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cdc.gov/coronavirus
Ischemic Stroke, COVID -19 and Influenza in
Adults Ages ≥65 Years:
Interpretation & Next Steps
Evelyn Twentyman, MD, MPH
ACIP MeetingFebruary 24, 2023
Statistical signal for
ischemic stroke identified in Vaccine Safety Datalink (VSD) Rapid Cycle Analysis (RCA) monitoringIschemic stroke, COVID -19, and influenza in review
New and published data regarding relationships of ischemic stroke, COVID -19, and influenza Work group interpretation and next steps
Statistical signal for
ischemic stroke identified in VSD RCA monitoringIschemic stroke, COVID -19, and influenza in review
New and published data regarding relationships of ischemic stroke, COVID -19, and influenza Work group interpretation and next steps
Statistical signal identified for ischemic
s
troke after Pfizer -BioNTech COVID -19
mRNA bivalent booster dose vaccination in age group 65+ years in VSD RCA
–Rate ratio has attenuated over timeReview of statistical signal
:
Supplemental analysis comparing b
oosted to un -boosted concurrent
comparators did not show an elevated rate ratio:
Comparing rates in an early (“risk”) interval with rates in a later (“comparison”) intervalComparing rates in the early (“risk”) interval among boosted people vs booster eligible un-boosted people
Stratified analysis evaluating people
w
ith coadministration of high -dose or
adjuvanted flu vaccination show a rate ratio of 1.65 (1.02—2.72; p=0.04)In the stratified analysis, rate ratio w
as not elevated in people who
received Pfizer- BioNTech bivalent
mRNA booster without simultaneous
flu vaccine
Separate analysis did no t detect an
elevated rate ratio for ischemic stroke after flu vaccine aloneReview of statistical signal: coadministration
*Coadministration refers to administration of >1 vaccine in the same day.Pfizer bivalent mRNA Coadministration*High -do se/ adjuvanted flu vaccine
No other VSD RCA pre -s pecified surveillance outcomes have signaled:
–
––
–
–––
–in any age groups,
fore ither of the mRNA COVID -19 bivalent booster vaccines, or
when data for the two mRNA vaccine types are combined.
No evidence of a safety signal for ischemic stroke in other safety monitoring
s
ystems, though analyses in these systems generally did not have the ability to
investigate coadministration with flu vaccine
Vaccine Adverse Events Reporting System (VAERS)
FDA Rapid Cycle Analysis (RCA) data in Centers for Medicare & Medicaid Services (CMS)Veterans Administration (VA) RCA in the VA Electronic Health Record (VA EHR)
Pfizer global monitoring
Other global public health and regulatory systems
•Canada
•European Union
•IsraelReview of statistical signal: not identified in any other
vaccine safety monitoring system
Statistical signal for
ischemic stroke identified in VSD RCAIschemic stroke, COVID -19, and influenza in review
New and published data regarding relationships of ischemic stroke, COVID -19, and influenza Work group interpretation and next steps
Incidence of AIS hospitalizations was 10 times higher during
the 3 days post COVID diagnosis (IRR 10.3, [9.9 –10.8])
compared with control periods, among Medicare beneficiaries
ages ≥65 years1
COVID cohort estimated incidence of AIS is 2.10% (1. 97—2.23)
within 6 months after COVID diagnosis2, though stroke and
COVID symptoms present concomitantly in >80% of cases3
COVID -1 9 patients who develop stroke are more likely to be of older age, have more severe COVID- 19 disease , and more
likely to have hypertension, diabetes, and coronary artery disease than those who do not
3
COVID -19v accination is associated with reduced risk of AIS
after COVID -19 (aHR 0.40 [0.26-0.63]; aHR 0.41 [0.26- 0.66] for
ages ≥65)4Percentage Hospitalized
COVID Patients Aged 65+
with Stroke:
COVID -NET, March
2020—October 2022COVID -19 disease and acute ischemic stroke (AIS)
1) Yang Q et al. Neurology 2022; 98(8): e778- 789. 2) Taquet M et al. Lancet Psychiatry 2021; 8(5): 416- 427. 3) Nannoni S et al. International Journal of Stroke 2021; 16(2):
137-149. 4) Kim Y et al. JAMA 2022; 328(9): 887- 889.1%2%3%
Alpha Delta Omicron
(early)Omicron
(late)2.2%
overall
Association between recent respiratory infection and increased stroke risk noted in
so
me observational studies 1,2
Two randomized studies assessing stroke as a specific outcome did not note a s
ignificant effect of influenza vaccination on stroke risk 3, 4
Stroke has been evaluated as an outcome in several observational studies, some of w
hich have reported decreased risk with vaccination 5-8
Benefit of influenza vaccination has been noted in some studies examining major c
ardiovascular outcomes (some including stroke within a composite outcome) 4,8
Limitations:
––––Potential reduction in stroke risk varies and is not seen in all studiesPopulations, study designs, outcome definitions, and analytic methods vary across studiesObservational data are more subject to biasOverall limited data concerning specific influenza vaccines and stroke -s
pecific riskInfluenza, Influenza Vaccination, and Stroke
1. Smeeth L et al, N Engl J Med 2004; 351: 2611 -8
2. Zurrú M C et al, Stroke 2009; 40: 1986 -90
3. Loeb M et al, Lancet Global Health 12 2022; 10: e1835 -e 1844
4. Phrommintikul A et al, Eur Heart J 2011; 32: 1730 –17355. Holodinsky JK et al, Lancet Resp Health 2022; 7: e914 -e922
6. Rodriguez -M artin S et al, Neurology 2022; 00: e2199 -e2160
7. Asghar Z et al, Vaccine 2015; 33: 5458 -5463
8. Chiang MH et al, Am Heart J 2017; 193: 1 -7
PCORnet©The National Patient -
Centered Clinical Research Network
Data includes el ectronic health records
associated with ambulatory, ED, and
inpatient settings
Covers a ll patients in participating
health systems, or ~ 10% of the US
population ages ≥65 years
Used to rapidly assess incidence of s
troke across diverse US population over
the late Omicron period within 2022, with recent COVID-19 or influenza and incidence overallHealthVerity
Data includes m edical claims from closed
payor systems related to ambulatory, ED, and inpatient settings
Data is l
inked to vaccination data from
the Federal Retail Pharmacy Program
Covers patients i nsured through
Medicare Advantage, or ~25% of the US population ages ≥65 years
Used to rapidly assess incidence of stroke a
cross insured US population, with
recent COVID-19 or influenza vaccination and incidence overallHealthcare data sources used to describe current
incidence of stroke
PCORnet©The National Patient -Centered
Clinical Research Network
Cohort definitions designed to capture
i
ncident stroke
––
–
–
–
–
–
––––
–
–
–
–ICD10 diagnosis (I63.X)Exclusion of
patients with history of stroke
Cohort definitions designed to capture p
atients with recent COVID -19 and influenza
Positive laboratory tests (COVID -19 and influenza)
ICD10 diagnoses (B97.29, U07.1, J10.1, J10.2, J11.1, J 11.2,
J09.X, J10.8X, J11.8X)COVID -19 m
edicationsNo COVID -19 i
n the 30 days prior
Description of incidence of stroke across:
Entire cohort, using average incidence over 32 days
Recent COVID or flu diagnosis: 3 days prior to 28 days p ostHealthVerity
Cohort definitions designed to capture i
ncident stroke
ICD10 diagnosis (I63.X)Inpatient place of serviceExclusion of
patients with history of stroke
Cohort definitions designed to capture r
ecent bivalent mRNA and influenza
vaccination
All applicable CVX, CPT/HCPCS, and NDC codesNo evidence of prior s
troke/TIA during observation
period or COVID -19 in the 30 days prior
Description of incidence of stroke across:
Entire cohort, using average incidence over 29 daysRecent vaccination: within 28 days following bivalent m
RNA vaccination, flu vaccination, or
coadministration of both vaccinesMethods used to describe current incidence of stroke
010002000300040005000600070008000900010000
*Average stroke incidence among adults aged 65+ in Sep -Dec 2022 in the full PCORnet cohort per million over 32 days.Stroke incidence among all adults ages ≥65 years, with COVID -19, and with
influenza during late Omicron: PCORnet , Sep- Dec 2022Stroke incidence per million
All adults ≥65 ,
over 32 days*All adults ages ≥65
(N=1,953,391)
Adults ages ≥65 with COVID-19 (N=77,981)
Adults ages ≥65 with influenza (N=11,396)
Adults ≥65 with
influenza ,
-3 to 28 daysAdults ≥65 with
COVID -19,
-3 to 28 daysGroups presented are of the
same agecategory and
adjusted time at risk. Crude
incidence within groups is not
otherwise adjusted.
010002000300040005000600070008000900010000
*Average stroke incidence among adults aged 65+ in Sep -Dec 2022 in the full PCORnet cohort per million over 32 days.Early stroke incidence among adults ages 65+ years with COVID -19, and with
influenza during late Omicron: PCORnet , Sep- Dec 2022Stroke incidence per million
All adults ≥ 65,
over 32 days*All adults ages ≥65
(N=1,953,391)
Adults ages ≥65 with COVID-19 (N=77,981)
Adults ages ≥65 with influenza (N=11,396)
Adults ≥65 with
influenza ,
-3 to 28 daysAdults ≥65 with
COVID -19,
-3 to 28 daysIncidence within -3
to 7 days of
COVID-19 disease
(93.5%)Incidence within -3
to 7 days of
influenza infection
(90.9%)
Groups presented are of the
same agecategory and
adjusted time at risk. Crude
incidence within groups is not
otherwise adjusted.
02004006008001000120014001600Stroke incidence among all adults ages ≥65 years and recently vaccinated
adults ages 65+ years during late Omicron: HealthVerity, Sep -Oct 2022
*Average stroke incidence among adults aged 65+ in Sep -Oct 2022 in the full HealthVerity cohort per million over 29 days.Stroke incidence per millionAll adults ages ≥65
(N=3,651,579)
Adults ages ≥65 with
recent bivalent mRNA
vaccination(N=593,766)
Adults ages ≥65 with
recent influenza
vaccination(N=875,170)
Adults ages ≥65 with
recent coadministration
of bivalent mRNA + influenza vaccines (N=164,836)
Adults ≥65 with
flu vaccine ,
0 to 28 daysAdults ≥ 65 with
bivalent mRNA ,
0 to 28 daysAdults ≥65 with
coadministration,
0 to 28 daysAll adults ≥65 ,
over 29 days*Groups presented are of the same
agecategory and adjusted time at
risk. Crude incidence within groups
is not otherwise adjusted.
Statistical signal for
ischemic stroke identified in VSD RCA monitoringIschemic stroke, COVID -19, and influenza in review
New and published data regarding relationships of ischemic stroke, COVID -19 disease, and
influenza Work group interpretation and next steps
Review of safety data is reassuring, and must continue. Priorities include:
–
–
–
–Continuing to closely follow the intermittently statistically significant signal in VSD,
w
ith continued review by VaST and colleagues
Continuing supplementary analyses to clarify the relationship between this signal an
d:
•any specific vaccine
•coadministration of vaccines
•confounding
Continuing the most intensive vaccine safety surveillance in US history
Review of healthcare data demonstrates high incidence of stroke at time of diagnosis w
ith COVID -19 or influenza. Priorities include:
Increasing awareness of the risk of stroke with COVID -1 9 disease and influenza
–Continuing to encourage uptake of the bivalent COVID -1 9 boostersWork group interpretation and next steps
The COVID -1 9 ACIP Work Group remains confident in current COVID -
19 vaccine recommendations.
–No changes to current recommendations regarding
coadministration of vaccines
CDC and partners anticipate the opportunity to review and consider
upc
oming analyses prior to the 2023 -2024 flu season.Work group interpretation and next steps
Tegan Boehmer
Matt Ritchey
Julia Raykin
Sharon Saydah
Stacey Adjei
Jennifer Wiltz
Jason Block
PCORnet Sites
Sara Baca
Lisa Groskopf
Jill Ferdinands
Janet Wright
Fátima Coronado
Sandra JacksonAcknowledgements
VaST Working Group
Lauri Markowitz
Robert Merritt
Xin (Cindy) Tong
Hilda Razzaghi
Catherin Bozio
Morgan Najdowski
Shikha Garg
Carrie Reed
Aaron Kite -Powell
Kathleen Hartnett
Fiona Havers
Chris Taylor
COVIDNetAdi Gundlappali
Aaron Harris
Emily Koumans
Pragna Patel
Jennifer Giovanni
Mark Swancutt
Karl Soetebier
Tom Shimabukuro
Eric Weintraub
Karen Broder
Immunization Safety
Office
Erika Edding
Aron HallSara Oliver
Katherine Fleming -
Dutra
Ruth Link -Gelles
Danielle Moulia
Megan Wallace
Monica Godfrey
Julianne Gee
Kelcie Landon
Ben Silk
Sarah Meyer
Elisha Hall
Melinda Wharton
Barbara Mahon
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TTY: 1 -888- 232-6348 www.cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position o f the Centers for Disease Control and Prevention.
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