H1‐antihistamines for chronic spontaneous urticaria

Maulina Sharma; Cathy Bennett<sup>a</sup>; Stuart N Cohen<sup>a</sup>; Ben Carter

doi:10.1002/14651858.CD006137.pub2

Cochrane Database of Systematic Reviews

Antihistamínicos H1 para la urticaria espontánea crónica

Información

DOI:

https://doi.org/10.1002/14651858.CD006137.pub2 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

14 noviembre 2014see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Piel

Copyright:

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Contraer

Autores

Maulina Sharma

Correspondencia a: Department of Dermatology, Derby Hospitals NHS Foundation Trust, London Road Community Hospital, Derby, UK

[email protected]
Cathy Bennett^a

Centre for Technology Enabled Health Research (CTEHR), Coventry University, Coventry, UK

Joint second author
Stuart N Cohen^a

Nottingham University Hospitals NHS Trust, Nottingham, UK

Joint second author
Ben Carter

Biostatistics and Health Informatics, King's College London; Institute of Psychiatry, Psychology & Neuroscience, London, UK

Contributions of authors

Link with editorial base and co‐ordinate contributions from co‐authors, supervision (AS, CB).
Draft protocol (AS, SNC, CC, LB, CH).
Run search (AS, SNC, MS, CB).
Identify relevant titles and abstracts from searches (AS, SNC, MS, CB).
Obtain copies of trials (AS, MS, SNC, CB).
Select trials (AS, SNC, MS, CB, CC).
Extract data from trials (AS, CB, MS, SNC, CC).
Enter data into RevMan (CB, MS, BC).
Carry out data analyses and draft Effects of Interventions section of the review (BC, CB, MS).
Interpret data (BC, CB, MS, SNC).
Draft final review (CB, MS, SNC, BC).
Update review (MS, CB, SNC, BC).

Disclaimer

The views and opinions expressed therein are those of the review authors and do not necessarily reflect those of the National Institute for Health Research (NIHR), the National Health Service (NHS) or the Department of Health, UK.

Sources of support

Internal sources

Queen's Medical Centre, UK.

External sources

The National Institute for Health Research (NIHR), UK.

The NIHR, UK, is the largest single funder of the Cochrane Skin Group

Declarations of interest

Maulina Sharma: "I have represented the Cochrane Skin Group as a stakeholder for a NICE (National Institute for Health and Care Excellence) scoping workshop for chronic spontaneous urticaria: omalizumab 2014. I have received an honorarium as a speaker for a general practitioner (GP) educational event, which was donated to the charitable funds of the department. I have attended training and continuing medical education (CME) events that may have been sponsored in part by pharmaceutical industry. I have been a subinvestigator for clinical trials conducted in the Department of Dermatology, George Eliot Hospitals NHS Trust, Nuneaton, UK (2005 to 2006), in particular, the CUTE study (NCT00264303). I was not involved in writing of the results and received no payments for my involvement with the clinical trials."
Cathy Bennett: "I am the proprietor of Systematic Research Ltd, a company providing research services; I am an employee of this company and received a consultancy fee for the production of this review. I have also received consultancy fees for other Cochrane reviews and work in evidence‐based medicine."
Stuart N Cohen: Nothing to declare.
Ben Carter: Nothing to declare.

Dr Karsten Weller was a clinical referee: "I received lecture fees or advisory board fees from Novartis, Uriach, FAES, MSD (Essex Pharma), UCB or was involved in clinical studies with drugs from these companies."

Acknowledgements

Many thanks to Dr Gudula Kirtschig and the Cochrane Skin Group for guidance and assistance with this project.

We would also like to thank Dr Chih‐Mei Chen, Dr Amy Stanway, Dr Lynda Binney and Dr Conrad Hauser, who were co‐authors on the protocol for this review.

Dr Jonathan Batchelor, Dr Carsten Flohr, Dr Marcello Di Bonito and Dr Kim Varma provided assistance with translations. Dr Sujoy Ray provided support with data extraction and risk of bias assessments.

We thank the following study investigators, who provided additional details of study results for included trials: Dr Ana Gimenez‐Arneau, Dr Ganesh Dakhale, Dr Gabriele Di Lorenzo, Prof Louis Dubertret, Dr Jean‐Jacques Grob, Dr Sanjeev Handa and Dr Arthur Helbling.

The Cochrane Skin Group editorial base wishes to thank Sam Gibbs, who was the Cochrane Dermatology Editor for this review; Jo Leonardi‐Bee, who was the Statistical Editor; Ching‐Chi Chi, who was Methods Editor; the clinical referees, Clive Grattan and Karsten Weller; and the consumer referee, who wishes to remain anonymous.

Version history

Published

Title

Stage

Authors

Version

2014 Nov 14

H1‐antihistamines for chronic spontaneous urticaria

Review

Maulina Sharma, Cathy Bennett, Stuart N Cohen, Ben Carter

https://doi.org/10.1002/14651858.CD006137.pub2

2006 Jul 19

H1‐antihistamines for chronic urticaria

Protocol

Amy D Stanway, Stuart N Cohen, Chih‐Mei Chen, Conrad Hauser, Lynda Binney

https://doi.org/10.1002/14651858.CD006137

Differences between protocol and review

We now use the term chronic spontaneous urticaria.

We changed the wording of the 'Types of participants' criteria to clarify that we mean angio‐oedema without weals rather than angio‐oedema without urticaria, as the latter uses the term ‘urticaria’ as a descriptor rather than a disease. We used 'autoinflammatory syndrome' rather than ‘associated abnormalities,’ as Muckle‐Wells and Schnitzler's syndrome are not urticaria.

We clarified that we have included any first‐generation ('sedating') or second‐generation ('non‐sedating') H1‐antihistamines at any dose (including topical interventions and H2RAs given concomitantly) given as single therapy or as combination therapy. Comparators consisted of no treatment, that is, placebo, or another active (pharmacological) compound. We included studies that compared the same drug but at different doses, but we excluded non‐pharmacological interventions such as acupuncture.

We collected additional data from the reports of studies, such as country and setting, to obtain further information about clinical heterogeneity between our included studies.

We did not carry out subgroup analyses on the basis of first‐generation ('sedating') and second‐generation ('non‐sedating') antihistamines, as included studies with relevant outcome data were too few to allow meaningful comparisons.

We clarified that duration of intervention is categorised as follows: up to two weeks (short‐term) and longer than two weeks up to three months (intermediate‐term). Our analyses are now subgrouped by duration of intervention, as we are not looking for a cure but would like to identify which antihistamine will suppress or give good or excellent response for urticaria immediately and over the longest time.

We excluded studies that investigated the effects of astemizole or terfenadine (withdrawn from use).

We described moderate statistical heterogeneity as > 50% in the protocol, but we revised this in the full review to moderate heterogeneity at I² > 60%.

For some comparisons, we used Fisher's exact test because of the small number of participants,

We had stated that we would use funnel plots when at least three studies were included in the meta‐analysis, but the Cochrane Handbook for Systematic Reviews of Interventions recommends a minimum of 10 studies for sufficient power.

We included in our methods section updated information about assessment of risk of bias using the 'Risk of bias' tool of The Cochrane Collaboration, and details about how we dealt with cross‐over trials are provided in the Unit of analysis issues section.

Notes

We provide brand names as a guide to the consumer and do not endorse any product over another.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Loratadine 10 mg versus placebo, Outcome 1 Proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines.

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Analysis 2.1

Comparison 2 Loratadine 10 mg versus cetirizine 10 mg, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.

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Analysis 3.1

Comparison 3 Loratadine 10 mg versus desloratadine 5 mg, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.

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Analysis 3.2

Comparison 3 Loratadine 10 mg versus desloratadine 5 mg, Outcome 2 Proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines.

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Analysis 4.1

Comparison 4 Loratadine 10 mg versus mizolastine 10 mg, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.

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Analysis 4.2

Comparison 4 Loratadine 10 mg versus mizolastine 10 mg, Outcome 2 Proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines.

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Analysis 4.3

Comparison 4 Loratadine 10 mg versus mizolastine 10 mg, Outcome 3 Proportion of participants with at least 50% improvement in QoL whilst taking H1‐antihistamines.

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Analysis 4.4

Comparison 4 Loratadine 10 mg versus mizolastine 10 mg, Outcome 4 Serious adverse events (i.e. serious enough to require withdrawal of treatment).

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Analysis 5.1

Comparison 5 Loratadine 10 mg versus emedastine 2 mg, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.

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Analysis 5.2

Comparison 5 Loratadine 10 mg versus emedastine 2 mg, Outcome 2 Proportion of participants with good or excellent response whilst taking H1‐antihistamines.

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Analysis 5.3

Comparison 5 Loratadine 10 mg versus emedastine 2 mg, Outcome 3 Serious adverse events (i.e. serious enough to require withdrawal of treatment).

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Analysis 6.1

Comparison 6 Loratadine 10 mg versus hydroxyzine 25 mg, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.

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Analysis 7.1

Comparison 7 Cetirizine 10 to 20 mg versus placebo, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.

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Analysis 7.2

Comparison 7 Cetirizine 10 to 20 mg versus placebo, Outcome 2 Serious adverse events (i.e. serious enough to require withdrawal of treatment).

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Analysis 8.1

Comparison 8 Cetirizine 10 mg versus hydroxyzine 25 mg, Outcome 1 Serious adverse events (i.e. serious enough to require withdrawal of treatment).

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Analysis 9.1

Comparison 9 Desloratadine 5 to 20 mg versus placebo, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.

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Analysis 9.2

Comparison 9 Desloratadine 5 to 20 mg versus placebo, Outcome 2 Serious adverse events (i.e. serious enough to require withdrawal of treatment).

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Analysis 10.1

Comparison 10 Hydroxyzine 25 mg versus placebo, Outcome 1 Serious adverse events (i.e. serious enough to require withdrawal of treatment to withdrawal).

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Analysis 11.1

Comparison 11 Levocetirizine 5 to 20 mg versus placebo, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.

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Analysis 12.1

Comparison 12 Rupatadine 10 to 20 mg versus placebo, Outcome 1 Proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines.

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Summary of findings for the main comparison. Cetirizine 10 to 20 mg versus placebo for chronic spontaneous urticaria

Cetirizine 10 to 20 mg versus placebo for chronic spontaneous urticaria
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: cetirizine 10 to 20 mg versus placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control (placebo)	Cetirizine 10 to 20 mg
Complete suppression of urticaria Global assessment of symptom scores	Study population		RR 2.72 (1.51 to 4.91)	178 (2 studies)	⊕⊕⊝⊝ Low^a,b	Favours cetirizine
	133 per 1000	363 per 1000 (201 to 655)
	Moderate
	146 per 1000	397 per 1000 (220 to 717)
Adverse events leading to withdrawal	Study population		RR 3 (0.68 to 13.22)	389 (3 studies)	⊕⊕⊝⊝ Low^a,b	Favours neither intervention nor control
	10 per 1000	30 per 1000 (7 to 132)
	Moderate
	14 per 1000	42 per 1000 (10 to 185)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aDesign limitation (risk of bias). ^bRelatively few participants and few events and/or wide confidence intervals.

Summary of findings for the main comparison. Cetirizine 10 to 20 mg versus placebo for chronic spontaneous urticaria

Desloratadine 5 to 20 mg versus placebo for chronic spontaneous urticaria
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: desloratadine 5 to 20 mg versus placebo
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control (placebo)	Desloratadine 5 to 20 mg
Complete suppression of urticaria: short‐term duration of intervention (desloratadine 5 mg) Global assessment of symptom scores	See comment	See comment	Not estimable	46 (1 study)	⊕⊕⊝⊝ Low^a,b	Favours neither intervention nor control Only 1 study, a conference abstract (Hoxha 2011)
Complete suppression of urticaria: short‐term duration of intervention (desloratadine 10 mg) Global assessment of symptom scores	See comment	See comment	Not estimable	46 (1 study)	⊕⊕⊝⊝ Low^a,b	Favours neither intervention nor control Only 1 study, a conference abstract (Hoxha 2011)
Complete suppression of urticaria: short‐term duration of intervention (desloratadine 20 mg) Global assessment of symptom scores	See comment	See comment	Not estimable	46 (1 study)	⊕⊕⊝⊝ Low^a,b	Favours desloratadine Only 1 study, a conference abstract (Hoxha 2011)
Complete suppression of urticaria: intermediate‐term duration of intervention (desloratadine 5 mg) Global assessment of symptom scores	See comment	See comment	Not estimable	80 (1 study)	⊕⊕⊝⊝ Low^a,b	Favours desloratadine Only 1 study (Di Lorenzo 2004)
Adverse effects leading to withdrawal: intermediate‐term duration of 5 mg of intervention	Study population		RR 1.46 (0.42 to 5.1)	466 (3 studies)	⊕⊕⊝⊝ Low^a,b	Favours neither intervention nor control
	17 per 1000	25 per 1000 (7 to 89)
	Moderate
	18 per 1000	26 per 1000 (8 to 92)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aDesign limitation (risk of bias). ^bRelatively few participants and few events and/or wide confidence intervals.

Levocetirizine 5 to 20 mg versus placebo for chronic spontaneous urticaria
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: levocetirizine 5 to 20 mg versus placebo
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control (placebo)	Levocetirizine 5 to 20 mg
Complete suppression of urticaria: short‐term duration of intervention (levocetirizine 5 mg) Global assessment of symptom scores	See comment	See comment	Not estimable	49 (1 study)	⊕⊕⊝⊝ Low^a,b	Favours neither intervention nor control Only 1 study, a conference abstract (Hoxha 2011)
Complete suppression of urticaria: short‐term duration of intervention (levocetirizine 10 mg) Global assessment of symptom scores	See comment	See comment	Not estimable	49 (1 study)	⊕⊕⊝⊝ Low^a,b	Favours neither intervention nor control Only 1 study, a conference abstract (Hoxha 2011)
Complete suppression of urticaria: short‐term duration of intervention (levocetirizine 20 mg) Global assessment of symptom scores	See comment	See comment	Not estimable	49 (1 study)	⊕⊕⊝⊝ Low^a,b	Favours levocetirizine Only 1 study, a conference abstract (Hoxha 2011)
Complete suppression of urticaria: intermediate‐term duration of intervention (levocetirizine 5 mg) Global assessment of symptom scores	See comment	See comment	Not estimable	100 (1 study)	⊕⊕⊝⊝ Low^a,b	Favours levocetirizine Only 1 study (Nettis 2006)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aDesign limitation (risk of bias). ^bRelatively few participants and few events and/or wide confidence intervals.

Rupatadine 10 to 20 mg versus placebo for chronic spontaneous urticaria
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: rupatadine 10 to 20 mg versus placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control (placebo)	Rupatadine 10 to 20 mg
Good or excellent response Global assessment of symptom scores	Study population		RR 1.35 (1.03 to 1.77)	245 (1 study)	⊕⊕⊝⊝ Low^a,b	Favours rupatadine
	509 per 1000	687 per 1000 (524 to 901)
	Moderate
	509 per 1000	687 per 1000 (524 to 901)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aDesign limitation (risk of bias). ^bRelatively few participants and few events and/or wide confidence intervals.

Loratadine 10 mg versus placebo for chronic spontaneous urticaria
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: loratadine 10 mg versus placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control (placebo)	Loratadine 10 mg
Good or excellent response Global assessment of symptom scores	Study population		RR 1.86 (0.91 to 3.79)	124 (2 studies)	⊕⊕⊝⊝ Low^a,b	Favours neither intervention nor control
	155 per 1000	289 per 1000 (141 to 588)
	Moderate
	160 per 1000	298 per 1000 (146 to 606)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aDesign limitation (risk of bias). ^bRelatively few participants and few events and/or wide confidence intervals.

Loratadine 10 mg versus cetirizine 10 mg for chronic spontaneous urticaria
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: loratadine 10 mg versus cetirizine 10 mg
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control (cetirizine 10 mg)	Loratadine 10 mg
Complete cessation of urticaria Global assessment of symptom scores	Study population		RR 1.05 (0.76 to 1.43)	103 (2 studies)	⊕⊕⊝⊝ Low^a,b	Combined short and intermediate‐term duration of intervention. Favours neither intervention nor control
	588 per 1000	618 per 1000 (447 to 841)
	Moderate
	574 per 1000	603 per 1000 (436 to 821)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aDesign limitation (risk of bias). ^bRelatively few participants and few events and/or wide confidence intervals.

Loratadine 10 mg versus desloratadine 5 mg for chronic spontaneous urticaria
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: loratadine 10 mg versus desloratadine 5 mg
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control (desloratadine 5 mg)	Loratadine 10 mg
Complete suppression of urticaria: intermediate‐term duration of intervention	Study population		RR 0.91 (0.78 to 1.06)	369 (2 studies)	⊕⊕⊝⊝ Low^a,b	Favours neither intervention nor control
	658 per 1000	598 per 1000 (513 to 697)
	Moderate
	670 per 1000	610 per 1000 (523 to 710)
Good or excellent response: intermediate‐term duration of intervention Global assessment of symptom scores	Study population		RR 1.04 (0.64 to 1.71)	410 (3 studies)	⊕⊕⊝⊝ Low^a,b	Favours neither intervention nor control No participants reported a good or excellent response in the loratadine group in Zou 2002 We found low levels of statistical heterogeneity in this analysis I² = 40%)
	263 per 1000	274 per 1000 (169 to 450)
	Moderate
	228 per 1000	237 per 1000 (146 to 390)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aDesign limitation (risk of bias). ^bRelatively few participants and few events and/or wide confidence intervals.

Loratadine 10 mg compared to mizolastine 10 mg for chronic spontaneous urticaria
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: loratadine 10 mg Comparison: mizolastine 10 mg
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control (mizolastine 10 mg)	Loratadine 10 mg
Complete cessation of urticaria: intermediate‐term duration of intervention Global assessment of symptom scores	Study population		RR 0.86 (0.64 to 1.16)	316 (3 studies)	⊕⊝⊝⊝ Very low^a,b,c	Overall, favours neither loratadine nor mizolastine In Guo 2003, more participants in mizolastine group had complete cessation of urticaria than in the other 2 studies (Liu 2003 and Yin 2003b)
	675 per 1000	581 per 1000 (432 to 783)
	Moderate
	667 per 1000	574 per 1000 (427 to 774)
Good or excellent response: intermediate‐term duration of intervention Global assessment of symptom scores	Study population		RR 0.88 (0.55 to 1.42)	314 (3 studies)	⊕⊕⊝⊝ Low^a,c	Favours neither loratadine nor mizolastine
	187 per 1000	165 per 1000 (103 to 266)
	Moderate
	174 per 1000	153 per 1000 (96 to 247)
Adverse events leading to withdrawal: intermediate‐term duration of intervention	Study population		RR 0.38 (0.04 to 3.6)	267 (2 studies)	⊕⊕⊝⊝ Low^a,c	Favours neither loratadine nor mizolastine
	15 per 1000	6 per 1000 (1 to 53)
	Moderate
	19 per 1000	7 per 1000 (1 to 68)
Proportion of participants with at least 50% improvement in QoL: intermediate‐term duration of intervention Symptom score reducing index (SSRI)	Study population		RR 3.21 (0.32 to 32.33)	252 (2 studies)	⊕⊝⊝⊝ Very low^a,b,c	Favours neither loratadine nor mizolastine No participants in the mizolastine group in Guo 2003 reported at least 50% improvement in QoL
	104 per 1000	334 per 1000 (33 to 1000)
	Moderate
	64 per 1000	205 per 1000 (20 to 1000)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aDesign limitation (risk of bias). ^bWidely differing estimates of the treatment effect (i.e. heterogeneity or variability in results) across studies. ^cRelatively few participants and few events and/or wide confidence intervals.

Loratadine 10 mg versus emedastine 2 mg for chronic spontaneous urticaria
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: loratadine 10 mg versus emedastine 2 mg
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control (emedastine 2 mg)	Loratadine 10 mg
Complete cessation of urticaria: intermediate‐term duration of intervention Global assessment of symptom scores	Study population		RR 1.04 (0.78 to 1.39)	161 (1 study)	⊕⊕⊕⊝ Moderate^a	Favours neither loratadine nor emedastine Only 1 study (Pons‐Guiraud 2006)
	524 per 1000	545 per 1000 (409 to 728)
	Moderate
	524 per 1000	545 per 1000 (409 to 728)
Good or excellent response: intermediate‐term duration of intervention Global assessment of symptom scores	Study population		RR 1.09 (0.96 to 1.24)	160 (1 study)	⊕⊕⊕⊝ Moderate^a	Favours neither loratadine nor emedastine Only 1 study (Pons‐Guiraud 2006)
	819 per 1000	893 per 1000 (787 to 1000)
	Moderate
	819 per 1000	893 per 1000 (786 to 1000)
Adverse events leading to withdrawal: intermediate‐term duration of intervention	Study population		RR 1.09 (0.07 to 17.14)	161 (1 study)	⊕⊕⊕⊝ Moderate^a	Favours neither loratadine nor emedastine Only 1 study (Pons‐Guiraud 2006)
	12 per 1000	13 per 1000 (1 to 204)
	Moderate
	12 per 1000	13 per 1000 (1 to 206)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aRelatively few participants and few events and/or wide confidence intervals.

Loratadine 10 mg versus hydroxyzine 25 mg for chronic spontaneous urticaria
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: loratadine 10 mg versus hydroxyzine 25 mg
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control (hydroxyzine 25 mg)	Loratadine 10 mg
Complete suppression of urticaria: short‐term duration of intervention Global assessment of symptom scores	Study population		RR 1 (0.32 to 3.1)	12 (1 study)	⊕⊕⊝⊝ Low^a,b	Favours neither intervention or control Only 1 study (Monroe 1992)
	500 per 1000	500 per 1000 (160 to 1000)
	Moderate
	500 per 1000	500 per 1000 (160 to 1000)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aDesign limitation (risk of bias). ^bRelatively few participants and few events and/or wide confidence intervals.

Cetirizine 10 mg versus hydroxyzine 25 mg for chronic spontaneous urticaria
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: cetirizine 10 mg versus hydroxyzine 25 mg
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control (hydroxyzine 25 mg)	Cetirizine 10 mg
Adverse events leading to withdrawal	Study population		RR 0.78 (0.25 to 2.45)	261 (2 studies)	⊕⊕⊝⊝ Low^a,b	Favours neither cetirizine nor hydroxyzine
	53 per 1000	41 per 1000 (13 to 130)
	Moderate
	54 per 1000	42 per 1000 (14 to 132)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aDesign limitation (risk of bias). ^bRelatively few participants and few events and/or wide confidence intervals.

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines Show forest plot	2	103	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.76, 1.43]

1.1 Short‐term duration of intervention	1	37	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.64, 2.01]
1.2 Intermediate‐term duration of intervention	1	66	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.69, 1.47]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines Show forest plot	2	178	Risk Ratio (M‐H, Random, 95% CI)	2.72 [1.51, 4.91]

1.1 Short‐term duration of intervention (cetirizine 10 mg)	1	56	Risk Ratio (M‐H, Random, 95% CI)	2.8 [1.17, 6.73]
1.2 Intermediate‐term duration of intervention (cetirizine 10 mg)	1	122	Risk Ratio (M‐H, Random, 95% CI)	2.66 [1.20, 5.90]
2 Serious adverse events (i.e. serious enough to require withdrawal of treatment) Show forest plot	3	389	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.68, 13.22]

2.1 Intermediate‐term duration of intervention (cetirizine 10 mg)	2	247	Risk Ratio (M‐H, Random, 95% CI)	4.60 [0.79, 26.67]
2.2 Intermediate‐term duration of intervention (cetirizine 10 to 20 mg)	1	142	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.07, 16.59]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Serious adverse events (i.e. serious enough to require withdrawal of treatment) Show forest plot	2	261	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.25, 2.45]

1.1 Intermediate‐term duration of intervention (cetirizine 10 mg)	1	123	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.27, 4.01]
1.2 Intermediate‐term duration of intervention (cetirizine 5 to 25 mg)	1	138	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.04, 3.13]

Hydroxyzine 25 mg versus placebo for chronic spontaneous urticaria
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: hydroxyzine 25 mg versus placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control (placebo)	Hydroxyzine 25 mg
Adverse events leading to withdrawal: intermediate‐term duration of intervention	Study population		RR 3.64 (0.77 to 17.23)	270 (2 studies)	⊕⊕⊝⊝ Low^a,b	Favours neither intervention nor control
	14 per 1000	53 per 1000 (11 to 250)
	Moderate
	15 per 1000	55 per 1000 (12 to 258)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aDesign limitation (risk of bias). ^bRelatively few participants and few events and/or wide confidence intervals.

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