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Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis

BMJ 2009; 339 doi: https://doi.org/10.1136/bmj.b5106 (Published 08 December 2009) Cite this as: BMJ 2009;339:b5106

Implications for future adverse effect studies of neuraminidase inhibitors

Jefferson and colleagues conducted a highly insightful study about
efficacy or effectiveness of neuraminidase inhibitors.[1] In the study,
they also examined frequency of adverse events, but concluded that
evidence of rarer adverse events was of poor quality or possibly under-
reported. Thus, they emphasized the need for new studies to monitor the
safety of neuraminidase inhibitors by governments.[1] We agree with that
opinion but, while we wait for new studies, a study conducted in Japan in
2005-2006 would be very informative.

The Japanese Ministry of Health, Labour, and Welfare funded two
epidemiological studies in the winter seasons of 2005-2006 and 2006-2007.
While the second, larger (>10,000) study is described elsewhere,[2, 3]
the first study is also informative because the study presented results
classified by disease duration. The first study mostly included 0-15 year-
old children (99.5%) (flu patients) across 12 prefectures in Japan, and
compared the incidence of adverse behaviors between patients who took
oseltamivir and those who did not.[4] Adverse behaviors were collected by
questionnaires completed by doctors (2,846 patients) or families (2,545
patients). The former focused on abnormal behavior overall, while the
latter focused on more specific behaviors (frightening episodes,
hallucinations, abrupt screaming/delirious speech, and abrupt anger). The
questionnaire also asked when patients started administering oseltamivir
or manifested outcomes in three time-scales (morning, afternoon, or night)
for each day after the onset of fever.

The major limitation of the study was the lack of information on
temporality if the start of oseltamivir and behaviors were coincident in
the same time-scale. In the report, the study group considered subjects
who started oseltamivir and manifested abnormal behaviors in the same time
-scale as those who manifested abnormal behaviors after the intake of
oseltamivir. Although the study group concluded that there was no
significant difference between the two groups over 7 days,[4] the relative
risk for abnormal behaviors in the afternoon on the first day was
consistently at least four times higher in the treated group including
starters (Table). However, similar findings were not observed after the
second day of the fever. We also showed results of alternative comparisons
to overcome the temporality problem. Although these adverse events are not
as severe as ones considered by Jefferson et al.,[1] the findings in this
Japanese epidemiological study (e.g., prevalence and elevated risks on the
first day) should provide further insight into the future studies.
Furthermore, it implies the existence of time-varying confounders or
effect modifications by disease duration, of which the latter seems more
likely.

References:

1.Jefferson, T., et al., Neuraminidase inhibitors for preventing and
treating influenza in healthy adults: systematic review and meta-analysis.
BMJ, 2009. 339: p. b5106.

2.Hirota, Y., [Interim report of investigations about the frequency
of associated symptoms with influenza] (in Japanese), in Report of
Research on Health Science. 2008, Ministry of Health, Labour, and Welfare
of Japan: Tokyo.

3.Yorifuji, T., E. Suzuki, and T. Tsuda, Oseltamivir and abnormal
behaviors: true or not? Epidemiology, 2009. 20: p. 619-21.

4.Yokota, S., [Investigations about the frequency of associated
symptoms with influenza] (in Japanese), in Report of Research on Health
Science. 2006, Ministry of Health, Labour, and Welfare of Japan: Tokyo.

Competing interests:
None declared

Table. Prevalence and risk ratios (RRs)* for abnormal behaviors in the afternoon (from noon to 6 p.m.) on the first day of fever in patients treated with oseltamivir (data in this table were retrieved from original report4)

	Pre/untreated group		Treated group, including starters†		Already treated group only‡
					
Abnormal behaviors (%)§	10 / 2185 (0.5)		12 / 636 (1.9)		6 / 329 (1.8)
  RR* (95% CI)	1 (Ref.)		4.1 (1.8 – 9.5)		4.0 (1.3 – 12.2)
Frightening episodes (%)§	7 / 1895 (0.4)		13 / 617 (2.1)		6 / 311 (1.9)
  RR* (95% CI)	1 (Ref.)		5.7 (2.3 – 14.2)		5.2 (1.8 – 15.4)
Hallucinations (%)§	1 / 1902 (0.1)		7 / 621 (1.1)		2 / 315 (0.6)
  RR* (95% CI)	1 (Ref.)		21.4 (2.6 – 173.9)		12.1 (1.1 – 132.8)
Abrupt screaming/delirious speech (%)§	11 / 1899 (0.6)		16 / 618 (2.6)		7 / 312 (2.2)
  RR* (95% CI)	1 (Ref.)		4.5 (2.1 – 9.6)		3.9 (1.5 – 9.9)
Abrupt anger (%)§	10 / 1896 (0.5)		12 / 615 (2.0)		6 / 309 (1.9)
  RR* (95% CI)	1 (Ref.)		3.7 (1.6 – 8.5)		3.7 (1.4 – 10.1)


* Risk ratios were estimated using the Pre/untreated group as a reference by Epi Info 3.3.2.

† Treated group includes subjects who started oseltamivir intake in the afternoon on the first day of the fever. In the analyses, we treated subjects who started oseltamivir and manifested abnormal behaviors in the afternoon as those who manifested abnormal behaviors after the intake of oseltamivir, as done by the original research group.


‡ Treated group includes only subject who started oseltamivir intake in the morning (between 6 am and noon) on the first day of the fever.

§ Number of cases with abnormal behaviors and the corresponding denominators (population at risk).

Abbreviations: RR, risk ratio; CI, confidence interval

Competing interests: Pre/untreated group Treated group, including starters† Already treated group only‡ Abnormal behaviors (%)§ 10 / 2185 (0.5) 12 / 636 (1.9) 6 / 329 (1.8) RR* (95% CI) 1 (Ref.) 4.1 (1.8 – 9.5) 4.0 (1.3 – 12.2)Frightening episodes (%)§ 7 / 1895 (0.4) 13 / 617 (2.1) 6 / 311 (1.9) RR* (95% CI) 1 (Ref.) 5.7 (2.3 – 14.2) 5.2 (1.8 – 15.4)Hallucinations (%)§ 1 / 1902 (0.1) 7 / 621 (1.1) 2 / 315 (0.6) RR* (95% CI) 1 (Ref.) 21.4 (2.6 – 173.9) 12.1 (1.1 – 132.8)Abrupt screaming/delirious speech (%)§ 11 / 1899 (0.6) 16 / 618 (2.6) 7 / 312 (2.2) RR* (95% CI) 1 (Ref.) 4.5 (2.1 – 9.6) 3.9 (1.5 – 9.9)Abrupt anger (%)§ 10 / 1896 (0.5) 12 / 615 (2.0) 6 / 309 (1.9) RR* (95% CI) 1 (Ref.) 3.7 (1.6 – 8.5) 3.7 (1.4 – 10.1)

18 December 2009
Takashi Yorifuji
Assistant Professor, Department of Epidemiology, Okayama University Graduate School
Toshihide Tsuda, Saori Kashima, Etsuji Suzuki, Hiroyuki Doi
2-5-1 Shikata-cho,Kita-ku, Okayama city,700-8558 Japan
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