MedCheck in English No.27

Supplementary appendix
2023-9-15
MedCheck Editorial teamTable. Venous thrombosis mortality risk after SARS-CoV-2 vaccination (Data: England)•

If the age distributions of death from venous thrombosis in vaccinee were equal to that in the venous
thrombosis patients reported in the ref. 12], standardised mortality ratios (SMRs) were 5.64 (Pfizer)
and 6.30 (AstraZeneca. If they were qual to that in the reference population, SMRs were 5.41 (Pfizer)
and 7.02 (AstraZeneca) (Appendix7-9)
p-ys：person-yearsAppendix1： Calculation of venous thrombosis
deaths following SARS-CoV-2 vaccination.
• Hippisley-Coxs' paper's subjects were vaccinees
for first dose aged 16 years and over in England.
• Table 1 of the paper lists the number ofvaccinees and Table 3 of the paper lists thenumber of cases of venous thrombosis within
28 days of vaccination.
• There were the number of venous thrombosis
within 28 days after vaccination, excluding
deaths in supplementary table 7a (Sensitivityanalysis - 1) ; therefore by subtracting cases
excluding deaths from cases including deaths,deaths can be calculated.
• There are case definitions for venous
thrombosis in supplementary table 1 ; these are
pulmonary embolism, portal vein thrombosis
and other venous embolisms (ICD-10: I26, I81,I82).

Appendix2: Venous thrombosis mortality rate
in general population in England(2015-2019)
Agegroup(years)Venous thrombosis
deaths within
five years[15](N)

Population fortotal
five years[14](N)

Venousthrombosis
mortality rate(/100,000 pys)

16-29
30-39
40-49
50-59
60-69
70-79
80-89
>90

65
176
427872
1,668
2,742
3,558
1,459

52,397,619
36,952,299
36,556,960
36,793,199
29,533,992
21,976,076
11,148,041
2,474,607

0.12
0.48
1.17
2.37
5.65
12.48
31.92
58.96

pys: person-years

Appendix3: Subjects and outcome in this research
England population aged
over 16 years
SARS-CoV-2
Unvaccinated persons

SARS-CoV-2 vaccinee(first dose)

Venous thrombosis mortality within 28
days after vaccine dose ・・・(a)Comparison for this research
Population in 2015-2019(general population)*

Venous thrombosis mortality during
2015-2019 five years・・・(b)Venous thrombosis mortality rate ratio=(a)/(b)・・・Outcome* Venous thrombosis incidence was written on supplementary table 6 in reference [12].

Appendix4-1: diagnostic overlap

Appendix 4-2：Image of diagnostic overlap
Arterial thrombosis

Thrombocytopenia
Venous thrombosis

Ischemic stroke
Myocardial infarction

CVST

Other rare thrombosis event•

Venous thrombosis includes cerebral venous sinus thrombosis and overlaps some thrombocytopenia cases. However, the number ofcerebral venous sinus thrombosis(CVST) deaths(AstraZeneca:0, Pfizer:0) and thrombocytopenia deaths (AstrZeneca:20 ,Pfizer:5)
are sufficiently small compared to venous thrombosis deaths (AstraZeneca: 499, Pfizer: 338) within 28 days following vaccination.
Therefore, it is reasonable to compare venous sinus thrombosis mortality between the vaccinee and the reference population.

•Ischemic heart disease and myocardial infarction are included in arterial thrombosis, and there is likely to be diagnostic overlap
between ischemic heart disease and myocardial infarction.

Appendix5:Culculation for person-time
following SARS-CoV-2 vaccination

Start of vaccine program

AstraZeneca: N= 19,608,008
Pfizer: N= 9,513,625

VaccineeFirst dose

1st dose28days

The area enclosed by the rectangle indicates the observed person-years of first-time
vaccine recipients.

Appendix6-1: Percent coverage of Pfizer’s vaccine
by age group
Age
group
(years)Vaccinated
[12]
(N)

Population in
2021 [14](N)

Percent coverageof vaccine
(%)

16-29

685,100

9,674,878

7.08%

30-39

786,815

7,753,274

10.15%

40-49

1,030,833

7,166,966

14.38%

50-59

1,486,062

7,724,309

19.24%

60-69

1,692,935

6,057,542

27.95%

70-79

1,934,771

4,875,028

39.69%

80-89

1,619,781

2,307,038

70.21%≥ 90

277,328

509,436

54.44%

Total

9,513,625

46,068,471

20.65%

Appendix6-2: Percent coverage of AstraZeneca’s
vaccine by age group
Agegroup(years)Vaccinated[12](N)

Population in
2021 [14](N)

Percent coverageof vaccine
(%)

16-29

1,060,982

9,674,878

10.97%

30-39

1,551,528

7,753,274

20.01%

40-49

3,803,176

7,166,966

53.07%

50-595,564,739

7,724,309

72.04%

60-69

3,988,397

6,057,542

65.84%

70-79

2,782,590

4,875,028

57.08%

80-89

643,058

2,307,038

27.87%≥ 90

213,537

509,436

41.92%

Total

19,608,007

46,068,471

42.56%

Appendix7. Predicted venous thrombosis deathsby age group (sensitivity analysis-1)
Age group Venous thrombosis cases*1 Predicted venous thrombosis deaths*2(years)
(N)
(N)
16-29
a1
A1=T×a1/t1
30-39
b1
B1=T×b1/t1
40-49
c1
C1=T×c1/t1
50-59
d1
D1=T×d1/t1
60-69e1
E1=T×e1/t1
70-79
f1
F1=T×f1/t1
80-89
g1
G1=T×f1/t1≥ 90
h1
H1=T×h1/t1
Total
t1(=a1+b1+c1+d1+e1+f1+g1+h1)
T*1:a1,b1,c1,d1,e1,f1,g1, and h1 were calculated from supplementary table 6 reported in the ref.[12].
*2: “T” was calculated according to the method in Appendix 1.

Appendix8. Predicted venous thrombosis deathsby age group (sensitivity analysis-2)
Age group(years)
16-29
30-39
40-49
50-59
60-69
70-79
80-89
≥ 90
Total

Venous thrombosis deathsin the reference population*1(N)a2b2c2d2e2
f2
g2
h2t2(=a2+b2+c2+d2+e2+f2+g2+h2)

Anticipated venous thrombosis
deaths*2(N)A2=T×a2/t2
B2=T×b2/t2
C2=T×c2/t2
D2=T×d2/t2
E2=T×e2/t2
F2=T×f2/t2
G2=T×g2/t2
H2=T×h2/t2
T*1:a2,b2,c2,d2,e2,f2,g2,and h2 were calculated from the reference population [15].
*2: “T” was calculated according to the method in Appendix 1.

Appendix9-1: Sensitivity analysis for Pfizer’s vaccine
Sensitivity analysis-1

Sensitivity analysis-2
MRR (95% CI)

MRR (95% CI)
16-29

30.73(3.65-115.44)

30-39

18.87(6.40-43.49)

40-49

14.25(7.56-24.55)

50-59

9.95(6.51-14.59)

60-69

7.01(5.20-9.25)

70-79

4.56(3.63-5.67)

80-89

2.77(2.27-3.34)

90 and over3.58(2.60-4.82)

SMR

5.41(4.74-6.17)
1

10100

Abbreviations
MRR: mortality rate ratio, 95%CI: 95% confidence interval, SMR: standardized mortality ratio

Appendix9-2: Sensitivity analysis for AstraZeneca’s vaccine
Sensitivity analysis-1

Sensitivity analysis-2
MRR (95% CI)

MRR (95% CI)

16-29

86.73(37.50-176.39)

16-29

29.29(5.80-90.09)

30-39

24.89(13.37-42.80)

30-39

14.13(6.01-28.44)

40-49

7.28(4.65-10.91)

40-49

5.70(3.42-8.97)

50-59

6.80(5.24-8.69)

50-59

3.92(2.78-5.39)

60-69

6.47(5.29-7.83)

60-69

4.39(3.44-5.53)

70-79

6.01(5.09-7.05)

70-79

4.68(3.88-5.61)

80-89

5.16(4.09-6.43)

80-89

10.28(8.73-12.04)

90 and over3.06(2.05-4.39)

90 and over6.87(5.29-8.79)

SMR

6.30(5.67-7.01)

SMR

7.02(6.37-7.75)

110100110100Abberviations
MRR: mortality rate ratio, 95%CI: 95% confidence interval, SMR: standardized mortality ratio

Appendix10: Hippisley-Coxs’ research methods
Vaccine dose②③④⑤Subjects: venous thrombosis
cases in vaccinee①Baseline

Pre-risk period (Day -28 to -1)

Day0

Risk period (Day1 to28)

Baseline

Timeline①,⑤ baseline period incidence rate:1.00②Pre-risk period (Day -28 to -1) IRR: 0.64(0.60-0.68) (Pfizer) or 0.69 (0.66-0.73) (AstraZeneca)③Day0 IRR: 0.35 (0.24-0.52) (Pfizer) or 0.46 (0.35-0.60) (AstraZeneca)
Onset of venous thrombosis④Risk period(Day 1 to 28)meta summary IRR:0.93(0.89-0.98)•Abbreviation IRR: incidence rate ratio (95% confidence interval)•

Self-controlled case series is a method where the sum of the blue line areas for each period is the respective observed person-years.

•People who develop venous thrombosis on the day of planned vaccination avoid vaccination. This is the reason incidence is lowest on the day0.

Appendix11-1: Incidence rate ratio for venous
thrombosis following Pfizer’s vaccine
Apparent IRR
Apparent venous thrombosis
IRRHVE adjusted IRR

Day1-70.92(0.83-1.01)
Day1-72.63(1.76-3.92)

Day8-140.99(0.90-1.08)
Day8-14

2.83(1.90-4.21)

Day15-21

0.91(0.82-0.99)
Day15-21

2.60(1.74-3.88)

Day2-280.89(0.81-0.99)
Day2-28

2.54(1.71-3.79)

0.93(0.89-0.98)
Day1-28 meta summary Day1-28 meta summary

2.66(1.80-3.92)

10.1

110

Abbreviations HVE: healthy-vaccinee effect, IRR: Incidence rate ratio
The apparent risk of developing venous thrombosis is below 1 (Apparent IRR), due to HVE ('all who were able to be vaccinated','healthy persons with the lowest frequency of venous thrombosis immediately before vaccination'). A comparison correcting for thisbias (incidence on the day of vaccination: 0.38, HVE adjusted IRR) shows an increased venous thrombosis after vaccination

Appendix11-2: Incidence rate ratio for venous
thrombosis following AstraZeneca’s vaccine
Apparent IRR
Day1-70.92(0.85-1.00)

Day8-141.10(1.02-1.18)

Day15-21

1.03(0.96-1.12)

Day2-280.97(0.89-1.06)

Day1-28 meta summary

1.00(0.93-1.09)

HVE adjusted IRR

1Abbreviations HVE: healthy-vaccinee effect, IRR: Incidence rate ratio
The apparent risk of developing venous thrombosis is below 1 (Apparent IRR), due to HVE ('all who were able to be vaccinated','healthy persons with the lowest frequency of venous thrombosis immediately before vaccination'). A comparison correcting for thisbias (incidence on the day of vaccination: 0.46, HVE adjusted IRR) shows an increased venous thrombosis after vaccination