In this study, adults prescribed oseltamivir had a significantly reduced risk of stroke or TIA in the 6 months following influenza diagnosis compared with those not prescribed antiviral therapy.
A large body of evidence from ex vivo and in vitroanimal and human studies has demonstrated that influenza results in increased local expression of proinflammatory cytokines, increased platelet aggregation, endothelial dysfunction, loss of the protective properties of high-density lipoprotein and elevation of systemic markers of inflammation [1
]. All these changes have the potential to either directly or indirectly stimulate thrombogenesis and exacerbate inflammation of atherosclerotic plaques, which, along with increased hemodynamic stress, could increase the risk of stroke.
Oseltamivir treatment in clinical trials lowered viral titer, the number of patients reporting fever and the duration of fever, and other symptoms compared with placebo [16
]. In addition, in a study of experimental human influenza A, patients treated with oseltamivir had lower levels of the proinflammatory cytokines interferon-γ, interleukin-6 and tumor necrosis factor-α in nasal washings, compared with the placebo group. In the placebo group, levels of these cytokines were 2- to 4-fold above baseline [26
]. Given the potential proinflammatory and prothrombotic consequences of influenza, it might be anticipated that a treatment that reduces levels of proinflammatory cytokines, inflammation, viral load and duration of illness would have a positive impact on the risk of thrombotic events such as stroke after influenza infection. This is reflected in the findings of our study.
Oseltamivir was associated with a protective effect on stroke and TIA in adults <65 years of age for up to 6 months after influenza diagnosis, and in the first month after influenza in those aged ≥65 years. However, rates of stroke or TIA were approximately 10 times lower in patients <65 years of age. This difference in rates of stroke or TIA is in accordance with other studies showing that prevalence of stroke increases with increasing age [27
Previous studies have demonstrated that the highest risk of cardiovascular events occurs in the first month after influenza infection and that the incidence of cardiovascular events declines gradually afterwards [3
]. Accordingly, we found that oseltamivir treatment exerts its greatest level of protection in the first month after influenza infection and the extent of protection decreases over the next few months.
Age-related variations in the occurrence of different types of stroke, such as the significant risk reduction within 1 month after influenza diagnosis, but not later, in older patients, could have a number of causes. For example, there is evidence that strokes due to thromboembolic events could account for a higher proportion of strokes in older patients [28
]. It could be argued that any treatment that reduces the risk of thromboembolism might thus have a greater immediate impact on stroke risk in the ≥65 years group. In addition, the lower IRRs observed overall in the first month after influenza could also be a reflection of variation in the types of stroke with time following influenza.
The sensitivity analysis showed that a history of AMI, which is widely considered to be a risk factor for stroke, had no impact on the effect of oseltamivir in reducing the risk of stroke or TIA.
The risk reductions observed with oseltamivir during influenza seasons were consistent with the overall findings of the study, which might be expected as patients diagnosed during influenza seasons accounted for approximately 85% of the study participants. The number of patients diagnosed outside the influenza season was thus relatively small, which may have hampered accurate statistical analysis. However, it could also be speculated that as influenza diagnoses were not confirmed by influenza tests, some of the patients diagnosed outside the influenza season could have had influenza-like illnesses other than influenza, in which case oseltamivir would not have been an effective treatment.
Several limitations in the design of this study should be acknowledged. Firstly, the database utilized included only patients covered by specific forms of health insurance and may not have been representative of the entire United States population. Secondly, the ICD-9-CM code for influenza was assigned from physicians’ diagnoses, without a requirement for either near-patient or laboratory testing for influenza virus. However, as many physicians use clinical diagnosis alone for influenza, this was considered adequate and may, in fact, better reflect real-life situations in physicians’ clinics. Our database captured a rather low number of elderly subjects by design and this has limited our ability to generalize our findings to subjects ≥65 years old. Finally, patients were not randomized to the oseltamivir and comparison cohorts. However, multivariate models were used to adjust for variations between the cohorts. Additionally, a propensity score analysis found that the incidence of stroke was not affected by the propensity to receive oseltamivir, indicating that there was no substantial confounding by indication.