cdc.gov/coronavirus

Ischemic Stroke, COVID-19 and Influenza in 

Adults Ages ≥65 Years:

Interpretation & Next Steps

Evelyn Twentyman, MD, MPH

ACIP Meeting

February 24, 2023
Statistical signal for 

ischemic stroke identified 

in Vaccine Safety Datalink 

(VSD) Rapid Cycle 

Analysis (RCA) monitoring

Ischemic 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 monitoring

Ischemic 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 

stroke after Pfizer-BioNTech COVID-19 

mRNA bivalent booster dose vaccination in 

age group 65+ years in VSD RCA 

– Rate ratio has attenuated over time

Review of statistical signal

:

 Supplemental analysis comparing 

boosted 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”) interval

Comparing rates in the early (“risk”) interval among 

boosted people vs booster eligible un-boosted people
 Stratified analysis evaluating people 

with 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 

was not elevated in people who 

received Pfizer-BioNTech bivalent 

mRNA booster without simultaneous 

flu vaccine

 Separate analysis did not detect an 

elevated rate ratio for ischemic stroke 

after flu vaccine alone

Review of statistical signal: coadministration

*Coadministration refers to administration of >1 vaccine in the same day.

Coadministration* Pfizer bivalent mRNA High-dose/ adjuvanted 

flu vaccine
 No other VSD RCA pre-specified surveillance outcomes have signaled:

–

–

–

–

–

–

–

–

in any age groups,

for either 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 

systems, 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

• Israel

Review of statistical signal: not identified in any other 

vaccine safety monitoring system
Statistical signal for 

ischemic stroke 

identified in VSD RCA

Ischemic 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-19 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 not3

 COVID-19 vaccination 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)4

Percentage Hospitalized 

COVID Patients Aged 65+ 

with Stroke: 

COVID-NET, March 

2020—October 2022

COVID-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 

some observational studies 1,2

 Two randomized studies assessing stroke as a specific outcome did not note a 

significant effect of influenza vaccination on stroke risk 3, 4

 Stroke has been evaluated as an outcome in several observational studies, some of 

which have reported decreased risk with vaccination 5-8

 Benefit of influenza vaccination has been noted in some studies examining major 

cardiovascular outcomes (some including stroke within a composite outcome) 4,8

 Limitations:

–

–

–

–

Potential reduction in stroke risk varies and is not seen in all studies

Populations, study designs, outcome definitions, and analytic methods vary across studies

Observational data are more subject to bias

Overall limited data concerning specific influenza vaccines and stroke-specific risk

Influenza, Influenza Vaccination, and Stroke

1. Smeeth L et al, N Engl J Med 2004; 351: 2611-8

2. Zurrú MC et al, Stroke 2009; 40: 1986-90

3. Loeb M et al, Lancet Global Health 12 2022; 10: e1835-e1844 

4. Phrommintikul A et al, Eur Heart J 2011; 32: 1730–1735

5. Holodinsky JK et al, Lancet Resp Health 2022; 7: e914-e922 

6. Rodriguez-Martin 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 PatientCentered Clinical Research Network

 Data includes electronic health records 

associated with ambulatory, ED, and 

inpatient settings

 Covers all patients in participating 

health systems, or ~10% of the US 

population ages ≥65 years

 Used to rapidly assess incidence of 

stroke across diverse US population over 

the late Omicron period within 2022, 

with recent COVID-19 or influenza and 

incidence overall

HealthVerity

 Data includes medical claims from closed 

payor systems related to ambulatory, ED, 

and inpatient settings

 Data is linked to vaccination data from 

the Federal Retail Pharmacy Program

 Covers patients insured through 

Medicare Advantage, or ~25% of the US 

population ages ≥65 years

 Used to rapidly assess incidence of stroke 

across insured US population, with 

recent COVID-19 or influenza vaccination 

and incidence overall

Healthcare data sources used to describe current 

incidence of stroke
PCORnet© The National Patient-Centered 

Clinical Research Network

 Cohort definitions designed to capture 

incident stroke –

–

–

–

–

–

–

–

–

–

–

–

–

–

–

ICD10 diagnosis (I63.X)

Exclusion of patients with history of stroke

 Cohort definitions designed to capture 

patients 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, J11.2, 

J09.X, J10.8X, J11.8X)

COVID-19 medications

No COVID-19 in 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 post

HealthVerity

 Cohort definitions designed to capture 

incident stroke

ICD10 diagnosis (I63.X)

Inpatient place of service

Exclusion of patients with history of stroke

 Cohort definitions designed to capture 

recent bivalent mRNA and influenza 

vaccination

All applicable CVX, CPT/HCPCS, and NDC codes

No evidence of prior stroke/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 days

Recent vaccination: within 28 days following bivalent 

mRNA vaccination, flu vaccination, or 

coadministration of both vaccines

Methods used to describe current incidence of stroke
0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

*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 2022 Stroke 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 days

Adults ≥65 with 

COVID-19, 

-3 to 28 days

Groups presented are of the 

same age category and 

adjusted time at risk. Crude 

incidence within groups is not 

otherwise adjusted. 
0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

*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 2022 Stroke 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 days

Adults ≥65 with 

COVID-19, 

-3 to 28 days

Incidence 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 age category and 

adjusted time at risk. Crude 

incidence within groups is not 

otherwise adjusted. 
0

200

400

600

800

1000

1200

1400

1600

Stroke 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 million

All 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 days

Adults ≥ 65 with 

bivalent mRNA, 

0 to 28 days

Adults ≥65 with 

coadministration, 

0 to 28 days

All adults ≥65,

over 29 days*

Groups presented are of the same 

age category and adjusted time at 

risk. Crude incidence within groups 

is not otherwise adjusted. 
Statistical signal for 

ischemic stroke 

identified in VSD RCA 

monitoring

Ischemic 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, 

with continued review by VaST and colleagues

Continuing supplementary analyses to clarify the relationship between this signal 

and:

• 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 

with COVID-19 or influenza. Priorities include:

Increasing awareness of the risk of stroke with COVID-19 disease and influenza

– Continuing to encourage uptake of the bivalent COVID-19 boosters

Work group interpretation and next steps
 The COVID-19 ACIP Work Group remains confident in current COVID19 vaccine recommendations.

–No changes to current recommendations regarding 

coadministration of vaccines

 CDC and partners anticipate the opportunity to review and consider 

upcoming 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 Jackson

Acknowledgements

 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

 COVIDNet

 Adi 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 Hall

 Sara Oliver

 Katherine FlemingDutra

 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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