Question | |
Should intranasal H1-antihistamines vs. no treatment be used for allergic rhinitis? | |
Population: | Patients with allergic rhinitis |
Intervention: | intranasal H1-antihistamines |
Comparison: | no treatment |
Main outcomes: | Nasal symptoms Ocular symptoms Quality of life Adverse events (any) Serious adverse events |
Setting: | |
Perspective: | |
Background: | Intranasal antihistamines are one possible therapeutic option in patients with AR, being often considered for patients with corticosteroid-phobia and displaying a fast onset of action. |
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., the improvement of nasal symptoms was assessed in patients under intranasal antihistamines (INCS) 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 82 randomised controlled trials (RCTs). INAH were associated with a significantly higher improvement in the TNSS when compared to placebo (mean difference=-0.80; 95%CI=-0.97;-0.64). INAH displayed a 100% probability of resulting in a small improvement when compared to placebo. For patients with perennial allergic rhinitis, it was possible to meta-analytically pool the four symptom TNSS results of 27 RCTs. INAH were not associated with a significantly higher improvement in the TNSS when compared to placebo (mean difference=-0.30; 95%CI=-0.71;0.11). INAH displayed a 44% probability of resulting in a clinically meaningful improvement when compared to placebo (in particular, a 43% probability of resulting in a small improvement). 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 perennial allergic rhinitis, it was possible to meta-analytically pool the four symptom TNSS results of 12 RCTs. INCS were associated with a significantly higher improvement in the TNSS when compared to placebo (mean difference=-0.47; 95%CI=-0.88;-0.06). INCS displayed a 60% probability of resulting in a clinically meaningful improvement when compared to placebo (in particular, a 58% probability of resulting in a small improvement, and a 2% probability of resulting in a large improvement). For seasonal allergic rhinitis, no primary studies were found assessing children or adolescents. 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 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 24 RCTs. INAH were associated with a significantly higher improvement in the TOSS when compared to placebo (mean difference=-0.45; 95%CI=-0.56;-0.34). INAH displayed a 81% probability of resulting in a clinically meaningful improvement when compared to placebo (in particular, a 81% probability of resulting in a small improvement). For patients with perennial allergic rhinitis, no primary studies were identified allowing for the comparison between INAH versus placebo on their effect on the TOSS. 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., no primary studies were found assessing children or adolescents. 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 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 34 RCTs. INAH were associated with a significant difference in RQLQ changes when compared to placebo (mean difference=-0.32; 95%CI=-0.40;-0.23). INAH displayed a 94% probability of resulting in a clinically meaningful improvement when compared to placebo (in particular, a 94% probability of resulting in a small improvement). For patients with perennial allergic rhinitis, it was possible to meta-analytically pool the RQLQ results of 15 RCTs. INAH were associated with a significant difference in RQLQ changes when compared to placebo (mean difference=-0.27; 95%CI=-0.49;-0.05). INAH displayed a 59% probability of resulting in a clinically meaningful improvement when compared to placebo (in particular, a 58% probability of resulting in a small improvement). 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 perennial allergic rhinitis, it was possible to meta-analytically pool the RQLQ results of 3 RCTs. INAH were not associated with a significantly higher improvement in the RQLQ when compared to placebo (mean difference=0.04; 95%CI=-0.12;0.20). INCS displayed a 31% probability of resulting in a clinically meaningful improvement when compared to placebo (in particular, a 8% probability of resulting in a small improvement, a 4% probability of resulting in a moderate improvement, and a 19% probability of resulting in a large improvement). For seasonal allergic rhinitis, it was possible to meta-analytically pool the RQLQ results of 4 RCTs. INAH were associated with a significantly higher improvement in the RQLQ when compared to placebo (mean difference=-0.21; 95%CI=-0.33;-0.09). INCS displayed a 59% probability of resulting in a clinically meaningful improvement when compared to placebo (in particular, a 27% probability of resulting in a small improvement, a 8% probability of resulting in a moderate improvement, and a 24% probability of resulting in a large improvement). The summary of findings tables supporting the research evidence and the underlying references can be found here. | ||
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 antihistamines (INAH) and compared with that registered in patients receiving placebo. A total of 14 randomised controlled trials (RCTs) reported data on the number of patients with seasonal allergic rhinitis reporting at least one adverse event. The meta-analytical incidence rate ratio was of 2.24 (95% confidence interval=1.38-3.62) [INAH was associated with 41 more cases per 1000 patients than placebo; 95%CI = 13 more cases to 83 more cases per 1000 patients. Trivial difference]. One RCT reported data on the number of patients with perennial allergic rhinitis reporting at least one adverse event. The meta-analytical incidence rate ratio was of 1.40 (95% confidence interval=0.85-2.30) [INAH was associated with 10 more cases per 1000 patients than placebo; 95%CI = 4 fewer cases to 31 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, and upper respiratory tract infection. 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 performed by Sousa-Pinto et al., a total of 11 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 1.08 (95%CI=0.67-1.75) [5 more cases per 1000 individuals; from 20 fewer cases to 45 more cases per 1000 individuals. These values were fully within the "trivial" category]. A total of 15 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 0.99 (95%CI=0.70-1.40) [1 fewer case per 1000 individuals; from 33 fewer cases to 44 more cases per 1000 individuals. These values were fully within the "trivial" category]. Most adverse events which were considered to be related to the treatment were mild and self-limited and comprised headache, epistaxis, nasal discomfort or upper respiratory tract infection. 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 INAH and in patients receiving placebo. 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., one RCT reported data on the number of patients with seasonal allergic rhinitis reporting at least one serious adverse event. No serious adverse events were reported in a total of 594 children treated with INAH (this compares to 1 serious adverse event in 594 children treated with placebo). One RCT reported data on the number of patients with perennial allergic rhinitis reporting at least one serious adverse event. No serious adverse events were reported in a total of 327 children treated with INAH (this compares to 0 serious adverse events in 162 children treated with placebo). | ||
Certainty of evidenceWhat is the overall certainty of the evidence of effects? | ||
Judgement | Research evidence | Additional considerations |
The certainty of evidence was low for 1 out of 6 analyses, and very low for 5 out of 6 analyses.
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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 sampleSeven 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 antihistamines (INAH), we can consider the following:
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Resources requiredHow large are the resource requirements (costs)?" | ||
Judgement | Research evidence | Additional considerations |
Cost of drugs We conducted a survey, having received responses from specialists from 41 countries (mostly in Europe, America and Asia). In 29 of these countries, intranasal antihistamines (INAH) were available. The costs of being treated for one year with INAH ranged from 18.0 US Dollars Power Purchase Parity (PPP) [Bangladesh] to 856.4 USD PPP [Colombia] (assuming full adherence to treatment and the choice of the least expensive INAH). This corresponds to weekly costs ranging from 0.35 USD PPP to 16.5 USD PPP. The yearly costs per country associated with the use of INCS 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
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Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)? | ||
Judgement | Research evidence | Additional considerations |
Given that intranasal antihistamines has been around for a long time, there is a reasonably high degree of certainty about the general costs. However, it should be noted that available evidence comes from a survey of experts and direct patient data. | ||
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 antihistamines were identified in the literature databases. However, through a supplementary search conducted on the INAHTA database and the HTA agency websites, one reimbursement recommendation (specifically for Azelastine/Fluticasone) was found on the CADTH website, which included cost-effectiveness data for Fluticasone Propionate (FP) and Azelastine (comparators for Azelastine-Fluticasone fixed combination). The manufacturer’s economic submission for drug Azelastine-Fluticasone informed that when azelastine was compared with a placebo, the ICER value was $27,207. The manufacturer's submission had several limitations that were noted in the 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 QALY. Below is a comparison of results from the base case scenario [submission model] and re-analysis [CDR multi-way reanalysis].  *from CDR report Considering the costs reported in the survey alongside the differences in QALYs reported in the CDR Pharmacoeconomic Review Report, 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, INAH would only not be cost-effective in two countries (Colombia and Syria).
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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 antihistamines (INAH) were reported to be available in 29 out of 41 countries (countries in green in the map below). In 13 countries, only one INAH was available.  Other equity-related aspects  | ||
AcceptabilityIs the intervention acceptable to key interest-holders? | ||
Judgement | Research evidence | Additional considerations |
We have included one study that provides data on the acceptability of intranasal antihistamines (INAH). (Ciprandi 2011) Satisfaction (patient) In a Satisfaction with Allergy Treatment survey conducted in 21 allergy centres in Italy, only one patient out of 22 (5%) treated with intranasal antihistamines was satisfied. [Ciprandi] Evidence from direct patient data: In the MASK-air dataset, there were 81 days in which INAH 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 60 (higher values indicating higher satisfaction) [IQR=57]. Switching rate Evidence from direct patient data: In the MASK-air dataset, in 84.8% of the days in which INAH have been used, they have been used in comedication. This compares with 50.1% for oral antihistamines, 51.0% for the fixed combination of INAH+intranasal corticosteroids, 56.2% for intranasal corticosteroids, and 83.0% for antagonists of leukotriene receptors. Compared to other rhinitis medication classes, INAH was associated with higher odds of being used in co-medication (OR=2.41; 95%CI=2.07-2.81) in a study using multivariable mixed-effects logistic regression models [Sousa-Pinto]. In 54.8% of days with INAH use, more than one INAH was used (that is, patients tried at least two INAH on the same day). This compares to 6.2% of days with intransal corticosteroids use, 4.1% of days with oral antihistamine use, 0.3% of days with fixed combination of INAH+intranasal corticosteroids use, and 0.4% of days with antagonists of leukotriene receptors use. Compliance (patient) Evidence from direct patient data: In complete weeks of MASK-air reporting during the pollen season, there were 19.6% in which INAH were used for 6 or 7 days. This compares with 36.0% for intranasal corticosteroids, 38.5% for oral antihistamines, and 31.7% for fixed combinations of INAH+intranasal corticosteroids. Onset of action In a rapid review of the literature, the median (min-max) onset of action of INAH was found to be 30 min (0.5 hrs) [15-240 min (0.25-4 hrs)] References:
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FeasibilityIs the intervention feasible to implement? | ||
Judgement | Research evidence | Additional considerations |
No specific study has assessed the feasibility of intranasal antihistamine use but intranasal antihistamines have been available for a long time. | ||
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 intranasal antihistamines. The following table presents a qualitative summary of topics which may be considered for the assessment of the planetary impact of intranasal antihistamines across the medication lifecycle.  A key consideration is the effectiveness of intranasal antihistamines, 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 |
In patients with allergic rhinitis, the ARIA guideline panel recommends using intranasal antihistamines over no treatment (strong recommendation based on moderate certainty of evidence). |
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 |
Considerations for children and adolescents: In a subgroup analysis of children and adolescents, INAH were associated with a significantly higher improvement versus placebo in the TNSS in patients with perennial allergic rhinitis but not in the RQLQ. There were no studies assessing TOSS. In patients with seasonal allergic rhinitis, INAH were associated with a significantly higher improvement in RQLQ versus placebo. There were no studies assessing TNSS or TOSS in this subgroup. INAH were not associated with a significantly higher risk ratio of developing at least one adverse event compared with placebo. Most adverse events which were considered to be related to the treatment were mild and self-limited. No serious adverse events were reported in children treated with INAH. 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. In patients with seasonal allergic rhinitis, INAH were associated with a significantly higher improvement in the TNSS, TOSS and RQLQ when compared with placebo in both subgroups. INAH were associated with a significantly higher risk ratio of developing at least one adverse event in patients without asthma but not in patients with asthma. For perennial allergic rhinitis, INAH were associated with a significantly higher improvement in RQLQ in patients without asthma but no evidence was found assessing this outcome in patients with asthma. No studies assessed TNSS or TOSS in either subgroup. INAH were not associated with a significantly higher risk ratio of developing at least one adverse event in patients without asthma. No evidence was found assessing this outcome in PAR patients with asthma. |
Implementation considerations |
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 (ocular symptoms), 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 health impact of the intervention. |