7/31/2019 13-3-mmrv

1/29

Evaluation of MMRV and FebrileSeizures: Updated VSD Analyses with

Chart Review Results

Nicola Klein, MD, PhDNorthern California Kaiser Permanente

and the Vaccine Safety Datalink MMRV Team

Meeting of the Advisory Committee on Immunization PracticesJune 25, 2009

7/31/2019 13-3-mmrv

2/29

CDC, our planners, and the VSD investigatorswish to disclose they have no financialinterests or other relationships with themanufacturers of commercial products,suppliers of commercial services, or

commercial supporters except as notedbelow:

Dr. Nicola Klein reports receiving research

support from Merck.

7/31/2019 13-3-mmrv

3/29

VSD and MMRV RCA Study Overview

VSD Comprised of 8 HMOs* Data on >8 million members

Rapid Cycle Analysis (RCA) overview. Utilizes data which is updated weekly on all vaccines and

all outcomes. Analyses on outcomes specific for each vaccine areconducted every week.

Each RCA study has a lead PI from one of the VSD sites.

Northern California KP is the lead for the MMRV RCAStudy

* Group Health Cooperative, KP Colorado, KP Northwest, Harvard Pilgrim HealthCare, Health Partners, Northern California KP, Marshfield Clinic and SouthernCalifornia KP.

7/31/2019 13-3-mmrv

4/29

MMRV Seizure Results PreviouslyPresented to ACIP

We monitored for seizures after first dose MMRV in the ERand inpatients during post-vaccine days 0-42 among 12-23month olds.

We detected a signal for seizures in the 042 day periodfollowing MMRV compared with historical rates in MMRrecipients.

Significant clustering of seizures on days 710 after both

MMRV (N= 43,353) and MMR + varicella (V; N= 314,599 )vaccines using temporal scan statistics.

We reviewed charts for febrile seizures 710 days aftervaccination for both MMRV (N=45) and MMR + V (N=132)

through 2007.

Odds Ratio 2.3 (95% CI 1.6, 3.2)1 additional febrile seizure for every 1,923

MMRV doses administered instead of MMR + V

7/31/2019 13-3-mmrv

5/29

Remaining Questions

1. Chart confirmation of febrile seizures outside 7-10day risk period.

2. The risk for seizures after MMRV vs MMR + V indifferent time windows:

- 0-42 days- 0-30 days, 5-12 days and 13-30 days to directlycompare with the Merck-sponsored Phase 4

study.

3. Further investigations of risk for seizures in 4-6

year olds, particularly evaluating for excess risk.

7/31/2019 13-3-mmrv

6/29

Seizures Days 0-42 after Vaccine, 2000-11/2008

0

5

10

15

20

25

30

35

40

45

50

0 5 10 15 20 25 30 35 40

Days after Vaccine

Rateper100KD

o

ses

MMRV MMR+V MMR VZV

Vaccine Days RR P ValueMMRV

(N=83,107)

8-10 7.6 0.0001

MMR + V(N=376,354)

7-10 4.0 0.0001

MMR(N=145,302) 7-11 3.7 0.0001

Varicella(N=107,744)

21-24 2.0 0.35

Seizures Among 12-23 Month Olds afterFirst Dose of Vaccine : 2000-2008

Temporal Scan

7/31/2019 13-3-mmrv

7/29

Fever 0-42 days after Vaccine, 12-23 Months of Age, 2000-11/2008

0

50

100

150

200

250

300

350

400

450

0 5 10 15 20 25 30 35 40

Days after Vaccine

Rateper100KD

oses

MMRV MMR+V MMR VZV

Outpatient Fever Visits Among 12-23 Month Oldsafter First Dose of Vaccine: 2000-2008

Vaccine Days RR P ValueMMRV

(N=83,107)7-10 6.1 0.0001

MMR + V(N=376,354)

7-10 4.4 0.0001

MMR(N=145,302)

7-10 4.3 0.0001

Varicella(N=107,744)

9-14 1.2 0.06

Temporal Scan

7/31/2019 13-3-mmrv

8/29

1. Chart confirmation of febrileseizures outside 7-10 day risk

period.

7/31/2019 13-3-mmrv

9/29

Chart Review Plan

1. All seizures 0-42 days after MMRV.

2. All seizures 7-10 days after MMR + Varicella.

3. A sample of seizures 0-6 and 11-42 days afterMMR + Varicella.

- Equivalent to the number of MMRV seizuresduring days 0-6 and 11-42.

7/31/2019 13-3-mmrv

10/29

Seizure Cases for Chart Review

Charts Reviewed

N=451

Not Acute SeizureN=8

No InformationN=19

Confirmed Acute SeizuresN=424 (94%)

Sampled for Chart ReviewN=491

Missing chartN=40

7/31/2019 13-3-mmrv

11/29

No Difference in Chart Confirmation Rate for AcuteSeizures Between MMRV and MMR + Varicella

MMRVN=183 (%)

MMR + VN=268 (%)

Total*N=451 (%)

Acute Seizure (any type) 172 (94) 252 (94)

5 (2)

11 (4)

Not an Acute Seizure 3 (2)

424 (94)

8 (2)

No Information 8 (4) 19 (4)

*12-23 Month Olds

7/31/2019 13-3-mmrv

12/29

Most Events Diagnosed as Febrile Seizures

MMRVN=183 (%)

MMR + VN=268 (%)

Total*

N=451 (%)Febrile seizure 160 (87) 232 (87)

36 (13)Febrile seizure not confirmed 23 (13)

392 (87)

59 (13)

*12-23 Month Olds

7/31/2019 13-3-mmrv

13/29

MMRV and MMR + V Have SimilarConfirmation Rates

MMRV(%)

MMR + V(%)

PValue

90 0.55

0.7482

Both* (%)(95% CI)

Confirmed FebrileSeizure: days 7-10 92 90 (87, 94)

83 (78, 88)Confirmed FebrileSeizure: days 0-6, 11-42

84

*12-23 Month Olds

7/31/2019 13-3-mmrv

14/29

Chart Review Findings AmongFebrile Seizure Cases in 12-23 Month Olds

MMRV(%)

MMR + V(%)

PValue

First Seizure Event* 16 22

29Positive Family Historyfor Seizure**

30

0.21

0.90

* Data missing from 58 charts (15%)

** Data missing from 186 charts (47%)

7/31/2019 13-3-mmrv

15/29

2. The risk for seizures after MMRV

vs MMR + V in different timewindows:

- 0-42 days- 0-30 days, 5-12 days and 13-30days to directly compare with the

Merck-sponsored Phase 4 study.

7/31/2019 13-3-mmrv

16/29

Risk of Febrile Seizure 7-10 days after MMRV

Compared to MMR + Varicella : 2000-2008Source Relative

Risk*95%

Confidence

Interval

P Value

MMRV vsMMR + V

AutomatedData

1.98 1.43, 2.73

1.44, 2.90

7/31/2019 13-3-mmrv

17/29

Risk of Febrile Seizure 0-42 days after MMRV

Compared to MMR + Varicella : 2000-2008

Source Relative

Risk*

95%

ConfidenceInterval

P Value

MMRV vs

MMR + V

Automated

Data

1.42 1.11, 1.81

1.11, 1.92

0.005

0.008MMRV vsMMR + V

ChartConfirmed FS

1.46

*Poisson Regression adjusted for age, VSD site and each year and each respiratory season.

Risk Difference6.2/10,000 doses (95% CI 2.0, 9.5)

7/31/2019 13-3-mmrv

18/29

Case Centered Logistic Regressions: ChartConfirmed Febrile Seizures MMRV vs MMR + V

RiskWindow

ControlWindow

Source OddsRatio*

(95% CI)

P Value

7-10 days 43-180 days ChartConfirmed FS

Chart

Confirmed FS

1.92(1.39, 2.66)

7/31/2019 13-3-mmrv

19/29

Post-Vaccination

Period (days)

Relative Risk*(95% CI)

P Value Risk Difference/10,000 doses

(95% CI)5-12 1.86 (1.32, 2.61) 0.0003

0.677

0.023

13-30 0.91 (0.60, 1.39)

4.1 (2.1, 5.4)

-0.4 (-2.9, 1.2)

0-30 1.44 (1.05, 1.97) 4.7 (0.7, 7.6)

Risk of Chart Confirmed Febrile Seizures MMRV

Compared to MMR + V During Different Post-VaccinationTime Windows: 2000-2008

*Poisson Regression adjusted for age, VSD site each year and each respiratory season.

7/31/2019 13-3-mmrv

20/29

3. Further investigations of risk forseizures in 4-6 year olds, particularly

evaluating for excess risk.

7/31/2019 13-3-mmrv

21/29

Days 7-10 Medical Record Review Among

4-6 Year Olds 4 seizures during days 7-10 after MMRV, 0 After MMR + V.

Only 1 of the 4 cases diagnosed as febrile seizure.

Risk Among 4-6 Year Olds During Days 7-10

Observed FebrileSeizures/doses

Upper Limit95% CI

MMRV 1/84,653 1/15,194MMR + V 0/64,663 1/17,259

At most, for every ~15,000 MMRV doses given, 1 seizure will

occur 7-10 days after vaccination, even if all the risk isexcess risk.

7/31/2019 13-3-mmrv

22/29

Summary Among 12-23 month olds after first vaccine

dose, fever and seizure are elevated 7-10days after all measles-containing vaccines.MMRV increases fever and seizure abouttwice as much as does MMR + V.

Analyses of chart reviewed febrile seizuresconfirmed a 2 fold increase risk of febrile

seizures on days 7-10 following MMRV ascompared to MMR + V.

S

7/31/2019 13-3-mmrv

23/29

Summary

The increased risk for seizures observed duringother time windows is due to the risk during the7-10 day window.

Among 12-23 month olds after first vaccinedose, for every 2,300 MMRV doses given insteadof MMR + V, 1 additional febrile seizure will

occur 7-10 days after vaccination.

Among 4-6 year olds, we found no evidence ofelevated seizure risk during the six weeks afterMMRV.For the 7-10 days after vaccination, we can rule

out an absolute risk greater than 1 febrile seizure

per 15,000 doses of MMRV.

Seizures Days 0 42 after Vaccine 2000 11/2008

7/31/2019 13-3-mmrv

24/29

Seizures Days 0-42 after Vaccine, 2000-11/2008

0

5

10

15

20

25

30

35

40

45

50

0 5 10 15 20 25 30 35 40

Days after Vaccine

Ratepe

r100KD

oses

MMRV MMR+V MMR VZV

MMRV vs MMR + VRelative

Risk 7-10Days

95%Confidence

Interval

2.04 1.44, 2.901 additional febrile seizure per

2,300 MMRV doses insteadof MMR + V

7/31/2019 13-3-mmrv

25/29

MMRV TeamNorthern California Kaiser Permanente Ned Lewis, MPH Bruce Fireman, MS Roger Baxter, MD Paula Ray, MPH Pat Ross Ajit DeSilva

Harvard Pilgrim Tracy Lieu, MD, MPH Katherine Yih, PhD, MPH

Ruihua Yin, MS Sharon Greene, PhD, MPH Martin Kulldorff, PhD

CDC

Eric Weintraub James Baggs, PhD Julianne Gee, MPH John Iskander, MD, MPH

Karen Broder, MD ACIP MMRV Vaccine Safety Working Group

The findings in this presentation are those of the authors and do not necessarilyrepresent the official position of the Centers for Disease Control and Prevention.

Many thanks to VSD

7/31/2019 13-3-mmrv

26/29

Additional Slides

7/31/2019 13-3-mmrv

27/29

Number of Seizures and Seizure Rates in

Automated Data Among 1223 Month Olds

MMRVN=83,107

MMR+VN=376,354

Days post-vaccination

Seizures UnadjustedRate/1000

person-years

Seizures UnadjustedRate/1000

person-years710 77 84.6 174 42.2042 189 19.5 598 13.7

512 84 46.1 213 25.81330 44 10.7 213 11.5030 147 21.2 478 15.2

189/83,107 =

1 in 439 DosesSeizure Rate

598/376,354 =

1 in 630 dosesSeizure Rate

Assessing Risk for Seizures after MMRV

7/31/2019 13-3-mmrv

28/29

Assessing Risk for Seizures after MMRVor MMR + V Using Case-Centered Method

1. Case-centered method is a variation of a self-controlled approach.

2. Included all seizures which occurred 0-180 days after

MMRV and MMR + V.

3. Comparing MMRV to MMR + V, was the seizure morelikely to occur during the control period (post-vaccinedays 43-180) or during a risk window (post-vaccine

days 7-10 or 0-42)?

7-10 days before seizure?

0-42 days before seizure?

43-180 days before seizure?

AllSeizures

0-180 days

MMRV vs MMR + V During Days 0-42 Days

7/31/2019 13-3-mmrv

29/29

s u g ays 0 aysAmong 12-23 Month Olds