Once upon a time in Europe, we find they are beset by a befuddling problem: no one uses oseltamivir.
“Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials.”
Ah, to have such problems.
These authors choose to address this dire problem in the most pragmatic fashion possible: rather than try to determine a subgroup of potential maximal benefit, just blindly give everyone oseltamivir in empiric fashion for influenza-like illness. It’s not what one would consider “high-value care”, but it certainly effectively eliminates the barriers to prescribing.
In this open-label trial, patients presenting with influenza-like illness to primary care were assigned to “usual care” or “usual care plus oseltamivir”. Across three influenza seasons, the authors recruited 3,266 participants across 15 countries in Europe. The outcomes were universally excellent: oseltamivir use decreased time to symptom resolution a mean of 1.02 days, effectively reducing mean suffering from 6.73 days to 5.71 days.
And, the better news, oseltamivir worked whether you had influenza or not – half the patients in the trial had confirmed influenza infection while half did not, and the hazard ratio for benefit was actually better [ed. not significantly so] in those who did not have influenza.
… and thus invalidates the entire trial as a giant placebo effect. The industry-funded authors of the most recent meta-analysis of industry-funded trials for the approval of oseltamivir said it best, after all:
“In the intention-to-treat-not infected population, the estimated time ratio was close to unity (time ratio 0·99, 95% CI 0·88–1·12; p=0·91), so only participants identified as influenza-infected benefited from oseltamivir.”
This trial does not show benefit to liberal oseltamivir use. There is no new indication hereby discovered regarding oseltamivir’s efficacy for non-influenza influenza-like viral illness – it simply shows people feel better when they get medicine (particularly when it is more expensive).
“Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial”
https://www.ncbi.nlm.nih.gov/pubmed/31839279
What exactly is meant by “time ratio”. Try as I have to look this up I am still lost, and it seems it’s kind of the crux of this.
From the Dobson paper:
“For time to alleviation of all symptoms, we initially assessed Kaplan-Meier plots by treatment group and we obtained a treatment effect estimate (time ratio) from a log-logistic accelerated failure time model adjusted for trial.15 We did not use proportional hazards models because non-proportionality of hazards was evident. We estimated treatment difference in median time to alleviation of symptoms adjusted for trial along with a bootstrap confidence interval (2000 repetitions, stratified by trial and treatment group).
We assessed statistical heterogeneity in time ratios across trials by a likelihood ratio test. As a sensitivity analysis, separate accelerated failure time models were fitted for each trial and log time ratios were meta-analysed with inverse-variance weighting. We did pre-specified exploratory subgroup analyses for age, high-risk participants, time from symptom onset to randomisation, virus type, and total baseline symptom score. We did likelihood ratio tests of interaction.”