects with symptoms of ragweed allergy and a positive skin prick test were randomized to receive either FPNS 100 ~tg in each nostril and a placebo pill once daily (n=29) or loratadine l0 mg and montelukast 10 mg orally and a placebo spray once daily (n=31) in the evening for 2 weeks. Subjects were evaluated at entry and at the end of treatment. Outcome measures were RhinoconjunctivitisQuality-of-Life-Questionnaire (RQLQ), daily nasal symptom scores, and the number of eosinophils and levels of eosinophil cationic protein (ECP) in nasal lavage. Compared to the first evaluation before starting active treatment, overall and individual domain scores of the RQLQ at the end of treatment were all reduced by both FPNS and L+M (p<0.01). These changes were all clinically meaningful with a change in the score of >0.5. Overall
Abstracts
S265
RQLQ scores were reduced from 2.8+0.2 (mean±sem) tol.4±0.2 with FPNS, and from 2.6_+0.2 (mean_+sem) to 1.7_+0.2 with L+M (p<0.01). When changes from baseline were compared between the 2 active treatments, there was a significantly higher reduction in the nasal symptom domain score by FPNS compared to L+M (-1.7_+0.3 vs -0.9_+0.3, mean_+sem, p<0.05) with the other domains being equivalent between the 2 treatments. Daily total nasal symptom scores were numerically less in subjects receiving FPNS, although the difference was not statistically significant (median scores 4.5 and 6.0 for FPNS and L+M, respectively). An anti-inflammatory effect of FPNS was demonstrated by a significant reduction in eosinophil numbers and ECP levels in nasal lavage (p<0.05), whereas treatment with L+M had no effect. Our data suggest that FPNS provides greater efficacy in treating ragweed SAR than the combination of L+M; however, a larger group of subjects would be needed to support this impression. Supported by a grant from GlaxoSmithKline and grant AI45583 from the NIH.
10The Importance of "Effect Size" in Studies of Allergic Rhinitis David Stempel*, Richard Stanford§ *Virginia Mason Medical Center, Seattle, WA §GlaxoSmithKline, Research Triangle Park, NC Allergic rhinitis is a high prevalence and high cost illness. Treatment options include non-sedating antihistamines (NSA) and intranasal corticosteroids (INCS) and more recently leukotriene receptor antagonists (LTRA). In determining the clinical benefits of a therapy the most important variable is the "effect size." Large sample sizes can be used to generate statistical significance in cases where the effect size is small for a common outcome and produce statistically significant results in the absence of clinical significance. The objective of this study was to compare the effect size of these three rhinitis treatments. A Medline search of published comparative studies of, NSA, INCS and LTRA was conducted and an evidence table was constructed to compare the identified studies. Studies were included for review if they were randomized, double blind, compared at least two active treatments, and reported numerical data of total nasal symptom scores as a primary outcome, Combination therapy was not included. In the 13 studies reviewed, the effect size difference significantly favored INCS versus NSA with a range of mean difference being 22% - 143%. (Consider that in the some of the NSA trials, placebo nasal spray demonstrated a clinical effect greater than oral placebo). Two studies compared 1NCS to LTRA; the effect size difference favored the INCS, (range 110% - 115%). One study comparing NSA to LTRA, no difference in effect size was detected with only a 4-5% difference from placebo. Although the studies are diverse the findings are consistent that large effect sizes are noted with INCS with clinically smaller effect size with NSA and LTRA. Caution needs to be employed when interpreting statistical significance of studies that have small effect size and large sample size. In the study by Pullerits (AJRCCM 1999;159:1814) there is a large effect size for symptom scores with BDP. There is statistical significance even with a small sample size (n= 11). In contrast, Meltzer (JAC12000; 105:917) demonstrated no statistical differences with sample sizes of 90-95 because of the small effect size with NSA and LTRA. In conclusion, when assessing statistical significance the magnitude of the effect size and sample Size need to be considered when determining clinical significance. Effect Size Comparison
Comparison INCS vs. NSA INCS vs. LTRA NSA vs. LTRA
Number of Studies
Effectsize difference (range)
10 2 1
22% - 143% 110% - 115% 5%