M
C

August-December

2021

Volume 7ED
N 21-22

HECKo

Editorial
Trick of clinical trials
New Products
Baricitinib for the treatment of COVID-19
Adverse Reactions
COVID-19 vaccine:

Strong association with cardiovascular death

CONTENTS （August-December 2021, Vol. 7, No. 21-22）
Editorial
Trick of clinical trials

26

New Products
Baricitinib for the treatment of COVID-19
Data are seriously inconsistent and unreliable

27

Adverse Reactions
Vaccines for COVID-19
Strong association with cardiovascular death
Causal link between vaccination and subsequent death
Mortality risk of vaccination is 7 times higher in 20s
3 teens died: Causal link is suspected

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32
38
41
44

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M
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ED

Editorial

HECK

Trick of clinical trials
Translated from the Editorial in Med Check(in Japanese) July 2021 ; 21 (96) ： 75

Large-scale randomised controlled

however, we have noticed that tricks aretrials (RCTs) are of paramount importanceincluded intentionally in quite a few clinicalto support the efficacy and safety oftrials. For example, among the 14 RCTs

pharmaceutical candidates and to provide

investigating mortality effects of antipyretic

the base of approval. The role of the national

therapy in patients with severe infections,

regulator is to identify falsified data inin 11 RCTs improper study design and/or

the dossier of approval and approve only

real biases (not a risk of bias) in baseline

effective and safe medicines through carefulcharacteristics (such as renal failure) were

examination. The reason why we emphasize

found. Meta-analysis results using data fromsuch an obvious thing here is that we were

3 remaining studies showed that antipyretic

surprised at the complexity of the tricks oftreatment significantly increased mortality by

RCTs of baricitinib (p27).

4.4 times (unpublished data).

We have never encountered such strange

Review by the national regulatory bodies

phenomena as in the RCTs of baricitinib:

has also been exhibiting complicated aspects.

the incidences of almost all adverse events

U.S. Food and Drug Administration (FDA)

were significantly lower in baricitinib

approved aducanumab (anti-amyloid β agent

group. Incidence of acute kidney injury

for Alzheimer disease) even though almost

was 33% lower, although dose-dependent

all experts in the advisory panel concluded

nephrotoxicity was evident in animal studies.

against approval due to insufficient evidence.

At first, we suspected the difference

U.S. Public Citizen Health Research Group,in the baseline characteristics of renal

one of the members of International Society

failure, but we found no difference.

of Drug Bulletins (ISDB) says " FDA’s decision

Proportion of corticosteroid users was

to approve aducanumab for Alzheimer’sslightly lower without significance. Afterdisease shows reckless disregard for science,

careful examination the mystery was solved.

severely damages agency’s credibility".

Infect ions were halved by baricit inib,

New pro ducts approved not only inalthough it is a strong immunosuppressantJapan, but also in the United States, can beand should increase infections (p27).

unreliable. Therefore, we have to carefully

Clinical trials should not have any tricks atfirst place as they are not a magic. In reality,

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Aug.-Dec. 2021/ Vol.7 No.21-22

examine tricks in clinical trials and in thereview process by regulators.

New Products
Baricitinib for the treatment of COVID-19(trade name Olumiant)Data are seriously inconsistent and unreliable
Translated and revised from Med Check (in Japanese) July 2021 ; 21 (96):82-85
Med Check Editorial Team

Abstract● Remdesivir and dexamethasone have already been approved for the treatment of COVID-19, but only
dexamethasone for severe cases is useful.
● In April 2021, the emergency use of a potent immunosuppressant, baricitinib in combination with remdesivir wasapproved for COVID-19.
● In a randomized controlled trial (RCT) using remdesivir in all adult patients with COVID-19, baricitinib and placebo
were compared as concomitant medications (ACTT-2 trial). The primary outcome (the median number of days torecovery) is reported to be significantly shorter for baricitinib by 1 day as compared to 8 days in the placebo group.
However, the patients who had the significantly shorter number of days to recovery were only those with severity
level 6 (using high-flow oxygen inhaler or non-invasive ventilator) at baseline, and no significant difference wasfound in other patients. This is an unnatural result.
● Since baricitinib is an immunosuppressant, infectious diseases other than COVID-19 should increase as adverse
events in baricitinib group as warned in the package insert. However, in baricitinib group, the incidence of infection
was only about half of that in the placebo group (odds ratio 0.54). This is totally incomprehensible.
● In this study, corticosteroid users were about 5.7 times more likely to have infections and 6.6 times more likely
to die from adverse events than non-users. It is inferred that the number of corticosteroid users was smaller inbaricitinib group, although the difference was not significant, and it is likely to have contributed to the unnatural
result.
● In the first place, ACTT-1 trial, which is supposed to be the evidence for the effect of remdesivir is not valid.
Moreover, it was also proven ineffective in the meta-analysis including the largest WHO trial. ACTT-2 study cannot
be the evidence for the efficacy of baricitinib as it involved concomitant use of the ineffective medicine.
Conclusion: Data manipulation is suspected. This study does not provide a basis for efficacy and safety.

Keywords:
immunosuppressants, steroids, infectious diseases, renal disorders, remdesivir

Introduction"rheumatoid arthritis (including prevention of structural
damage to joints) for which existing treatments are

Baricitinib (trade name: Olumiant) was approved ininadequate [2]” in Japan in July 2017. In December

April 2021 for the treatment of COVID-19, following

2020, an indication of refractory atopic dermatitis,

remdesivir and dexamethasone, on the condition that itin which corticosteroids and tacrolimus had been

is used in combination with remdesivir [1].

ineffective, was added. Strictly speaking, it is not a drug

Baricitinib was already approved for the indication ofwith a new ingredients, but with an expanded indication
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Aug.-Dec 2021/ Vol.7 No.21-22 ・ Page 27

New Products(new indication).

Usually, infectious diseases heal naturally because

What is ACTT-2 trial?

the body develops fever and releases cytokines, such

ACTT-2 trial is a randomized placebo controlled trial

as interferon, to kill the virus. However, in COVID-19,(RCT), involving 1033 adult in-patients with COVID-19

the causative virus, SARS-CoV-2 (novel coronavirus), may(Note). Baricitinib or placebo was used in 515 patients

have a property to escape the attack of cytokines, andand 518 patients, respectively, for up to 14 days, and thecytokines are overproduced, causing cytokine storms. It

efficacy and safety were compared [1,4].

is thought that it may attack the host's tissues and leadto aggravation [3].

The primary outcome was time to recovery, and thesecondary outcome was clinical symptoms at day 14.

Baricitinib inhibits the action of a protein called Janus“Recovery” in the primary outcome was defined as

kinase (JAK), which is deeply involved in the action ofscores 1 (not hospitalized, no limitations on activities) to 3

a protein and one of the cytokines called interleukin-6(hospitalized, not requiring supplemental oxygen and(IL-6). This JAK inhibitory effect is thought to suppress

no longer requires ongoing medical care) in an 8-point

cytokine storms and inflammation [1].

ordinal scale (Table).

It is expected that this effect will contribute to

In addition, there is a risk of developing venous

the prevention of COVID-19 aggravation, and an

thromboembolism (VTE) due to SARS-CoV-2 infection

international joint clinical trial (ACTT-2) was launched initself. Moreover, the results of clinical trials for otherMay 2020. Six months later, in November, in the United

indications, such as rheumatoid arthritis, have shown

States, Food and Drug Administration (FDA) granted anthat baricitinib has a risk of developing VTE. For theseemergency use authorization and baricitinib was began

reasons, in ACTT-2 study, prophylactic measures

to be used in critically ill patients as "a drug that may

for VTE were taken in all patients unless they have

help prevent the aggravation of COVID-19." In Japan, it

contraindications, such as an active bleeding event or

was approved as a COVID-19 therapeutic agent based ona history of heparin-induced thrombosis. At baseline or

the results of the ACTT-2 study [1].

during the study period, heparin (including small molecule

ACT T-2 study [1,4] reported that the efficacy

heparin) was mainly used in 495/507 patients (97.6%)

o u t w e i g h e d t h e h a r m f o r C OV I D - 1 9 . H o w e v e r,

in baricitinib group and 498/509 patients (97.8%) in

baricitinib has already been used for rheumatoid

placebo group for the purpose of preventing thrombosis.

arthritis, and the following adverse reactions related toimmunosuppressive action have been reported; serious
infections including herpes zoster and tuberculosis,
malignant tumors, cytopenia, lipid abnormalities, venous

Note :The patients included were those who had at least oneof the following conditions, were moderately or severely ill,and fall under scores 4-7 in Table; (1) Radiographic infiltrates byimaging (chest x-ray, CT scan, etc.), (2) SpO2 ≦ 94% on room air,thromboembolism and diverticulitis [2]. It never is a safe(3) Requiring supplemental oxygen, (4) Requiring mechanicaldrug.

ventilation or extracorporeal membrane oxygenation (ECMO).

In addition, infliximab and etanercept were usedunsuccessfully to prevent cytokine storms in severe
sepsis. Many clinical trials have been conducted toinvestigate the effect of tocilizumab for COVID-19, but
no efficacy has been proven [5].
It is thought that corticosteroid, dexamethasone iseffective not because it suppresses immune function, but
because it temporarily replaces glucocorticoid that has
declined to be excreted in spite of increased demand due
to aggravation [6].
This article analyzes the result of ACTT-2 and evaluates
the efficacy and safety for COVID-19.
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Aug.-Dec. 2021/ Vol.7 No.21-22

Table: Ordinal scale for severity

Effective only for score 6 (if no bias in baselinecharacteristics)

Adverse events and bias in baseline characteristics
The incidence of all adverse events in ACTT-2 study

The primary outcome, median time to recovery (28was significantly lower in baricitinib group: 41.4%

days after randomization), was 7 days in baricitinib groupin baricitinib group and 47.5% in placebo group (p =and 8 days in placebo group, and it was reported that

0.0495). The incidence of adverse events that had led

baricitinib significantly shortened the time to recovery

to death was 3.7% and 6.1%, respectively, and noby 1 day. The hazard ratio was 1.16 (95% CI: 1.01-1.32).

significant difference was found. However, the incidence

However, when time to recovery was compared basedof adverse events that had led to discontinuation wason the severity at enrollment, it was shortened only inreported to be significantly lower in baricitinib grouppatients with a score of 6 (hospitalized, on non-invasive(6.7% vs. 11.6%, odds ratio:0.54, p = 0.007). The difference

ventilation or high flow oxygen devices) in baricitinib group.

in the incidence of acute renal injury or renal failure

Time to recovery was 10 days in baricitinib group andwas particularly marked (1.4% vs. 4.1%, odds ratio:0.33,

18 days in placebo group.

p=0.008) (Figure 2).

In patients with milder (scores 4 and 5) or severer (score

In general, if the baseline characteristics of treatment7) conditions at enrollment, there was no difference ingroup and control group are similar, even if the targetedtime to recovery between baricitinib group and placebo

outcome, reduction of a disease, is achieved in thegroup. In patients with score 4 (no supplemental oxygen

former, the incidence of adverse events tend to be similar

required), time to recovery was shorter in placebo group:in both groups or slightly higher in treatment group.

5 days in baricitinib group and 4 days in placebo group.

Moreover, even if the incidence of minor adverse events

In patients with score 5 (supplemental oxygen only), it was

is significantly higher in treatment group, if there is no

5 days in baricitinib group and 6 days in placebo group.

significant difference in the incidence of major adverse

In patients with score 7 (invasive mechanical ventilation or

events, it is considered that benefit outweighs harm.

ECMO), there was no significant difference (hazard ratio:
1.08, 95% CI: 0.59-1.97) (Figure 1).

However, in ACTT-2 study, how adverse eventsoccurred is totally different from the general tendency

Furthermore, exactly the same tendency was observed

mentioned above. The study showed unprecedented

in one of the secondary outcomes, "clinical status using

results, in which all serious adverse events, particularly

ordinal scale at 14 days after randomization".
Mortality rate at day 28 from the start of the study
was 5.1% in baricitinib group, and 7.8% in placebogroup (hazard ratio:0.65, 95% CI :0.39-1.09), which showed

Figure2: Infectious diseases are reduced by
an immunosuppressant?

lower tendency in baricitinib group, although it was not
significant.
Figure1: Time to recovery (median days at the time point of day 28)

AEs: Adverse Events, AKI/RF: Acute kidney injuries or Renal failure,* Since the median cannot be estimated for severity score 7 group atbaseline, the lower limit of the 95% CI is shown.

Immunosuppressants usually increase new infections, but baricitinib showed
the opposite results.
There is a possibility of substantial bias in any baseline characteristics. Thatmay be the reason why there were fewer important adverse events inbaricitinib group.

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Aug.-Dec 2021/ Vol.7 No.21-22 ・ Page 29

New Products
Figure3: Corticosteroid users are at high risk of new infections
and deathcorticosteroid users, respectively (Figure 3). Furthermore,
the analysis of the data in the supplementary appendix
of the published paper [4] showed that the risk of new
infection was 5.7 times higher in corticosteroid users(Figure 3).

Therefore, the slight difference in the number ofcorticosteroid users in baricitinib group has reduced
new infection and its complication, such as sepsis andacute renal failure, and has slightly shorten the time torecovery apparently. As a result, it helped to produce
favorable result for baricitinib group.
Figure 3 is made by using the data from Table 18 in p.25 of the examination
report by PMDA [1]. The proportion of corticosteroid users tended to belower in baricitinib group (20.8% vs. 23.2% , odds ratio: 0.87, p = 0.31). Even
though this is a slight difference, if presence or absence of corticosteroids has
produced difference in prognosis as shown in this figure, it may affect thecourse of the diseases and may result in the differences of adverse events asshown in the Figure 2.

In addition, a toxicity study conducted with baricitinib
for the indication of rheumatoid arthritis showed dosedependent increase in renal toxicities in animals [2].
Considering these, it is extremely unnatural that acuterenal disorder occurred markedly less frequently inbaricitinib group.
Further examination revealed that no difference wasobserved in baseline renal function in both groups.

that led to discontinuation including acute renal injury

However, as explained above, suppose that the slightand renal failure, occurred significantly less frequently in

difference in the number of corticosteroid users hastreatment group. At the time of initial examination of thegreatly affected the outcome, the difference in all adverse

study, we strongly suspected that baseline renal function

events and apparent efficacy can be explained. Thismay be seriously biased. However, we found totally nostrongly implies the possibility of data manipulation.

bias in the baseline renal function.

Venous thromboembolism ( VTE) can also occur

Among all the adverse events reported, infection

as a complication of COVID-19 itself [7]. In addition,is the most problematic. Since baricitinib is a potent

baricitinib increases the risk. Therefore, thrombolytic

immunosuppressant, it usually increases infection in

agents were used in almost all the patients. Nevertheless,treatment group. This is also warned in the package

it occurred more frequently in baricitinib group than in

insert. However, the incidence of infection was also

placebo group and this cannot be overlooked as a serious

significantly lower in baricitinib group: 47 cases (9.3%) in

harm.

baricitinib group and 81 cases (15.9%) in placebo group(odds ratio:0.54, 95%CI:0.37-0.7 p=0.0014)(Figure 2).

WHO does not recommend remdesivir

The original data were not included in the main report

Remdesivir is used as a basal agent for the treatment[4a], and this is calculated based on the total numberof COVID-19 in this study. However, ACTT-1 study,of infection-related adverse events in Table S11 inwhich is used as evidence to support the efficacy ofSupplement of the published paper [4b].

remdesivir, is not reliable [8]. Moreover, a meta-analysis

At baseline, the number of corticosteroid users waswhich included the largest study conducted by the Worldsmaller in baricitinib group, although the difference was

Health Organization (WHO) showed that remdesivir is

not significant: 20.7% in baricitinib group and 23.2% in

ineffective, thus WHO does not recommend its use [9].

placebo group. However, the analysis of the data from

From these facts, it can be concluded that thatthe examination report by Pharmaceuticals and Medical

baricit inib + remdesivir combinat ion therapy is

Devices Agency (PMDA) [1] revealed that the risk of fatal

ineffective for severe pneumonia caused by COVID-19.

adverse events and serious adverse events is 6.6 times

Baricitinib should not be used.

and 7 times higher in corticosteroid users than in nonPage 30 ・ MED CHECK

Aug.-Dec. 2021/ Vol.7 No.21-22

In practiceApparent efficacy, such as faster recovery by 1 day andtendency of improved clinical symptoms as comparedwith placebo group, were observed only in the subgroup

References
1) Olmient. Examination Report by PMDA (Use for pneumonia by SARS-CoV-2
infection)2) Olmient. Examination Report by PMDA and summary basis of approval (Use for"Rheumatoid Arthritis when other treatment is ineffective")3) Felsenstein S, Herbert JA, McNamara PS, Hedrich CM. COVID-19: Immunology andtreatment options. .Clin Immunol. 2020 Jun;215:108448. PMID: 32353634

of patients whose severity was score 6, and this is4a) A.C. Kalil et al. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19.

unnatural. Moreover, it is thought that the difference4b) Supplementary to ref.4a)

in baseline characteristics which exacerbates infection
affected these outcomes favorably for baricitinib group.
Therefore, it is concluded that neither efficacy nor

N Engl J Med . 2021 Mar 4;384(9):795-807. PMID: 33306283
https://www.nejm.org/doi/suppl/10.1056/NEJMoa2031994/suppl_file/
nejmoa2031994_appendix.pdf5) Ghosn L, Chaimani A, Evrenoglou T et al Interleukin-6 blocking agents for treating
COVID-19: a living systematic review. Cochrane Database Syst Rev. 2021 Mar 18;3:
CD013881. PMID: 33734435

safety of baricitinib has been proven, and it should not6) MedCheck Editorial Board, Corticosteroid supplementation: Lifesaving effect in

be used for the treatment of COVID-19.

7) Wichmann D, Sperhake JP, Lütgehetmann M et al. Autopsy Findings and Venous

severe cases. MedCheck 2021: 21 (93): 13-14 (in Japanese)
Thromboembolism in Patients With COVID-19: A Prospective Cohort Study. Ann
Intern Med. 2020 Aug 18;173(4):268-277. PMID: 32374815
8) MedCheck Editorial Board, Remdesivir (trade name: Becklely)- Most likely
ineffective for COVID-19. MedCheck in Englich 2020: 6 (18):39-45
https://www.npojip.org/english/MedCheck/Med % 20Check % 20Tip-18-2020-08-2.pdf9) MedCheck Editorial Board, Remdesivir: No effect in WHO study. MedCheck 2021:
21 (93): 12-13 (in Japanese).

MED CHECK

Aug.-Dec 2021/ Vol.7 No.21-22 ・ Page 31

Adverse Reactions
COVID-19 vaccine:

Strong association with cardiovascular death,especially hemorrhagic stroke and venous thrombosis

Med Check Editorial Team

Abstract● We analysed 196 death cases reported after inoculation of Pfizer-BioNTech COVID-19 vaccine (COMIRNATY) by
June 9 in Japan. Japanese Ministry of Health, Labour, and Welfare (MHLW) virtually denied the causality of all cases
without conducting appropriate epidemiological analysis.
● Mortality odds ratio (MOR) was calculated as the indicator of disproportionality in cause of death. We compared
odds of cause of death after inoculation and death in Japanese vital statistics in 2019 as control non-vaccinatedpopulation. MOR was obtained by using the numbers of death from non-cardiovascular system as the reference
causes for two age groups: vaccinated medical workers (20 to 74 year of age) and elderly ( ≧ 65years) separately.
●Of 31 deaths among vaccinated medical workers (both sexes), 26 (84%) died from cardiovascular diseases, suchas stroke, myocardial infarction, venous thrombosis and pulmonary embolism (VT/PE) and heart failure, while 22%
died in the general population. MOR is 19.4 (p<0.0001). MOR of hemorrhagic stroke (40.7) and VT/PE (114.0) were
extremely high.
● Of the reported vaccinated elderly death cases, 69% died from cardiovascular causes, while 26% died in thegeneral population. MOR is 5.9 (p<0.0001). MOR of hemorrhagic stroke (12.8) and VT/PE (24.9) were also very high.
● These suggest that COVID-19 vaccination is closely associated with the risk of death from cardiovascular causes,
especially hemorrhagic stroke and VT/PE.

Keywords:
subarachnoid hemorrhage, intracerebral hemorrhage, hemorrhagic stroke, myocardial infarction,
sudden cardiac death, reporting odds ratio, mortality odds ratio, MOR, COVID-19 vaccine

hemorrhagic stroke became 4 in a short period of time

Introduction(Web MedCheck No195 (April 26, 2021) [3]), and it has

On October 22, the Ministry of Health, Labor andbeen increasing since then.

Welfare (MHLW) announced that they had received

Since April 12, vaccination to the elderly ( ≧ 65) has

1312 reports of death after vaccination for COVID-19 by

begun, and a total of 196 death cases were reported by

October 15, 202l [1].

June 4, according to the data released by MHLW on June

Regarding 2 death case reports from hemorrhagic

9 [4,5].

stroke, including subarachnoid hemorrhage, after

We restricted to analyze the death cases inoculated

COVID-19 vaccination of medical workers in Japan,

by May 30, because (1) vaccination to non-elderly/non-we warned that "never twice without three times" inmedical workers has begun on June 1. (2) Distribution

the Web MedCheck No193 (March 31, 2021) [2]. Afterof medical workers' age is not much different from thatthe warning, the number of death case reports fromin the general population. However, (3) vaccinated non-Page 32 ・ MED CHECK

Aug.-Dec. 2021/ Vol.7 No.21-22

COVID-19 Informationelderly/non-medical workers were much older than thegeneral population.

About mortality odds ratio (MOR)

Among them, the number of death cases of people who

We used an epidemiological method "mortality odds

were assumed to be medical workers was 31 (17 women,

ratio (MOR) " to detect disproportionality of cause of

14 men) on June 4. Total 11 of them (10 females and 1

death [7-9]. This method is based on the followingmale) had hemorrhagic stroke, including 8 subarachnoid

principle: if an exposure induces a specific diseasehemorrhages and 3 intracerebral hemorrhages.

leading to death, mortality odds of interest (cause of death

In addition, it is noted that many deaths fromcardiovascular causes such as ischemic stroke,of interest/other causes) in exposure group is significantly

higher than that in non-exposed group.

myocardial infarction, mesenteric thrombosis, sudden

In the case of COVID-19 vaccine, if the odds ofcardiopulmonary arrest, heart failure and even venous

a particular cause of death in vaccinated people isthrombosis with pulmonary embolism were reported.

significantly higher than that in the general population,

MHLW virtually denied the causality of all cases
only by the information of case reports. They have notthere may be causal link between the cause of death and
COVID-19 vaccination.

conducted appropriate epidemiological analysis andIn general, when there are 3 or more events,

only say that vaccinees' mortality rate from hemorrhagicand proportional reporting ratio (PRR) is equal to

stroke is less than that in the general population andhigher than 2.0 with statistical significance, signalsthat therefore vaccination is not related to the increaseof disproportionate reporting is suggested [10]. In

of mortality risk from hemorrhagic stroke. However, they

the case where reporting odds ratio (ROR) , MOR ornever take into account that vaccinees are far healthierproportional mortality ratio (PMR) are applied, signals ofand have lower mortality rate than in the generaldisproportionate reporting may be the same.

population. This is the "healthy user bias" or "healthy

We have not experienced such a vaccine that is

vaccinee effect", a typical example of confounding bias,

targeted to almost all adult ages during the same period.

which MedCheck has repeatedly emphasized [6].

It is not possible to compare adverse reactions to other

This article analyzes association between COVID-19

pharmaceuticals other than vaccines either. Therefore,

vaccination and death especially from cardiovascular

we used mortality data from the vital statistics in 2019diseases.

as control non-exposed mortality.

Figure 1: Comparison of cause of death: vaccinated and general population

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Adverse Reactions
As medical workers' ages are between 20 and 74, weused the mortality data with the same age group fromthe vital statistics in 2019 in Japan.

Cardiovascular cause of death weredisproportionately highWe classified reported cause of deaths into thefollowing categories:

control are 83.9 % and 21.8% respectively. Those invaccinated elderly and corresponding control are 68.8%
and 25.8 % respectively as shown in Figure 1.

Preferred MOR and the ordinary MOR
We calculated MOR by two age groups: vaccinatedmedical workers (20 to 74 year of age) and elderly ( ≧65years) separately.

(1) Hemorrhagic: hemorrhagic stroke (subarachnoid

We preferred MOR which used the numbers of death

hemorrhage and intracerebral hemorrhage) and hemorrhage

from non-cardiovascular causes as the reference as

in any part of body,shown in Figure 2, because the referent cause of death(2) Arterial: arterial dissection, myocardial infarction,for ordinary MOR method includes other types ofischemic stroke or thrombosis of other arteries,

cardiovascular deaths which are also disproportionately(3) Venous: venous thrombosis and/or pulmonary

higher than the general population as shown in Figure 3.

embolism (VT/PE),

Hence, preferred MOR reflects the disproportionality(4) Other CV (cardiovascular): cardiac or cardiopulmonary

more accurately than the ordinary MOR.

arrest, heart failure, sudden death etc.
(5) Non-cardiovascular: include infection, senility,

Hemorrhagic stroke and VT/PE occurredanaphylaxis etc., andespecially disproportionately(6) Unknown cause.

Among 17 female medical workers who diedafter COVID-19 vaccinat ion, 2 (12%) died fromThe distributions of causes are shown in Figure

non-cardiovascular cause and 10 (59%) died from

1 excluding unknown cause (6) among the elderly.

hemorrhagic stroke. In female general population (total

Proportions of causes of death classified (1) to (4)102,669), 83,651 (81.5%) died from non-cardiovascularamong vaccinated (both medical workers and elderly)

causes and 4,583 (4.5%) died from hemorrhagic stroke.

were all larger than those among corresponding general

MOR from hemorrhagic stroke in female medical

population. Proportions of all cardiovascular causes ofworkers is 91.3 (p<0.0001).

death in vaccinated medical workers and corresponding

Sex adjusted MORs for death from hemorrhagic

Figure 2: Difference of two methods for calculation of MOR

The referent cause of death for ordinary MOR method includes other types of cardiovascular deaths which are also disproportionately higher than the general
population.

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Aug.-Dec. 2021/ Vol.7 No.21-22

COVID-19 Information
Figure 3: Preferred MORs for various cardiovascular causes (sex adjusted)stroke in medical workers and in elderly is 40.7

methods for calculation of MOR. Figure 4 shows the(95%CI:14.1-117.5, p<0.0001) and 12.8 (7.4-22.0,

comparison of results from preferred MOR methods and

p<0.0001) respectively (Figure 3).

ordinary MOR method.

Sex adjusted MORs for death from venous causes are
114.0 (21.7-597, p<0.0001) and 24.9 (7.7-80.5, p<0.0001)

The dead after vaccination are previously

respectively (Figure 3).

healthy people on dutyWith MOR, absolute mortality risk between those

Men died from other cardiovascular diseases

vaccinated and those in the general population cannot

In men, thrombosis and sudden death are morebe compared. Hence we tried to estimate the mortality

prominent than hemorrhagic stroke in both medical

risk in those vaccinated considering that the medical

workers and the elderly.

workers are far healthier than the general population.

For example, a 79-year-old man (Case 48, [5]) developed

In other words, we tried to estimate the mortality risk inan acute myocardial infarction and was hospitalized.

those vaccinated by taking "healthy vaccinee effects" into

Four days later he also developed an ischemic stroke

account.

caused by a thrombosis of a large artery "left middle
cerebral artery" followed by a cerebral herniation andcardiopulmonary arrest.

According to the data released by the MHLW, thenumber of inoculations by May 30 was 9.76 million

It is extremely rare that 2 serious events, myocardial

for the first dose and 3.3 million for the second dose.

infarction and ischemic stroke, occur one after another

The number of inoculations for medical workers canin a short period of time. However, MHLW experts

be calculated by subtracting the number of the elderly

assessed the causality and denied the causation for three(5.31 million and 390,000 dose respectively) from the total

cases, but all other cases were classified as "cannot benumber of doses respectively: The first dose was 4.45

evaluated due to a lack of information" and no death

million and the second dose was 2.91 million.

cases was classified as even "cannot be denied". Hence,
they practically denied causality in all death cases.

For the purpose of know ing how healthy thevaccinated people are compared to the general
population, we calculated the age adjusted total mortality

Sensitivity analyses were done by using ordinary

risk ratio of vaccinated medical workers (20-74 years old)
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Adverse Reactions
Figure 4: MORs by two different methods

Preferred MORs are much larger than the ordinary MORs (by 1.8 to 5.1 times) except of total cardiovascular system which are theoreticallyequal to each other.

compared with the general population. As a result, themortality to adjust the health status. Adjusted risk ratio

total mortality risk ratio of vaccinated female medical

is 12.23 (5.55- 26.94, by Fixed effect) or 14.23 (5.95- 34.04

workers to the general population was 0.065 (95%CI:

by Random effect).

0.040-0.107, p <0.00001: Fixed effect) or 0.101 (0.0620.165, p <0.00001: Random effect) .

These results also support the increased risk of deathfrom hemorrhagic stroke among vaccinated people.

There is no evidence from clinical trial results thatthe vaccine increased or reduced overall mortality. If
increased, the above is underestimated and should notaffect the judgment that vaccinated people are healthierthan the general population. There is also no possibility
that death from COVID-19 in vaccinated medical workers
have decreased within 30 days after the second dose.
Hence, in any case, the main reason of very low risk ofdeath after vaccination in the medical workers is simply
that they are healthy. Hence, vaccinated medical workers
are about 10 to 15 times healthier than the general
population.
Similarly, the risk ratio of hemorrhagic stroke offemale medical workers was calculated: 0.80 (0.43-1.48,
by Fixed effect) or 1.44 (0.70-2.97, by Random effect).

The risk ratio of hemorrhagic stroke of vaccinatedfemale medical workers was divided by the risk of total
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Aug.-Dec. 2021/ Vol.7 No.21-22

Causal inference and biological plausibility
We discussed causality including biological plausibility
in the other article in this issue [11].

COVID-19 Information
References
1) The Japanese Ministry of Health, Labour and Welfare (MHLW) Health Science
Council Vaccination and Vaccine Subcommittee Vaccine Reaction Study Group(August 4 2021)
https://www.mhlw.go.jp/stf/shingi2/0000208910_00028.html (in Japanese)2) WebMedCheckNo193 https://www.npojip.org/sokuho/210331.html (in Japanese)3) WebMedCheckNo195 https://www.npojip.org/sokuho/210426.html (in Japanese)4) The Japanese Ministry of Health, Labour and Welfare (MHLW) Health Science
Council Vaccination and Vaccine Subcommittee Vaccine Reaction Study Grouphttps://www.mhlw.go.jp/stf/shingi/shingi-kousei_284075.html (in Japanese)
Jun. 9 2021: https://www.mhlw.go.jp/stf/newpage_19142.html (in Japanese)5) Reported death cases：https://www.mhlw.go.jp/content/10906000/000790071.
pdf(June 9 2021) (in Japanese)
6) MedCheck Editorial Team: Fundamentals of Medical Research Methods: (inJapanese) https://www.npojip.org/chk_tip/2020No92-furoku.pdf
7) Miettinen OS, Wang JD. An alternative to the proportionate mortality ratio. Am J
Epidemiol 1981; 114: 144–148.
PMID: 7246522
8) van Puijenbroek EP, Bate A, Leufkens HG et al. A comparison of measures ofdisproportionality for signal detection in spontaneous reporting systems foradverse drug reactions. Pharmacoepidemiol Drug Saf. 2002 Jan-Feb;11(1):310PMID: 11998548
9) Rothman KJ, Lanes S, Sacks ST. The reporting odds ratio and its advantages overthe proportional reporting ratio.
Pharmacoepidemiol Drug Saf. 2004 Aug;13(8):519-23. PMID: 15317031
10) European Medicines Agency. Guideline on the use of Statistical Signal Detection
Methods in the Eudravigilance Data Analysis System
https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/
guideline-use-statistical-signal-detection-methods-eudravigilance-data-analysissystem_en.pdf11) MedCheck Editorial Team: Causal link between vaccination and subsequent death
MedCheck in English. 2021: 6(21):

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Adverse Reactions
Causal link between vaccination andsubsequent deathTranslated and revised from Med Check (in Japanese) Sept. 2021 ; 21 (97):110-111
Med Check Editorial Team

Keywords:
COVID-19 vaccine, death after vaccination, incubation period, foreign cells, cell-mediated immunity, inflammation"Causality cannot be denied" even by MHLW’ s

median was 5 days. For elderly people, the peak is on thestandard

next day of inoculation (median is 2 days). At any age, theThe Ministry of Health, Labour and Welfare (MHLW)
announced that among 919 death case reports by July

number of death reports after 3 weeks post inoculationis only 2%.

30, causality with vaccination were denied in 3 cases,

When spontaneously infected with COVID-19, theand for the remaining 916 cases, the causality could

peak of time from infection to symptom onset (incubation

not be evaluated due to a lack of information or otherperiod) is 4 days, and the median is also 4 days [4] (Figure

reasons [1].

B).

However, the MHLW itself stated in a Q & A regarding

The fact that the number of days from inoculation to

the classification of adverse events that cases ofdeath is concentrated in a short period of time and that it"unknown causality" should be classified as "Causality

is similar to the incubation period of COVID-19 strongly

cannot be denied" [2].

suggests causality between vaccination and death.

Moreover, as pointed out in another article in this issue[3], proportion of death from vascular diseases including

Many cases could be omitted in the deaths ofhemorrhagic stroke after COVID-19 vaccination isthe elderly

disproportionately higher compared with the general

One of the reasons why the number of days to death

population. Here we show some other important

after vaccination is shorter for elderly people than thosefacts that indicate causality between vaccination andunder 65 years old is that they often die suddenly from

subsequent death.

some symptoms such as aspiration associated withvomiting which may not cause death in younger people.

Frequency should not change if there is no

In Norway, 1 in 1300 people aged 75 and over who

causality

received vaccination has died, and the relationship with

If there is no causal relationship between COVID-19

the vaccine has been suspected [5].

vaccination and subsequently reported death, change in

In addition, some death cases which may be reported

the number of reported deaths should not depend on theif occurred in younger people, may not be reported fornumber of days after vaccination until death.

elderly people. Particularly death cases except thoseoccurred very shortly after inoculation may easily beDays to death is similar to incubation period of

omitted.

COVID-19
However, as shown in Figure A, in medical workers
or people under the age of 65, the number of reported
death reaches a peak on 4 days after vaccination. The
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Aug.-Dec. 2021/ Vol.7 No.21-22

Mechanisms of SARS-CoV-2 infection andincubation period
If SARS-CoV-2 infects a person, it is trans-located toCOVID-19 Information
the blood stream, and may be taken up into vascular(macrophages) where spike protein is made and isendothelial cells from the site where the receptor ACE2 isreleased into bloo d stream. Lipid nanoparticles

abundant on the inner surface of blood vessels. Infectedcontaining mRNA may be taken into some endothelial

endothelial cells are recognized as foreign body by thecells by perhaps endocytosis in which spike protein may

host's immune system (cell-mediated immunity), and are

be made and released into blood stream. Released andattacked and eliminated. Children and people in their 20s

circulating spike proteins in blood stream are taken up

have less ACE2 receptors and far safer than old people.

into vascular endothelial cells from the site where the

The cells on the inner surface of blood vessels are
originally normal tissues and are essential parts for living

receptor ACE2 is abundant on the inner surface of bloodvessels.

organisms. If they are eliminated, the part of the vessels

Similar to infection, endothelial cells which are "asmay be injured with wounds. The injured tissues must be

if infected" by spike protein and/or lipid nanoparticles

repaired. An inflammatory reaction occurs to repair thecontaining mRNA are recognized as foreign bodies

tissue. This inflammatory response is a symptomatology

by the host's immune system, and are attacked andof infection, such as fever, increased white blood cell

eliminated. Children and people in their 20s have lesscount, increased heart rate, and increased respiratory

ACE2 receptors and far safer than old people.

rate. It usually takes 3 to 5 days to develop symptoms,
with a median of 4 days [4].

Endothelial cells containing foreign substances are
subject to "be eliminated" by the immune system.
Around the damaged endothelium, blood coagulates andBiologically plausible: Days to deaths are similar

thrombus is made followed by myocardial infarction

to the incubation period

and/or ischemic stroke. If the damage of an inner surface

mRNA vaccine is encapsulated in lipid nanoparticles.

of blood vessel is serious in a large artery, dissecting

After injection, through lymphatic vessels, it entersaneurysm or rupture of a small aneurysm may occur. If

the blood stream and is taken up by immune cells

a small aneurysm ruptures in the subarachnoid space,

Figure: Distribution of days to death after vaccination and incubation period of COVID-19

For elderly people, data from table by May 30 are analyzed.
For medical workers and people under 65 years old, data by July 21 is analyzed.

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Adverse Reactions
subarachnoid bleeding occurs. If a very small artery

References

ruptures inside the cerebrum, intra-cerebral bleeding1) The Japanese Ministry of Health, Labour and Welfare (MHLW) Health Scienceoccurs.

Council Vaccination and Vaccine Subcommittee Vaccine Reaction Study Group(August 4 2021) https://www.mhlw.go.jp/stf/shingi2/0000208910_00028.html

With regard to Pfizer vaccines, myocarditis [6,7] hasbeen a problem in the United States. Hemorrhagic(in Japanese)
2) ICH-E2 (Clinical Safety Data Management: Definitions and Standards for Expedited
Reporting https://www.pmda.go.jp/files/000156127.pdf

stroke, arterial thrombosis as well as dissecting3) MedCheck Editorial Team. High incidence of vascular deaths after COVID-19

aneurysm and venous thrombosis and/or pulmonary4) Estimating the incubation period of new coronavirus infections based onembolism may all be causally linked to vaccination of

information from active epidemiological studies IASR 2021: 42 (6): 131-132:
https://www.niid.go.jp/niid/images/idsc/ iasr / 42/496.pdf
https://www.niid.go.jp/niid/images/iasr/2021/6/496d06f02.gif

COVID-19.
Therefore, the fact that the number of days to deaths
after inoculation is similar to the incubation periodof COVID-19 in the medical workers or people under theage of 65 is biologically plausible and this also supports
the causality.

Page 40 ・ MED CHECK

vaccination. death MedCheck in English. 2021: 6(21):Aug.-Dec. 2021/ Vol.7 No.21-22

5) Torjesen I. COVID-19: Doctors in Norway told to assess severely frail patients for
vaccination. https://www.bmj.com/content/bmj/372/bmj.n167.full.pdf
6) Shimabukuro T. COVID-19 Vaccine Safety Updates VRBPAC 2021-6-10
https://www.fda.gov/media/150054/download
7) Marshall M, Ferguson ID, Lewis P, et al. Symptomatic acute myocarditis in sevenadolescents following Pfizer-BioNTech COVID- 19 vaccination.

COVID-19 Information

Mortality risk of vaccination is 7 times
higher than that of COVID-19 in 20s
Translated and revised from Med Check in Japanese No97(Sept. 2021)
Med Check Editorial Team

Keywords:
COVID-19 vaccine, death after vaccination, incubation period, foreign cells, cell-mediated immunity, inflammation

Introduction

inoculated for medical workers (age: 20 to 74) was 7.36
million doses (4.45 million persons) [4]. In the preliminary

Disproportionate increase of death from cardiovascularsurvey of 18,794 medical workers (men 34% and women

diseases was observed both among medical workers and66%), age distribution was 21%, 24%, 25%, 21%, 8%

elderly people who received COVID-19 vaccine comparedand 1% for 20s, 30s, 40s, 50s 60s, and 70s, respectively

with general population [1]. Distribution of the number[5]. Hence, it was estimated about 1.55 million doses (0.94

of days to death from inoculation of COVID-19 vaccine

million persons) were for those in their 20s. Of these, 3

is similar to that of incubation period of COVID-19

death cases above (2 men and 1 woman) were reported.

[2]. Based on such evidence and biological plausibility,

Mortality risk based on the number of inoculatedcausality between death from cardiovascular diseases

persons is 3 out of 940,000 persons (3.2/million) in 20s.

and COVID-19 is substantially supported [2].

On the other hand, mortality risk from COVID-19 is

Here we analyze the risk ratio of death from COVID-19

7 out of 11.8 million persons in the same age groupvaccination and that from COVID-19 by age especiallyby June 2, 2021 (0.6/million) [6] or 10 out of the same

people in their 20s, because some death cases withpopulation by August 11 (0.8/million) [7].

people in their 20s have been reported.

Therefore, the mortality risk ratio after vaccination in
20s is 5.4 by June 2 (or 3.8 by August 11) compared with

Reported death cases with people in their 20s [3]mortality risk from COVID-19.

A 25-year-old man: It was reported that he completed

Sex adjusted risk ratio is 7.0 by June 2 (or 4.7 bysuicide due to psychosis. However, actually heAugust 11). Figure A shows sex adjusted risk ratio by age

accidentally died following abnormal behavior due tobased on the COVID-19 death on June 2.

febrile delirium after vaccination.
A 26-year-old woman: She was found dead at home

Risk ratio may be between 5 and 52 in 20s

4 days after vaccination. Postmortem CT scan revealed

Japanese Ministry of Health, Labour and Welfare

subarachnoid hemorrhage and cerebellar hemorrhage.

(MHLW) requires reports of serious cases and deaths

A 26-year-old man: He was found dead 5 days after

within 28 days after inoculation regardless of causal

vaccination by his family. Postmortem CT scan showed

relationships, but they do not necessarily require

no lesions and he was diagnosed with cardiopulmonary

reports of serious cases and deaths beyond 28 daysarrest.

post-inoculation. Hence, if all deaths, including thosethat occurred beyond 28 days after vaccination, wereMortality risk of vaccination in people in their 20s
is 5 times higher than that of COVID-19
In the end of May 2021, the number of vaccinations

reported, risk may become higher.
By using person-year methods, mortality risk fromvaccination in 20s is about 40 times higher than
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Adverse Reactions
Figure: Mortality Risk Ratio of vaccinated medical workers to death from COVID-19
A. Risk ratio based on person vaccinatedB. Risk ratio based on person-year

RR: Risk ratio. All data are adjusted by sex for every age group. Death after vaccination is data released by MHLW [4]. The number of deathfrom COVID-19 is based on the data from MHLW [6]

COVID-19 mortality risk (sex adjusted RR is 52.3).

The clinical trial of AstraZeneca's vaccine for children

However, the mortality rate beyond 28 days should beaged 6 to 17 years old was interrupted [8]. It was due

lower than that within 28 days, so the mortality risk ratio

to 79 cases of thrombosis with thrombocytopenia ofafter vaccination in 20s may be between 5 to 40 times

which 19 have died were reported in adults, as the UK

higher compared with death from COVID-19 (sex adjusted

Medicines and Healthcare products Regulatory Agency

risk ratio may be between 7 and 52).

(MHRA) announced on April 7, 2021 [9].

The estimated number of vaccinations inoculated for

According to a report on the outbreak inpeople in their 20s by July 23 is somewhat inaccurate

Massachusetts, more vaccinated people were diagnosed

because vaccination to people other than medicalwith COVID-19 than non-vaccinated people, mostworkers aged under 65 years started in June, but olderof which were delta strain infected: odds ratio=

people were recommended to be vaccinated earlier than

1.26,p=0.025[10,11].

younger people. Therefore, the age distribution of people

Hospitalization rate was 1% in the outbreak invaccinated is totally unknown. If people aged under 65

Massachusetts. No death was reported among 469

years had COVID-19 vaccine proportionally as generalconfirmed COVID-19 patients. Hence, the mortality risk

population, number of vaccination in people in theirfrom delta strain COVID-19 is not high. It is far lower

20s is estimated to be 3 million doses (about 2 million

than the case mortality rate (almost 6%) in May 2020 inpersons).

the United States. Although delta strain is very infectious,

By July 30, 1 week later, 7 people had died after

it does not seem to be very toxic at least in the U.S. where

vaccination (Note 1). By using these data, mortality risk

1 out of 9 people have already had confirmed COVID-19

ratio of vaccinated people to COVID-19 mortality risk

overall case fatality rate is 1.68 % on August 19 [12], anddoes not change significantly.

most people have been infected at least once with SARSCoV-2.

Harm of vaccination in children may be enormous

In Japan, the fifth epidemic period began in early

There were no deaths due to COVID-19 infection

July, and on August 13, more than a month later, newunder the age of 20 until September 1, 2021. If children

infections were confirmed in more than 20,000 people

in this age group are vaccinated, it may cause death.

a day. The number of deaths has gradually increased toMortality risk from vaccination may be lower in children

over 20 per day, and it is estimated that the number willthan people in their 20s. Even so, the mortality risk ratio

increase in the future.

cannot be calculated because the number of death from

However, the case mortality rate between August 17

COVID-19 is "0" in Japan until September 1, 2021(Note 2).

and 31 (0.26%) is less than one-tenth of that around May

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COVID-19 Information
last year (more than 5%)(Note 3).

References
1) MedCheck Editorial Team. Disproportionate increase of circulatory deaths after

Even if children and adolescents and people in their
20s are infected, it is naturally mild or asymptomatic
because they have less SARS-CoV-2 receptor ACE2 thanadults especially old people.

COVID-19 vaccination MedCheck in English. 2021: 6(21):2)MedCheck Editorial Team. Causal link between vaccination and subsequent death
MedCheck in English. 2021: 6(21):3) The Japanese Ministry of Health, Labour and Welfare (MHLW) Health Science
Council Vaccination and Vaccine Subcommittee Vaccine Reaction Study Group (inJapanese) May 26 2021: https://www.mhlw.go.jp/stf/newpage_18848.html
4) ibid (in Japanese) Jun. 9 2021:
https://www.mhlw.go.jp/stf/newpage_19142.html

It is a ridiculous to consider vaccination for school
children.
Note1: According to the materials released by the MHLW [13] Case
No 8716, a 27-year-old man seems to be Mr. Yusuke Kinoshita, aprofessional pitcher of Chunichi Dragons. He was given the firstdose of the vaccine (Moderna) on June 28. Eight days later, on July
6 during training, he was found crouching and lost consciousness.
Paramedics confirmed cardiac arrest. He resumed heartbeat
after about 40 minutes at the hospital where he was transferred.
He had no abnormalities on coronary angiography and no
myocarditis on myocardial biopsy, but had mitral regurgitation.
If acute necrosis of the papillary muscle to which the mitral valve
chordae tendineae attach occurred, it might lead to massive5) Survey at the beginning of administration of the COVID-19 vaccine (cohort
survey).
https://www.mhlw.go.jp/content/10906000/000745208.pdf
6) Trends of new coronavirus infection (preliminary figures) (As of 18:00 on June 2,2021) https://www.mhlw.go.jp/content/10906000/000776153.pdf
7) Trends of new coronavirus infection (preliminary figures) (As of 18:00 on August
11, 2021) https://www.mhlw.go.jp/content/10906000/000818427.pdf8) BBC. Covid: Child jabs halted in trial as adult clot link probed (April 6)
https://www.bbc.com/news/health-56656356
9) UK MHRA issues new advice, concluding a possible link between COVID-19
Vaccine AstraZeneca and extremely rare, unlikely to occur blood clots.
https://www.gov.uk/government/news/mhra-issues-new-advice-concluding-apossible-link-between-covid-19-vaccine-astrazeneca-and-extremely-rare-unlikelyto-occur-blood-clots
10) CDC, Outbreak of SARS-CoV-2 Infections, Including COVID-19 Vaccine
Breakthrough Infections, Associated with Large Public Gatherings. MMWR: 2021:
70: 1-5https://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm7031e2-H.pdf
11) MedCheck Editorial Team. Vaccinated people also get symptomatic COVID-19
frequently. MedCheck 2021: 21(97): 109 (in Japanese)

regurgitation followed by acute pulmonary edema, shock, and

12).Worldometers: https://www.worldometers.info/coronavirus/

cardiopulmonary arrest and loss of consciousness. It is one of13) The Japanese Ministry of Health, Labour and Welfare (MHLW) Health Science

the conditions with an extremely high case fatality rate. Papillarymuscle ruptures that lead to cardiopulmonary arrest can occur
after an acute myocardial infarction. If so, an association withvaccination is suspected. He died on August 3, 36 days after theCouncil Vaccination and Vaccine Subcommittee Vaccine Reaction Study Group (inJapanese)https://www.mhlw.go.jp/stf/shingi/shingi-kousei_284075.html
August 4 2021: https://www.mhlw.go.jp/stf/shingi2/0000208910_00028.html
case No. 8716 https://www.mhlw.go.jp/content/10601000/000816280.pdf

inoculation.
Note2: Susequently 3 death from COVID-19 among people under
the age of 20 were reported until November 2, 2021 (see p44-45)
Note3 : This case mortality rate is calculated as follows:
Numerator: number of death between August 17-31, 2021 (591)
Denominator: number of people with confirmed new infection
between August 3-17. 2021(223,330)
However, age and sex adjusted case mortality rate during thefifth epidemic period (early July to October 2021) is not changed
significantly compared with that during the first to the third
epidemic period. Odds ratio is 1.10 (95% confidence interval:
0.995- 1.21, p=0.0629)

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Adverse Reactions
COVID-19 vaccination: 3 teens diedCausal link is suspectedTranslated and revised from Web-MedCheck in Japanese No197(Oct. 30, 2021)
Med Check Editorial TeamThe Ministry of Health, Labour and Welfare (MHLW)

artery causing its obstruction. A healthy 16-year-old boy

announced on October 22, 2021 that they received

with no underlying disorder suffered from thrombosis ofa total of 1308 reports of death after inoculation of

the intestinal (perhaps mesenteric) artery on the 6th day

COVID-19 vaccine by October 15, (1268 and 44 reportsof vaccination, suffered from cardiac arrest and died 22

after Pfizer's and Moderna's, respectively) [1]. These deathdays after vaccination. It would be extremely rare for thiscases include 3 teens (all males) for whom brief case-to happen by chance.

reports are available [1].

In the vital statistics 2019, among those between the

In addition, the approximate numbers of vaccinatedages of 10 and 14, 2 males died of myocardial infarction,

people by age (every 10 years) until October 8 are

but death from cerebral infarction and other arterial

available [2]. By using these data, causality between theembolisms or thrombosis was 0 among those between

deaths of the 3 teens and vaccination is discussed.

the ages of 10 and 19.
Therefore, it is almost certain that this boy died

Case 1: Pfizer vaccine, death case number 1167 [3]A 16-year-old male received the 1st inoculation onprobably from intestinal thrombosis which was causedby the vaccine.

August 10, 2021. He had no underlying illness. On the
6th day after vaccination, he suddenly arrested. His

Case 2: Pfizer vaccine, death case number 961 [3]spontaneous circulation was resumed from ventricular

A 16-year-old male received the 1st inoculation on July

fibrillation after treatment by DC defibrillator. He was15, 2021, died on July 23, 2021. Underlying disorder:

intubated and mechanically ventilated but died on

attention deficit hyperactivity disorder. The psychiatrist

September 1, 2021 (22nd day of vaccination).

had previously prescribed medication, but recently hehad stopped taking it by himself and self-harm wasobserved.

Cause of death:
Reported: Non-obstructive intestinal ischemia
Corresponding MedDRA PT: Intestinal ischemia
Evidence basis for determining the cause: CT, blood
test, electrocardiogram

Cause of death:
Reported: Suicide (falling from the top floor of thecondominium)

Corresponding MedDRA PT: Suicide attempted
Causality assessment:

Evidence basis for determining the cause: Unknown

Reported: cannot be assessed
Experts: γ (cannot be assessed) with the following

comments: A 16-year-old male who suddenly arrested 6
days after the first vaccination and died. It is difficult toevaluate the cause with the current information.
Comments by MedCheck:Causality assessment:
Reported: Not related (Possibility of other causes: Yes,
attention deficit hyperactivity disorder)

Specialists: γ (cannot be assessed) without comments
Comments by MedCheck:"Intestinal ischemia" that caused sudden cardiac arrest

There is another case of "suicide" after COVID-19

may be due to a blood clot in the fairly large mesentericvaccination. A 25-year-old male had a fever after

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COVID-19 Information
receiving the COVID-19 vaccine (Pfizer), which might

Comments by MedCheck:have resulted in transient "febrile delirium". However, heAccording to the vital statistics in 2019 [6], the total

was diagnosed with a psychosis and was recommended

number of deaths from hemorrhagic stroke in those agedof consultation by psychiatrist. While he was being

10 to 19 (total population: 15 million) was 26. Mortalitytransported to a psychiatric hospital by car, he jumped

rate is 1.7 per million person-years. Since this is theout of the car and died accidentally. Then, the doctormortality rate in person-years, the rate in 9 hours after

determined the cause of death as "suicide" [4].

an action (in this case, vaccination to the event) should

Detailed information on the situation before falling

be divided by 365 and should be multiply by 9/24.

from the top floor of the condominium in this 16-year-

Therefore, the probability that the hemorrhagic stroke

old male case is unknown. However, it is not so difficult

happens in 9 hours in this age group is estimated as

to imagine that he had some feeling of illness after

0.0018 per million person-9 hours (1.7 x 9/24/365).

vaccination and he temporarily fell into a delirious state

As of October 8, it is estimated that there are 4.4

and could not take risk avoidance behavior at the top of

million people aged 12 to 19 who have been vaccinatedthe condominium and has fallen.

at least once [2]. Among these, one person died 9

It might be similar to the cases of accidental deaths

hours after inoculation. Hence, 1/4.4 million died fromcaused by delirium after taking Tamiflu. In these cases,

hemorrhagic stroke during 9 hours. The estimatedtransient abnormal behavior leading to death in an

mortality rate is 0.23 per million person-9 hours. In

unavoidable state of danger was mistakenly judged as

simple terms, the mortality rate of 0.23 out of 1 million"suicide".

is about 130 times the mortality rate of spontaneous
hemorrhagic stroke (0.0018 out of 1 million).

Case 3: Moderna vaccine, death case number 36 [5]A 15-year-old male received the first inoculation on
September 16, 2021. He lost consciousness 9 hours after
the inoculation. He died on September 20, 2021.

Hemorrhagic stroke is common after COVID-19
vaccine in adults
Among the vaccinated medical workers and theUnderlying disorder: He had cerebral arteriovenous

elderly, deaths from cardiovascular diseases, such as

malformation.

hemorrhagic stroke, arterial thrombosis, and venous

Approximately 9 hours after the inoculation on

thrombosis, were disproportionately reported. These

September 16, he suffered from headache, vomiting,deaths from cardiovascular causes and vaccination, andand loss of consciousness, and was transported by

the effects of vaccination are strongly suspected [7-9].

ambulance. He was diagnosed with cerebral hemorrhage
with ventricular perforation from cerebral arteriovenous

Hemorrhagic stroke and ar terial cause ismalformation by CT.

disproportionately high in teens
Among teens, 2 of the 3 deaths were sudden deaths

Cause of death:
Reported: Cerebral hemorrhage with ventricularperforation from cerebral arteriovenous malformation
Corresponding MedDRA PT: cerebral hemorrhage,ventricular perforation, condition aggravated

due to cerebral hemorrhage and abdominal artery
thrombosis. Mortality odds ratio for hemorrhagic strokeby comparing non-cardiovascular causes as the referenceis 58.3 (95%CI: 3.5-957, p<0.0001) and for arterial cause
MOR=252.5 (95%CI:14.1-4523, p<0.0001).

Evidence basis for determining the cause: CT(cerebral hemorrhage/ventricular perforation from cerebral

Mortality rate is higher in vaccinated than that

arteriovenous malformation)in general population
Proportion of reported deaths among those who wereCausality assessment:
Reported: cannot be assessed (Possibility of other causes:
Yes, cerebral arteriovenous malformation)

Specialists: γ (cannot be assessed) without comments

vaccinated is 0.68 per million (3/4.4 million vaccinated).
All 3 died or almost died within 8 days. In addition, somewill die during the following one year after inoculation.
If it is assumed that the vaccinated children and
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Aug.-Dec 2021/ Vol.7 No.21-22 ・ Page 45

adolescents will not die during the following one year,

References

mortality rate is 0.68 per million person-years. On the1) Ministry of Health, Labor and Welfare October 22, 2021 (in Japanese)other hand, among those between 10 to 19 year of age, 32) National Institute of Infectious Diseases: COVID-19 Vaccine (as of October 8,

died due to COVID-19 during about one and a half years
from the start of the COVID-19 epidemic. The mortality

https://www.mhlw.go.jp/stf/shingi2/0000208910_00033.html
2021) (in Japanese)
https://www.niid.go.jp/niid/images/epi/corona/60/covid19_vaccine_202110008.
pdf3) List of cases reported as deaths after COVID-19 vaccination (Comirnaty

rate is 0.22 per million person-years.

intramuscular injection, Pfizer Inc.)

Mortality rate of deaths after vaccination are about
3 times higher than that from COVID-19 (P=0.148). The
association is not statistically significant, but it meansthat 80 to 90% can be considered correct, and if deathoccurs subsequently, association may become significant.
Therefore, it seems better to think that the risk ofdeath from vaccines is about 3 times higher for children(in Japanese) https://www.mhlw.go.jp/content/10601000/000846547.pdf
4) Summary of cases reported as deaths after COVID-19 vaccination (Case 46,
p73-74) (in Japanese)
https://www.mhlw.go.jp/content/10906000/000784439.pdf
5) List of cases reported as death after COVID-19 vaccination (Moderna
intramuscular injection, Takeda Pharmaceutical Co. Ltd) (in Japanese) https://www.
mhlw.go.jp/content/10601000/000846548.pdf6) Vital Statistics 2019, Volume 2 1-1. Number of deaths, cause of death, ICD-10
code A to T (in Japanese)
7) MedCheck Editorial team：COVID-19 vaccine: strong association withcardiovascular death, especially hemorrhagic stroke and venous thrombosis.
MedCheck in English 2021: 7: 32-37.

and adolescents than death from COVID-19.
The regulators will continue to endorse vaccinationin children, but these data suggest that the risk of8) MedCheck Editorial team：Causal link between vaccination and subsequent death.
MedCheck in English 2021: 7: 38-40.
9) MedCheck Editorial team：Mortality risk is at least 7 times higher than that by
COVID-19 in 20s. MedCheck in English 2021: 7: 41-43.

vaccinating children and adolescents outweighs thebenefits.

M
C

ED

HECK

2021

Vol.7

No.21-22

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD)Managing Editor: SAKAGUCHI, Keiko
Editorial Staff: NAKANISHI,Takeaki(Pharmacist); TAKANO, Yoshihiko(MD[pediatrician]/Pharmacist) ; UMEDA, Tadahito (MD[psychiatrist]) ;YANAGI,
Motokazu (MD); YASUDA, Yoshinobu (Pharmacist)
Translators: NAKAMURA, Akari

Page 46 ・ MED CHECK

Aug.-Dec. 2021/ Vol.7 No.21-22

Advisors:HONZAWA,Tatsuo (MD[GP]) ; IKEDA,Akiko (Pharmacist) ;KIM,Mieko (Pharmacist) ; KUDO,Shino (Pharmacist) ; MITA,Yasuko(Pharmacist) ; MUKAI, Junji (Pharmacist) ; SUMIDA, Sachie (MD[Dermatologist]); TERAOKA, Akio (Pharmacist) ; TOI, Chihiro (Pharmacist);
WADA,Masahide (MD[GP])Editorial Officer: SAKAGUCHI, Keiko
Production Team: UMEKI, Yukiko; SAKAGUCHI, Keiko; MATSUMOTO, Koji
Information Technology (IT): KURODA, Akira (Systems Engineer)
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