Do high-dose or adjuvanted influenza vaccines increase the risk of stroke in older adults?

That was a question addressed in a research letter published in the Journal of the American Medical Association Network Open. FDA researchers examined the issue following a previous FDA study that raised concerns about elevated stroke risk after flu vaccines in adults aged 65 years and older.

The earlier study investigated stroke risk following COVID-19 bivalent and influenza vaccines among Medicare beneficiaries aged 65 years or older in 2022 and 2023. The self-controlled case series (SCCS) study found no consistent evidence of stroke risk in the days following COVID-19 bivalent vaccination. It did detect an association between stroke and influenza vaccination, however.

The recent investigation was launched to determine whether stroke risk increased following influenza vaccination, with researchers focusing on the 2016–2017, 2017–2018, and 2018–2019 influenza seasons.

The researchers evaluated the risk of nonhemorrhagic stroke (NHS), transient ischemic attack (TIA), NHS and/or TIA (NHS/TIA), and hemorrhagic stroke (HS) following exposure to a high-dose or adjuvanted influenza vaccine among adults 65 years or older (primary analysis) and by age subgroup (65-74, 75-84, and ≥85 years). They compared fixed risk windows (1-21 and 22-42 days) were compared with a control window (43-90 days).

For each influenza season, the study period began on the first Sunday of August and ended 1 day before the start of the subsequent season. The 14.7 million participants did not reside in a nursing home and were enrolled in fee-for-service Medicare for at least a year before vaccination. Data were analyzed from August 7, 2016, to August 3, 2019.

The Medicare beneficiaries who received influenza vaccines across the three influenza seasons had a median age of 74 years and were 57.75% female.
    
The results indicated that 29,730 stroke cases occurred in 2016–2017, 34,518 in 2017–2018, and 36,869 in 2018–2019. “In 2016 to 2017, there was an association for HS during the 22- to 42-day risk window (IRR [incidence rate ratio], 1.14 [95% CI, 1.02-1.28]; RD [risk difference], 0.84 [95% CI, 0.14-1.54]) compared with the control interval,” the authors explained. “However, no association was identified in 2017 to 2018 or 2018 to 2019. Temporal scans identified case clusters in control windows for several outcomes in 2017 to 2018 and 2018 to 2019.”

Subgroup analyses, meanwhile, showed associations for HS during the 22- to 42-day risk window in those aged 65 to 74 years in 2016–2017 (IRR, 1.24; 95% CI, 1.02-1.51; RD, 0.83; 95% CI, 0.07-1.59) and aged 75 to 84 years in 2017–2018 (IRR, 1.19; 95% CI, 1.03-1.37; RD, 1.56; 95% CI, 0.25-2.87), according to the report. “In 2018 to 2019, we identified associations in the subgroup 85 years or older for NHS (IRR, 1.17 [95% CI, 1.06-1.29]; RD, 6.40 [95% CI, 2.34-10.47]) and NHS/TIA (IRR, 1.14 [95% CI, 1.06-1.23]; RD, 8.66 [95% CI, 3.51-13.81]) during the 1- to 21-day risk window,” the researchers wrote.

“Although we detected associations in the primary and age subgroup analyses, we did not observe consistent increased stroke risk following high-dose or adjuvanted influenza vaccination from 2016 to 2019,” the authors concluded, pointing out that while the multiple tests conducted may have increased type I error rate, their system was designed to be sensitive and looked for consistency when interpreting results.

“The associations we identified were not consistent across outcomes, risk windows, age subgroups, and influenza seasons,” the study team added. “Additionally, clusters observed in the temporal scan were not consistent with the associations identified through the SCCS framework.”

The investigators cautioned that their study has some limitations, especially that they included only vaccinated beneficiaries. “While influenza infection is a known trigger for stroke, we could not account for any protective effect of vaccination,” the investigators noted. “The clinical significance of any potential risk of stroke following vaccination must be carefully considered with known benefits of influenza vaccination.”

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