We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database.
SELECTION CRITERIA: We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20
oseltamivir (9623 participants) and 26
zanamivir trials (14,628 participants). Inadequate reporting put most of the
zanamivir studies and half of the
oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of
oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the
oseltamivir studies and there was also evidence of selective reporting for both the
zanamivir and
oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances. Time to first symptom alleviation. For the treatment of adults,
oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P < 0.0001). This represents a reduction in the time to first alleviation of symptoms from 7 to 6.3 days. There was no effect in asthmatic children, but in otherwise healthy children there was (reduction by a mean difference of 29 hours, 95% CI 12 to 47 hours, P = 0.001).
Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days, P < 0.00001), equating to a reduction in the mean duration of symptoms from 6.6 to 6.0 days. The effect in children was not significant. In subgroup analysis we found no evidence of a difference in treatment effect for
zanamivir on time to first alleviation of symptoms in adults in the
influenza-infected and non-
influenza-infected subgroups (P = 0.53). Hospitalisations. Treatment of adults with
oseltamivir had no significant effect on hospitalisations: risk difference (RD) 0.15% (95% CI -0.78 to 0.91). There was also no significant effect in children or in prophylaxis.
Zanamivir hospitalisation data were unreported. Serious
influenza complications or those leading to study withdrawal. In adult treatment trials,
oseltamivir did not significantly reduce those complications classified as serious or those which led to study withdrawal (RD 0.07%, 95% CI -0.78 to 0.44), nor in child treatment trials; neither did
zanamivir in the treatment of adults or in prophylaxis. There were insufficient events to compare this outcome for
oseltamivir in prophylaxis or
zanamivir in the treatment of children.
Pneumonia.
Oseltamivir significantly reduced self reported, investigator-mediated, unverified
pneumonia (RD 1.00%, 95% CI 0.22 to 1.49); number needed to treat to benefit (NNTB) = 100 (95% CI 67 to 451) in the treated population. The effect was not significant in the five trials that used a more detailed diagnostic form for
pneumonia. There were no definitions of
pneumonia (or other complications) in any trial. No
oseltamivir treatment studies reported effects on radiologically confirmed
pneumonia. There was no significant effect on unverified
pneumonia in children. There was no significant effect of
zanamivir on either self reported or radiologically confirmed
pneumonia. In prophylaxis,
zanamivir significantly reduced the risk of self reported, investigator-mediated, unverified
pneumonia in adults (RD 0.32%, 95% CI 0.09 to 0.41); NNTB = 311 (95% CI 244 to 1086), but not
oseltamivir.
Bronchitis,
sinusitis and
otitis media.
Zanamivir significantly reduced the risk of
bronchitis in adult treatment trials (RD 1.80%, 95% CI 0.65 to 2.80); NNTB = 56 (36 to 155), but not
oseltamivir. Neither NI significantly reduced the risk of
otitis media and
sinusitis in both adults and children. Harms of treatment.
Oseltamivir in the treatment of adults increased the risk of
nausea (RD 3.66%, 95% CI 0.90 to 7.39); number needed to treat to harm (NNTH) = 28 (95% CI 14 to 112) and
vomiting (RD 4.56%, 95% CI 2.39 to 7.58); NNTH = 22 (14 to 42). The proportion of participants with four-fold increases in antibody titre was significantly lower in the treated group compared to the control group (RR 0.92, 95% CI 0.86 to 0.97, I(2) statistic = 0%) (5% absolute difference between arms).
Oseltamivir significantly decreased the risk of diarrhoea (RD 2.33%, 95% CI 0.14 to 3.81); NNTB = 43 (95% CI 27 to 709) and
cardiac events (RD 0.68%, 95% CI 0.04 to 1.0); NNTB = 148 (101 to 2509) compared to placebo during the on-treatment period. There was a dose-response effect on psychiatric events in the two
oseltamivir "pivotal" treatment trials, WV15670 and WV15671, at 150 mg (standard dose) and 300 mg daily (high dose) (P = 0.038). In the treatment of children,
oseltamivir induced
vomiting (RD 5.34%, 95% CI 1.75 to 10.29); NNTH = 19 (95% CI 10 to 57). There was a significantly lower proportion of children on
oseltamivir with a four-fold increase in
antibodies (RR 0.90, 95% CI 0.80 to 1.00, I(2) = 0%). Prophylaxis. In prophylaxis trials,
oseltamivir and
zanamivir reduced the risk of symptomatic
influenza in individuals (
oseltamivir: RD 3.05% (95% CI 1.83 to 3.88); NNTB = 33 (26 to 55);
zanamivir: RD 1.98% (95% CI 0.98 to 2.54); NNTB = 51 (40 to 103)) and in households (
oseltamivir: RD 13.6% (95% CI 9.52 to 15.47); NNTB = 7 (6 to 11);
zanamivir: RD 14.84% (95% CI 12.18 to 16.55); NNTB = 7 (7 to 9)). There was no significant effect on asymptomatic
influenza (
oseltamivir: RR 1.14 (95% CI 0.39 to 3.33);
zanamivir: RR 0.97 (95% CI 0.76 to 1.24)). Non-
influenza,
influenza-like illness could not be assessed due to data not being fully reported. In
oseltamivir prophylaxis studies, psychiatric adverse events were increased in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07 to 2.76); NNTH = 94 (95% CI 36 to 1538) in the study treatment population.
Oseltamivir increased the risk of
headaches whilst on treatment (RD 3.15%, 95% CI 0.88 to 5.78); NNTH = 32 (95% CI 18
to 115), renal events whilst on treatment (RD 0.67%, 95% CI -2.93 to 0.01); NNTH = 150 (NNTH 35 to NNTB > 1000) and
nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116).
AUTHORS' CONCLUSIONS: