Question | |
Should second-generation oral H1-antihistamines vs. first-generation oral H1-antihistamines be used for the treatment of allergic rhinitis? | |
Population: | Patients with allergic rhinitis |
Intervention: | second-generation oral H1-antihistamines |
Comparison: | first-generation oral H1-antihistamines |
Main outcomes: | Nasal symptoms Ocular symptoms Quality of life Adverse events (any) Serious adverse events |
Setting: | |
Perspective: | Clinical recommendation – patient perspective |
Background: | Oral antihistamines are widely used for the treatment of allergic rhinitis. First-generation oral antihistamines are still frequently used in several countries, in part due to their low cost and over-the-counter availability. However, second-generation oral antihistamines are associated with improved safety profiles and reduced sedation. |
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 |
Nasal symptoms In a systematic review with network meta-analysis performed by our team, the improvement of nasal symptoms was assessed in patients under second-generation oral antihistamines (OAH) and compared with that registered in patients receiving first-generation OAHs. We considered the Total Nasal Symptom Score (TNSS) computed based on four symptoms. However, for most OAH – particularly first-generation OAH –, pivotal randomised trials (RCTs) are old and have computed the TNSS based on three symptoms or other metrics. Among the 37 RCTs assessing the improvement of the total nasal symptom score (TNSS; combination of four nasal symptoms and scale of 0-12) in patients with seasonal allergic rhinitis, only one RCT assessed a first-generation OAH (dexchlorpheniramine), comparing it with a second-generation OAH (terfenadine). The second-generation OAH was associated with a lower improvement in the TNSS when compared to the first-generation OAH (mean difference=1.50; 95%CI=0.46;2.54). 97.1% probability of resulting in a non-trivial difference. By contrast, some RCTs not included in the systematic review conducted by our team (e.g., because of differences in the way outcomes were registered) did not find differences in the improvement of nasal symptoms when comparing second-generation versus first-generation OAH [Katelaris, Wilken], even though others tended to favour first-generation OAH [Druce]. For patients with perennial allergic rhinitis, no primary studies were identified allowing for the comparison between first-generation versus second-generation OAHs on their effect on the TNSS. Subgroup considerations: Children and adolescents No evidence from RCTs in our systematic review was found for children and adolescents. A RCT performed in children with perennial allergic rhinitis favoured second-generation OAH vis-à-vis first-generation OAH in the improvement of nasal symptoms [Lai]. Ocular symptoms In a systematic review with network meta-analysis performed by our team, no primary studies assessing the improvement of ocular symptoms in patients under first-generation OAHs were identified. Subgroup considerations: Children and adolescents No evidence from RCTs was found for children and adolescents. Quality-of-life In a systematic review with network meta-analysis performed by our team, the improvement of quality-of-life was assessed in patients under second-generation OAHs and compared with that registered in patients receiving first-generation OAHs. Among the 22 randomised controlled trials (RCTs) assessing the improvement of the rhinocojunctivitis quality of life questionnaire (RQLQ; scale of 0-6) in patients with seasonal allergic rhinitis, a single RCT assessed a first-generation OAH (chlorpheniramine). Even though point estimates tended to favour second-generation OAH, no significant difference in RQLQ improvement was observed between second- and first-generation OAHs (mean difference=-0.13; 95%CI=-0.61;0.35). 63.6% probability of resulting in a trivial difference. For patients with perennial allergic rhinitis, no primary studies were identified allowing for the comparison between first-generation versus second-generation OAHs on their effect on the RQLQ. Subgroup considerations: Children and adolescents In a systematic review with network meta-analysis performed by Sousa-Pinto et al., no evidence from RCTs was found for children and adolescents. A RCT performed in children with perennial allergic rhinitis did not find differences between second-generation OAH vis-à-vis first-generation OAH in the improvement of nasal symptoms [Lai]. References: 1. Katelaris C. Comparative effects of loratadine and azatadine in the treatment of seasonal allergic rhinitis. Asian Pac J Allergy Immunol. 1990;8(2):103-7. 2. Wilken JA, Kane RL, Ellis AK, et al. A comparison of the effect of diphenhydramine and desloratadine on vigilance and cognitive function during treatment of ragweed-induced allergic rhinitis. Ann Allergy Asthma Immunol. 2003;91(4):375-385. 3. Druce HM, Thoden WR, Mure P, et al. Brompheniramine, Loratadine, and Placebo in Allergic Rhinitis: A Placebo-Controlled Comparative Clinical Trial. J Clin Pharmacol. 2013;38(4):382-389. Lai DS, Lue KH, Hsieh JC, et al. The comparison of the efficacy and safety of cetirizine, oxatomide, ketotifen, and a placebo for the treatment of childhood perennial allergic rhinitis. Ann Allergy Asthma Immunol. 2002;89(6):589-598. | ||
Undesirable EffectsHow substantial are the undesirable anticipated effects? | ||
Judgement | Research evidence | Additional considerations |
Adverse events Following the systematic review performed by our team, the frequency of patients developing at least one adverse event was assessed in patients under second-generation oral H1-antihistamines (OAH) and compared with that registered in patients receiving first-generation OAH. A total of 36 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 0.80 (95% confidence interval=0.59; 1.09) [second-generation OAH was associated to 134 fewer cases per 1000 patients than first-generation OAH; 95%CI = 275 fewer cases to 60 more cases per 1000 patients. Point estimate pointing to a small difference; confidence interval compatible with a moderate to trivial difference]. No evidence was found for perennial allergic rhinitis. Subgroup considerations: Children and adolescents No evidence from RCTs was found for children and adolescents. Serious adverse events Considering the systematic review performed by our team, no evidence from RCTs was found in terms of serious adverse events. Outside the systematic review performed by our team, evidence from another systematic review points to a deleterious impact of first-generation OAH on performance [Bender], with existing studies pointing to the risks of first-generation OAH on driving performance [Ramaekers]. Such an effect was not observed with second-generation OAH. Self-reported sedation is also higher with first-generation OAH [Bender]. Subgroup considerations: Children and adolescents No evidence from RCTs was found for children and adolescents. Pharmacovigilance data In an additional analysis of pharmacovigilance data on patients under 1st generation OAH or 2nd generation OAH (regardless of allergic rhinitis diagnosis), the following results were found:  Importantly, 1st generation OAH are currently frequently used for sedative purposes, which explains why sedation is more frequently reported with 2nd generation OAH compared to 1st generation OAH. In terms of important adverse events, these were less frequent with 2nd generation OAH versus 1st generation OAH (RR = 0.32, IC95%=0.31-0.33). References: 1. Bender BG, Berning S, Dudden R, Milgrom H, vu Tran Z. Sedation and performance impairment of diphenhydramine and second-generation antihistamines: A meta-analysis. J Allergy Clin Immunol. 2003;111(4):770-776. 2. Ramaekers JG, O’Hanlon JF. Acrivastine, terfenadine and diphenhydramine effects on driving performance as a function of dose and time after dosing. Eur J Clin Pharmacol. 1994;47(3):261-166. | ||
Certainty of evidenceWhat is the overall certainty of the evidence of effects? | ||
Judgement | Research evidence | Additional considerations |
The certainty of evidence was very low for 2 out of 3 analyses, and low for 1 out of 3 analyses.
Reference: | ||
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 second-generation versus first-generation oral antihistamines (OAH), we can consider the following:
| ||
Resources requiredHow large are the resource requirements (costs)?” | ||
Judgement | Research evidence | Additional considerations |
We did not identify any studies that related to resources that satisfactorily addressed comparison of second-generation vs. first-generation oral H1-antihistamine. In Portugal, based on official prices, the minimal costs for one month of treatment with second-generation oral antihistamines is of 6.52 US Dollar Power Purchase Parity (USD PPP). This compares to 3.85 USD PPP for first-generation antihistamines. | ||
Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)? | ||
Judgement | Research evidence | Additional considerations |
Prices are official but are based on data from a single country. | ||
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-effectiveness studies that satisfactorily addressed comparison of second-generation vs. first-generation oral H1-antihistamine. Using data from the MASK-air® app, and considering data from VAS EQ-5D as a proxy variable of utilities, we would have second generation OAH being associated with a median VAS value of 83/100 compared to 77/100 for first-generation OAH. This corresponds to a difference of 6/100. Assuming – based on Portuguese data – a difference of costs of 32.04 USD PPP [(6.52 USD PPP x 12 months) – (3.85 USD PPP x 12 months)], this would correspond to an incremental cost-utility ratio of 32.04/0.06 = 534 USD PPP per “QALY” gained. While these results suggest that second generation OAH may be cost-effective, several aspects should be considered:
| ||
EquityWhat would be the impact on health equity? | ||
Judgement | Research evidence | Additional considerations |
We did not identify any equity studies that satisfactorily addressed comparison of second-generation vs. first-generation oral H1-antihistamine. Other equity-related aspects  | ||
AcceptabilityIs the intervention acceptable to key interest-holders? | ||
Judgement | Research evidence | Additional considerations |
SATISFACTION One international survey presenting data on patient satisfaction was identified. [Ferrer 2010]. This study investigated parent and physician satisfaction with the efficacy and tolerability of oral antihistamine treatment in children revealed that the satisfaction for efficacy was generally rated higher for the second-generation antihistamines (levocetirizine, cetirizine, desloratadine, loratadine and fexofenadine,with the exception of azelastine) compared with the first-generation antihistamines (chlorpheniramine, cyproheptadine, clemastine, diphenhydramine and promethazine), except for hydroxyzine, which had a mean (–SD) efficacy score of 7.84 (–1.64).   MASK-air data Compliance In complete weeks of MASK-air reporting, there were 32.6% in which second generation OAH were used for 6 or 7 days. This compares with 3.6% for first generation OAH. Satisfaction In the MASK-air dataset, there were 18,939 days in which second generation OAH were used and for which patients provided information on how satisfied they were with their treatments. The median results of the visual analogue scale were of 82 (higher values indicating higher satisfaction) [IQR=54]. In the MASK-air dataset, there were 90 days in which first generation OAH 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 54 (higher values indicating higher satisfaction) [IQR=28]. Comedication In an unadjusted comparison, first generation oral antihistamines were associated with higher use of co-medication than second generation oral antihistamines (56.3% versus 51.8%). References: 1. Ferrer M, Morais-Almeida M, Guizova M, Khanferyan R. Evaluation of treatment satisfaction in children with allergic disease treated with an antihistamine: an international, non-interventional, retrospective study. Clin Drug Investig. 2010;30(1):15-34. doi: 10.2165/11530910-000000000-00000. PMID: 19995095 | ||
FeasibilityIs the intervention feasible to implement? | ||
Judgement | Research evidence | Additional considerations |
We did not identify any feasibility studies that satisfactorily addressed comparison of second-generation vs. first-generation oral H1-antihistamine | ||
Planetary healthWhat would be the impact on planetary health? | ||
Judgement | Research evidence | Additional considerations |
There is currently no evidence on the comparative impact of second- and first-generation oral antihistamines 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 adults with allergic rhinitis, the ARIA guideline panel recommends using second-generation oral antihistamines over first-generation oral antihistamines (strong recommendation based on very low certainty of evidence). |
Justification |
The decision is mostly grounded on safety concerns associated with first-generation oral antihistamines, namely their sedative effect and deleterious impact on performance (e.g., driving performance). In addition, first-generation oral antihistamines display lower acceptability and reduced equity. On the other hand, even though second-generation oral antihistamines may be associated with higher costs, they appear to be cost-effective. |
Subgroup considerations |
For preschool and school children, the ARIA guideline panel recommends using second-generation oral antihistamines over first-generation oral antihistamines. For older people, the ARIA guideline panel recommends using second-generation oral antihistamines over first-generation oral antihistamines, particularly considering the higher safety of the former. |
Implementation considerations |
None specific. |
Monitoring and evaluation |
Research priorities |
Research priorities by domain of the certainty of evidence assessment: Considering that first-generation oral antihistamines are not part of the treatment mainstay of allergic rhinitis and that they have important safety concerns, we are not suggesting that new randomized controlled trials evaluating these medications should be conducted. However, we advocate the conduction of future studies based on observational data (particularly secondary data associated with the use of first- and second-generation oral antihistamines in routine practice) and following the best causal inference approaches to deal with confounding. This need stems from the following gaps in available evidence:
EtD criteria for which research is most needed: In addition to desirable and undesirable effects, studies using observational secondary data can further provide information on the comparison between first-generation and second-generation oral antihistamines on the following criteria:
|