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Amantadine et rimantadine pour la grippe A chez les enfants et les personnes âgées

Appendices

Appendix 1. MEDLINE search strategy

We combined the MEDLINE search strategy with the Cochrane highly sensitive search strategy for identifying randomised trials in MEDLINE: sensitivity‐ and precision‐maximising version (2008 revision); Ovid format (Lefebvre 2011).

MEDLINE (OVID)
1 exp Influenza, Human/
2 influenza*.tw.
3 flu.tw.
4 exp Influenzavirus A/
5 or/1‐4
6 exp Amantadine/
7 amantadine.tw,nm.
8 symmetrel.tw,nm.
9 Rimantadine/
10 rimantadine.tw,nm.
11 flumadine.tw,nm.
12 or/6‐11
13 5 and 12

Appendix 2. EMBASE.com search strategy

#13. #9 AND #12
#12. #10 OR #11
#11. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross‐over':ab,ti OR volunteer*:ab,ti OR allocat*:ab,ti OR assign*:ab,ti OR ((singl* OR doubl*) NEAR/2 (blind* OR mask*)):ab,ti
#10. 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp
#9. #3 AND #8
#8. #4 OR #5 OR #6 OR #7
#7. rimantadine:ab,ti OR flumadine:ab,ti
#6. 'rimantadine'/de
#5. amantadine:ab,ti OR symmetrel:ab,ti
#4. 'amantadine'/de
#3. #1 OR #2
#2. influenza*:ab,ti OR flu:ab,ti
#1. 'influenza'/de OR 'influenza virus a'/exp

Appendix 3. Previous searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 3); MEDLINE (1966 to July 2007); and EMBASE (1980 to July 2007).

The MEDLINE and CENTRAL search strategies are shown below. We combined the MEDLINE search string with the Cochrane highly sensitive search strategy phases one and two as published in Appendix 5b of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005). We adapted the search strategy to search EMBASE.

MEDLINE (OVID)
1 exp INFLUENZA/
2 influenza.mp.
3 or/1‐2
4 exp AMANTADINE/
5 amantadine.mp.
6 exp RIMANTADINE/
7 rimantadine.mp.
8 or/4‐7
9 3 and 8

EMBASE (Embase.com)
1 exp INFLUENZA/
2 influenza.ti. or influenza.ab.
3 or/1‐2
4 exp AMANTADINE/
5 amantadine.ti. or amantadine.ab.
6 exp RIMANTADINE/
7 rimantadine.ti. or rimantadine.ab.
8 or/4‐7
9 3 and 8
10 Randomized Controlled Trial/
11 Controlled Study/
12 exp RANDOMIZATION/
13 Single Blind Procedure/
14 Double Blind Procedure/
15 Crossover Procedure/
16 Phase 3 Clinical Trial/
17 Phase 4 Clinical Trial/
18 or/10‐17
19 9 and 18

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 1

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

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 2

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

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 1 Fever day 3.
Figuras y tablas -
Analysis 1.1

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 1 Fever day 3.

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 2 Malaise day 6.
Figuras y tablas -
Analysis 1.2

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 2 Malaise day 6.

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 3 Cough day 7.
Figuras y tablas -
Analysis 1.3

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 3 Cough day 7.

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 4 Conjunctivitis day 5.
Figuras y tablas -
Analysis 1.4

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 4 Conjunctivitis day 5.

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 5 Eye symptoms day 5 (pain on movement and visual distortion).
Figuras y tablas -
Analysis 1.5

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 5 Eye symptoms day 5 (pain on movement and visual distortion).

Comparison 2 Amantadine and rimantadine compared to placebo and to specific treatment in the prophylaxis of influenza A in children, Outcome 1 Infection.
Figuras y tablas -
Analysis 2.1

Comparison 2 Amantadine and rimantadine compared to placebo and to specific treatment in the prophylaxis of influenza A in children, Outcome 1 Infection.

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 1 RMT (proved and clinical infection).
Figuras y tablas -
Analysis 3.1

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 1 RMT (proved and clinical infection).

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 2 RMT Monto (100 + 200) and Patriarca.
Figuras y tablas -
Analysis 3.2

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 2 RMT Monto (100 + 200) and Patriarca.

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 3 RMT 200.
Figuras y tablas -
Analysis 3.3

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 3 RMT 200.

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 4 RMT 100.
Figuras y tablas -
Analysis 3.4

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 4 RMT 100.

Comparison 4 Use of different doses of rimantadine for prophylaxis and treatment of influenza A in the elderly, Outcome 1 Clinical and laboratory infection.
Figuras y tablas -
Analysis 4.1

Comparison 4 Use of different doses of rimantadine for prophylaxis and treatment of influenza A in the elderly, Outcome 1 Clinical and laboratory infection.

Comparison 5 Rimantadine compared to zanamivir in the elderly, Outcome 1 RMT and zanamivir.
Figuras y tablas -
Analysis 5.1

Comparison 5 Rimantadine compared to zanamivir in the elderly, Outcome 1 RMT and zanamivir.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 1 Diarrhoea.
Figuras y tablas -
Analysis 6.1

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 1 Diarrhoea.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 2 Exanthema.
Figuras y tablas -
Analysis 6.2

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 2 Exanthema.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 3 Muscular, limb pain.
Figuras y tablas -
Analysis 6.3

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 3 Muscular, limb pain.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 4 Headache.
Figuras y tablas -
Analysis 6.4

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 4 Headache.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 5 Stimulation/insomnia.
Figuras y tablas -
Analysis 6.5

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 5 Stimulation/insomnia.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 6 Dizziness.
Figuras y tablas -
Analysis 6.6

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 6 Dizziness.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 7 Dyspnoea.
Figuras y tablas -
Analysis 6.7

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 7 Dyspnoea.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 8 Central nervous system symptoms.
Figuras y tablas -
Analysis 6.8

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 8 Central nervous system symptoms.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 9 Change in behaviour.
Figuras y tablas -
Analysis 6.9

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 9 Change in behaviour.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 10 Gastrointestinal symptoms.
Figuras y tablas -
Analysis 6.10

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 10 Gastrointestinal symptoms.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 11 Hyperreactivity.
Figuras y tablas -
Analysis 6.11

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 11 Hyperreactivity.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 12 Tinnitus.
Figuras y tablas -
Analysis 6.12

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 12 Tinnitus.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 13 Cerebellar ataxia.
Figuras y tablas -
Analysis 6.13

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 13 Cerebellar ataxia.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 14 Malaise.
Figuras y tablas -
Analysis 6.14

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 14 Malaise.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 15 Nausea/vomiting.
Figuras y tablas -
Analysis 6.15

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 15 Nausea/vomiting.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 16 Arrhythmia.
Figuras y tablas -
Analysis 6.16

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 16 Arrhythmia.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 1 Stimulation/insomnia.
Figuras y tablas -
Analysis 7.1

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 1 Stimulation/insomnia.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 2 Confusion.
Figuras y tablas -
Analysis 7.2

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 2 Confusion.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 3 Fatigue.
Figuras y tablas -
Analysis 7.3

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 3 Fatigue.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 4 Vomiting.
Figuras y tablas -
Analysis 7.4

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 4 Vomiting.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 5 Headache.
Figuras y tablas -
Analysis 7.5

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 5 Headache.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 6 Impaired concentration.
Figuras y tablas -
Analysis 7.6

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 6 Impaired concentration.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 7 Rash or allergic reaction.
Figuras y tablas -
Analysis 7.7

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 7 Rash or allergic reaction.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 8 Seizures or clonic twitching.
Figuras y tablas -
Analysis 7.8

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 8 Seizures or clonic twitching.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 9 Dry mouth.
Figuras y tablas -
Analysis 7.9

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 9 Dry mouth.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 10 Dizziness.
Figuras y tablas -
Analysis 7.10

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 10 Dizziness.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 11 Anxiety.
Figuras y tablas -
Analysis 7.11

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 11 Anxiety.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 12 Nausea.
Figuras y tablas -
Analysis 7.12

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 12 Nausea.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 13 Depression.
Figuras y tablas -
Analysis 7.13

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 13 Depression.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 14 Loss of appetite.
Figuras y tablas -
Analysis 7.14

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 14 Loss of appetite.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 1 Confusion.
Figuras y tablas -
Analysis 8.1

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 1 Confusion.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 2 Depression.
Figuras y tablas -
Analysis 8.2

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 2 Depression.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 3 Impaired concentration.
Figuras y tablas -
Analysis 8.3

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 3 Impaired concentration.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 4 Insomnia or sleeplessness.
Figuras y tablas -
Analysis 8.4

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 4 Insomnia or sleeplessness.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 5 Loss of appetite.
Figuras y tablas -
Analysis 8.5

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 5 Loss of appetite.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 6 Rash or allergic reaction.
Figuras y tablas -
Analysis 8.6

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 6 Rash or allergic reaction.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 7 Seizure or clonic twitching.
Figuras y tablas -
Analysis 8.7

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 7 Seizure or clonic twitching.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 8 Dry mouth.
Figuras y tablas -
Analysis 8.8

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 8 Dry mouth.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 9 Fatigue and drowsiness.
Figuras y tablas -
Analysis 8.9

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 9 Fatigue and drowsiness.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 10 Headache.
Figuras y tablas -
Analysis 8.10

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 10 Headache.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 11 Body weakness or debility.
Figuras y tablas -
Analysis 8.11

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 11 Body weakness or debility.

Comparison 9 Additional comparison: RMT compared to placebo in the prophylaxis of influenza A in children and the elderly, Outcome 1 Infection.
Figuras y tablas -
Analysis 9.1

Comparison 9 Additional comparison: RMT compared to placebo in the prophylaxis of influenza A in children and the elderly, Outcome 1 Infection.

Amantadine compared with placebo for prevention and treatment of influenza A in children

Patient or population: children with no influenza A infection (prevention) or with influenza A infection (treatment)

Settings: all

Intervention: amantadine

Comparison: placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Amantadine

Cases of influenza A during prophylaxis

(follow‐up:14 to 18 weeks)

Medium risk population

RR 0.11 (0.04 to 0.3)

773
(2)

⊕⊕⊝⊝
low1,2

10 per 100

1 per 100
(0 to 3)

Fever after initiation of treatment

(follow‐up: 3 days)

Medium risk population

RR 0.37 (0.08 to 1.75)

104
(2)

⊕⊕⊝⊝
low3,4

23 per 100

9 per 100
(2 to 40)

Cough after initiation of treatment

See comment

See comment

Not estimable

0

(0)

See comment

No selected trial

Dizziness

(follow‐up: 7 days)

Medium risk population

RR 6.63 (0.32 to 137.33)

599
(2)

⊕⊝⊝⊝
very low3,4

0 per 100

0 per 100
(0 to 0)

Nausea/vomiting

(follow‐up: 7 days)

Medium risk population

RR 0.54 (0.15 to 2)

599
(2)

⊕⊝⊝⊝
very low3,4,5

13 per 100

7 per 100
(2 to 27)

Stimulation/insomnia

(follow‐up: 7 days)

Medium risk population

RR 0.46 (0.12 to 1.74)

599
(2)

⊕⊕⊝⊝
low3,4

3 per 100

7 per 100
(2 to 27)

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.

*The basis for the assumed risk (e.g. median control group risk across studies) was calculated on the basis of control event rate. 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).

1Allocation concealment not used or unclear.

2Sparse data.

3Allocation concealment unclear.

4Sparse data, confidence intervals do not rule out potential for null effect or harm.

5High heterogeneity unexplained.

Figuras y tablas -

Rimantadine compared with placebo for prevention and treatment of influenza A in children

Patient or population: children with no influenza A infection (prevention) or with influenza A infection (treatment)

Settings: any

Intervention: rimantadine

Comparison: control (placebo or acetaminophen)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Rimantadine

Cases of influenza A during prophylaxis (follow‐up: 1 to 35 days)

Medium risk population

RR 0.49 (0.21 to 1.15)

178
(3)

⊕⊕⊝⊝
low1,2

24 per 100

12 per 100
(5 to28)

Fever after initiation of treatment

(follow‐up: 3 days)

Medium risk population

RR 0.36 (0.14 to 0.91)

69
(1)

⊕⊕⊕⊝
moderate2

38 per 100

14 per 100
(5 to 34)

Cough after initiation of treatment

(follow‐up: 7 days)

Medium risk population

RR 0.83 (0.63 to 1.1)

69
(1)

⊕⊕⊕⊝
moderate2

81 per 100

67 per 100
(51 to 89)

Dizziness

(follow‐up: 35 days)

Medium risk population

RR 3.21 (0.14 to 75.68)

56
(1)

⊕⊝⊝⊝
very low1,2

0 per 100

0 per 100
(0 to 0)

Nausea/vomiting

(follow‐up: 7 to 35 days)

Medium risk population

RR 0.96 (0.1 to 9.01)

125
(2)

⊕⊕⊝⊝
low2

2 per 100

2 per 100
(0 to 15)

Stimulation/insomnia

See comment

See comment

Not estimable

0
(0)

See comment

No selected trial

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.

*The basis for the assumed risk (e.g. median control group risk across studies) was calculated on the basis of control event rate. 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).

1Allocation concealment unclear.

2Sparse data and confidence intervals do not rule out the potential for no effect or harm

Figuras y tablas -

Amantadine compared with placebo for prevention and treatment of influenza A in the elderly

Patient or population: elderly people with no influenza A infection (prevention) or with influenza A infection (treatment)

Settings: any

Intervention: amantadine

Comparison: control

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Amantadine

Cases of influenza A during prophylaxis

See comment

Not estimable

0
(0)

See comment

No selected trial

Fever after initiation of treatment

See comment

Not estimable

0
(0)

See comment

No selected trial

Cough after initiation of treatment

See comment

Not estimable

0
(0)

See comment

No selected trial

Dizziness

See comment

Not estimable

0
(0)

See comment

No selected trial

Nausea

See comment

Not estimable

0
(0)

See comment

No selected trial

Vomiting

See comment

Not estimable

0
(0)

See comment

No selected trial

Stimulation/insomnia

See comment

Not estimable

0
(0)

See comment

No selected trial

Figuras y tablas -

Patient or population: elderly people with no influenza A infection (prevention) or with influenza A infection (treatment)

Settings: any

Intervention: rimantadine

Comparison: placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Rimantadine

Cases of influenza A during prophylaxis

Medium risk population

RR 0.45 (0.14 to 1.41)

103
(2)

⊕⊝⊝⊝
very low1,2

17per 100

7 per 100
(2 to 23)

Fever after initiation of treatment

See comment

0
(0)

See comment

See comment

No selected trial

Cough after initiation of treatment

See comment

0
(0)

See comment

See comment

No selected trial

Dizziness

(follow‐up: 12 weeks)

Medium risk population

12 per 100

11 per 100 (2 to 70)

RR 0.94
(0.15 to 5.97)

35

(1)

⊕⊕⊝⊝
low2,3

Nausea

(follow‐up: 8 to 12 weeks)

Medium risk population

RR 1.99 (0.45 to 8.75)

233
(2)

⊕⊝⊝⊝
very low1,2,4

8 per 100

15 per 100
(3 to 66)

Vomiting

(follow‐up: 8 to 12 weeks)

Medium risk population

RR 0.99 (0.38 to 2.6)

233
(2)

⊕⊕⊝⊝
low1,2

7 per 100

7 per 100
(3 to 17)

Stimulation/insomnia (follow‐up: 8 to 12 weeks)

Medium risk population

RR 1.61 (0.43 to 6.02)

233
(2)

⊕⊕⊝⊝
low1,2

7 per 100

11 per 100
(3 to 40)

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.

*The basis for the assumed risk (e.g. median control group risk across studies) was calculated on the basis of control event rate. 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).

1Allocation concealment unclear and 1 study had high withdrawal rate.

2Sparse data and confidence interval do not rule out no effect or harm.

3Allocation concealment unclear

4High heterogeneity unexplained.

Figuras y tablas -
Comparison 1. Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Fever day 3 Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 AMT

2

104

Risk Ratio (M‐H, Random, 95% CI)

0.37 [0.08, 1.75]

1.2 RMT

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.14, 0.91]

2 Malaise day 6 Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 RMT

1

69

Risk Ratio (M‐H, Random, 95% CI)

1.04 [0.63, 1.70]

3 Cough day 7 Show forest plot

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.63, 1.10]

3.1 RMT

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.63, 1.10]

4 Conjunctivitis day 5 Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 RMT

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.17 [0.01, 3.49]

5 Eye symptoms day 5 (pain on movement and visual distortion) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 RMT

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.58 [0.10, 3.24]

Figuras y tablas -
Comparison 1. Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children
Comparison 2. Amantadine and rimantadine compared to placebo and to specific treatment in the prophylaxis of influenza A in children

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Infection Show forest plot

5

951

Risk Ratio (M‐H, Random, 95% CI)

0.25 [0.09, 0.66]

1.1 AMT

2

773

Risk Ratio (M‐H, Random, 95% CI)

0.11 [0.04, 0.30]

1.2 RMT

3

178

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.21, 1.15]

Figuras y tablas -
Comparison 2. Amantadine and rimantadine compared to placebo and to specific treatment in the prophylaxis of influenza A in children
Comparison 3. Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 RMT (proved and clinical infection) Show forest plot

3

191

Risk Ratio (M‐H, Random, 95% CI)

0.74 [0.13, 4.07]

2 RMT Monto (100 + 200) and Patriarca Show forest plot

2

103

Risk Ratio (M‐H, Random, 95% CI)

0.45 [0.14, 1.41]

3 RMT 200 Show forest plot

2

75

Risk Ratio (M‐H, Random, 95% CI)

0.44 [0.12, 1.63]

4 RMT 100 Show forest plot

2

130

Risk Ratio (M‐H, Random, 95% CI)

1.42 [0.10, 21.10]

Figuras y tablas -
Comparison 3. Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly
Comparison 4. Use of different doses of rimantadine for prophylaxis and treatment of influenza A in the elderly

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical and laboratory infection Show forest plot

1

54

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.21, 4.20]

1.1 RMT

1

54

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.21, 4.20]

Figuras y tablas -
Comparison 4. Use of different doses of rimantadine for prophylaxis and treatment of influenza A in the elderly
Comparison 5. Rimantadine compared to zanamivir in the elderly

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 RMT and zanamivir Show forest plot

2

545

Risk Ratio (M‐H, Random, 95% CI)

4.63 [1.46, 14.72]

Figuras y tablas -
Comparison 5. Rimantadine compared to zanamivir in the elderly
Comparison 6. Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Diarrhoea Show forest plot

3

655

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.42, 1.47]

1.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.81 [0.43, 1.53]

1.2 RMT

1

56

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.02, 8.41]

2 Exanthema Show forest plot

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.21, 2.34]

2.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.21, 2.34]

3 Muscular, limb pain Show forest plot

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.46, 1.59]

3.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.46, 1.59]

4 Headache Show forest plot

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.73 [0.52, 1.03]

4.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.73 [0.52, 1.03]

5 Stimulation/insomnia Show forest plot

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.46 [0.12, 1.74]

5.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.46 [0.12, 1.74]

6 Dizziness Show forest plot

3

655

Risk Ratio (M‐H, Random, 95% CI)

4.69 [0.53, 41.75]

6.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

6.63 [0.32, 137.33]

6.2 RMT

1

56

Risk Ratio (M‐H, Random, 95% CI)

3.21 [0.14, 75.68]

7 Dyspnoea Show forest plot

1

159

Risk Ratio (M‐H, Random, 95% CI)

0.37 [0.02, 9.02]

7.1 AMT

1

159

Risk Ratio (M‐H, Random, 95% CI)

0.37 [0.02, 9.02]

8 Central nervous system symptoms Show forest plot

1

76

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.01, 4.70]

8.1 RMT

1

76

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.01, 4.70]

9 Change in behaviour Show forest plot

1

76

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.01, 4.70]

9.1 RMT

1

76

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.01, 4.70]

10 Gastrointestinal symptoms Show forest plot

1

76

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.08, 18.05]

10.1 RMT

1

76

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.08, 18.05]

11 Hyperreactivity Show forest plot

1

56

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.02, 8.41]

11.1 RMT

1

56

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.02, 8.41]

12 Tinnitus Show forest plot

1

56

Risk Ratio (M‐H, Random, 95% CI)

3.21 [0.14, 75.68]

12.1 RMT

1

56

Risk Ratio (M‐H, Random, 95% CI)

3.21 [0.14, 75.68]

13 Cerebellar ataxia Show forest plot

1

69

Risk Ratio (M‐H, Random, 95% CI)

2.61 [0.11, 61.80]

13.1 RMT

1

69

Risk Ratio (M‐H, Random, 95% CI)

2.61 [0.11, 61.80]

14 Malaise Show forest plot

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.41, 1.96]

14.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.41, 1.96]

15 Nausea/vomiting Show forest plot

4

724

Risk Ratio (M‐H, Random, 95% CI)

0.61 [0.24, 1.58]

15.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.54 [0.15, 2.00]

15.2 RMT

2

125

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.10, 9.01]

16 Arrhythmia Show forest plot

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

16.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 6. Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children
Comparison 7. Adverse effects of rimantadine compared to placebo in the elderly

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Stimulation/insomnia Show forest plot

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.61 [0.43, 6.02]

1.1 RMT

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.61 [0.43, 6.02]

2 Confusion Show forest plot

2

233

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.40, 1.56]

2.1 RMT

2

233

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.40, 1.56]

3 Fatigue Show forest plot

2

233

Risk Ratio (M‐H, Random, 95% CI)

0.81 [0.41, 1.60]

3.1 RMT

2

233

Risk Ratio (M‐H, Random, 95% CI)

0.81 [0.41, 1.60]

4 Vomiting Show forest plot

2

233

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.38, 2.60]

4.1 RMT

2

233

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.38, 2.60]

5 Headache Show forest plot

1

198

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.21, 3.38]

5.1 RMT

1

198

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.21, 3.38]

6 Impaired concentration Show forest plot

1

198

Risk Ratio (M‐H, Random, 95% CI)

0.5 [0.10, 2.41]

6.1 RMT

1

198

Risk Ratio (M‐H, Random, 95% CI)

0.5 [0.10, 2.41]

7 Rash or allergic reaction Show forest plot

1

198

Risk Ratio (M‐H, Random, 95% CI)

3.53 [0.18, 67.28]

7.1 RMT

1

198

Risk Ratio (M‐H, Random, 95% CI)

3.53 [0.18, 67.28]

8 Seizures or clonic twitching Show forest plot

1

198

Risk Ratio (M‐H, Random, 95% CI)

2.0 [0.23, 17.54]

8.1 RMT

1

198

Risk Ratio (M‐H, Random, 95% CI)

2.0 [0.23, 17.54]

9 Dry mouth Show forest plot

1

198

Risk Ratio (M‐H, Random, 95% CI)

0.7 [0.23, 2.12]

9.1 RMT

1

198

Risk Ratio (M‐H, Random, 95% CI)

0.7 [0.23, 2.12]

10 Dizziness Show forest plot

1

35

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.15, 5.97]

10.1 RMT

1

35

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.15, 5.97]

11 Anxiety Show forest plot

1

35

Risk Ratio (M‐H, Random, 95% CI)

2.83 [0.92, 8.74]

11.1 RMT

1

35

Risk Ratio (M‐H, Random, 95% CI)

2.83 [0.92, 8.74]

12 Nausea Show forest plot

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.99 [0.45, 8.75]

12.1 RMT

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.99 [0.45, 8.75]

13 Depression Show forest plot

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.63 [0.53, 4.98]

13.1 RMT

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.63 [0.53, 4.98]

14 Loss of appetite Show forest plot

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.11 [0.56, 2.17]

14.1 RMT

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.11 [0.56, 2.17]

Figuras y tablas -
Comparison 7. Adverse effects of rimantadine compared to placebo in the elderly
Comparison 8. Adverse effects related to different doses of rimantadine in the elderly

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Confusion Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.41, 1.65]

1.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.41, 1.65]

2 Depression Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.44 [0.12, 1.65]

2.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.44 [0.12, 1.65]

3 Impaired concentration Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.11, 3.98]

3.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.11, 3.98]

4 Insomnia or sleeplessness Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.26, 3.97]

4.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.26, 3.97]

5 Loss of appetite Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.27, 1.46]

5.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.27, 1.46]

6 Rash or allergic reaction Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.34 [0.04, 3.21]

6.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.34 [0.04, 3.21]

7 Seizure or clonic twitching Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.11 [0.01, 2.07]

7.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.11 [0.01, 2.07]

8 Dry mouth Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.43, 3.11]

8.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.43, 3.11]

9 Fatigue and drowsiness Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.14 [0.45, 2.87]

9.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.14 [0.45, 2.87]

10 Headache Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.30, 3.42]

10.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.30, 3.42]

11 Body weakness or debility Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.38, 2.18]

11.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.38, 2.18]

Figuras y tablas -
Comparison 8. Adverse effects related to different doses of rimantadine in the elderly
Comparison 9. Additional comparison: RMT compared to placebo in the prophylaxis of influenza A in children and the elderly

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Infection Show forest plot

5

281

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.27, 0.92]

1.1 RMT

5

281

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.27, 0.92]

Figuras y tablas -
Comparison 9. Additional comparison: RMT compared to placebo in the prophylaxis of influenza A in children and the elderly