Question | |
Should a combination of an intranasal H1-antihistamine and an intranasal glucocorticosteroid vs. no treatment be used for the treatment of allergic rhinitis? | |
Population: | Patients with allergic rhinitis |
Intervention: | a combination of an intranasal H1-antihistamine and an intranasal glucocorticosteroid |
Comparison: | no treatment |
Main outcomes: | Nasal symptoms Ocular symptoms Quality of life Adverse events (any) Serious adverse events |
Setting: | |
Perspective: | |
Background: | Fixed combinations of intranasal antihistamines (INAH) + intranasal corticosteroids (INCS) are one of the mainstays for the treatment of allergic rhinitis, combining some of the advantages of INCS with those of INAH. However, INAH+INCS may not be affordable in all countries. |
Conflict of interests: | AWMF conflict of interest declaration and management policies were applied, the assessment performed by the AWMF with guidance and help from Juan Jose Yepes Nuñez. Due to the CoI assessment results, the following panel members recused from voting (determining the direction and strength of the recommendation): Bousquet, Canonica, Jacomelli, Klimek, Papadopoulos, Pereira and Zuberbier T. The voting members were: Bedbrook, Bognanni, Dykewicz, Gilles, Lourenço, Neves, Palamarchuk, Parmelli, Savouré, Schunemann, Sousa-Pinto, Valiulis, Ventura, Vieira, Williams, Yepes Nuñez and Zuberbier J. |
Assessment
ProblemIs the problem a priority? | ||
Judgement | Research evidence | Additional considerations |
Allergic rhinitis (AR) is a common condition affecting 18.1% of the population, and its symptoms can significantly reduce the quality of life and pose a high economic burden (mainly because of indirect costs related to lost school days and workdays). [Savoure] Studies of patients consulting general practitioners for AR reported that 18–48 % had symptoms that were not controlled by pharmacotherapy. [Bousquet, Bhattacharyya, Vandenplas] Despite the bothersome nature of symptoms, AR is often trivialized by the patient - only 45% seek medical advice or treatment for their condition, which results in under-treatment and poor control of symptoms. [Linneberg] Problems related to disease Economic burden A systematic review performed to estimate the financial burden of AR in European countries [Linneberg] suggests that the GP services bore the majority of the direct costs for AR. However, the majority of the overall cost burden correspond to indirect costs caused by high absenteeism and presenteeism. In the United States, annual costs for medications for rhinitis patients can be estimated at approximately $1.3 billion. In total, direct costs are estimated to be >$4.6 billion for rhinitis management, including treatment, allergy testing, clinical visits and hospital procedures. [Roland] Similar findings were found for Asia. An analysis of the indirect costs associated with insufficiently treated AR and urticaria patients revealed an annual burden of USD 105.4 billion. This translates to a cost ranging from USD 1,137 to USD 2,195 per patient due to absenteeism and presenteeism [ Kulthanan] Clinical burden The median prevalence of allergic rhinitis was found to be 18.1%, based on a dataset that included 310 reported prevalences. The prevalence of AR ranged from as low as 1.0% to as high as 54.5%.
These statistics indicate that AR is a relatively common condition affecting a significant portion of the population, with variations in prevalence observed across different regions or studies. [Savouré] References:
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Desirable EffectsHow substantial are the desirable anticipated effects? | ||
Judgement | Research evidence | Additional considerations |
Nasal symptoms In a systematic review with network meta-analysis performed by Sousa-Pinto et al., nasal symptoms were assessed in patients under fixed combinations of intranasal corticosteroids and H1-antihistamines (INCS+INAH) and compared with that registered in patients receiving placebo. For patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the total nasal symptom score (TNSS; combination of four nasal symptoms and scale of 0-12) results of 78 randomised controlled trials (RCTs). INCS+INAH were associated with a significantly higher improvement in the TNSS when compared to placebo (mean difference=-1.44; 95%CI=-1.68;-1.21). INCS+INAH displayed a 100% probability of resulting in a clinically meaningful improvement when compared to placebo (95% with a moderate effect). For patients with perennial allergic rhinitis, it was possible to meta-analytically pool the four symptom TNSS results of 24 RCTs. INCS+INAH were associated with a significantly higher improvement in the TNSS when compared to placebo (mean difference=-0.81; 95%CI=-1.38;-0.24). INCS+INAH displayed a 89% probability of resulting in a clinically meaningful improvement when compared to placebo (15% with a moderate effect) Subgroup considerations: Studies including vs. not including patients with asthma A subsequent subgroup analysis of the network meta-analysis performed by Sousa-Pinto et al. was performed, grouping trials according to whether they had excluded patients with asthma. The following results were found:  Subgroup considerations: Children and adolescents In a systematic review with network meta-analysis performed by Sousa-Pinto et al., for patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the four symptom TNSS results of 9 RCTs. INCS+INAH were associated with a significantly higher improvement compared to placebo on changes to TNSS (mean difference=-0.57, 95%CI=-1.07; -0.06). For patients with perennial allergic rhinitis, no studies were available. Ocular symptoms In a systematic review with network meta-analysis performed by Sousa-Pinto et al., the improvement of ocular symptoms was assessed in patients under INCS+INAH and compared with that registered in patients receiving placebo. For patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the total ocular symptom score (TOSS; combination of three nasal symptoms and scale of 0-9) results of 54 RCTs. INCS+INAH were associated with a significantly higher improvement in TOSS when compared to placebo (mean difference=-0.64; 95%CI=-0.76;-0.51). INCS+INAH displayed a 100% probability of resulting in a small clinically meaningful improvement when compared to placebo. For patients with perennial allergic rhinitis, no RCTs were found. Subgroup considerations: Studies including vs. not including patients with asthma A subsequent subgroup analysis of the network meta-analysis performed by Sousa-Pinto et al. was performed, grouping trials according to whether they had excluded patients with asthma. The following results were found:  Overall symptoms No studies comparing the effectiveness of INCS+INAH vs placebo for seasonal allergic rhinitis (SAR) were identified. A single RCT compared the effectiveness of INCS+INAH vs placebo for perennial allergic rhinitis (PAR). At 4 weeks, the TSS was significantly lower in the assessed fixed combination (azelastine-fluticasone) group compared to placebo treated patients (p = 0.003). Quality-of-life In a systematic review with network meta-analysis performed by Sousa-Pinto et al., the improvement of quality-of-life was assessed in patients under INCS+INAH and compared with that registered in patients receiving placebo. For patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the rhinocojunctivitis quality of life questionnaire (RQLQ; scale of 0-6) results of 31 RCTs. INCS+INAH were associated with a significant difference in RQLQ changes when compared to placebo (mean difference=-0.65; 95%CI=-0.76;-0.53). INCS+INAH displayed a 100% probability of resulting in a clinically meaningful improvement when compared to placebo (49% with a moderate effect). For patients with perennial allergic rhinitis, it was possible to meta-analytically pool the RQLQ results of 13 RCTs. INCS+INAH were associated with a significant difference in RQLQ changes when compared to placebo (mean difference=-0.42; 95%CI=-0.78;-0.06). INCS+INAH displayed a 67% probability of resulting in a clinically meaningful improvement when compared to placebo (4% with a moderate effect). Subgroup considerations: Studies including vs. not including patients with asthma A subsequent subgroup analysis of the network meta-analysis performed by Sousa-Pinto et al. was performed, grouping trials according to whether they had excluded patients with asthma. The following results were found:  | ||
Undesirable EffectsHow substantial are the undesirable anticipated effects? | ||
Judgement | Research evidence | Additional considerations |
Adverse events Following the systematic review performed by Sousa-Pinto et al., the frequency of patients developing at least one adverse event was assessed in patients under intranasal corticosteroids + intranasal H1-antihistamines (INCS+INAH) and compared with that registered in patients receiving placebo. A total of 75 randomised controlled trials (RCTs) reported data on the number of patients with seasonal allergic rhinitis reporting at least one adverse event. The meta-analytical risk ratio was of 1.67 (95% confidence interval=1.33-2.04) [INCS+INAH was associated with 71 more cases per 1000 patients than placebo; 95%CI = 37 more cases to 112 more cases per 1000 patients. Trivial difference]. A total of 30 RCTs reported data on the number of patients with perennial allergic rhinitis reporting at least one adverse event. The meta-analytical risk ratio was of 0.91 (95% confidence interval=0.54-1.54) [INCS+INAH was associated with 26 fewer cases per 1000 patients than placebo; 95%CI = 160 fewer cases to 135 more cases per 1000 patients. Trivial difference] Most adverse events which were considered to be related to the treatment were mild and self-limited and comprised headache, epistaxis, nasal discomfort, upper respiratory tract infection and bitter taste. Subgroup considerations: Studies including vs. not including patients with asthma A subsequent subgroup analysis of the network meta-analysis performed by Sousa-Pinto et al. was performed, grouping trials according to whether they had excluded patients with asthma. The following results were found:  Serious adverse events Following the systematic review performed by Sousa-Pinto et al., the frequency of patients developing at least one serious adverse event was assessed both in patients under INCS+INAH and in patients receiving INCS. The following results were observed for seasonal allergic rhinitis:  The following results were observed for perennial allergic rhinitis:  Subgroup considerations: Children and adolescents In a systematic review performed by Sousa-Pinto et al., 0 serious adverse events were registered in 398 children with seasonal allergic rhinitis treated with INAH+INCS (data from 2 RCTs). No evidence on the frequency of serious AE in children with perennial allergic rhinitis treated with INAH+INCS. | ||
Certainty of evidenceWhat is the overall certainty of the evidence of effects? | ||
Judgement | Research evidence | Additional considerations |
The certainty of evidence was moderate for 3 out of 7 analyses, high for 0 out of 9 analyses, and very low for 3 out of 7 analyses.
| Moderate for SAR and Very Low for PAR. | |
ValuesIs there important uncertainty about or variability in how much people value the main outcomes? | ||
Judgement | Research evidence | Additional considerations |
Utility values Symptoms Regarding specific symptoms, in two studies, utilities (measured by VAS) were lower for severe nasal congestion and severe rhinorrhea compared to severe sneezing, severe throat itching, and severe itchy eyes (certainty of evidence: low). When utilities were elicited with the standard gamble technique, severe itchy eyes were rated by US patients as the least preferred AR symptom (certainty of evidence: low).  Studies of rating or ranking of outcomes Adults
 Children/caregivers sample Seven studies assessing children or their caregivers were included in the relative importance analysis. Most of these studies only assessed symptom-related attributes. Similarly to the adult population, a nasal symptom was frequently ranked as the most or second most important attribute (certainty of evidence: low). In particular, nasal congestion was identified as the most important attribute in five studies (certainty of evidence: low).  | ||
Balance of effectsDoes the balance between desirable and undesirable effects favor the intervention or the comparison? | ||
Judgement | Research evidence | Additional considerations |
Taking into account both benefits and harms of intranasal corticosteroids + intranasal H1-antihistamines (INCS+INAH) versus placebo, we can consider the following:
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Resources requiredHow large are the resource requirements (costs)?" | ||
Judgement | Research evidence | Additional considerations |
We conducted a survey, having received responses from specialists from 41 countries (mostly in Europe, America and Asia). The costs of being treated for one year with intranasal corticosteroids + intranasal antihistamines (INCS+INAH) ranged from 32.4 US Dollars Power Purchase Parity (PPP) [Bangladesh] to 1209.0 USD PPP [Argentina] (assuming full adherence to treatment and the choice of the least expensive INCS+INAH). This corresponds to weekly costs ranging from 0.62 USD PPP to 23.3 USD PPP. The yearly costs per country associated with the use of INCS+INAH are displayed in the following map:  Evidence from direct patient data: A preliminary analysis of MASK-air data using the WPAI:AS questionnaire has identified that the overall median work impairment (including both absenteeism and presenteeism) stood at 3.1% (90% CrI: 0.0-28.6%) for well-controlled weeks, ascending to 25.6% (90% CrI: 0.0-65.9%) and 65.4% (90% CrI: 36.6-93.7%) for partially- and poorly-controlled weeks, respectively. In Germany, this translates into median weekly monetary losses of 24.0 USD PPPs for well-controlled weeks, 196.7 USD PPPs for partially-controlled weeks, and 555.4 USD PPPs for poorly controlled weeks (difference of 531.4 USD per week from poor to good control). For other Western European countries, the difference ranges from 262 to 490 USD. References: 1. https://www.lancsmmg.nhs.uk/media/1726/ryaltris-new-medicine-recommendation.pdf | ||
Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)? | ||
Judgement | Research evidence | Additional considerations |
Given that combinations of intranasal steroids and intranasal antihistamines has been around for a long time, there is a reasonably high degree of certainty about the general costs. The available data are available from a survey of experts. | ||
Cost effectivenessDoes the cost-effectiveness of the intervention favor the intervention or the comparison? | ||
Judgement | Research evidence | Additional considerations |
No published cost utility or cost-effectiveness analyses for nasal corticosteroids were identified in the literature databases. However, through a supplementary search conducted on the INAHTA database and the HTA agency website, one reimbursement recommendation (specifically for Azelastine/Fluticasone) was found on the CADTH website, which included cost-effectiveness data for Fluticasone/Azelastine versus placebo. The manufacturer’s economic submission for drug Dymista reported that, based on a cost-utility analysis, AZE/FP had an ICUR of $31,936 per QALY compared with placebo. The manufacturer's submission had several limitations, that were noted in CDR PHARMACOECONOMIC REVIEW REPORT such as the source of input data (efficacy data), the time horizon of the analysis, the assessment of adverse events' impact on quality of life, and adjustments of Quality-Adjusted Life Years (QALY). ICUR value was higher in re-analysis [CDR multi-way reanalysis]: ICUR of AZE/FP vs. placebo: $40,861 per QALY. In addition, indirect costs (i.e., gains resulting from increased work productivity) have not been considered in this study, so that these ICUR may correspond to conservative estimates. Evidence from direct patient data: Considering the costs reported in the survey alongside the differences in QALYs reported in the CDR Pharmacoeconomic Review Report, INCS+INAH would be cost-effective for all countries at a willingness to pay threshold of $50,000/QALY gained (only direct costs with medication being considered). Considering the conservative willingness to pay threshold of 1 time the GDP per capita, INCS+INAH would only not be cost-effective in three countries (Argentina, Colombia and Syria). References: 1. CDR PHARMACOECONOMIC REVIEW REPORT FOR DYMISTA. https://www.cadth.ca/sites/default/files/cdr/pharmacoeconomic/SR0408_Dymista_PE_Report.pdf | ||
EquityWhat would be the impact on health equity? | ||
Judgement | Research evidence | Additional considerations |
Availability We conducted a survey, having received responses from specialists from 41 countries (mostly in Europe, America and Asia). Intranasal corticosteroids + intranasal antihistamines (INCS+INAH) are available in 36 out of the 41 assessed countries. In 22 countries, only one INCS+INAH was available. Other equity-related aspects We did not identify any health equity studies that satisfactorily addressed a combination of an intranasal H1-antihistamine and an intranasal glucocorticosteroid vs. no treatment. However, we were able to map the following aspects related equity:  | ||
AcceptabilityIs the intervention acceptable to key interest-holders? | ||
Judgement | Research evidence | Additional considerations |
During the systematic search, we identified one study that satisfactorily addressed combination of an intranasal H1-antihistamine and an intranasal glucocorticosteroid vs. no treatment. [Canonica] Satisfaction 70% of patients were satisfied/extremely satisfied with its ability to prevent/treat AR by Aze/Flu, relieve symptoms and with its onset of action. Treatment satisfaction and effectiveness were significantly improved when MP-AzeFlu was taken as recommended [Canonica] Evidence from direct patient data: In the MASK-air dataset, there were 2834 days in which INAH+INCS (fixed combinations) were used in monotherapy and for which patients provided information on how satisfied they were with their treatments. The median results of the visual analogue scale were of 83 (higher values indicating higher satisfaction) [IQR=24]. Compliance Evidence from direct patient data: In patients adherent to the app, in complete weeks of MASK-air reporting during the pollen season, there were 31.7% in which INCS+INAH were used for 6 or 7 days. This does not apply to all patients. Co-medication rate Evidence from direct patient data: In the MASK-air dataset, in 51.0% of the days in which INCS+INAH have been used, they have been used in comedication. Compared to other rhinitis medication classes, INCS+INAH was associated with lower odds of being used in co-medication (OR=0.75; 95%CI=0.71-0.80) in a study using multivariable mixed-effects logistic regression models Onset of actionFrom a rapid review of the literature, the median [min-max] onset of action of fixed combinations of intranasal corticosteroids + intranasal antihistamines was found to be:
References: 1. Canonica, G. W., Klimek, L., Acaster, S., Dollner, R., Kaulsay, R., Lo, S. H., … Zieglmayer, P. (2021). Burden of allergic rhinitis and impact of MP-AzeFlu from the patient perspective: pan European patient survey. Current Medical Research and Opinion, 37(7), 1259–1272. https://doi.org/10.1080/03007995.2021.1911973 | ||
FeasibilityIs the intervention feasible to implement? | ||
Judgement | Research evidence | Additional considerations |
We did not identify any feasability studies that satisfactorily addressed combination of an intranasal H1-antihistamine and an intranasal glucocorticosteroid vs. no treatment. | ||
Planetary healthWhat would be the impact on planetary health? | ||
Judgement | Research evidence | Additional considerations |
To assess planetary health, it is usual to perform lifecycle assessment studies, that is, studies assessing the environmental impact of interventions from cradle-to-grave. In a rapid review of the literature, we were unable to find LCA studies assessing fixed combinations of intranasal antihistamine + intranasal corticosteroid. The following table presents a qualitative summary of topics which may be considered for the assessment of the planetary impact of fixed combinations of intranasal antihistamine + intranasal corticosteroid across the medication lifecycle.  A key consideration is the effectiveness of fixed combinations of intranasal antihistamine + intranasal corticosteroid, compared to no treatment, in reducing healthcare resource utilization. | ||
Summary of judgements
Judgement | |||||||
|---|---|---|---|---|---|---|---|
Problem | No | Probably no | Probably yes | Yes | Varies | Don't know | |
Desirable Effects | Trivial | Small | Moderate | Large | Varies | Don't know | |
Undesirable Effects | Trivial | Small | Moderate | Large | Varies | Don't know | |
Certainty of evidence | Very low | Low | Moderate | High | No included studies | ||
Values | Important uncertainty or variability | Possibly important uncertainty or variability | Probably no important uncertainty or variability | No important uncertainty or variability | |||
Balance of effects | Favors the comparison | Probably favors the comparison | Does not favor either the intervention or the comparison | Probably favors the intervention | Favors the intervention | Varies | Don't know |
Resources required | Large costs | Moderate costs | Negligible costs and savings | Moderate savings | Large savings | Varies | Don't know |
Certainty of evidence of required resources | Very low | Low | Moderate | High | No included studies | ||
Cost effectiveness | Favors the comparison | Probably favors the comparison | Does not favor either the intervention or the comparison | Probably favors the intervention | Favors the intervention | Varies | No included studies |
Equity | Reduced | Probably reduced | Probably no impact | Probably increased | Increased | Varies | Don't know |
Acceptability | No | Probably no | Probably yes | Yes | Varies | Don't know | |
Feasibility | No | Probably no | Probably yes | Yes | Varies | Don't know | |
Planetary health | Reduced | Probably reduced | Probably no impact | Probably increased | Increased | Varies | Don't know |
Type of recommendation
Conclusions
Recommendation |
For patients with severe allergic rhinitis, in whom monotherapy is unlikely to lead to significant improvement in symptoms, the ARIA guideline panel recommends using intranasal corticosteroids and intranasal H1-antihistamines over no treatment (strong recommendation based on moderate certainty of evidence for seasonal allergic rhinitis and very low certainty of evidence for perennial allergic rhinitis). |
Justification |
This recommendation is mostly grounded (i) on a favourable balance of effects, (ii) large savings and cost-effectiveness, and (iii) acceptability of the intervention. |
Subgroup considerations |
The recommendation is applicable to children and adolescents: A subsequent subgroup analysis assessing the treatment of AR with INCS+INAH in children was also performed. INCS+INAH were associated with a significantly higher improvement compared to placebo on changes to TNSS in seasonal allergic rhinitis. No serious adverse events were reported. There was no evidence regarding perennial allergic rhinitis in this subgroup. A subsequent subgroup analysis of the network meta-analysis performed by Sousa-Pinto et al. was performed, grouping trials according to whether they had excluded patients with asthma. For seasonal allergic rhinitis, in both subgroups, INCS+INAH were associated with a significantly higher improvement in TNSS, TOSS and RQLQ versus placebo. The risk ratio of adverse events was significantly higher for INCS+INAH in both subgroups (RR= 1.86 [1.32;2.62] in the subgroup including asthma patients and RR= 1.58 [1.21;2.07] in the subgroup without asthma patients). For perennial allergic rhinitis, no studies excluding asthma patients were available. |
Implementation considerations |
The implementation may differ based on country and on accessibility to other medications for allergic rhinitis. |
Monitoring and evaluation |
Research priorities |
- Need for studies in specific subgroups of participants or presentation of results by subgroup. Such subgroups include: children and adolescents (perennial allergic rhinitis), older patients, patients with multimorbidity (asthma and conjunctivitis), and patients from ethnic minorities. - Need for studies - particularly randomised controlled trials - evaluating participants with mild allergic rhinitis. - Need for studies evaluating the planetary impact of the intervention. |