Question | |
Should a combination of an intranasal H1-antihistamine and an intranasal glucocorticosteroid vs. an intranasal H1-antihistamine alone 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: | an intranasal H1-antihistamine alone |
Main outcomes: | Nasal symptoms Ocular symptoms Quality of life Adverse events (any) Serious adverse events |
Setting: | |
Perspective: | |
Background: | Intranasal corticosteroids + intranasal antihistamines have been proposed as the first-line treatment of allergic rhinitis by previous guidelines. However, some patients are corticosteroid-phobic or have glaucoma. Thus, intranasal antihistamines alone may be of interest. |
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. |
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 intranasal antihistamines (INAH). 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 INAH alone (mean difference=-0.64 ; 95%CI=-0.89;-0.39). INCS+INAH displayed a 25% probability of resulting in a small clinically meaningful improvement when compared to INAH. For patients with perennial allergic rhinitis, it was possible to meta-analytically pool the four symptom TNSS results of 24 RCTs. INCS+INAH were not associated with a significantly higher improvement in the TNSS when compared to INAH alone (mean difference=-0.51; 95%CI=-1.21;0.19). INCS+INAH displayed a 45.2% probability of resulting in a clinically meaningful improvement when compared to INAH, including a 4% probability of resulting in a moderate improvement and a 41% 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 A systematic review with network meta-analysis was performed by Sousa-Pinto et al., but no studies were available assessing the TNSS for either seasonal or perennial allergic rhinitis. 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 INAH. 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 INAH (mean difference=-0.19; 95%CI=-0.33;-0.05). INCS+INAH displayed a 1% probability of resulting in a clinically meaningful improvement (99% probability of resulting in a trivial improbement) when compared to INAH. 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:  Subgroup considerations: Children and adolescents A systematic review with network meta-analysis was performed by Sousa-Pinto et al., but no studies were available assessing the TOSS for either seasonal or perennial allergic rhinitis. 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 INAH. 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 were associated with a significantly higher improvement in the RQLQ when compared to INAH (mean difference=-0.33; 95%CI=-0.44;-0.21). INCS+INAH displayed a 83% probability of resulting in a small clinically meaningful improvement when compared to INAH. For patients with perennial allergic rhinitis, it was possible to meta-analytically pool the RQLQ results of 13 RCTs. INCS+INAH were not associated with a significant difference in RQLQ changes when compared to INAH (mean difference=-0.15; 95%CI=-0.57;0.27). INCS+INAH displayed a 16% probability of resulting in a clinically meaningful improvement when compared to INAH. 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 RQLQ results of 4 RCTs. INCS+INAH were not associated with a significant difference compared to INAH on changes to RQLQ (mean difference=-0.07; 95%CI=-0.28;0.14). For patients with perennial allergic rhinitis, no studies were available. | ||
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 intranasal antihistamines (INAH). 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 1.04 (95% confidence interval=0.84-1.30) [INCS+INAH was associated with 5 more cases per 1000 patients than INAH; 95%CI = 17 fewer cases to 32 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 0.79 (95% confidence interval=0.42-1.49) [INCS+INAH was associated with 63 fewer cases per 1000 patients than INAH; 95%CI = 172 fewer cases to 143 more cases per 1000 patients. Small to 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. In an additional analysis of pharmacovigilance data comparing INCS+INAH and INAH, the following results were found (right = more common with INAH; left = more common with INAH+INCS):  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 1.11 (95%CI=0.58-1.2.13) [INCS+INAH was associated with 12 more cases per 1000 individuals than INAH; from 45 fewer cases to 120 more cases per 1000 individuals. Trivial difference]. For patients with perennial allergic rhinitis, no studies were available. 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 INAH. 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. This compares to 0 serious adverse events in 694 children treated with INAH. No evidence on the frequency of serious AE in children with perennial allergic rhinitis treated with INAH+INCS. This compares to 0 serious adverse events in 327 children treated with INAH. | ||
Certainty of evidenceWhat is the overall certainty of the evidence of effects? | ||
Judgement | Research evidence | Additional considerations |
The certainty of evidence was moderate for 5 out of 9 analyses, high for 2 out of 9 analyses, and very low for 2 out of 9 analyses. Desirable effects:
Undesirable effects:
| Moderate certainty of evidence for seasonal allergic rhinitis; very low certainty of evidence for perennial allergic rhinitis. | |
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 intranasal H1-antihistamines (INAH), 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). In 27 of these countries, both intranasal corticosteroids (INCS) and 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:  The costs of being treated for one year with 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 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:  In 23 out of the 27 countries where both INCS+INAH and INAH were reported to be available, INAH were associated with lower costs than INCS+INAH:  Evidence from direct patient data: An 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 2. CDR PHARMACOECONOMIC REVIEW REPORT FOR DYMISTA, https://www.cadth.ca/sites/default/files/cdr/pharmacoeconomic/SR0408_Dymista_PE_Report.pdf 3. Cardell L-O, Olsson P, Andersson M, et al. TOTALL: high cost of allergic rhinitis-a national Swedish population-based questionnaire study. NPJ primary care respiratory medicine. 2016;26:15082 4. Fairchild CJ, Durden E, Cao Z, Smale P. Outcomes and cost comparison of three therapeutic approaches to allergic rhinitis. American journal of rhinology & allergy. 2011;25(4):257-262. | ||
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 antihistamines and intranasal antihistimines alone and 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: 1. Available evidence comes from a survey of experts 2. There is substantial difference in costs for specific interventions | ||
Cost effectivenessDoes the cost-effectiveness of the intervention favor the intervention or the comparison? | ||
Judgement | Research evidence | Additional considerations |
The only cost-effectiveness study performed reported that azelastine-fluticasone had an ICUR of $38,546 per QALY compared with azelastine. Usually, a willingness to pay threshold of $ 50,000 per QALY (or of 1-3 times the country GDP per capita per QALY) is used. The ICUR is below the $50 000 per QALY willingness to pay threshold, suggesting that azelastine-fluticasone is cost-effective. Considering the costs reported in the survey alongside the differences in QALYs reported in the CDR Pharmacoeconomic Review Report, INAH would be dominated by INCS+INAH in 4 out of 27 countries (more expensive and associated with lower gains QALYs; assumption of full adherence to treatment and the choice of the least expensive medication of each class). In all remaining countries, INCS+INAH would be cost-effective at a willingness to pay threshold of $50,000/QALY gained. Considering the conservative willingness to pay threshold of 1 time the GDP per capita, INCS+INAH would only not be cost-effective in one country (Syria). INCS+INAH would be cost-effective in all assessed countries (considering both the willingness-to-pay threshold of $50,000/QALY gained or that of 1 time the GDP per capita) if considering differences in VAS EQ-5D assessed using MASK-air data (inverse probability weighting methods were used to account for confounding). | ||
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. In 13 countries, only one INAH was available. INCS + intranasal antihistamines (INCS+INAH) were reported to be available in 36 out of 41 countries. In 22 countries, only one INCS+INAH was available.  Other equity-related aspects We were able to map the following aspects related to equity:  | ||
AcceptabilityIs the intervention acceptable to key interest-holders? | ||
Judgement | Research evidence | Additional considerations |
Compliance Evidence from direct patient data: In complete weeks of MASK-air reporting during the pollen season, there were 31.7% in which fixed combinations of INCS+INAH were used for 6 or 7 days. This compares with 12.2% for INAH. Satisfaction 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]. 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]. In multivariable linear regression models adjusted for the CSMS of the previous day (a proxy variable of the rhinitis control level before medication use) and for the patients’ ARIA score (an indicator of disease severity), INAH+INCS were associated with higher VAS satisfaction than INAH (average difference: 2.45; 95%CI=-2.59;7.49). Switching rate We found one study [Fairchild] that provide data on the acceptability of intranasal H1-antihistamine and an intranasal glucocorticosteroid vs. an intranasal H1 antihistamine alone. Unsatisfactory treatment indication (augmentation with a prescription oral antihistamine or another intranasal therapy) occurred in the 35,24% of patients in combined INAH+INCS cohort in comparison to the 22,52% in the INAH 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. This compares with 84.8% for INAH. Iin a study using multivariable mixed-effects logistic regression models [Sousa-Pinto], INAH+INCS (OR=0.75; 95%CI=0.71-0.80) were also associated with lower odds of being used in co-medication. On the other hand, INAH were associated with higher odds of being used in co-medication (OR=2.41; 95%CI=2.07-2.81). In multivariable linear regression models adjusted for the CSMS of the previous day (a proxy variable of the rhinitis control level before medication use) and for the patients’ ARIA score (an indicator of disease severity), INAH were associated with higher odds of being used of co-medication than INCS+INAH (OR=2.39; 95%CI=1.07;5.33). Onset of action A rapid review of the literature on the onset of action of intranasal corticosteroids + intranasal antihistamines and intranasal antihistamines was carried out. The following results were found:  References: 1. Fairchild CJ, Durden E, Cao Z, Smale P. Outcomes and cost comparison of three therapeutic approaches to allergic rhinitis. Am J Rhinol Allergy. 2011 Jul-Aug;25(4):257-62. doi: 10.2500/ajra.2011.25.3636. Epub 2011 May 31. PMID: 21639996. | ||
FeasibilityIs the intervention feasible to implement? | ||
Judgement | Research evidence | Additional considerations |
We did not identify any feasibility studies that satisfactorily addressed comparison of intranasal H1-antihistamine and an intranasal glucocorticosteroid vs. an intranasal H1-antihistamine alone. | ||
Planetary healthWhat would be the impact on planetary health? | ||
Judgement | Research evidence | Additional considerations |
There is currently no evidence on the comparative impact of intranasal glucocorticosteroids and intranasal H1-antihistamines versus intranasal glucocorticosteroids on planetary health. Key considerations include the availability of locally produced medications, as well as medication effectiveness 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 suggests using a fixed combination of an intranasal antihistamine and an intranasal glucocorticosteroid over an intranasal antihistamine (conditional recommendation based on moderate certainty of evidence for seasonal allergic rhinitis and on very low certainty of evidence for perennial allergic rhinitis). |
Justification |
This recommendation is mostly grounded (i) on a favourable balance of effects, (ii) cost-effectiveness, and (iii) acceptability of the intervention. |
Subgroup considerations |
Considerations for children and adolescents: The recommendation is applicable to children and adolescents, even though evidence is scarcer. In the subgroup of children and adolescents, INCS+INAH were not associated with a significant difference compared to INAH alone on changes to TNSS or TOSS in patients with seasonal allergic rhinitis. On the other hand, a significantly higher improvement in RQLQ was observed. For patients with perennial allergic rhinitis no studies were available. The subgroup analysis of the network meta-analysis performed by Sousa-Pinto et al., grouping trials according to whether they had excluded patients with asthma, showed a significant improvement in TNSS and TOSS in the subgroup of seasonal allergic rhinitis patients without asthma but not in the subgroup which included them. The opposite was observed for RQLQ, with results showing a significant improvement only when all seasonal allergic rhinitis patients were considered but not when asthma patients were excluded. Only 5 RCTs on the comparison of INCS+INAH vs INAH alone assessed patients with perennial allergic rhinitis and the only outcome measured was the TNSS for which no significant difference was observed. The probability of a relevant clinical improvement did not reach 50% for any assessed outcomes. |
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 (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 health impact of the interventions. |