Question | |
Should intranasal H1-antihistamines vs. intranasal chromones be used for the treatment of allergic rhinitis? | |
Population: | Patients with allergic rhinitis |
Intervention: | intranasal H1-antihistamines |
Comparison: | intranasal chromones |
Main outcomes: | Nasal symptoms Ocular symptoms Quality of life Adverse events (any) Serious adverse events |
Setting: | |
Perspective: | |
Background: | Intranasal antihistamnes and intranasal chromones are two alternatives that are often used in allergic rhinitis patients, including those with corticosteroid-phobia or who desire 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. |
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:
| ||
Desirable EffectsHow substantial are the desirable anticipated effects? | ||
Judgement | Research evidence | Additional considerations |
We found two RCTs comparing an intranasal H1-antihistamines (levocabastine) against an intranasal chromone (disodium cromoglycate). In one RCT assessing levocabastine (N=40) versus cromoglycate (N=42), no significant differences were found in mean TNSS (Levocabastine: 0.96 +/- 0.59; Cromoglycate: 1.07 +/- 0.59, p = 0.23) and mean TSS (Levocabastine: 0.97 +/- 0.58; Cromoglycate: 1.04 +/- 0.58) during the treatment period. Consistently, no significant differences were found between patients treated with levocabastine vs cromoglycate in terms of symptom free days. In the other RCT assessing levocabastine (N=18) versus cromoglycate (N=19), in terms of the global evaluation of treatment effectiveness, 89% of the the levocabastine-treated patients had a good or excellent response to treatment, while only 32% in the cromoglycate treated patients had a good or excellent response to treatment (p = 0.003). The severest nasal symptom improved more in the levocabastine group (mean = - 1.8) than in the cromoglycate group (mean = -1.11, p<0.05). The mean VAS scores calculated from the diaries for nasal symptoms were lower for the levocabastine-treated group (median = 23.5) than for the cromoglycate (44; p = 0.03). Improvement in ocular symptoms was higher with levocabastine (-1.92) than with cromoglycate (-0.69, p = 0.03). References: Schata M, Jorde W, Richarz-Barthauer U. Levocabastine nasal spray better than sodium cromoglycate and placebo in the topical treatment of seasonal allergic rhinitis. J Allergy Clin Immunol. 1991 Apr;87(4):873-8. doi: 10.1016/0091-6749(91)90136-c. PMID: 1672878. Lange B, Lukat KF, Rettig K, Holtappels G, Bachert C. Efficacy, cost-effectiveness, and tolerability of mometasone furoate, levocabastine, and disodium cromoglycate nasal sprays in the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2005 Sep;95(3):272-82. doi: 10.1016/S1081-1206(10)61225-2. PMID: 16200819. | ||
Undesirable EffectsHow substantial are the undesirable anticipated effects? | ||
Judgement | Research evidence | Additional considerations |
We found two RCTs comparing an intranasal H1-antihistamines (levocabastine) against an intranasal chromone (disodium cromoglycate). In the first RCT, adverse events were experienced by 45% in the levocabastine group and 48% in the cromoglycate group. No discontinuations due to adverse events. In the second RCT, adverse events were experienced by 4/18 in the levocabastine group and 3/19 in the cromoglycate group. In both groups, 3 patients withdrew due to adverse events. References: Schata M, Jorde W, Richarz-Barthauer U. Levocabastine nasal spray better than sodium cromoglycate and placebo in the topical treatment of seasonal allergic rhinitis. J Allergy Clin Immunol. 1991 Apr;87(4):873-8. doi: 10.1016/0091-6749(91)90136-c. PMID: 1672878. Lange B, Lukat KF, Rettig K, Holtappels G, Bachert C. Efficacy, cost-effectiveness, and tolerability of mometasone furoate, levocabastine, and disodium cromoglycate nasal sprays in the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2005 Sep;95(3):272-82. doi: 10.1016/S1081-1206(10)61225-2. PMID: 16200819. | ||
Certainty of evidenceWhat is the overall certainty of the evidence of effects? | ||
Judgement | Research evidence | Additional considerations |
Very low due for all assessed outcomes to concerns with risk of bias, indirectness, imprecision and inconsistency. | ||
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).  Inc - Certainty of evidence was lowered due to inconsistency; R- Certainty of evidence was lowered due to risk of bias; Ind- Certainty of evidence was lowered due to indirectness; Imp- Certainty of evidence was lowered due to imprecision, ⨁⨁⨁⨁ high certainty of evidence, ⨁⨁⨁◯ moderate certainty of evidence, ⨁⨁◯◯ low certainty of evidence 4 We rated down the certainty of evidence for indirectness because an indirect measurement tool was used to elicit the utility of outcomes with scale of 0 to 1, where 0 indicated the worst symptom(s) and 1 represented no symptom(s).5 Small sample size of the included study. 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 H1-antihistamines (INAH) versus intranasal chromones, we can consider the following:
No evidence was found for perennial allergic rhinitis. | ||
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 16 of these countries, both intranasal H1-antihistamines (INAH) and intranasal chromones 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 INAH are displayed in the following map:  The costs of being treated for one year with intranasal chromones ranged from 8.4 US Dollars Power Purchase Parity (PPP) [Bangladesh] to 326.6 USD PPP [Italy] (assuming full adherence to treatment). This corresponds to weekly costs ranging from 0.16 USD PPP to 6.3 USD PPP. The yearly costs per country associated with the use of intranasal chromones are displayed in the following map:  In 16 countries where both INAH and intranasal chromones were reported to be available, INAH were associated with higher costs than intranasal chromones in 10 countries:  | ||
Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)? | ||
Judgement | Research evidence | Additional considerations |
Evidence on the costs of intranasal H1-antihistamines and intranasal chromones was obtained from a survey of experts. | ||
Cost effectivenessDoes the cost-effectiveness of the intervention favor the intervention or the comparison? | ||
Judgement | Research evidence | Additional considerations |
We did not identify any cost-utility studies that satisfactorily addressed comparison of intranasal H1-antihistamines vs. intranasal chromones. | ||
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. Intranasal chromones were reported to be available in 18 out of 41 countries.  Other equity-related aspects  | ||
AcceptabilityIs the intervention acceptable to key interest-holders? | ||
Judgement | Research evidence | Additional considerations |
Co-medication use 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 87.1% for chromones, 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. 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 2.3% of days with chromones use, 6.2% of days with intranasal 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 12.2% in which INAH were used for 6 or 7 days. This compares to 15.1% for chromones, 36.0% for INCS, 38.5% for OAH, and 31.7% for fixed combinations of INAH+INCS. Satisfaction Evidence from direct patient data: In the MASK-air dataset, there were only 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 the MASK-air dataset, there were only 164 days in which chromones 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 80 (higher values indicating higher satisfaction) [IQR=38]. 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), chromones were associated with lower VAS satisfaction than INAH (average difference: -3.02; 95%CI=-13.37;7.32). | ||
FeasibilityIs the intervention feasible to implement? | ||
Judgement | Research evidence | Additional considerations |
We did not identify any studies that adequately addressed the feasibility of intranasal H1-antihistamines vs. chromones. | ||
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 H1-antihistamines and intranasal chromones 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 suggest using intranasal antihistamines over intranasal chromones (conditional recommendation based on very low certainty of evidence for seasonal and perennial allergic rhinitis). |
Justification |
This decision is mostly grounded on advantages in terms of desirable effects and acceptability as evidenced by MASK-air direct patient data. |
Subgroup considerations |
For preschool and school children, the ARIA guideline panel suggest using intranasal antihistamines over intranasal chromones. |
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, older patients, patients with multimorbidity (asthma and conjunctivitis), and patients from ethnic minorities.- Need for more well-conducted randomised controlled trials, particularly evaluating participants with perennial allergic rhinitis and those with mild allergic rhinitis.- Need for studies evaluating the cost-effectiveness and planetary health impact of the interventions. |