MC

ED

Volume 9

September

HECK

2023

N 27
o

Editorial

Be Vigilant On a New Anti-Alzheimer's Drug

Lecanemab for Alzheimer's disease
SARS-CoV-2 vaccines Increase death from
Arrythmia and Venous Thrombosis
Vaccines and monoclonal antibodies: ineffective
CONTENTS (September 2023, Vol. 9, No. 27)
Editorial
Be Vigilant On a New Anti-Alzheimer's Drug
New Products
Lecanemab for Alzheimer's disease
No evidence to delay progress, should not be approved

20
21

COVID-19 Information
SARS-CoV-2 Vaccine Increases Arryuthmia Mortality
SARS-CoV-2 Vaccine Increases Venous Thrombosis Mortality
Vaccines and monoclonal antidies: ineffective

26
30
34

MED CHECK

Sep. 2023/ Vol.9 No.27 ・ Page 19

ED
HECK

Be Vigilant on New Anti-Alzheimer's Drug Approval

Editorial

M
CTranslated and revised from the Editorial in Med Check(in Japanese) May 2023 ; 23 (107)：51

Bruce Willis, a 67-year-old American actor known for the “Die Hard" film series, is suffering fromdementia, his family announced (BBC and The Mainichi, Feb. 17, 2023). Willis announced his retirement
last spring after being diagnosed with aphasia, and his family was deeply saddened. Since then, his

conditions have progressed and the name of the disease was identified. In a statement on social
media, they said it was a "relief to finally have a clear diagnosis". It is not the diagnosis of dementia
that is painful, but the fact that they do not see a way to deal with the disease that adds to theirsuffering.
The importance of palliative care has been emphasized for a long time, but if you think about it
dispassionately, palliative care awaits us all with any chronic diseases. Even patients with hypertension
have great possibility to end up in palliative care. In the case of dementia, there may be substantial
differences in the level and duration of suffering which both patients and their family might undergo.
As cognitive function declines, so do life functions. A person who has been fine may gradually lose

Editorial

the ability to go shopping, fill out paperwork, or use an ATM, all of which are signs of impaired
daily functioning. In the advanced stage, wandering or violence may appear. From a palliative care
perspective, it is necessary to provide appropriate support for these impairments of the patients andburden to their family members.

Lecanemab was granted traditional approval in July 2023 in the United States, and the Japanese
government’s panel agreed to approve it in August 2023. In a randomized controlled trial published

online in the major medical journal in November 2022, which is the basis for approval, reported aslightly smaller decline in cognitive scores (CDR-SB). However, the results are unreliable because ofmasking failure and high rate of dropouts as described in detail in this issue. Whether the progressionof cognitive impairment can be prevented remains unresolved. It has not been proven that lecanemab
reduced caregiving burden of family.

Nevertheless, the price of Leqembi® (product name of lecanemab in the US) is $26,500 per year only
for itself, exclusive of costs for essential tests such as PET scan and MRI.

In the near future, there will be a significant increase in the burden of medical costs, including
treatment for COVID-19. If this is inevitable, then medical costs, medical personal, and health andnursing-care insurance systems should be allocated to truly effective medical care with the highest
priority. The implementation of health policy based on scientific evidence is called into question.

Page 20 ・ MED CHECK

Sep. 2023/ Vol.9 No.27

New Products
Agent for Alzheimer’s Disease: Lecanemab
No evidence to delay progress, should not be approved
Translated and revised from Med Check (in Japanese) May 2023; 23 (107) ：56-60
Med Check Editorial Team

Abstract●Lecanemab is in the approval process in Japan. This article examines this agent in prior to approval. Based on
the idea that Alzheimer's disease could be prevented by reducing the amount of amyloid-β in the brain, which isthought to cause the disease, more than 20 compounds have been tried, but without success.
●Amyloid-β is an important neurotransmitter that acts on receptors involved in cognitive function. It is produced
as needed, and an equal amount is eliminated to maintain a balance. However, when its elimination is slowed by
infection or prolonged excess stress which themselves cause neuronal death due to excitotoxicity, it accumulates
in the brain and continues to stimulate receptors and releases neurotransmitters involved in cognitive functionand excitement, leading to neuronal death through excitotoxicity and development of Alzheimer's disease.
●Lecanemab is a monoclonal antibody that binds to amyloid-β (protofibril) in the brain. It received accelerated
approval in the U.S. in January 2023 based on the Phase 2 trial showing reduction of amyloid-β detected by PET
scan, and received traditional approval in July based on the Phase 3 trial, published in November 2022.
●In the Phase 3 trial, the lecanemab group reportedly yielded significantly better results in Clinical Dementia
Rating (CDR) compared with the control group. However, due to the nature of the drug, there was a high incidenceof adverse reactions, and significantly more participants in the lecanemab group were withdrawn from the study
without undergoing the dementia assessment. It is very doubtful that the lecanemab group yielded positive results
if these individuals had been included in the CDR. In addition, the most important indicator, such as reduction in
caregivers’ burden or admission to institutions, were not compared. Thus, the efficacy of lecanemab has not been
proven. See also supplementary appendix.
Conclusion: Lecanemab should not be approved, and even if approved, it should not be used.

Keywords:
amyloid-β, mild cognitive impairment, oxidative stress, inflammation, immedioate adverse events, delayed adverse events, infusion
reactions, excitotoxicity, neuronal death

Introductiondisease could be prevented by reducing amyloid-β [1,2].
However, more than 20 compounds that have been tried to

As the baby boomer generation ages, medical care for

reduce amyloid-β (Aβ) by various ways including Aβ antigens,dementia will become increasingly important in Japan. At thisAβ aggregation inhibitors, γ-secretase inhibitors and anti- Aβtime, there is growing interest in drugs that slow down the

monoclonal antibodies have all failed [3-5].

progression of Alzheimer’s disease, the most common form ofdementia.
Based on the hypothesis that Alzheimer’s disease is caused

EMA did not approve aducanumabby the accumulation of a protein called amyloid-β in the brain,

Aducanumab [4], reported in Med Check No. 97 (Inwhich causes nerve damage, it has been believed that theJapanese) , and lecanemab, discussed in this issue, are

MED CHECK

Sep. 2023/ Vol.9 No.27 ・ Page 21

New Products
Med Check’s Evaluation: No use
Generic name: lecanemab
Indications: Treatment of Alzheimer’s disease. It should beinitiated in patients with mild cognitive impairment or mild
dementia (U.S)
Dosage and administration: Confirm the presence ofamyloid beta pathology prior to initiating treatment:
Intravenous infusion
Drug price: about 26,500 USD/year in the U.S. (3.4 million
JPY/year)

Manufacturer: Eisai Co., Ltd. (approval process in Japan)(LTP) and memory seem to be mediated by α7 nACh receptors(α7-nAChRs) , as they are not observed in α7-nAChRs

knockout mice [5]. Accordingly, physiological concentrationsof Aβ were shown to potentiate presynaptic α7-nAChRs,
stimulating the release of glutamate and aspartate, the two
major excitatory neurotransmitters involved in hippocampal
LTP [5]. Glutamate and aspartate are also important for
activity, and emotion including happiness.
Amyloid-β is produced as needed in healthy individuals
and rapidly cleared when not needed. The concentration ofamyloid-β in the brain is strictly controlled by producing andclearing equally not to accumulate in excess [12].
However, overstimulation or overactivation of this receptor

monoclonal antibodies that bind to amyloid-β protofibril andleads to overproduction of dopamine and glutamate andare thought to reduce it (both manufactured by Eisai). For more

induce excitotoxicity, causing neuronal death in addition to thedetails, read Med Check No. 97, but to understand lecanemab,

excitotoxicity induced by continuous stress, with continuous

this article briefly discusses aducanumab.

ischemia or infection as shown in the next paragraph.

The results of clinical trials of aducanumab showed that

Rats continuously injected with amyloid-β in the ventricles

clinical symptoms did not improve even though amyloid-βof the brain have been used as a model animal for Alzheimer's

was reduced [3,6]. In the U.S., aducanumab was granted withdisease because their cognitive function is impaired [13].

accelerated (provisional) approval based only on the resultof the Phase 2 trial which showed reduction in amyloid-β in

Infection and stress prevent the clearance

diagnostic imaging, not on improvement in clinical symptomsof amyloid-β[7].

Approximately two-thirds of amyloid-β is cleared from theOn the other hand, the European Medicines Agency (EMA)

brain by P-glycoprotein (Note 1) in endothelial cells of blood

did not approve aducanumab because the overall benefit/risk

vessel in the brain, and the remaining one-third is taken up bybalance of aducanumab (product name: Aduhelm) is negative

cells in the brain for degradation [12]. However, when hyper-[6]. Biogen, the marketing authorization holder in Europe,

cytokinemia due to infection or oxidative stress occurs, thewithdrew its application for aducanumab from the EMA [8].

function of P-glycoprotein is impaired [14,15], resulting indelayed clearance from the brain and accumulation [12]. At

Amyloid-β is a key neurotransmitterhigh concentrations, amyloid-β binds to each other. The twobound together are called dimers. When they become dimers

Let's take a look at what amyloid-β (Aβ) really is.

and more are bound together, they are extremely difficult to be

We have a protein called Amyloid-β precursor protein (APP)

cleared and remain in the brain [16]. Hyper-cytokinemia andin our body. It is widely produced by brain neurons, vascularoxidative stress themselves injure neurons leading to neuronaland blood cells in our body [9]. APP spans the cell membrane,

death through excitotoxicity.

which separates the inside and outside of the cell. Aβ is
formed from APP being cleaved by 2 enzymes (β-secretase andNote 1: P-glycoprotein is a type of transporter that pumps substancesγ-secretase) as needed, and is a peptide consisting of about 40

out. It is found in vascular endothelial cells and in the intestinal

amino acids linked together [9].
In the brain, receptors called nicotinic acetylcholine (nAch)
receptor are present, which are essential for cognitive function

epithelium, where it plays an important role in the movement of
substances. In the brain, P-glycoprotein is found in the endothelial
cells of blood vessels and plays a central role in the function of theblood-brain barrier, which prevents toxic substances from entering thein humans and in other animals. In the brains of people withbrain and removes foreign substances produced in the brain. However,dementia, these nAch receptors and neurons having theseduring infection or oxidative stress, the function of P-glycoprotein is

receptors are reduced [10].
The physiological effects of Aβ on long-term potentiation
Page 22 ・ MED CHECK

Sep. 2023/ Vol.9 No.27

slowed down [14,15].

New Products
The True Cause of Alzheimer's Diseaseof about 6000 potential participants, about 1800 people (30%)
were carefully selected and randomly divided into two groups

Various mechanisms have been proposed for the reduction(900 each) : a lecanemab group and a placebo group. Thisin nicotinic acetylcholine receptors in the brains of patients

article examines the fairness in allocation to the two groups,

with dementia as causes [10,11]. Given the important role

which is the most important issue in clinical trials.

of amyloid-β in cognitive function, continuous stress with

Like aducanumab [4], lecanemab causes both immediate andischemia itself leading to excitotoxicity with neuronal deathdelayed inflammatory reactions.

and accumulation of amyloid-β in the brain, the fact that

The immediate type causes anaphylaxis-like symptoms,

excess amyloid-β overstimulates nAch receptor leading tosuch as fever, chills, headache, rash, vomiting, dyspnea,

overproduction of glutamate, excitotoxicity and neuronal

hypotension and shock within a very short time after

death, it may be difficult to slowing the progression of

intravenous injection. Although anaphylaxis itself is extremely

Alzheimer’s disease only by reducing amyloid-β in the brain.

rare, these anaphylaxis-like reactions are more common,Hence, even if amyloid-β in the brain is reduced by someoccurring in 26% of patients in the lecanemab group (7% in themeans, such as drugs, acetylcholine would not work on deadplacebo group). This is called infusion reaction.

neurons having nAch receptors. Moreover, unless reduced

If a severe symptom occurs, it is almost certain that

activity of P-glycoprotein were recovered by proper means,lecanemab was used, and if not, it is more likely that placebo

amyloid-β may continuously increase and cause constant

was used. In other words, at the early stage, both the doctors

damage to neurons. This is why it is repeatedly said thatand the volunteers in the study know on which side they havelecanemab is a drug that does not improve Alzheimer's disease

been assigned to.

but only slows its progression.
The inflammatory response that accompanies the clearanceof amyloid-β as a foreign substance must be also considered.

Lecanemab binds to amyloid-β and forms an antigenantibody complex (immune complex) that the body recognizes
as a foreign body and tries to eliminate, triggering a delayed
inflammatory response. This delayed inflammatory response

Accelerated approval of lecanemab in theis called amyloid-related imaging abnormalities (ARIA). In

U.S. was the result of a Phase 2 trial

addition to brain edema (ARIA-E), ARIA with hemorrhagic

This article has discussed above that amyloid-β is ansign (ARIA-H: hemorrhage and/or hemosiderin deposition) is

important neurotransmitter and not the actual cause ofoften observed on MRI. It may be asymptomatic or may

Alzheimer's disease, and that the disease is not improved by

be accompanied by symptoms, such as headache, visual

reducing amyloid-β. In addition, amyloid-β captured as anabnormalities, confusion, etc. ARIA-E occurs in 13% ofimage does not correlate with cognitive function [3,6], so

patients in the lecanemab group (2% in the placebo group) andmuch so that several review papers have stated that "drugARIA-H in 14% of patients in the lecanemab group (8% in thedevelopment based on the amyloid-β hypothesis should beplacebo group). Macrohemorrhage was observed in 5 (0.6%)

reviewed" [5,17,18]. With these considerations in mind, let us

in lecanemab group and only 1 in placebo group. Since theylook at clinical trials.

are significantly more common in the lecanemab group, theyIn the U.S., lecanemab was granted with accelerated

indicate which group the patients were assigned to.

approval in January 2023 based on the results of the Phase 2
trial showing reduction of amyloid-β accumulation by PET
scan [7]. It received traditional approval in July based on thephase 3 trial [19] published in November 2022.

Cognitive function improperly assessed due
to frequent dropouts
In the Phase 3 study, there were 2.5 times as many

A health ministry panel reviewing lecanemab adopted its

participants in the lecanemab group as in the placebo group

approval in Japan August 21, 2023 based on the same phase 3

who discontinued the study because of adverse events (6.9%

trial as in the US.

vs. 2.9%, difference 4.0%, p=0.00008) (Figure). There were also

1.8 times more participants in the lecanemab group than in the

Almost no masking in Phase 3 trial
Let's talk about the Phase 3 trial of lecanemab. From a poolplacebo group who were excluded from the dementia scoreassessment (4.3% vs. 2.5%, difference 1.9%, p=0.027) (Figure).
Of particular concern is that the higher the level of the
MED CHECK

Sep. 2023/ Vol.9 No.27 ・ Page 23

New Products
Figure : Proportion of participants who discontinued and the reasonsmITT population is defined as the group of
randomly assigned participants who received
at least one dose of lecanemab or placebo andwho had a baseline assessment and at least one
postdose primary emcacy (CDR-SB) measurement.
It is possible to exclude lecanemab users withsevere adverse events and poor symptom
improvement from the evaluation at the final
phase, leading to the possibility to overestimate
the efficacy of lecanemab.
Compared with the standard ITT analysis method,it has been pointed out that the mITT method
significantly overestimates the efficacy ofinterventions [21].

antigen, amyloid-β, the stronger the delayed response (ARIA).

2170 USD) per session at one facility.

Thus, those who were excluded from the dementia score

Note 3: Clinical Dementia Rating Scale (CDR) is one of the assessment

assessment may have had more severe dementia, and those
who were able to undergo the assessment may have had
relatively mild dementia.

indices for determining the severity of dementia. It is not only anassessment of cognitive function, but also takes into account thesituation at home and care situation. The assessment is not based ona cognitive function score on the test, but on the following 6 items:

The amount of amyloid-β accumulation is measured by(1) Memory, (2) Orientation, (3) Judgment and problem solving, (4)using a PET scan (Note 2). While the amount of amyloid-βCommunity affairs, (5) Home and hobbies (6) Personal care. Theseslightly increased in the placebo group, it reportedly decreased

items are rated as follows: healthy=0, suspected dementia=0.5, mildfrom 78 centiloids (the unit of measurement of amyloid-β in the
PET scan) at baseline by 71% reduction (55 centiloids less) at 1.5

years.

dementia=1, moderate dementia= 2, and severe dementia=3. The
total score is called CDR-SB (SB: sum of boxes). The score for the most
severely affected person is 18 (3×6) [20]. It is considered that 0.5-6
points indicates mild cognitive impairment to mild dementia [19].

On the other hand, the key primary endpoint, the CDRSB score (Note 3) (0.5 to 6 points for mild dementia; the higher
the score, the more severe the dementia), was 3.24 points atbaseline for the placebo group and worsened by 1.66 points to
4.90 points at 18 months. The score for the lecanemab groupworsened by 1.21 points from 3.17 points to 4.38 points.
As the difference in deterioration from baseline between theplacebo and lecanemab groups was 27% (p<0.001), this alone
makes the difference look significant.
However, in terms of the number of points achieved, while
it was 4.90 points in the placebo group, it was 4.38 points inthe lecanemab group, showing only a difference of 10.6%(originally 2.2% less in the lecanemab group, so only 8% difference
if this is taken into account).

The difference is uncertain if dropouts areincluded
It cannot be said that cognitive function testing was fairly
compared, because testing was not conducted on those who
discontinued because of adverse events, but only on those who
continued in the study. It produces the results significantly infavor of the lecanemab group, which had more dropouts. It
is doubtful that there would be a significant difference in thelecanemab group if cognitive function tests were performedon patients who dropped out of the study.
The editorials of the British Medical Journal (EMJ) strongly
criticized the possible masking failure, the high incidenceof adverse events with lecanemab, and the uncertainty as toNote 2: Positron Emission Tomography (PET) is a computed

whether the reduction in amyloid-β and cognitive decline

tomography technique using positron detection. While CT andwould be meaningful in practice (since 70% of the study

MRI are mainly used to observe morphology, it is used to observe
biological functions. A substance that readily binds to amyloid-β is

candidates were excluded from the trial) [22]. However, it did notinjected into the brain, and detection of areas in the brain that emit

criticize that the cognitive function tests were performed inradiation reveals the accumulation of amyloid-β. Currently, PET scanfavor of the lecanemab group.

is conducted at patients’ own expenses, and costs 300,000 yen (about

Page 24 ・ MED CHECK

Sep. 2023/ Vol.9 No.27

In order to eliminate the bias in favor of the lecanemab

New Products
group, it is necessary to evaluate an objective indicator,

In practicesuch as how many admissions to institutions is reduced, as a
primary endpoint and assess all assigned patients (all patients

It has not been proven that lecanemab slows down the

who received at least one dose of experimental substance). as

progression of cognitive impairment. It should not be

controls, rather than a surrogate endpoint of cognitive function

approved in Japan, and even if approved, it should not be

testing. Based on the published study results, it cannot be

used.

said that lecanemab has an effect to control progression of
Alzheimer's disease.

References
1) Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress andproblems on the road to therapeutics. Science. 2002 Jul 19;297(5580):353-6. doi:
10.1126/science.1072994.PMID: 12130773
2) Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO
Mol Med. 2016 Jun 1;8(6):595-608. doi: 10.15252/emmm.201606210. PMID: 27025652
3) Public Citizen Health Research Group. Comments Regarding the Centers for Medicare

See also Supplementary Appendix

12) Qosa H, Abuasal BS, Romero IA et al. Differences in amyloid-β clearance across mouseand human blood-brain barrier models: kinetic analysis and mechanistic modeling.
Neuropharmacology. 2014:79:668-78. doi: 10.1016/j.neuropharm.2014.01.023. PMID:
24467845
13) Nitta A, Fukuta T, Nabeshima T et al. Continuous infusion of beta-amyloid protein into
the rat cerebral ventricle induces learning impairment and neuronal and morphologicaldegeneration. Jpn J Pharmacol. 1997 Jan;73(1):51-7. doi: 10.1254/jjp.73.51. PMID:
9032134

and Medicaid Services’ National Coverage Determination Analysis for Monoclonal14) Hama R, Bennett CL. The mechanisms of sudden-onset type adverse reactions to

Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-

oseltamivir. Acta Neurol Scand. 2017 Feb;135(2):148-160. doi: 10.1111/ane.12629.

00460N) https://www.citizen.org/wp-content/uploads/2598.pdf
4) MedCheck editorial team. A Candidate drug for Alzheimer’s disease: Aducanumab--Do
not have illusion on ineffective and harmful agent. Med Check (in Japanese).
2021:21(97):100-102.
https://www.npojip.org/chk_tip/No97-f04.pdf Web information: (in Japanese):https://www.npojip.org/chk_tip/No97-f07.pdf
5) Ricciarelli R, Fedele E. The Amyloid Cascade Hypothesis in Alzheimer’s Disease: It's Timeto Change Our Mind. Curr Neuropharmacol. 2017;15(6):926-935.doi:10.2174/157015
9X15666170116143743.PMID:28093977
6) Committee for Medicinal Products for Human Use (CHMP) EMA/CHMP/557556/2022(2021/12/16), EMA Withdrawal Assessment report on aducanumab https://www.ema.
europa.eu/en/documents/withdrawal-report/withdrawal-assessment-report-aduhelm_
en.pdf7) FDA Grants Traditional Approval for LEQEMBI® (lecanemab-irmb) for the Treatment of
Alzheimer’s Disease 2021/6/8 https://www.eisai.com/news/2023/news202349.html
8) Withdrawal letter by Biogen (2022/4/20)
https://www.ema.europa.eu/en/documents/withdrawal-letter/withdrawal-letteraduhelm_en.pdf9) Hampel H, Hu Y, Hardy J. The amyloid-β pathway in Alzheimer’s disease: a plain
language summary. Neurodegener Dis Manag. 2023 Jun;13(3):141-149. doi: 10.2217/
nmt-2022-0037. Epub 2023 Mar 30. PMID: 36994753
10) Kihara T, Shimohama S. Alzheimer’s disease and acetylcholine receptors. Acta
Neurobiol Exp (Wars). 2004; 64(1): 99-105. PMID: 15190684

Epub 2016 Jun 30. PMID: 27364959
15) Sita G, Hrelia P, Tarozzi A, Morroni F. P-glycoprotein (ABCB1) and Oxidative Stress:
Focus on Alzheimer’s Disease. Oxid Med Cell Longev. 2017;2017: 7905486. doi:
10.1155/2017/7905486. Epub 2017 Nov 26. PMID: 29317984
16) Ito S, Ohtsuki S, Kamiie J et al. Cerebral clearance of human amyloid-peptide(1-40)
across the blood-brain barrier is reduced by self-aggregation and formation of lowdensity lipoprotein receptor-related protein-1 ligand complexes. J Neurochem 2007:
103:2482–2490. doi: 10.1111/j.1471-4159.2007.04938.x. PMID: 17908238
17) Castello MA, Soriano S. On the origin of Alzheimer’s disease. Trials and tribulations of
the amyloid hypothesis. Ageing Res Rev. 2014 Jan;13:10-2. doi: 10.1016/
j.arr.2013.10.001. Epub 2013 Nov 16.PMID: 24252390
18) Høilund-Carlsen PF, Barrio JR, Alavi A et al. Amyloid Hypothesis: The Emperor's New
Clothes? J Alzheimer’s Dis. 2020;78(4):1363-1366. doi: 10.3233/JAD-200990.PMID:
3316493819) van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease.
N Engl J Med. 2023 Jan 5;388(1):9-21. doi: 10.1056/NEJMoa2212948. Epub 2022 Nov
29.PMID: 36449413
20) https://hokuto.app/calculator/fPr1Uj1wzQazBlsO3Ehc
21) Abraha I, Cherubini A, Cozzolino F et al. Deviation from intention to treat analysis in
randomised trials and treatment effect estimates: meta-epidemiological study. BMJ.
2015;350:h2445. doi:10.1136/bmj.h2445. PMID: 26016488
22) Walsh S, Merrick R, Richard E et al. Lecanemab for Alzheimer’s disease. BMJ. 2022
Dec 19;379:o3010. doi: 10.1136/bmj.o3010.PMID: 36535691

11) Findley CA, Bartke A, Hascup KN et al. Amyloid Beta-Related Alterations to Glutamate
Signaling Dynamics During Alzheimer’s Disease Progression. ASN Neuro. 2019 JanDec;11:1759091419855541. doi: 10.1177/1759091419855541. PMID: 31213067

MED CHECK

Sep. 2023/ Vol.9 No.27 ・ Page 25

COVID-19 Information
SARS-CoV-2 vaccine increases arrythmia mortality
Translated and revised from Med Check(in Japanese) Jul. 2023 ; 23 (107)：61-63
Med Check Editorial Team

Abstract● SARS-CoV-2 vaccine induces various adverse reactions. There are some case reports after receiving SARSCoV-2 vaccine. This article investigates the association between the vaccine and arrythmia mortality, using datafrom England. Arrythmia mortality rate in vaccinated compared with that in the general population in 2017-19(mortality rate ratio in epidemiological term).

●Mortality rate from arrhythmia after receiving Pfizer’s SARS-CoV-2 vaccine was 5.89-fold for both sexes (male: 9.22fold, female: 3.77-fold), 6.70-fold (male: 10.15-fold, female: 4.42-fold) after the first dose and 5.03-fold (male: 8.17-fold,female:3.10-fold) after the second dose. The actual risk may be over 15-fold, when healthy-vaccinee effect is taken

into account.
●SARS-CoV-2 vaccine package inserts do not mention 'arrhythmia' as a post-vaccination adverse reaction. As aresult, few adverse reactions to vaccines have been reported in Japan. A system is needed, as the United Kingdom,that links information on vaccinees with the cause of death in subsequent deaths in order to accurately assess
serious adverse reactions to vaccine.

Conclusions: SARS-CoV-2 vaccine increases mortality of arrythmia more than 15-fold;
the risk is especially higher in male.

Keywords:
SARS-CoV-2 vaccine, demographic statistics, England, healthy-vaccinee effectIntroduction

Many arrythmia cases were reported following SARSCoV-2 vaccine [7-22]. The aim of this article is to investigate

Med Check Editorial Team pointed out that SARS-

the relationship between SARS-CoV-2 vaccine and arrythmia

CoV-2 vaccine increases hemorrhagic stroke mortality

death. We primarily analysed the most commonly used[1], myocarditis mortality [2], and that the proportion of

Pfizer’s vaccines worldwide, with AstraZeneca’s vaccines as a

circulatory deaths were extremely high in those who received

sub-analysis.

SARS-CoV-2 vaccine [3].
Patone et al. investigated myocarditis, pericarditis andarrythmia after receiving SARS-CoV-2 vaccine in England

Note : The Patone et al used "self-controlled case series" method. To examine
the risk of arrhythmia, people were considered eligible for inclusion if they
had received at least one vaccine dose, were at least 16 years old and wereby self-controlled case series (SCCS) [4]. The apparent risk

admitted to hospital with, or died from arrhythmia during the study period. The

for arrythmia incidence rate ratios (IRRs) within 28 days

reference population was not those unvaccinated but individuals themselves

after receiving SARS-CoV-2 vaccine were from 0.89 to 0.95.

who had arrhythmia. The incidence rate of arrhythmia after receiving vaccine

However, the IRRs for the day of vaccine dose were about
one-third, which was due to healthy-vaccinee effect [5,6].
Hence the actual IRRs for arrythmia were estimated to beabout 3-fold in those vaccinated (Note).
Page 26 ・ MED CHECK

Sep. 2023/ Vol.9 No.27

was compared with that during assumed vaccine-free period (more than 28
days before and after vaccination). Incidence rate ratio (IRR) was 0.33 (95%
confidence interval 0.30-0.38) on the day of vaccination and was 0.32 (0.290.37) on the 21st day (day of the second dose). These data indicate that on the
day of vaccination, subjects were healthier than during control periods.

COVID-19 Information
Research methods

6.07 (2.96-15.14), 10.15 (9.13-11.27), and 4.42 (3.96-4.91) for
both sexes, for male, and for female respectively. After the

Numbers vaccinateed and arrythmia deaths within 28 days

second dose, they were 5.03 (1.95-13.01), 8.17 (7.20-9.23)

after SARS-CoV-2 vaccination were reported by vaccine

and 3.10 (2.71-3.52), respectively. Very high mortality risks

type and by sex in the supplementary table 1 in the paper

for arrythmia were associated with Pfizer’s SARS-CoV-2[4]. Arrythmia mortality rates (/100,000 person-years) within

vaccination in both sexes especially high in male.

28 days after the first dose and second dose of SARS-

These were observed without adjusting for healthy vaccinee

CoV-2 vaccine were calculated (details were shown in Table

effect. Details, including crude mortality rate ratios wereand Appendix1,2).Arrythmia mortality rate in the reference

shown in the Table and Figure. Results for the AstraZeneca’s

population (general population) was also calculated based on

SARS-CoV-2 vaccine which were similar to Pfizer’s vaccine

demographics and mortality statistics of England in 2017-

were presented in Appendix 3, 5 and 6.

2019 (Table and Appendix3). Subsequently, we compared thesecardiac arrythmia mortality rates.
Arrythmia was defined following supplementary table 11 in
the paper [4].

Accurate risk estimates inherently require age adjustment,
since both percent coverage vaccinated and arrhythmia
mortality rates vary by age group (Appendix 3 and 7) .
However, the number of deaths by age group required for thisBased on this information, arrhythmia mortality rates

calculation could not be ascertained from the paper [4].

in the general population were higher and and the SARS-Therefore, we calculated the age-standardized mortality

CoV-2 vaccinated population was larger in female than inrate ratio (standardized mortality ratio: SMR) based on the two

male. Therefore, sex was considered a confounding factor inassumptions below;

this research and the mortality raate ratios (MRR) for male,

1. equal to the age distribution of arrythmia cases after

female and for total adjusted for sex using meta-analysis were

vaccination.

calculated.

2. equal to the age distribution of arrythmia deaths in thegeneral population,

Arrythmia mortality increased by 3 to 10-fold in

Under the assumption 1. the SMRs for the overall dose, the

SARS-CoV-2 vaccinatedfirst and the second dose for Pfizer’s vaccine were 4.53(4.28-

Compared with the 2017-2019 general population, MRR for4.80), 5.80 (5.39-6.25) and 3.46 (3.17-3.79), respectively.

arrythmia (95% confidence interval) for both sexes following

Under the assumption 2, they were 4.57 (4.32-4.83), 6.00

Pfizer’s SARS-CoV-2 vaccine overall adjusted by sex was(5.57-6.46) and 3.43 (3.14-3.74), respectively.

5.89 (2.45-14.17). They were 9.22 (8.51-9.98) for male andDetails and results for the AstraZeneca’s vaccine were

3.77 (3.47-4.09) for female. After the first dose, they were

presented in the Appendix 7 and 8.

Table : Mortality risk from arrythmia after SARS-CoV-2 vaccine compared with general population in England.

*Calculations were shown in Appendix 2-1.

MED CHECK

Sep. 2023/ Vol.9 No.27 ・ Page 27

COVID-19 Information
Figure :Sex adjusted arrythmia mortality rate ratio for Pfizer’s SARS-CoV-2 vaccine*Arrhythmia mortality rate in the general
population is higher in female than that in maleand crude mortality rate ratios in female were
far lower than in male. Therefore, mortality rate
ratios for both sexes were calculated adjusting
sex as a confounding factor. Sex adjusted pooledmortality rate ratios were shown using a randomeffects model, because the I²values were over
90% (very different mortality rate ratio by sex).

that the post-vaccination deaths disclosed by Japanese

The actual risk is more than 15-fold, taking into

government were only about one-sixtieth of those that should

account healthy-vaccinee effect.

have been occured [2]. In Japan, as of 14 February 2022[26],As the Med Check Editorial Team has emphasized, theit is estimated that approximately 99.83 million people haveactual risk is higher when healthy-vaccinee effect (bias) is

received the first dose of the vaccine and 99.12 million people

taken into account, because this confounding bias leads tohave received up to the second dose (80% of all vaccinations byunderestimation of vaccine harm.

Pfizer Vaccine). In contrast, according to Japanese government

In general, the more serious the harmful reaction, thedata as of 10 March 2023 [27], the number of reported

stronger the healthy-vaccinee effect works [6]. Even if 0.33

arrhythmia deaths within 28 days after vaccination, reflectingof arrhythmia IRR was applied as healthy vaccinee effect, thethe two doses up to 14 February 2022, was only 49.

risk was estimated to be three times higher than the apparent
arrythmia mortality risk (about 5-fold) yielding 15-fold.

According to the Japanese Vital Statistics [28], the numberof arrhythmia deaths in the three-year period 2017-2019 was

The risk of arrhythmia mortalities was higher across theapproximately 130 times the number of myocarditis deaths.

board for the first dose of vaccination than for the second

Therefore, when compared with the number of reported post-

dose. This may be because those who did not suffer from avaccination myocarditis deaths [2], most post-vaccination

serious adverse reaction after the first dose could receive thearrhythmia deaths are probably not reported.

second dose [5].

All post-vaccination deaths should be
Extremely few reports on post-vaccination

investigated and disclosed

arrhythmia deaths in JapanAt a Ministry of Health, Labour and Welfare (MHLW)"Arrhythmia" is not warned as one of the adverse reactions

subcommittee meeting held on 7 March 2023 [29], the futurein the package insert of the SARS-CoV-2 vaccine [25].

target population for SARS-CoV-2 vaccine and vaccination

However, as very high risk was shown in this article using

intervals were discussed based on the assumption that "there

data on SARS-CoV-2 vaccination and subsequent deaths

are no serious adverse reactions to SARS-CoV-2 vaccine",

in England, there may be causal relationsship between thestating that "at this time, no serious concerns affecting

SARS-CoV-2 vaccine and arrhythmia deaths.

the promotion of vaccination are considered to have been

When investigating the risk of myocarditis mortality after

identified".

SARS-CoV-2 vaccination in Japan, we made a comparison

However, there are significant omissions in Japanese reports

with the general population not only for myocarditis deathson harmful reactions following SARS-CoV-2 vaccination. In

but also for all-cause deaths. Then, the comparison revealed

addition, almost all observational studies investigating adverse

Page 28 ・ MED CHECK

Sep. 2023/ Vol.9 No.27

COVID-19 Information
reactions to vaccine have been lacking adjustment of healthyvaccinee effect.
First, both vaccine efficacy and harm need to be assessedtaking into account the healthy-vaccinee effect. In addition,
spontaneous reporting of serious adverse reactions after
vaccination alone does not eliminate under-reporting [30].
In order to accurately assess the harms of the SARS-CoV-2
vaccine, it is necessary to establish a system that can link thevaccination registry to all post-vaccination deaths (timing ofdeath, causes of death), as in England, which was examined inthis study.
It is then necessary to systematically examine the effects
and harms of vaccines, taking into account the healthyvaccinee effect, and to discuss whether the previous vaccine
promotion policy was appropriate in order to review thepolicy.
References
1) MedCheck editorial team. SARS-CoV-2 vaccine induced haemorrhagic stroke -Forthcases: strong causal relationship Available at: https://npojip.org/sokuho/No195.pdf(Accessed 10 July 2023, in Japanese)
2) Watanabe S, and Hama R. SARS-CoV-2 vaccine and increased myocarditis
mortality risk: A population based comparative study in Japan. Doi: https://doi.
org/10.1101/2022.10.13.22281036
3) MedCheck editorial team. Cerebral haemorrhage and vascular disease deaths are
more frequent after SARS-CoV-2 vaccine - strong association with cerebral haemorrhage,
thrombosis and sudden death. MedCheck 2021; 21 (96): 86-91 (in Japanese).
4) Patone M, Mei XW, Handunnetthi L, et al. Risks of myocarditis, pericarditis, and cardiac
arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nat Med.
2022;28(2):410-422.
5) MedCheck editorial team. Non-COVID-19-related deaths were reduced in thevaccinated population -Robust evidence for healthy vaccinee effect-.MedCheck 2022; 9(24): 24-31.
6) MedCheck editorial team. To Be Vaccinated or Not? Points You should Know -SARSCoV-2 Vaccines Doubles the Risk of COVID-19! - 2022; 8 (25): 40-52.
7) Okuyama T, Kabutoya T, Gonda Y, et al. Syncope after COVID-19 Vaccination in16) Kimball E, Buchwalder K, Upchurch C, et al. Intermittent complete heart block withventricular standstill after Pfizer COVID-19 booster vaccination: A case report. J Am Coll
Emerg Physicians Open 2022;3(2): e12723. doi: 10.1002/emp2.12723.
17) Etienne H, Charles P, Pierre T. Transient but recurrent complete heart block in apatient after COVID-19 vaccination - A case report. Ann Med Surg (Lond) 2022;
78:103694. doi: 10.1016/j.amsu.2022.103694
18) Eldokla AM, Numan MT. Postural orthostatic tachycardia syndrome after mRNA
COVID-19 vaccine. Clin Auton Res 2022;32(4):307-11. doi: 10.1007/s10286-022-00880-3
19) Abrich VA, Olshansky B. Torsades de pointes following vaccination for COVID-19.
HeartRhythm Case Rep 2022;8(6):393-97. doi: 10.1016/j.hrcr.2022.04.003
20) Tate C, Demashkieh L, Hakmeh W. Isolated Tachycardia Presenting After PfizerBioNTech COVID-19 Vaccination. Cureus 2021;13(7): e16706. doi: 10.7759/cureus.16706
21) Reddy S, Reddy S, Arora M. A Case of Postural Orthostatic Tachycardia Syndrome
Secondary to the Messenger RNA COVID-19 Vaccine. Cureus 2021;13(5): e14837. doi:
10.7759/cureus.14837
22) Aiba T, Ishibashi K, Hattori K, et al. Frequent Premature Ventricular Contraction
and Non-Sustained Ventricular Tachycardia After the SARS-CoV-2 Vaccination in PatientWith Implantable Cardioverter Defibrillator Due to Acquired Long-QT Syndrome. Circ J
2021;85(11):2117. doi: 10.1253/circj. CJ-21-0515
23) Office for National Statistics Estimates of the population for the UK,

a Young Man with Unmasking Brugada Syndrome. Intern Med 2023 doi: 10.2169/

England and Wales, Scotland and Northern Ireland https://www.ons.gov.uk/

internalmedicine.1250-22

peoplepopulationandcommunity/populationandmigration/populationestimates/

8) Chen CY, Hsieh MT, Wei CT, et al. Atrial Fibrillation After mRNA-1273 SARS-CoV-2

datasets/populationestimatesforukenglandandwalesscotlandandnorthernireland)

Vaccination: Case Report with Literature Review. Risk Manag Healthc Policy 2023;

24) Nomis official census and labour market statistics Mortality statistics - underlying

16:209-14. doi: 10.2147/RMHP.S402007
9) Sangpornsuk N, Rungpradubvong V, Tokavanich N, et al. Arrhythmias after SARS-CoV-2
Vaccination in Patients with a Cardiac Implantable Electronic Device: A Multicenter
Study. Biomedicines 2022;10(11) doi: 10.3390/biomedicines10112838
10) Pons-Riverola A, Manas P, Claver E, et al. Third-degree atrioventricular blockassociated with the SARS-CoV-2 mRNA vaccine. Rev Esp Cardiol (Engl Ed) 2022 doi:
10.1016/j.rec.2022.10.004
11) Park J, Kim S, Lee J, et al. A case of transient POTS following COVID-19 vaccine. Acta
Neurol Belg 2022;122(4):1081-83. doi: 10.1007/s13760-022-02002-2
12) Mehrabi Nasab E, Athari SS. The first report of 2:1 atrioventricular block following
COVID-19 vaccination. Clin Case Rep 2022;10(5): e05797. doi: 10.1002/ccr3.5797
13) Marco Garcia MT, Torres Lana A, Anta Agudo MB, et al. Tachycardia as an undescribedadverse effect to the Comirnaty(c) vaccine (BNT162b2 Pfizer-BioNTech Covid-19
vaccine): Description of 3 cases with a history of SARS-CoV-2 disease. Enferm Infecc
Microbiol Clin (Engl Ed) 2022;40(5):276-77. doi: 10.1016/j.eimce.2022.03.002
14) Lin YT, Chen PY, Su YJ. Paroxysmal supra-ventricular ventricular tachycardia after
AstraZeneca COVID-19 vaccine injection. New Microbes New Infect 2022; 45:100965.
doi: 10.1016/j.nmni.2022.100965

cause, sex and age (https://www.nomisweb.co.uk/query/construct/summary.asp?mode=construct&version=0&dataset=161#
25) Pfizer vaccine package insert. Available from: https://www.fda.gov/media/144246/
download (Accessed 10 July 2023)
26) Japan’s Prime Minister's Office. SARS-CoV-2 vaccine coverage. Available from: https://www.kantei.go.jp/jp/headline/kansensho/vaccine.html (Accessed 10 July, 2023)
27) Japan’s Ministry of Health, Labor and Welfare. 92th meeting of the working group on
adverse reactions to vaccine on 10 March 2023. Available from: https://www.mhlw.
go.jp/stf/shingi2/0000208910_00059.html (Accessed 10 July, 2023, in Japanese)
28) Japan’s Statistics Bureau of the Ministry of Internal Affairs and Communications.
Available from: https://www.e-stat.go.jp/en/stat-search/files?page=1&toukei=0020052
4&tstat=000000090001&cycle=7&month=0&tclass1=000001011679&tclass2val=0&me
tadata=1&data=1 (Accessed 10 July, 2023)
29) Japan’s Ministry of Health, Labor and Welfare. Meeting material No.1-1 forworking group of vaccine on 7 March 2023. Available from: https://www.mhlw.go.jp/
content/10601000/000961882.pdf (Accessed 10 July 2023, in Japanese)30) Rothman KJ. Epidemiology An Introduction 2nd ed. New York: Oxford University Press;2012. pp 249-51.

15) Lim KH, Park JS. COVID-19 Vaccination-Induced Ventricular Fibrillation in an Afebrile
Patient With Brugada Syndrome. J Korean Med Sci 2022;37(42): e306. doi: 10.3346/
jkms.2022.37. e306

MED CHECK

Sep. 2023/ Vol.9 No.27 ・ Page 29

COVID-19 Information

Vaccine increases venous thrombosis mortality
Translated and revised from Med Check(in Japanese) Jul. 2023 ; 23 (108)：88-89
Med Check Editorial Team

Abstract●Med Check Editorial Team pointed out an association between the SARS-CoV-2 vaccine and thrombosis deathsin 2021; now this article investigates the association between the SARS-CoV-2 vaccine (mainly Pfizer’s) and venous
thrombosis mortality, using data from England.
●Venous thrombosis mortality after Pfizer’s SARS-CoV-2 vaccine was approximately 9.6-fold compared withthe reference population (2015-2019). Age-adjusted mortality rate ratios (standardised mortality ratios) wasapproximately 5.4 to 5.6. The actual risk would be considered to be 15 times higher, when we take into accounthealthy-vaccinee effect.
●Adapting these results to Japan, it is possible that within 28 days of the first dose of SARS-CoV-2 vaccine,
approximately 480 people may have died from venous thrombosis. Japanese demographic statistics estimate
an increase of approximately 300 venous thrombosis deaths in 2021, which raises the possibility of vaccine
involvement.
●Japanese government should investigate all adverse reactions to the vaccine, including deaths from venous
thrombosis.

Conclusions: SARS-CoV-2 vaccine increases mortality from venous thrombosis more than five-fold.

Keywords:
SARS-CoV-2 vaccine, demographic statistics, England, healthy-vaccinee effectIntroduction[12,13].
Of these, based on the Hippisley-Coxs’ paper [12], the

Med Check Editorial Team pointed out in June 2021 thenumber of venous thrombosis deaths in people who received

harm of the SARS-CoV-2 vaccine in hemorrhagic stroke andone dose of Pfizer's or AstraZeneca's vaccine was calculated

arterial and venous system disease deaths [1]. This was due toand the risk of SARS-CoV-2 vaccine-induced venous

the extremely high proportion of venous system thrombosis

thrombosis death was estimated.

(venous thrombosis plus pulmonary embolism) as a cause ofdeath compared with the general population; mortality odds
ratio was 26 for healthcare workers and 12 for the elderly.

Research methods

Subsequently, several case reports of venous thrombosis

Venous thrombosis mortality rate (/100 000 person-years)

after vaccination have been reported [2-10], and a death caseafter the first dose of SARS-CoV-2 vaccine was calculated

have also been reported where the autopsy revealed venous

from information in the Hippisley-Coxs’ paper [12] (Appendix

thrombosis [11]. Furthermore, some epidemiological studies1) , and venous thrombosis mortality rate in the generalinvestigating the incidence of venous thrombosis by vaccine

population was calculated from the 2015-2019 England’s

type and the number of vaccinations have been publishedvital statistics [14,15]. Subsequently, these venous thrombosis

Page 30 ・ MED CHECK

Sep. 2023/ Vol.9 No.27

COVID-19 Informationmortality rates (/100,000 person-years) were compared

Venous thrombosis mortality increased 5-fold to
10-fold in vaccinated population(Appendix 2-4).

Venous thrombosis mortality rate ratios comparing

Comparison of venous thrombosis mortality ratevaccinated with general population were 9.63 for Pfizer’s
vaccine and 6.89 for AstraZeneca’s vaccine. These indicate

Vaccinee: 9,513,625 and 19,608,007 people aged 16

that SARS-CoV-2 vaccines may induce death from venous

years and over living in England received the first dose ofthrombosis as adverse reactions (Table: mortality rate ratio).

Pfizer′s and AstraZeneca’s vaccines respectively between 1

Accurate risk estimates inherently require age adjustment,

December 2020 and 24 April 2021. In the case of the Pfizer

since both percent coverage vaccinated and venous thrombosis

vaccine, more than half of the people would have received

mortality rates vary by age group (Appendix 2,6). However,the second dose after approximately 21 days [16], but for

the number of deaths by age group required for this calculation

convenience, 28 days was used as the observation period

could not be ascertained from the Hippisley-Coxs' paper [12].

(Appendix 5). The results were shown in Table (vaccinated,

Therefore, the age adjusted mortality ratio (standardised

oerson-years).
There were 338 and 499 venous thrombosis deaths withinmortality ratio: SMR) was calculated, assuming the two cases

below:

28 days of vaccination from Pfizer’s and AstraZeneca’s

1. Equal to the age distribution of venous thrombosis cases

vaccine respectively. Approximately 1 in 30,000 to 40,000

after vaccination reported in the ref. [12].

people died of venous thrombosis within 28 days of

2. Equal to the age distribution of venous thrombosis

vaccination. The venous thrombosis mortality rates, expressed

deaths in the general population,in person-times, were approximately 46 (Pfizer) and 33

Under the assumption 1. the SMR was 5.64 (Pfizer) and 6.30

(AstraZeneca) per 100,000 person-years, respectively (Table:(AstraZeneca).

vaccinated, venous thrombosis mortality rates).

Under the assumption 2. the SMR was 5.41 (Pfizer) and 7.02

General population (reference): The venous thrombosis(AstraZeneca) (Appendix 7-9).

mortality rate (/100,000 person-years) for the five-year period
2015-2019 was calculated by obtaining the population aged 15

The actual risk is more than 13 times higher,

years and older from demographics [14] and then extracting

taking into account healthy-vaccinee effect.

the number of venous thrombosis deaths by age from mortality

As the Med Check Editorial Team had emphasized, thestatistics [15]. In a total of 227.83 million person-years overactual risk is higher when healthy vaccinee effect is taken into

a five-year period, approximately 11,000 people died fromaccount.

venous thrombosis, giving a mortality rate of approximately

When venous thrombosis incidence is used as an endpoint

4.8 deaths per 100,000 person-years (Table: general population).

by self-controlled case series (SCCS) [12], the apparent venous

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 (Astra Zeneca. If they were qual to that in the reference population, SMRs were 5.41 (Pfizer)
and 7.02 (Astra Zeneca) (Appendix7-9) p-ys：person-years

MED CHECK

Sep. 2023/ Vol.9 No.27 ・ Page 31

COVID-19 Information
thrombosis incidence rate ratio (IRR) after 1-28 days oftype, the number of vaccinations, time of death or overlapping

vaccination was 0.93-fold (95% confidence interval: 0.89-0.98)

causes of death, only 38 venous thrombosis deaths were listed.

(Pfizer) and 1.00-fold (0.93-1.09) (AstraZeneca).

Japanese government should clarify the causal relationshipHowever, if we focus on the IRR on the day of vaccination:

between the vaccine and serious adverse reaction, including

0.35 (0.24-0.52) (Pfizer) and 0.46 (0.35-0.69) (AstraZeneca), thevenous thrombosis deaths. To this end, the cause and time ofapparent venous thrombosis risk is underestimated at least

death should be investigated and published for all cases of

0.35 to 0.46 times (approximately one-third to half), respectively

post-vaccination deaths.

due to healthy-vaccinee effect. The actual risk of venous
thrombosis is, therefore, 0.93/0.35 = 2.26 times (Pfizer) and1.00/0.46 = 2.17 times (AstraZeneca), respectively (Appendix
10-11 for calculation methods and detailed results).

The healthy-vaccinee effect for venous thrombosis
incidence rate ratio applied to mortality rate ratio for venous
thrombosis adjusted mortality rate ratio would be 5.41/0.35 =15.46 times (Pfizer) and 6.30/0.46 = 13.70 times (AstraZeneca).
Since the healthy-vaccinee effect is stronger for more serious
events [17], the actual venous thrombosis mortality rate
ratio may be greater. The risk of post-vaccination venous
thrombosis mortality is therefore estimated to be greater than
15-fold (Pfizer) and 13-fold (AstraZeneca).

References
1) MedCheck Editorial Team. Cerebral haemorrhage and vascular disease deaths are
more frequent after SARS-CoV-2 vaccine - strong association with cerebral haemorrhage,
thrombosis and sudden death. MedCheck 2021; 21 (96): 86-91 (in Japanese).
2) Al-Maqbali JS, Al Rasbi S, Kashoub MS, et al. A 59-Year-Old Woman with Extensive Deep
Vein Thrombosis and Pulmonary Thromboembolism 7 Days Following a First Dose of the
Pfizer-BioNTech BNT162b2 mRNA COVID-19 Vaccine. Am J Case Rep 2021;22: e932946.
3) Borisoff BD, Bohn KD, Sager J, et al. Unprovoked Submassive Saddle Pulmonary
Embolism in an Adult Male After Pfizer COVID-19 Vaccination. Cureus 2022;14(8):The number of disclosed post-vaccination
deaths in Japan is too low.
In Japan, about 80% of the SARS-CoV-2 vaccine used
to date is the Pfizer’s vaccine; approximately 78.49 million
persons had received their first dose of the Pfizer vaccine ofthe original strain [18] by the end of 2021. Japan’s venous
thrombosis mortality rate for 2015-2019 (aged 10 years ande27717. doi: 10.7759/cureus.27717.
4) Houghton DE, Wysokinski W, Casanegra AI, et al. Risk of venous thromboembolism
after COVID-19 vaccination. J Thromb Haemost 2022;20(7):1638-44. doi: 10.1111/
jth.157254.
5) Hviid A, Hansen JV, Thiesson EM, et al. Association of AZD1222 and BNT162b2
COVID-19 Vaccination With Thromboembolic and Thrombocytopenic Events in Frontline
Personnel: A Retrospective Cohort Study. Ann Intern Med 2022;175(4):541-46. doi:
10.7326/M21-24525.
6) Kan Y, Asada M, Uesawa Y. Trends in reporting embolic and thrombotic events after
COVID-19 vaccination: A retrospective, pharmacovigilance study. PLoS One 2022;17(8):e0269268. doi: 10.1371/journal.pone.0269268

over) was 1.60 (/100 000) [19,20], which is approximately one7) Miri C, Bouchlarhem A, Boulouiz S, et al. Pulmonary embolism with junctional

third of the mortality rate in England.

2022; 80:103983. doi: 10.1016/j.amsu.2022.103983

In light of this, if the data from England, where the SMR fortachycardia: A serious complication after COVID-19 vaccination. Ann Med Surg (Lond)
8) Mouta Nunes de Oliveira P, Mendes-de-Almeida DP, Bertollo Gomes Porto V, et al.
Vaccine-induced immune thrombotic thrombocytopenia after COVID-19 vaccination:

venous thrombosis was five times higher than in the general

Description of a series of 39 cases in Brazil. Vaccine 2022;40(33):4788-95. doi: 10.1016/

population after vaccination with Pfizer's vaccine is applied

9) Petrochko JM, Pateman Aciu SM, Sheth SU. Portal vein thrombosis after second Pfizer/

to Japan, it is estimated that approximately 480 people diedj.vaccine.
BioNTech coronavirus disease 2019 vaccine. J Vasc Surg Cases Innov Tech 2022;8(4):66769. doi: 10.1016/j.jvscit.2022.08.028

of venous thrombosis after vaccination. In fact, the number10) Wong HL, Tworkoski E, Ke Zhou C, et al. Surveillance of COVID-19 vaccine safetyof venous thrombosis deaths (aged 10 years and over) in 2021,

among elderly persons aged 65 years and older. Vaccine 2023;41(2):532-39. doi:

the year in which SARS-CoV-2 vaccination program began inJapan, approximately 300 more than the estimated number ofvenous thrombosis deaths in 2021 (1,686) was estimated basedon trends in venous thrombosis deaths from 2011 to 2020;
this may be associated with the vaccine [19]. However, as of
28 April 2023, the Japan sub-committee Ministry of Health,Labour and Welfare document [21] (approximately 81 million
people who had received the first dose of Pfizer's vaccine by this10.1016/j.vaccine.2022.11.069
11) Suzuki H, Ro A, Takada A, et al. Autopsy findings of post-COVID-19 vaccination deathsin Tokyo Metropolis, Japan, 2021. Leg Med (Tokyo) 2022; 59:102134. doi: 10.1016/
j.legalmed.2022.102134
12) Hippisley-Cox J, Patone M, Mei XW, et al. Risk of thrombocytopenia andthromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: selfcontrolled case series study. BMJ 2021;374: n1931. doi: 10.1136/bmj. n1931
13) Li X, Burn E, Duarte-Salles T, et al. Comparative risk of thrombosis withthrombocytopenia syndrome or thromboembolic events associated with different
covid-19 vaccines: international network cohort study from five European countries andthe US. BMJ 2022;379: e071594. doi: 10.1136/bmj-2022-071594
14) Office for National Statistics Estimates of the population for the UK,
England and Wales, Scotland and Northern Ireland https://www.ons.gov.uk/

date) showed only 12 venous thrombosis deaths within 28 days

peoplepopulationandcommunity/populationandmigration/populationestimates/

after vaccination. Even if calculated without regard to vaccine(Accessed 7 July 7, 2023)

Page 32 ・ MED CHECK

Sep. 2023/ Vol.9 No.27

datasets/populationestimatesforukenglandandwalesscotlandandnorthernireland

COVID-19 Information
15) Nomis official census and labour market statistics Mortality statistics - underlying
cause, sex and age (https://www.nomisweb.co.uk/query/construct/summary.asp?mode=construct&version=0&dataset=161# (Accessed 7 July 7, 2023)
16) Patone M, Mei XW, Handunnetthi L, et al. Risks of myocarditis, pericarditis, andcardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nat
Med. 2022;28(2):410-422.
17) MedCheck editorial team. To Be Vaccinated or Not? Points You should Know -SARSCoV-2 Vaccines Doubles the Risk of COVID-19! - 2022; 8 (25): 40-52.
18) Japan’s Prime Minister's Office. SARS-CoV-2 vaccine coverage. Available from: https://www.kantei.go.jp/jp/headline/kansensho/vaccine.html (Accessed 7 July 7, 2023)
19) Vital statistics of Japan. General mortality. Available from:https://www.e-stat.go.jp/en/stat-search/files?page=1&layout=datalist&toukei=0045001
1&tstat=000001028897&cycle=7&tclass1=000001053058&tclass2=000001053061&tc
lass3=000001053065&result_page=1&cycle_facet=cycle&tclass4val=0&metadata=1&d
ata=1 (Accessed 7 July 7, 2023)
20) Japan’s Statistics Bureau of the Ministry of Internal Affairs and Communications.
Available from: https://www.e-stat.go.jp/en/stat-search/files?page=1&toukei=0020052
4&tstat=000000090001&cycle=7&month=0&tclass1=000001011679&tclass2val=0&me
tadata=1&data=1 (Accessed 7 July 7, 2023)
21) Japan’s Ministry of Health, Labor and Welfare. Meeting material: “The summary list ofdeath cases after SARS-CoV-2 vaccination for 28 April 2023 meeting of the working
group on adverse reactions to SARS-CoV-2 vaccine. Available from: https://www.mhlw.
go.jp/stf/shingi2/0000208910_00060.html (in Japanese, Accessed 7 July 7, 2023)

MED CHECK

Sep. 2023/ Vol.9 No.27 ・ Page 33

COVID-19 Information

Vaccines and monoclonal antibodies: ineffective
Translated and revised from Med Check (in Japanese) Jul. 2023; 23 (108)：86-87
Med Check Editorial Team

Abstract●New variants and subvariants of SARS-CoV-2 are rapidly emerging one after another. In Japan, as of May 8,2023, Omicron subvariant XBB accounts for 81% and 93 % (including EG.5.1) as of August 14, 2023.
● SARS-CoV-2 vaccines and monoclonal antibodies are no longer effective against the XBB subvariants. It may
also be ineffective against EG.5.1, because subvariant EG.5.1 has more immune escape compared with othervariants.
●As for antiviral agents, molnupiravir is ineffective. Among several oral antivirals against SARS-CoV-2, only
nilmatrelvir/ritonavir (Paquirovid®) has been confirmed to be effective.
Conclusions:Vaccines and monoclonal antibodies cannot control infection with rapidly
mutating SARS-CoV-2.
See also Supplementary Appendix

Keywords:
SARS-CoV-2, Omicron, XBB subvariant, SARS-CoV-2 vaccine, nilmatrelvir, molnupiravir

Introduction

How vaccine effectiveness can be demonstrated

Subvariant of SARS-CoV-2 are emerging one after another.

Many viral infections have the characteristic of becoming

In Japan, the main prevailing subvariant strain was Omicronprevalent, peaking, and subsiding at a certain time/season

BA.2 in May 2022, BA.5 in July of the same year, and XBB

every year, and then the cycle is repeated at the similar timein March 2023. Omicron subvariant XBB accounts for 81% of

the following year [5]. One such example was polio fromcases as of May 8, 2023. Including EG.5.1 which also emerged

1955 to the early 1960s, but after the emergency introduction

from XBB subvariant (XBB.1.9.2), Omicron subvariant XBB

of a live oral vaccine in 1961 in Japan, the number of infectedaccounts for 94 % (97.5% including CH.1.1) as of August 28,

people decreased dramatically [6]. In other words, after the2023 [1].

introduction of the vaccine, the epidemics that had previously

Up until now, attempts have been made to develop new
substances including vaccines to prevent infection and illness

spiked every summer disappeared. In typical cases like polio,
anyone can judge that the vaccine was effective.

caused by SARS-CoV-2. However, Med Check has pointed

On the other hand, SARS-CoV-2 infection/vaccine isout that vaccines have not reduced infection and illness caused

completely different. Since vaccination began in Japan, as

by SARS-CoV-2 (COVID-19) [2,3] but rather have increasedsame as other countries, the virus has rapidly mutated into

them [4]. This article reports the latest information related toalpha and delta strains, and from December 2021, whenthese and also discusses why they are ineffective in detail.

booster vaccinations began, the virus has mutated even more
rapidly into Omicron BA1, BA2, BA5, BQ and XBB variants.
Vaccinated people are originally healthier and less likely todevelop COVID-19 than those unvaccinated (healthy-vaccinee

Page 34 ・ MED CHECK

Sep. 2023/ Vol.9 No.27

COVID-19 Information
effect), therefore, at first glance, vaccinated people would be

producing new antibody to neutralise a newly infected variant

apparently less likely to develop the disease than unvaccinatedof SARS-CoV-2, if one has already been received vaccine

people after receiving SARS-CoV-2 vaccine [4].

against or infected with original strain of SARS-CoV-2 [12].

However, even after the vaccination coverage exceededThis is one of the most important reasons for ineffectiveness

80% of the total population, epidemics were repeated atof SARS-CoV-2 vaccines against variant SARS-CoV-2

intervals of about 3 to 6 months [1]. The COVID-19 epidemic

including bivalent vaccines.

has almost ended in the UK [7], where the positive rate ofanti-N antibodies (Note), which indicates SARS-CoV-2

Monoclonal antibodies are also ineffective

infection, reached 86% in February 2023. On the other hand,against Omicron variants

in Japan, it is only about 42% in February 2023 [7]. Therefore,

As of June 2023, three types of anti-SARS-CoV-2

Japan is never at the complete convergence stage of epidemic

monoclonal antibodies have been approved in Japan, namely

of COVID-19.

Sotrovimab (Zebudy®), casilibimab/imdevimab (lonapleeve®),

Note : Various kinds of antibody are produced in a body of SARSCoV-2 infected person. The container that stores the viral genes isand quixagevimab/silgavimab (Evasheed®).
The NEJM paper [13] reports the neutralizing power ofcalled a nucleocapsid (N), and the antibody against this is called anvarious anti-SARS-CoV-2 monoclonal antibodies currently

anti-N antibody. Vaccination does not increase this type of antibody,being developed, including the above three. There were aand it becomes positive only after infection with SARS-CoV-2 itself.

few antibodies that have neutralizing effect against the origin

Therefore, if the anti-N antibody is positive, it is evidence of infection

strain through Omicron subvariant BA.5, but it was almost

with SARS-CoV-2.

ineffective against the subvariant BQ.1 and completely
ineffective against subvariant XBB [13].

Vaccines are ineffective against Omicron
variants

Molnupiravir is also ineffective

Compared with those who received third doses of theoriginal vaccine, additional fourth doses did not prevent the

Med Check pointed out that the randomised controlled

epidemic of Omicron BA1.

trial (RCT) of mornupiravir (Lovegerio®) was not reliable

Moreover, it was speculated that the additional booster was

due to various doubts, such as serious imbalance of baseline

associated with increase of COVID-19 infection by more thancharacteristics favoring the mornupiravir group [14-16]. A

two-folds [4].

paper published in the Lancet demonstrated it [17]. After

In addition, not only the original vaccine but also theDecember 2021 in the UK, a total of 26,411 people withbivalent vaccine compatible with Omicron was considered to

COVID-19 infection were allocated almost equally to the

be ineffective because the increase in neutralizing antibody

molnupiravir group and the regular treatment group. The

titer against the Omicron BA1 strain was about one-eighth ofincidences of hospitalisation or death were both 1% with nothe neutralizing antibody titer against the original strain [8].

difference [17].

Since then, several research results on neutralizing
antibodies against the Omicron BA5 strain and the currently

Only nilmatrelvir is effective

prevalent XBB strain have been reported. On average, theneutralizing antibody titers of the BA5 subvariant were

The antiviral agent nirmatrelvir, which inhibits proteases

about 1/10 of the original antibody titers. In addition, theessential for viral replication, retained antiviral activity inneutralizing antibody titer of the XBB subvariant was

vitro against Omicron variant [13]. In fact, nilmatrelvir/

extremely low, less than 1/140 of the original antibody titer [9-ritonavir (Pakilobid®) reduced hospitalization or mortality due11]. In other words, the effect of the bivalent vaccine against

to SARS-CoV-2 infection in RCTs conducted from June to

the XBB subvariants is almost nil. Monoclonal antibodies are

December 2021, when alpha and delta strains were prevalent.

also ineffective against BQ1.1 and XBB subvariants.

It was reported that it was effective in reducing it by nearly

These phenomena may be the results of the immune

90% [18].

mechanisms explained as “the doctrine of original antigenic

In an RCT during the transition from the BA.1 strain to thesin” or simply as “imprinting”. These mechanisms inhibit

BQ.1 subvariant (January to November 2022), hospitalization or
MED CHECK

Sep. 2023/ Vol.9 No.27 ・ Page 35

COVID-19 Information
death within 30 days of SARS-CoV-2 infection decreased by

Furthermore, we believe that it is necessary to confirm theapproximately 40% (reinfection was reduced by approximately

degree of mutation in the infectious disease we are trying to30%) [19]. Two observational studies also reported that it

control in the early stage, and to monitor its properties andreduced hospitalization/death [20,21].

make an early decision as to whether it can be controlled with

What are the conditions for it to work?

vaccines or monoclonal antibodies.
See also Supplementary Appendix

The characteristics of the smallpox (variola) virus that waseradicated by vaccination include: (1) humans are the only
host, (2) there is no persistent infection, (3) it is antigenicallysingle (no mutations), and (4) the vaccine effect is strong andlong-lasting [22].
On the other hand, the influenza virus does not cause
persistent infection, but it infects non-humans such as pigs
and birds, and mutations are common. Vaccination is carried

References
1) Our world in Data. COVID-19 Data Explorer, variants, Japanout every year as a countermeasure against seasonal influenza

https://ourworldindata.org/explorers/coronavirus-data-explorer?facet=none&country=

infection, but it is actually ineffective [23].

Color+by+test+positivity=false

Similarly, traditional coronaviruses to which SARS-CoV-2
belongs are virus that host both humans and animals. There
are many subtypes and no vaccine could be developed. Even
when SARS-CoV-2 vaccines were first developed, theireffectiveness only lasted for two to three months, and theyquickly became ineffective against mutated strains (variants)
including booster dose of bivalent vaccines.

~JPN&Metric=Variants&Interval=7-day+rolling+average&Relative+to+Population=true&2) MedCheck editorial team. Editorial: Reliance on vaccines will not end infections,
MedCheck 2022: 22(101): 55. https://www.npojip.org/chk_tip/101-Editorial.pdf
3) MedCheck editorial team. Vaccination also reduces non-COVID-19 deaths - irrefutableevidence of healthy vaccination bias (in Japanese), Web MedCheck No 203 (2022/4/27)
https://www.npojip.org/sokuho/220427.html
4) MedCheck editorial team. COVID-19 information: Vaccines increase infections(in Japanese). MedCheck 2023: 23 (106): 36-37. https://medcheckjp.org/wp-content/
uploads/2023/03/106f05.pdf
5) National Institute of Infectious Diseases https://www.niid.go.jp/niid/images/idwr/pdf/
latest.pdf6) Hirayama M. History of emergency introduction of live polio vaccine and its

Since monoclonal antibodies have extremely highsubsequent polio, Pediatric Immunity, 2007: 19(2): 189-196. https://www.jspid.

specificity for the target antigen, it can be easily inferred7) Ministry of Health, Labor and Welfare, National Institute of Infectious Diseases,

theoretically that they will lose their effectiveness if theantigen mutates.

jp/wp-content/uploads/pdf/01902/019020189.pdf
Analysis of infection rate using donated blood specimens in February 2023
https://www.niid.go.jp/niid/ja/2019-ncov/2484-idsc/12061-covid19-84.html
8) MedCheck editorial team. To be Vaccinated, or Not ? Points You should Know

The authors in the aforementioned papers discussed theneed to develop new vaccines [9] and monoclonal antibodies[13] against new variants. However, due to mutation rate of
the SARS-CoV-2 virus and due to the “doctrine of original
antigenic sin” or “imprinting”, newly developed vaccines are
already ineffective.

SARS-CoV-2 Vaccines Doubles the Risk of COVID-19!(in Japanese) MedCheck
2022:22(104):128-139.
https://www.npojip.org/sokuho/207-f2.pdf
9) Kurhade C, Zou J, Xia H et al. Low neutralization of SARS-CoV-2 Omicron BA.2.75.2,
BQ.1.1 and XBB.1 by parental mRNA vaccine or a BA.5 bivalent booster. Nat Med. 2023
Feb;29(2):344-347. doi: 10.1038/s41591-022-02162-x. Epub 2022 Dec 6.PMID:
36473500
10) Wang Q, Iketani S, Li Z et al. Alarming antibody evasion properties of rising SARSCoV-2 BQ and XBB subvariants. Cell. 2023 Jan 19;186(2):279-286.e8. doi: 10.1016/
j.cell.2022.12.018. Epub 2022 Dec 14.PMID: 36580913
11) Miller J, Hachmann NP, Collier AY et al. Substantial Neutralization Escape by SARSCoV-2 Omicron Variants BQ.1.1 and XBB.1. N Engl J Med. 2023 Feb 16;388(7):662-664.

Conclusions
Japanese law, as amended in May 2022, makes it easier for
new substances to be approved for serious diseases prevalent
among the population if there is a presumption of efficacy inthe absence of suitable alternatives[24,25].
However, in order to determine whether it is truly usefulfor prevention and treatment of infectious diseases, rigorous
randomized controlled trials are still essential before approval,
and it is also essential to conduct an unbiased investigation ofeffectiveness and harms after approval.
Page 36 ・ MED CHECK

Sep. 2023/ Vol.9 No.27

doi: 10.1056/NEJMc2214314. Epub 2023 Jan
18.PMID: 36652339
12) MedCheck editorial team. To be Vaccinated, or Not ? Points You should Know SARSCoV-2 Vaccines Doubles the Risk of COVID-19! MedCheck in English 2022: 8(25): 40-52.
https://www.npojip.org/english/MedCheck/Med%20Check%20Tip-25-2023-02.pdf
13) Imai M, Ito M, Kiso M et al. Efficacy of Antiviral Agents against Omicron Subvariants
BQ.1.1 and XBB. N Engl J Med. 2023 Jan 5;388(1):89-91. doi: 10.1056/NEJMc2214302.
Epub 2022 Dec 7.PMID: 36476720
14) MedCheck editorial team, COVID-19 drug Molnupiravir (Lagevrio®) - Is it true that
hospitalizations were halved? MedCheck 2022:22(100):46-48.
15) MedCheck editorial team, Oral formulation for COVID-19 Molnupiravir (Lagevrio®)
No evidence of efficacy, ineffective in high-risk patients such as diabetes, Web
MedCheck No.202 (2022/1/28) https://www.npojip.org/ chk_tip/No100-f05.pdf
16) Hama R. Imbalance in baseline characteristics in molnupiravir trials. BMJ. 2022 Apr
26;377:o977. doi: 10.1136/bmj.o977.PMID: 35473695 available at: MedCheck News
No.204 (2022/4/28) https://www.npojip.org/sokuho/220428.html

COVID-19 Information
17) Butler CC, Hobbs FDR, Gbinigie OA et al. PANORAMIC Trial Collaborative Group.
Molnupiravir plus usual care versus usual care alone as early treatment for adults with
COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platformadaptive randomised controlled trial. Lancet. 2023 Jan 28;401(10373):281-293. doi:
10.1016/S0140-6736(22)02597-1. Epub 2022 Dec 22.PMID: 36566761
18) Hammond J, Leister-Tebbe H, Gardner A et al. Oral Nirmatrelvir for High-Risk,
Nonhospitalized Adults with Covid-19. N Engl J Med. 2022 Apr 14;386(15):1397-1408.
doi: 10.1056/NEJMoa2118542. Epub 2022 Feb 16.PMID: 35172054
19) Xie Y, Bowe B, Al-Aly Z. Nirmatrelvir and risk of hospital admission or death in adults
with covid-19: emulation of a randomized target trial using electronic health records.
.BMJ. 2023 Apr 11;381:e073312. doi: 10.1136/bmj-2022-073312.PMID: 37041016
20) Shah MM, Joyce B, Plumb ID et al. Paxlovid Associated with Decreased Hospitalization
Rate Among Adults with COVID-19 - United States, April-September 2022. MMWR Morb
Mortal Wkly Rep. 2022 Dec 2;71(48):1531-1537. doi: 10.15585/mmwr.mm7148e2.
PMID: 36454693
21) Dryden-Peterson S, Kim A, Kim AY et al. Nirmatrelvir Plus Ritonavir for Early COVID-19
in a Large U.S. Health System : A Population-Based Cohort Study. Ann Intern Med. 2023
Jan;176(1):77-84. doi: 10.7326/M22-2141. Epub 2022 Dec 13.PMID: 36508742
22) Edited by Shinichi Yoshida et al.Toda New Bacteriology 34th Edition(in Japanese).
Virology Overview; p528.
23) MedCheck editorial team, Influenza Vaccines: Ineffective and Harmful, Do Not Use(inJapanese). MedCheck 2023:23(105):12.
24) Ministry of Health, Labor and Welfare Partial Revision of Law Concerning Securing
Quality, Efficacy and Safety of Pharmaceuticals and Medical Devices (Pharmaceuticals
and Medical Device Law) in 2020 (Emergency Approval System)
https://www.mhlw .go.jp/stf/seisakunitsuite/bunya/0000179749_00006.html
25) MedCheck editorial team, Editorial: Do not approve invalid substances (in Japanese).
MedCheck 2023:23(105):3. https://medcheckjp.org/wp-content/
uploads/2023/01/105f03.pdf

MED CHECK

Sep. 2023/ Vol.9 No.27 ・ Page 37

M
C

ED

2023

Vol.9

No.27

HECK

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD)Managing Editor: SAKAGUCHI, KeikoE d i t o r i a l S t a f f : N A K A N I S H I ,Ta ke a k i ( P h a r m a c i s t ) ; TA K A N O,
Yo s h i h i ko ( M D [ p e d i a t r i c i a n ] / P h a r m a c i s t ) ; U M E DA , Ta d a h i t o(MD[psychiatrist]) ; WATANABE,shintaro (MD); YANAGI, Motokazu (MD);YASUDA, Yoshinobu (Pharmacist)

Page 38 ・ MED CHECK

Sep. 2023/ Vol.9 No.27

Translators: NAKAMURA, Akari
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)
Copyright JIP
http://medcheckjp.org
Registered address:#602, Katsuyama 2-14-8, Tennouji-ku,
Osaka JAPAN 543-0043