Cochrane reviewers respond to ECDC consultation

Announcement Date: March 14, 2016

Hama R, Jefferson T, Heneghan C .

Cochrane reviewers’ comments on the ECDC draft preliminary Scientific Advice paper “Expert Opinion on neuraminidase inhibitors for prevention and treatment of influenza – review of recent systematic reviews and metaanalyses”

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Table of contents:

Introduction
As ECDC advice has many limitations, we would like to comment on it as the following contents
shows:
Contents of our comments:
1. On the analysis methods
1.1. On the principles of analysis methods in general
1.2. For the systematic review of treatment
1.2.1. The population: ITT population should be used for efficacy analysis.
1.2.2. Exclusion or inclusion of high dose groups
1.2.3. All hospitalizations
1.2.4. Pneumonia and bronchitis
1.2.5. Note that reduction of antibody production is related to the mechanism of action of symptom relief
1.2.6. Efficacy in non-influenza ILI
1.3. For the systematic review of prophylaxis: Discussions are needed by taking “false negative effect” into
account both for
ECDC advice and for our own.
2. On the data of individual results.
2.1. Treatment trials
2.1.1. Efficacy: complication especially on serious events leading to treatment withdrawal and hospitalization.
2.1.2. Harm: antibody production, QT interval, cardiovascular events.
2.1.2.1. Antibody production
2.1.2.2. QT interval and other cardiovascular events
2.1.2.3. Psychiatric events, injury and poisoning
2.2. Prophylaxis trials
2.2.1. Efficacy in prophylaxis trials:
2.2.2. Harm in prophylaxis trials:
2.2.2.1. Psychiatric reactions
2.2.2.2. Injury and poisoning
2.2.2.3. Other adverse reactions
2.2.2.3.1. Renal impairment
2.2.2.3.2. Hyperglycemic of diabetic events, and pain in limbs
2.2.2.3.3. Headaches
3. Evidence from non-randomized studies
3.1. Epidemiological studies suggesting neuropsychiatric adverse reactions to oseltamivir:
3.1.1. Prospective cohort studies and their systematic review and meta-analysis.
3.1.2. Proportional reporting ratio for abnormal behaviours especially of fatal outcome.
3.2. Adverse effects on mortality
3.2.1. Observational studies do not support protective effect on mortality
3.2.2. Epidemiological evidence suggesting sudden deterioration leading to death following oseltamivir use:
3.3. Adverse effect on pregnant women, fetus and newborns
4. No discussion on the mechanisms of action and reactions of oseltamivir
4.1. Oseltamivir act on the central nervous system (CNS) both as depressant and as stimulants.
4.1.1. Juvenile (7-day-old) rats and mature rats (intraduodenally and intravenously)
4.1.2. Oseltamivir has hypothermic effect on animals by inhibiting nicotinic acetylcholine receptor.
4.1.3. Oseltamivir induces abnormal behaviours by inhibiting MAO-A.
4.1.4. Oseltamivir has various other effects on CNS such as impairment of sensory system, impairment of
cognition, impairment of alertness other than respiratory depression.
4.2. Oseltamivir has symptom relieving effects by inhibiting host’s endogenous neuraminidase, not by inhibiting
viral load.
4.2.1 Label of oseltamivir does not state viral load reduction
4.2.2. Experiments indicate inhibition of host’s endogenous neuraminidase, but not viral load
4.3. Inhibiting host’s endogenous neuraminidase may be related with adverse effects of NIs
5. Efficacy and effectiveness in risk groups
6. Conflict of Interest
7. Conclusion