Different medications for seasonal allergic rhinitis in adults: A systematic review and meta-analysis

Abstract

BACKGROUND

While the efficacy of medications such as fluticasone furoate (FF), fluticasone propionate (FP), and azelastine-fluticasone (AF) has been substantiated in comparison to their respective placebo controls, uncertainties persist regarding the comparative effectiveness of different intranasal agents.

AIM

To evaluate the efficacy of FP, FF, and AF in the treatment of adult patients with seasonal allergic rhinitis (SAR) using a meta-analytic approach.

METHODS

A computer search was conducted in Cochrane Library, PubMed, and EMBASE databases to identify randomized controlled trials assessing the effectiveness and safety of FF, FP, and AF in treating SAR. Data on treatment safety and efficacy were extracted and analyzed through meta-analysis.

RESULTS

A total of 20 studies were included, comprising 10590 participants. The results of the direct meta-analysis indicated that, compared to placebo, both relative Total Nasal Symptom Score (rTNSS) and relative Total Ocular Symptom Score (rTOSS) significantly decreased post-intervention [mean difference (MD) = -1.48, 95% confidence interval (CI): -1.73 to -1.22; MD = -0.66, 95%CI: -0.82 to -0.49], with similar findings observed across the FF, FP, and AF subgroups. The network meta-analysis results showed that for improving rTNSS and rTOSS, the SUCRA values ranking from highest to lowest were AF, FP, FF, and placebo. Improvements in rTNSS and rTOSS with FP, FF, and AF were all significantly greater than those observed with placebo, with AF demonstrating superior efficacy compared to both FP and FF. No statistically significant difference in rTNSS improvement was found between FP and FF, although FP exhibited significantly greater improvement in rTOSS compared to FF.

CONCLUSION

In adult patients with SAR, the combination of azelastine and fluticasone shows a significant effect in improving nasal and ocular symptoms, with FP demonstrating marked improvement in ocular symptoms compared to FF.

Key Words: Seasonal allergic rhinitis; Fluticasone propionate; Fluticasone furoate; Azelastine-fluticasone

Core Tip: We have collected the relevant literature on the efficacy of nasal corticosteroids in treating olfactory dysfunction in allergic rhinitis, which has been publicly published both domestically and internationally in recent years, and conducted a meta-analysis to provide evidence-based medical evidence for clinical nursing of this disease.

INTRODUCTION

Seasonal allergic rhinitis (SAR) is an IgE-mediated type I hypersensitivity reaction that occurs in response to airborne allergens, including pollen and fungal spores. This condition manifests with symptoms such as sneezing, itching, and nasal congestion, and can also lead to ocular, respiratory, and systemic reactions[1,2]. The prevalence of SAR is notably high, with an incidence rate reaching up to 16% among the United States population, significantly affecting sleep quality, daily functioning, productivity, attention, and emotional well-being[3]. Standard management approaches for SAR typically involve a multifaceted strategy that includes allergen avoidance, pharmacotherapy, and, where appropriate, immunotherapy. First-line treatments consist of intranasal corticosteroids, oral antihistamines, and leukotriene receptor antagonists[4]. Current guidelines recommend initiating treatment for individuals aged 12 years and older with intranasal corticosteroids as monotherapy rather than in combination with oral antihistamines[5].

Despite the existence of effective therapeutic options, SAR continues to pose a considerable health burden, underscoring the need for ongoing research and refined management strategies[6,7]. Fluticasone furoate (FF) is a corticosteroid that exerts its anti-inflammatory effects through binding to intracellular glucocorticoid receptors, thereby modulating gene expression, inhibiting the release of inflammatory mediators, and alleviating tissue edema and inflammation. Common side effects may include oral candidiasis, pharyngitis, and dysphonia[8]. FF and fluticasone propionate (FP) are second-generation intranasal corticosteroids noted for their pronounced lipophilicity, high receptor affinity, enhanced anti-inflammatory potency, and lower systemic bioavailability, which collectively contribute to a more favorable safety profile[9]. Clinical studies have reported that FF achieves an efficacy rate exceeding 90% in the treatment of allergic rhinitis, concurrently alleviating ocular symptoms[10]. The novel formulation combining azelastine hydrochloride and FP, known as AF, has demonstrated the capacity to attenuate allergic responses by reducing the release of inflammatory mediators. This combination offers new insights into the pathophysiology of allergic rhinitis, particularly regarding its effects on mast cell degranulation, the integrity of nasal epithelial barriers, and the modulation of transport proteins[11].

While the efficacy of medications such as FF, FP, and AF has been substantiated in comparison to their respective placebo controls, uncertainties persist regarding the comparative effectiveness of different intranasal agents. Consequently, the primary objective of this study was to critically analyze and synthesize all available evidence from randomized controlled trials (RCTs) to provide a comprehensive meta-analytic estimate of the efficacy of each specific medication.

MATERIALS AND METHODS

We conducted a systematic review of RCTs assessing the efficacy of FF, FP, and the azelastine-fluticasone (AF) combination in treating adult patients with SAR. This review is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Literature sources and search strategy

A comprehensive computer-based search was performed across databases such as PubMed, Web of Science, and EMBASE for RCTs investigating the application of FF, FP, and AF in adult patients with SAR. The search was limited to English-language publications and covered the literature from the inception of these databases until September 2024. The search keywords included fluticasone, FP, FF, AF, and SAR. An example of the search strategy utilized in the PubMed database is presented in Table 1.

Table 1 PubMed search strategy.

Search	Query	Results
#1	((((Fluticasone[title/abstract]) OR (Fluticasone Furoate[title/abstract])) OR (Azelastine Fluticasone[title/abstract])) OR (Fluticasone Propionate[title/abstract])) OR (MP29-02[title/abstract])	4558
#2	Allergic rhinitis[title/abstract]	22643
#3	#1 AND #2	476

Inclusion criteria

Included studies were determined based on the PICOS criteria: (1) P (Population): Patients aged ≥ 12 years diagnosed with SAR; (2) I (Intervention): Studies that included at least one of the following treatments: FF, FP, or AF; (3) C (Comparison): Studies that compared at least one treatment different from the intervention group, including FF, FP, AF, or placebo; (4) O (Outcomes): Studies that reported at least one outcome measure, such as Total Nasal Symptom Score (TNSS) or Total Ocular Symptom Score (TOSS); and (5) S (Study design): Prospective RCT.

Studies were excluded if they did not report relevant clinical outcomes, lacked sufficient data for extraction and calculation, involved fewer than 10 patients in a single group, or did not specify intervention duration.

Data extraction

Data were extracted using a pre-designed Excel template, which included details such as the first author's name, publication date, sample size, age, sex, intervention type, and dosage, along with specified outcome data and publication bias information. Two independent researchers utilized a specially constructed online form to extract and cross-check data from each included study. Any discrepancies were resolved by a third researcher.

Quality assessment

The quality of the studies included in this review was evaluated independently by two researchers utilizing the Cochrane Risk of Bias Tool. The assessment focused on seven key domains: Random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, management of incomplete outcome data, selective reporting, and the presence of other biases. Each domain was classified as having a low risk, unclear risk, or high risk of bias. Additionally, a visual representation illustrating publication bias was created to enhance the comprehensiveness of the assessment.

Statistical analysis

Statistical analyses were performed using R, specifically employing the "meta" and "gemtc" packages for conventional meta-analysis and network meta-analysis. Heterogeneity was assessed using the I² statistic; an I² value exceeding 50% indicated high heterogeneity, prompting subgroup analysis or the use of a random-effects model. Conversely, an I² value of 50% or less suggested no significant heterogeneity, allowing a fixed-effects model to be employed. For quantitative outcomes, means, SD, and sample sizes were extracted for analysis, and mean differences (MD) along with 95% confidence intervals (CIs) were calculated as effect sizes. A statistically significant difference was indicated when the 95%CI for MD did not include zero.

RESULTS

Literature screening process

A total of 4021 records were retrieved from the database search, along with 16 records identified through manual search. After removing duplicates, 2369 records were screened by title, leading to the review of 458 abstracts and 247 full-text articles. Ultimately, 20 studies were included in this review. The literature screening process is illustrated in Figure 1.

Figure 1 Literature screening flowchart. RCT: Randomized controlled trial.

Basic information of included studies

In total, 20 studies were included, comprising 10590 participants. Among these, 17 studies were two-arm trials, while 3 were three-arm trials. Nine studies compared FF with placebo, including the work by Andrews et al[12], which differentiated between various types of seasonal allergies, resulting in a total of 10 data sets analyzed. Eight studies compared FP with placebo, with Andrews et al's study also distinguishing among different seasonal allergy types[12]. Additionally, 8 studies compared FF with placebo, 1 compared FP, FF, and placebo, 2 compared FP, AF, and placebo, and 1 compared AF with FP. Basic information on the included studies is summarized in Table 2. The risk of bias assessment is depicted in Figure 2.

Figure 2  Risk of bias chart.

Table 2 Basic information of included literature.

Ref.	Year	Treatment	Follow-up	Number of participants
				Total	Active treatment	Placebo
Fokkens et al[13]	2007	Fluticasone furoate 110 μg (QD) and placebo	2 wk	285	141	144
Kaiser et al[14]	2007	Fluticasone furoate 110 μg (2 sprays/nostril QD) and placebo	2 wk	299	151	148
Martin et al[15]	2007	Fluticasone furoate 110 μg (2 sprays/nostril QD) and placebo	2 wk	255	127	128
Andrews et al[12]	2009	Fluticasone furoate 110 μg (QD) and placebo	2 wk	453	224	229
		Fluticasone furoate 110 μg (QD) and placebo	2 wk	625	312	313
Jacobs et al[16]	2009	Fluticasone furoate 110 μg (QD) and placebo	2 wk	302	152	150
Okubo et al[17]	2009	Fluticasone furoate 110 μg (QD) and placebo	2 wk	223	151	72
		Fluticasone propionate 200 μg (BID) and placebo	2 wk	223	148	75
Han et al[18]	2011	Fluticasone furoate 110 μg (QD) and placebo	2 wk	137	67	70
Given et al[19]	2010	Fluticasone furoate 110 μg (QD) and placebo	4 wk	315	160	155
Maspero et al[20]	2010	Fluticasone furoate 110 μg (QD) and placebo	2 wk	1141	570	571
van Bavel et al[21]	1994	Fluticasone propionate 200 μg (2 sprays/nostril QD) and placebo	2 wk	155	78	77
Bronsky et al[22]	1996	Fluticasone propionate 200 μg (2 sprays/nostril QD) and placebo	4 wk	232	117	115
Howland et al[23]	1996	Fluticasone propionate 200 μg (2 sprays/nostril QD) and placebo	2 wk	154	77	77
Alvarado-Valdés et al[24]	1997	Fluticasone propionate 200 μg (2 sprays/nostril QD) and placebo	2 wk	211	105	106
Stern et al[25]	1997	Fluticasone propionate 200 μg (QD) and placebo	4-6 wk	254	190	64
Dykewicz et al[26]	2003	Fluticasone propionate 200 μg (QD) and placebo	4 wk	241	122	119
Hampel et al[27]	2010	Azelastine-fluticasone 137 μg (1 spray/nostril BID) and placebo	2 wk	304	153	151
		Fluticasone propionate 200 μg (2 sprays/nostril QD) and placebo	2 wk	302	151	151
Carr et al[28]	2012	Fluticasone propionate 200 μg (2 sprays/nostril QD) and placebo	2 wk	1704	846	858
		Azelastine-fluticasone 137 μg (1 spray/nostril BID) and placebo	2 wk	1706	848	858
Ford et al[29]	2015	Fluticasone propionate 200 μg (2 sprays/nostril QD) and placebo	2 wk	341	170	171
Ratner et al[30]	2009	Fluticasone propionate 200 μg (2 sprays/nostril QD) and azelastine-fluticasone 137 μg (1 spray/nostril BID)	2 wk	102	50	52
Ratner et al[31]	2015	Fluticasone propionate 200 μg (2 sprays/nostril QD) and placebo	2 wk	626	314	312

Meta-analysis results

Direct meta-analysis: A total of 22 studies reported changes in relative TNSS (rTNSS) following interventions with FF, FP, AF, and their respective placebos. Specifically, 10 studies compared FF with placebo, 10 compared FP with placebo, and 2 compared AF with placebo. Subgroup analyses based on intervention type revealed significant heterogeneity within the FF, FP, and AF subgroups; thus, a random-effects model was employed for analysis. The results indicated a significant reduction in overall rTNSS when compared to placebo (MD = -1.48, 95%CI: -1.73 to -1.22), with similar findings observed across the FF, FP, and AF subgroups. The forest plot illustrating rTNSS for different interventions is shown in Figure 3A.

Figure 3 Forest plot. A: Forest plot of relative Total Nasal Symptom Score for different intervention methods; B: Forest plot of relative Total Ocular Symptom Score for different intervention methods. AF: Azelastine-fluticasone; FP: Fluticasone propionate; FF: Fluticasone furoate.

Thirteen studies reported changes in relative TOSS (rTOSS) following interventions with FF, FP, AF, and their respective placebos, with 8 studies comparing FF with placebo, 4 comparing FP with placebo, and 1 comparing AF with placebo. Subgroup analyses based on intervention type indicated significant heterogeneity within the FF, FP, and AF subgroups, warranting the use of a random-effects model for analysis. The results demonstrated a significant decrease in overall rTOSS compared to placebo (MD = -0.66, 95%CI: -0.82 to -0.49), with consistent findings across the FF, FP, and AF subgroups. The forest plot illustrating rTOSS for different interventions is presented in Figure 3B.

Network meta-analysis results

To further explore the differences among FF, FP, and AF in improving rTNSS and rTOSS, a network meta-analysis was conducted on the included studies. For the rTNSS measure, direct comparisons were available between FF and FP, as well as between FP and AF; however, no direct comparison existed between FF and AF. The network diagram illustrating the relationships among different treatment modalities for rTNSS is shown in Figure 4A. In the case of rTOSS, a direct comparison was available between FP and AF, but no direct comparisons were found between FF and FP or between FF and AF. The network diagram for rTOSS is illustrated in Figure 4B.

Figure 4 Network relationship diagram. A: Network diagram illustrating the relationships among different treatment modalities for relative Total Nasal Symptom Score (rTNSS). For the rTNSS measure, direct comparisons were available between FF and fluticasone propionate (FP), as well as between FP and azelastine-fluticasone (AF); however, no direct comparison existed between FF and AF; B: Network diagram for rTOSS. A direct comparison was available between FP and AF, but no direct comparisons were found between FF and FP or between FF and AF. AF: Azelastine-fluticasone; FP: Fluticasone propionate; FF: Fluticasone furoate.

In the network meta-analysis for rTNSS, inconsistency model testing revealed no significant inconsistency, allowing for the use of a consistency model for analysis. The results of the network meta-analysis indicated that the SUCRA values ranking from high to low were as follows: AF (99.6%), FP (54.4%), FF (46.0%), and placebo (0.0%). The SUCRA values for rTNSS across different interventions are displayed in Figure 5A. In the rTOSS network meta-analysis, inconsistency model testing showed significant inconsistency, necessitating the use of an inconsistency model for analysis. The network meta-analysis results indicated SUCRA values ranking from high to low as follows: AF (99.5%), FP (66.4%), FF (34.1%), and placebo (0.0%). The SUCRA values for rTOSS across different interventions are presented in Figure 5B.

Figure 5 SUCRA comparison of different treatment methods. A: The results of the network meta-analysis indicated that the SUCRA values ranked from high to low as follows: Azelastine-fluticasone (AF) (99.6%), fluticasone propionate (FP) (54.4%), fluticasone furoate (FF) (46.0%), and placebo (0.0%); B: The network meta-analysis results indicated SUCRA values ranked from high to low as follows: AF (99.5%), FP (66.4%), FF (34.1%), and placebo (0.0%). AF: Azelastine-fluticasone; FP: Fluticasone propionate; FF: Fluticasone furoate.

A league table was constructed to display the comparative results for rTNSS and rTOSS among different treatment modalities. For rTNSS, improvements with FP, FF, and AF were all significantly greater than those observed with placebo, with AF demonstrating significantly greater improvement than both FP and FF. No statistically significant difference was found between FP and FF. In terms of rTOSS, FP, FF, and AF also showed significant improvements compared to placebo, with AF outperforming both FP and FF, and FP showing significantly greater improvement than FF. The league table summarizing the comparative results among different treatment modalities is presented in Table 3.

Table 3 League table of different treatment methods, mean difference (95%CI)¹.

	Relative total nasal symptom score
Relative total ocular symptom score	Placebo	-1.43 (-1.78 to -1.08)	-1.36 (-1.70 to -1.02)	-2.28 (-2.95 to -1.60)
	1.00 (0.66-1.34)	Fluticasone propionate	0.07 (-0.40-0.54)	-0.84 (-1.51 to -0.18)
	0.63 (0.47-0.79)	-0.37 (-0.75-0.00)	Fluticasone furoate	-0.91 (-1.66 to -0.17)
	1.40 (1.04-1.76)	0.53 (0.14-0.92)	0.77 (0.38-1.16)	Azelastine-fluticasone

¹The results below each treatment method column are the relative total ocular symptom score comparison results between the modified treatment method and the baseline treatment method; the results above each treatment method column are the relative total nasal symptom score comparison results between the modified treatment method and the baseline treatment method.

DISCUSSION

This study systematically evaluated the efficacy of various formulations of fluticasone, including FF, FP, and AF, in adult patients with SAR. Both direct meta-analysis and network meta-analysis were performed to assess changes in the rTNSS and rTOSS following interventions. The findings from the direct meta-analysis revealed that, in comparison to placebo, both rTNSS and rTOSS demonstrated significant reductions post-intervention (MD = -1.48, 95%CI: -1.73 to -1.22), with similar outcomes observed across the FF, FP, and AF subgroups. The network meta-analysis further indicated that for improvements in rTNSS and rTOSS, the SUCRA values ranked as follows: AF, FP, FF, and placebo. Notably, improvements in rTNSS and rTOSS with FP, FF, and AF were all significantly greater than those seen with placebo, with AF showing superior efficacy compared to both FP and FF. No statistically significant difference in rTNSS improvement was noted between FP and FF, although FP exhibited a significantly greater improvement in rTOSS compared to FF[13-31].

While SAR is not classified as a life-threatening condition, its symptoms, such as persistent nasal congestion, sneezing, and rhinorrhea, can substantially impair patients' quality of life and increase the risk of complications, including sinusitis and nasal polyps. Patients with SAR require effective symptom relief and management, necessitating medications that provide robust efficacy and rapid onset of action. FP is a highly effective intranasal corticosteroid that is widely employed in the treatment of allergic rhinitis, significantly alleviating nasal symptoms, including congestion, rhinorrhea, and eosinophil counts, with a rapid onset of action within 24 h[32]. The propionate ester side chain endows FP with high lipophilicity, allowing it to exhibit superior efficacy at lower doses compared to other corticosteroids, achieving clinical potency at least twice that of budesonide and beclomethasone without increasing systemic side effects[33]. Due to rapid hepatic metabolism, FP demonstrates low systemic bioavailability, thereby minimizing potential adverse effects; even with a twice-daily oral dose of 10 mg, its systemic bioavailability remains below 1%[34].

FF, a novel glucocorticoid, received FDA approval for allergic rhinitis in 2003 and was subsequently introduced to the Chinese market in 2013. FF features a trifluorinated molecular structure similar to FP, differentiated by the addition of a furoate ester at the 17α-OH group[35]. Like FP, FF exhibits high lipophilicity and rapid binding to glucocorticoid receptors, characterized by a slow dissociation rate that enhances receptor affinity and prolongs tissue retention, potentially improving its anti-inflammatory efficacy. FF has been shown to have longer pulmonary absorption and retention times compared to FP[36,37]. Moreover, FF has demonstrated potent anti-inflammatory activity both in vitro and in vivo, with once-daily administration providing 24 h of symptom relief[38]. Evidence of sustained suppression of exhaled nitric oxide for approximately 18 d following treatment cessation supports its prolonged anti-inflammatory effects[39]. These properties contribute to the efficacy of FF in managing allergic rhinitis, potentially enhancing patient adherence and reducing the necessity for polypharmacy. Daily administration of FF nasal spray has been proven effective in treating SAR induced by grass pollen[40].

AF, a novel intranasal formulation combining azelastine hydrochloride and FP, is delivered in a single spray. A meta-analysis encompassing eight studies indicated that AF significantly outperformed both azelastine and FP alone in reducing overall nasal symptom scores compared to placebo[41]. Safety studies involving children aged 4 to 11 years have demonstrated good tolerability for AF, with a low incidence of treatment-related adverse events[42]. A multicenter, prospective, non-interventional, real-world study indicated that AF effectively alleviated symptoms and improved patient-reported quality of life, as evidenced by enhanced sleep quality and reduced impairment in work, study, social, and outdoor activities after 14 d. The quality of life benefits of AF appeared consistent across various phenotypes of IgE-mediated diseases[43]. AF also demonstrated significant advantages in alleviating both nasal and ocular symptoms compared to monotherapy with azelastine or FP[44,45].

This study is not without limitations. Although there is a substantial body of RCTs comparing FP and FF with their respective placebos, the number of studies comparing AF with placebo is limited. Furthermore, there are currently no RCTs directly comparing AF with FF. While indirect comparisons suggest that AF may be the optimal choice for improving nasal and ocular symptoms, the relatively small number of studies associated with AF underscores the need for further large-scale direct comparative investigations to validate these conclusions, which should be a focus for future research.

CONCLUSION

In adult patients with SAR, the AF combination demonstrates significant efficacy in improving both nasal and ocular symptoms, with FP showing marked improvement in ocular symptoms compared to FF.