Question | |
Should ocular H1-antihistamines vs. oral H1-antihistamines be used for the treatment of ocular symptoms in patients with allergic rhinitis? | |
Population: | Patients with allergic rhinitis |
Intervention: | ocular H1-antihistamines |
Comparison: | oral H1-antihistamines |
Main outcomes: | Ocular symptoms Adverse events (any) Serious adverse events |
Setting: | |
Perspective: | Clinical recommendation – patient perspective |
Background: | Oral antihistamines are frequently used not only to control nasal but also ocular symptoms. However, some patients may prefer ocular antihistamines due to their faster 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 |
Conducting a rapid evidence review, we identified two systematic reviews evaluating ocular medications for allergic rhinitis[1,2]. We sought to retrieve primary studies corresponding to randomised controlled trials (RCTs) (i) comparing ocular antihistamines (OcAH) versus placebo or oral H1-antihistamines (OAH), and (ii) with a follow-up period of at least 14 days for seasonal allergic rhinitis or 28 days for perennial allergic rhinitis. None of the retrieved trials evaluated nasal symptoms or quality of life. All identified trials compared OcAH versus placebo (i.e., no RCTs were identified directly comparing OcAH vs OAH). Ocular symptoms For patients with seasonal allergic rhinitis, we performed a network meta-analysis to obtain indirect evidence for the comparison between OcAH and OAH. We included the retrieved RCTs comparing OcAH versus placebo [3-5], as well as the references obtained in a previous systematic review conducted by our team and evaluating OAH [6]. We were able to meta-analytically pool the total ocular symptom score (TOSS) results of 15 RCTs, computed based on three ocular symptoms and a scale of 0-9. The improvement in TOSS observed in patients under OAH was higher than that observed for OcAH (mean difference=-0.52; 95%CI=-1.09;0.04). 63.6% probability of a small but meaningful difference; 6.6% probability of a moderate difference. For patients with perennial allergic rhinitis, no primary studies were identified comparing OAH versus placebo on their effect on TOSS. This precluded the comparison between OcAH and OAH. Subgroup considerations: Children and adolescents In children, no primary studies were identified comparing OAH versus placebo on their effect on TOSS. This precluded the comparison between OcAH and OAH. References
| ||
Undesirable EffectsHow substantial are the undesirable anticipated effects? | ||
Judgement | Research evidence | Additional considerations |
Conducting a rapid evidence review, we identified two systematic reviews evaluating ocular medications for allergic rhinitis[1,2]. We sought to retrieve primary studies corresponding to randomised controlled trials (RCTs) (i) comparing ocular antihistamines (OcAH) versus placebo or oral H1-antihistamines (OAH), and (ii) with a follow-up period of at least 14 days for seasonal allergic rhinitis or 28 days for perennial allergic rhinitis. All identified trials compared OcAH versus placebo (i.e., no RCTs were identified directly comparing OcAH vs OAH). Adverse events We performed a network meta-analysis to obtain indirect evidence for the comparison between OcAH and OAH. We included the retrieved RCTs comparing OcAH versus placebo [3-6], as well as the references obtained in a previous systematic review conducted by our team and evaluating OAH [7]. For patients with seasonal allergic rhinitis, a total of 36 randomised controlled trials (RCTs) reported data on the number of patients reporting at least one adverse event. The meta-analytical risk ratio was of 1.33 (95% confidence interval=1.03; 1.69) [OcAH was associated to 74 more cases per 1000 patients than OAH; 95%CI = 7 more cases to 154 more cases per 1000 patients. Trivial to small difference]. For patients with perennial allergic rhinitis, a total of 15 RCTs reported data on the number of patients reporting at least one adverse event. The meta-analytical risk ratio was of 1.92 (95% confidence interval=1.14; 3.23) [OcAH was associated to 276 more cases per 1000 patients than OAH; 95%CI = 42 more cases to 668 more cases per 1000 patients. Trivial to large difference]. Subgroup considerations: Children and adolescents A total of 3 RCTs reported data on the number of children with seasonal allergic rhinitis reporting at least one adverse event [8-10]. The meta-analytical risk ratio was of 0.60 (95% confidence interval=0.34;1.04) [OcAH was associated to 117 fewer cases per 1000 patients than OAH; 95%CI = 192 fewer cases to 12 more cases per 1000 patients. Trivial to moderate difference]. In children with perennial allergic rhinitis, no primary studies were identified comparing OcAH versus placebo on their effect on TOSS. This precluded the comparison between OcAH and OAH. Serious adverse events For seasonal allergic rhinitis, considering RCTs in which OAH were compared to placebo or other OAHs, a total of 8 serious adverse events were reported in 6485 patients using OAH. None of the serious adverse events were considered to be related to the use of the treatment. On the other hand, two RCTs in which OcAH were compared to placebo provided information about serious adverse events [3-5] (indicating no serious adverse events in a total of 283 patients using OcAH). No evidence from RCTs was found for perennial allergic rhinitis. Subgroup considerations: Children and adolescents No RCTs were found presenting data on the frequency of serious adverse events in children under OAH or OcAH. References:
| ||
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 all three analyses (ocular symptoms in seasonal allergic rhinitis, adverse events in seasonal allergic rhinitis and adverse events in perennial allergic rhinitis). References: | ||
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 (CoE: low). When utilities were elicited with the standard gamble technique, severe itchy eyes were rated by US patients as the least preferred AR symptom (CoE: 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 (CoE: low). In particular, nasal congestion was identified as the most important attribute in five studies (CoE: 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 ocular antihistamines (OcAH) versus oral antihistamines (OAH), we can consider the following:
| The intervention is considered to be ocular antihistamines, while the comparison is considered to be oral antihistamines. | |
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 51 countries (mostly in Europe, America and Asia). The costs of being treated for one year with ocular antihistamines ranged from 13.2 US Dollars Power Purchase Parity (PPP) [Bangladesh] to 947.3 USD PPP [Argentina] (assuming full adherence to treatment and the choice of the least expensive ocular antihistamine). This corresponds to weekly costs ranging from 0.25 USD PPP to 18.2 USD PPP. The yearly costs per country are displayed in the following map:  The costs of being treated for one year with oral antihistamines (OAH) ranged from 4.7 US Dollars Power Purchase Parity (PPP) [Hong Kong] to 743.3 USD PPP [Argentina] (assuming full adherence to treatment and the choice of the least expensive OAH). This corresponds to weekly costs ranging from 0.1 USD PPP to 14.3 USD PPP. The yearly costs per country are displayed in the following map:  In 39 out of the 44 countries where both ocular and oral antihistamines were reported to be available, ocular antihistamines were associated with higher costs than oral antihistamines:  | The interpretation is that ocular antihistamines are associated with moderate costs compared to oral antihistamines | |
Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)? | ||
Judgement | Research evidence | Additional considerations |
Available evidence comes 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-effectiveness studies that satisfactorily addressed the comparison of ocular antihistamines vs. oral antihistamines. Considering the costs reported in the survey alongside differences in VAS EQ-5D assessed using MASK-air data (inverse probability weighting methods were used to account for confounding), ocular antihistamines would be cost-effective in relation to oral antihistamines in all evaluated countries at a willingness-to-pay threshold of 50 000 US Dollar PPP per QALY gained. When considering the conservative willingness-to-pay threshold of one time the GDP per capita, ocular antihistamines would not be cost-effective in three countries (Syria, Mexico and Chile). However, randomized controlled trials indicate that oral antihistamines are more effective than ocular antihistamines. That would render ocular antihistamines a dominated strategy (that is, simultaneously, more costly and less effective than oral antihistamines). | Ocular antihistamines can eventually be cost-effective in high income countries but may not be cost-effective in low- and middle- income countries. | |
EquityWhat would be the impact on health equity? | ||
Judgement | Research evidence | Additional considerations |
We conducted a survey, having received responses from specialists from 51 countries (mostly in Europe, America and Asia). At least one oral antihistamine was reported to be available in all 51 countries, while ocular antihistamines were reported to be available in 44 countries.  | Ocular antihistamines are more expensive, less widely available and are not in the WHO List of Essential Medicines (in contradistinction to oral antihistamines) | |
AcceptabilityIs the intervention acceptable to key stakeholders? | ||
Judgement | Research evidence | Additional considerations |
Co-medication use Evidence from direct patient data: In the MASK-air dataset, in 88.7% of the days in which ocular antihistamines have been used (N=25,449), they have been used in comedication. This compares with 50.1% for oral antihistamines. 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), ocular antihistamines were associated with higher odds of being used of co-medication than oral antihistamines (OR=20.03; 95%CI=13.73;29.24). Compliance (patient) Evidence from direct patient data: In complete weeks of MASK-air reporting during the pollen season, there were 19.6% in which ocular antihistamines were used for 6 or 7 days. This compares with 38.5% for oral antihistamines. Satisfaction Evidence from direct patient data: In the MASK-air dataset, there were 840 days in which ocular antihistamines 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 86 (higher values indicating higher satisfaction) [IQR=19]. There were 7679 days in which oral antihistamines 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 84 (higher values indicating higher satisfaction) [IQR=30]. 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), ocular antihistamines were non-significantly associated with higher VAS satisfaction than oral antihistamines (average difference: 0.99; 95%CI=-1.68;3.64). Onset of action In a rapid review of the literature on the onset of action of ocular and oral antihistamines, we identified two randomized controlled trials performing conjunctival allergen challenges and reporting that ocular antihistamines were associated with faster relief of ocular itching compared to oral antihistamines [1-2]. In both these studies, for the first 10-15 minutes after exposure, the level of ocular itching relief was significantly higher in the ocular antihistamine than in the oral antihistamine group. References: 1. Abelson MB, Welch DL. An evaluation of onset and duration of action of patanol (olopatadine hydrochloride ophthalmic solution 0.1%) compared to Claritin (loratadine 10 mg) tablets in acute allergic conjunctivitis in the conjunctival allergen challenge model. Acta Ophthalmol Scand Suppl. 2000;230:60-63. 2. Chin J, Quealy K, Gomes P, Greiner J. A Comparison of the Onset of Action and Duration of Action of Olopatadine Hydrochloride Ophthalmic Solution 0.7% to Loratadine 10 mg in Preventing Ocular Itching in Subjects with Allergic Conjunctivitis. J Allergy Clin Immunol. 2023;151(2):AB106. | Judgement on a comparative perspective – ocular antihistamines are probably less well accepted than oral antihistamines, considering that ocular antihistamines (i) require most often co-medication, (ii) are associated with lower medication adherence, and (iii) there are no significant differences in treatment satisfaction. However, for patients who wish a very fast onset of action, ocular antihistamines may be preferrable. | |
FeasibilityIs the intervention feasible to implement? | ||
Judgement | Research evidence | Additional considerations |
We did not identify any studies that adequately addressed the feasibility of ocular versus oral H1-antihistamines. | ||
Planetary healthWhat would be the impact on planetary health? | ||
Judgement | Research evidence | Additional considerations |
We did not identify any studies that satisfactorily investigated ocular compared with oral antihistamines in terms of planetary health. Key considerations include the availability of locally produced medications, as well as medication effectiveness in reducing healthcare resource utilization. Regarding the latter aspect, it is important to note that ocular antihistamines (i) appear to be less effective than oral antihistamines, and (ii) are associated with a higher frequency of use in co-medication (if a patient not only has ocular symptoms but also nasal or other symptoms, it expected that further medication will be needed). Therefore, it is expected that ocular antihistamines display a worse impact on planetary health than oral medications. | ||
Summary of judgements
Judgement | |||||||
|---|---|---|---|---|---|---|---|
Problem | No | Probably no | Probably yes | Yes | Varies | Don’t know | |
Desirable Effects | Trivial | Small | Moderate | Large | Varies | Don’t know | |
Undesirable Effects | Trivial | Small | Moderate | Large | Varies | Don’t know | |
Certainty of evidence | Very low | Low | Moderate | High | No included studies | ||
Values | Important uncertainty or variability | Possibly important uncertainty or variability | Probably no important uncertainty or variability | No important uncertainty or variability | |||
Balance of effects | Favors the comparison | Probably favors the comparison | Does not favor either the intervention or the comparison | Probably favors the intervention | Favors the intervention | Varies | Don’t know |
Resources required | Large costs | Moderate costs | Negligible costs and savings | Moderate savings | Large savings | Varies | Don’t know |
Certainty of evidence of required resources | Very low | Low | Moderate | High | No included studies | ||
Cost effectiveness | Favors the comparison | Probably favors the comparison | Does not favor either the intervention or the comparison | Probably favors the intervention | Favors the intervention | Varies | No included studies |
Equity | Reduced | Probably reduced | Probably no impact | Probably increased | Increased | Varies | Don’t know |
Acceptability | No | Probably no | Probably yes | Yes | Varies | Don’t know | |
Feasibility | No | Probably no | Probably yes | Yes | Varies | Don’t know | |
Planetary health | Reduced | Probably reduced | Probably no impact | Probably increased | Increased | Varies | Don’t know |
Type of recommendation
Conclusions
Recommendation |
For adolescents and adults with seasonal allergic rhinitis, the ARIA guideline panel suggest against using ocular H1-antihistamines over oral antihistamines (conditional recommendation based on very low certainty of evidence), except for very fast relief of ocular symptoms. |
Justification |
The decision is mostly grounded on the fact that ocular antihistamines are associated with less efficacious, are less affordable, are associated with more equity-related concerns, tend to be associated with lower acceptability and may be associated with a worse planetary health impact. |
Subgroup considerations |
For preschool and school children with seasonal allergic rhinitis, the ARIA guideline panel suggest against using ocular H1-antihistamines over oral antihistamines except for very fast relief of ocular symptoms. For patients with seasonal allergic conjunctivitis with no nasal symptoms, the ARIA guideline panel still suggest against using ocular H1-antihistamines over oral antihistamines, except for very fast relief of ocular symptoms. In fact, the randomised controlled trials that evaluated ocular antihistamines with a follow-up period of at least 14 days included patients with allergic conjunctivitis (even if some did not have symptoms on allergic rhinitis). For patients with seasonal allergic rhinitis presenting with both nasal and ocular symptoms, the ARIA guideline panel suggest against using ocular H1-antihistamines over oral antihistamines. Overall, no evidence was found for perennial allergic rhinitis. |
Implementation considerations |
None specific. |
Monitoring and evaluation |
Research priorities |
Research priorities by domain of the certainty of evidence assessment:
EtD criteria for which research is most needed:
|