MC

December

2019

Volume 5

ED
N 15

HECK

o

Problems in Selection of Members for Guidelines
Hypertension Guidelines Part 1, Part 2
Diovan Scandal
High Risk of Death from Tamiflu and Xofluza
CONTENTS （December 2019, Vol. 5, No. 15）
Editorial
The Japanese Hypertension Guidelines 2019
Problems in Selection of Members
Review
Critical Assessment of Hypertension Guidelines Part 1
Scientific evidence for the hypertension guidelines 2019 is poor

37

38

Critical Assessment of Hypertension Guidelines Part 2
NICE (UK) recommends treatment if blood pressure is 160/100 or over44

Neglect of Correcting Scientific Fraud: Ruling over Diovan Scandal

48

Advrse Reactions
Tamiflu: Death After Abnormal Behaviour in Teenagers Revisited

50

High Risk of Death from Tamiflu and Xofluza

52

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December 2019/ Vol.5 No.15

M
C

ED

Editorial

HECK

The Japanese Hypertension Guidelines 2019:
Problem in Selection of Members
Translated from the Editorial in Med Check(in Japanese) Sep 2019 ; 19 (99),

Guidelines are recognized as highly
reliable sources of medical information. They
not only affect the prescribing behaviourof many doctors, but also are used as goodevidence in medical litigation.
It would be a suicidal act to choose
persons who would reduce its credibility as
a committee member.
Two of the reviewers of the Guidelines for
the Management of Hypertension 2019 by
the Japanese Society of Hypertension (2019GL) are the authors of the papers among 12
retracted valsaltan scandal papers whichwere revealed to have fabricated data
[1-4]. This alone reduces the reliability ofthis guidelines significantly. Furthermore,
it indicates that the Japanese Society ofHypertension, the parent body of thisguidelines, did not learn any lessons fromthe valsaltan scandals.
In addition, there is a problem in theselection of committee members of the 2019
GL in terms of conflict of interest.
There is a database called Money Database(http://db.wasedachronicle.org/) jointly
operated by Waseda Chronicle and Medical
G o ve r n a n c e R e s e a r c h I n s t i t u t e . T h i s
database is a tool that allows you to see howmuch money each pharmaceutical company
has provided to individual doctors in Japan.
Only the data of the year 2016 are available
as of now.

Using this database, we investigated theamount of money paid by pharmaceuticalcompanies in 2016 to the six board membersof the 2019 GL. As a result, it was found thateach of them has received 3,080,000 yen( 860,000 to 6.1 million ) or 28,000 US dollars( 7,900 to 56,000 US dollars ) from an averageof 10.8 companies ( 5 to 17 companies) in theyear of 2016 only. Can we expect these board
members to make a fair decision regarding
hypertension management or medication?
Since the treatment descriptions in thehypertension guidelines are dominated bydrug therapy, recommendations regarding thetherapy should be made only by members withno or minimal funding from pharmaceuticalcompanies.

References
1) Yui Y. Concerns about the Jikei Heart Study. Lancet 2012;379 (9824):e48
2) NPOJIP: Comments on the Diovan (valsaltan) case, before the ruling at theTokyo High Court: https://www.npojip.org/sokuho/181118.html(in Japanese)3) NPOJIP: Defendants were acquitted by the Tokyo High Cort.
https://www.npojip.org/sokuho/181121.html (in Japanese)
4) NPOJIP: Neglect of Correcting Scientific Fraud: Ruling over Diovan Scandal.
MedCheck 2019: 5 (15): 48-49.

MED CHECK

December 2019/ Vol.5 No.15 ・ Page 37

Review
The 2019 annual theme: Criticism on treatment guidelines series (11) Part 1

The Scientific Evidence for the Hypertension
Guidelines 2019 is Poor
The target blood pressure below 130/80 is dangerous
Synopsis from Med Check in Japanese September 2019 ;19(85): 104-109.
Med Check Editorial Team

Summary● The Japanese Society of Hypertension changed the target blood pressure to less than 140/90 in the 2014
Guidelines (2014 GL) revision, assuming that the old target of less than 130/85, which had been used since 2000,
was not based on evidence. However, in the guideline revised in April 2019 (2019 GL), it was lowered again to lessthan 130/80.
● The 2019 GL is based on the results from a meta-analysis of 19 randomized controlled trials (RCTs) comparing theintensive antihypertensive group (intensive group) and the milder antihypertensive group (milder group). Although
the results indicated significant reduction in cardiovascular morbidity and mortality, there was no significant
difference in total mortality.
● All studies included in the meta-analysis are open trials in which both investigators and participants know whichgroup they were assigned to. Even if the outcomes are assessed blindly by PROBE method, it has fundamental
limitations in ruling out bias.
● Among the 19 studies, many of them had favourable baseline characteristics for the intensive group, and there
was a serious contradiction in the results of SPRINT, a pivotal study for the revision of 2019 GL.
Conclusion: The 2019 guidelines on hypertension are not based on scientific evidence. Do not follow the 2019 GL.

Keywords:
hypertension, guidelines, target blood pressure level, 2019 GL, SPRINT, SPS3

target of blood pressure below 130/85 mmHg (mmHg isIntroduction
In the second article ( No.76 ) [1] of the Treatment

omitted thereafter).

Guidelines Criticism Series, we presented that general

The Japanese Hypertension Society revised the 2014

health check-up would find minor illnesses leading

guidelines ( 2014 GL ) [3]. They stated that there wasto unnecessary medical interventions which would

no evidence for the blood pressure target of less thanconversely shorten life span especially of the elderly.

130/85, which had been used since 2000. They changed

In the third article (No.77) [2] of the series, we showed

the target blood pressure to less than 140/90.

that one out of every 3 to 4 adults and one out of two

However, in the guidelines revised in April 2019

in the elderly takes anti-hypertensive drugs, due to the(2019GL) [4], the target blood pressure was lowered toprevalence of general health check-up and hypertension

less than 130/80. What is the evidence for this revision?

guidelines 2000 that recommended drug therapy with aPage 38 ・ MED CHECK

December 2019/ Vol.5 No.15

The reason behind 2014 revision

are comparison between the intensive antihypertensive

In the 2014 GL, authors recognized that the target

group (intensive group) and the mild antihypertensive

blood pressure below 130/85 in hypertension guidelines

group (mild group) and are not placebo-controlled trials.

from 2000 to 2009 had no scientific evidence andAs a result, the intensive group had significantly fewerchanged the target to less than 140/90. The reason is as

cardiovascular events ( meta-analysis of 14 trials ) andfollows:

significantly fewer strokes (meta-analysis of 13 trials) than“The target blood pressure of less than 130/85,
which has been set since 2000, is the same as the target

the mild group. However, it was also reported that there
was no difference in all-cause mortality [4,9].

recommended by the 1999 WHO guidelines. However,this target level is based on the results of the HOT study.

If no improvement in total mortality, lowering blood

In this study, three groups with different target diastolicpressure has no value

blood pressure were compared: 90 mmHg or lower, 85

Med Check is a member of the International Society

mmHg or lower and 80 mmHg or lower. The target bloodof Drug Bulletins (ISDB). ISDB and we believe that livingpressure was set based on the findings that there waslong and healthy is an important goal when consideringno increase in cardiovascular risk in the lowest blood

prevention of chronic illnesses [11]. This is becausepressure target group, although no significant difference

even if myocardial infarction or stroke, which is strongly

was observed in cardiovascular prognosis among 3

related to high blood pressure, is reduced, there is nogroups."meaning if death from other diseases increases. In fact,

The authors of the 2014 GL explained "There was

ACE inhibitors reduce total mortality, but angiotensin

a gap between the initiation criteria for treatment

receptor blocker (ARB) does not. The result of a meta-of hypertension and the blood pressure goal" andanalysis has shown that ARB rather increases cancer [12],"We found that the results of intervention trials thatsepsis and death from sepsis [13].

supported target blood pressure lower than 140/90

The 2019 GL [4] reported that according to the meta-

mmHg were poor, so we set the antihypertensive goal atanalysis results of 19 studies, intensively lowering bloodless than 140/90 mmHg. ''pressure did not reduce all-cause mortality.

In the HOT study [5], which was the pivotal evidence

If the blood pressure was very high, such as 115

for targeting "less than 130/85", achieved diastolicor higher for diastolic blood pressure, hypotensive

blood pressure 81 mmHg in the lowest blood pressure

drug treatment reduced all-cause mortality comparedgroup, but the systolic blood pressure was barely lessto placebo [14]. However, the effect of hypotensive

than 140 (139.7) [6]. Even so, the combined outcome

treatment on the people with mild high blood pressure

including myocardial infarction, stroke and death did(140-159/90-99) has been denied by the results of thenot significantly decrease, although only some tendency

Cochrane's systematic review and meta-analysis of

to decrease was observed. Moreover, all-cause mortality

placebo-controlled RCTs [15]. Treatment for 4 to 5 years

rate was 11% higher in the lowest target group than inwith antihypertensive drugs as compared to placebo did

the highest (p = 0.32) [6]. Again, the decrease in systolic

not reduce total mortality (RR 0.85, 95% CI 0.63, 1.15).

blood pressure was only barely below 140, and the result

Treatment with antihypertensive drugs as compared to

did not justify lowering blood pressure to less than 130.

placebo did not reduce coronary heart disease (RR 1.12,
95% CI 0.80, 1.57), stroke (RR 0.51, 95% CI 0.24, 1.08), or

No difference in total mortality in the 2019 GL analysis

total cardiovascular events (RR 0.97, 95% CI 0.72, 1.32).

Japanese 2019 GL recommends to lower blood

Withdrawals due to adverse effects were increased bypressure to below 130/80, following the guidelines

drug therapy (RR 4.80, 95%CI 4.14, 5.57), absolute riskof US ACC/AHA [7] and European ESC/ESH [8]. The

increase (ARI) 9%.

recommendation of the Japanese 2019 GL [4] is based

In their systematic review and meta-analysis using

on a meta-analysis [9] of 19 randomized controlledindividual patients data of randomized controlled trials

trials (RCT), including SPRINT study [10]. All these RCTs

comparing lower targets for systolic/diastolic blood

MED CHECK

December 2019/ Vol.5 No.15 ・ Page 39

Review
Reviewpressure (<135/85 mmHg) and standard targets (<140-160

Only 10 trials out of 14 trials achieved systolic blood/ 90-100 mmHg ), Saiz et al [16] found no change inpressure below 130

total mortality ( risk ratio (RR) 1.06, 95%CI: 0.91-1.23 )There were 14 trials in which the target systolic andor cardiovascular mortality (RR 1.03, 95% CI: 0.82-1.29;

diastolic blood pressure levels were below 130 andmoderate-quality evidence).

80, respectively. (Among them, 5 trials aimed at loweringsystolic blood pressure below 120 and diastolic blood

The trials, basis of 2019 GL, are not double blinded
Since all 19 RCTs are comparison of the intensive

pressure below 75.) In only 10 trials, these goals wereactually achieved.

and mild antihypertensive treatment groups and it
is impossible to conceal the allocation, not only the

Trials which achieved less than 130/80 were full of flaws

investigators, but also the subjects knew which group

One of the major problems is that in 7 trials out

they were assigned to.

of 19 trials ( almost 40% of the trials ), the baseline

In such a non-blinded open trial, patients are at risk

characteristics may be more favourable for the intensive

for being treated unfavourably or favourably by thegroup than for the mild group, especially differences areinvestigator who know the allocation. For example, theyremarkable for the important risk factors for total deathmight be removed from the trial (withdrawn) if serious

or cardiovascular diseases.

events occurred in the participants assigned to the

In particular, in 5 trials out of the 10 trials in which

intensive group, or outcome events might be assessed

the target of less than 130 was actually achieved,favourably by the investigator.

significant bias or tendency for bias was observed in

In order to make fairer judgment, there is PROBE

favour of baseline characteristics of intensive group.

(prospective randomised open blinded end-point) method in

For example, in the SPS3 trial [19], which is consideredwhich the result is judged by investigators who do not

as an important trial as SPRINT [10], baseline systolicknow the allocation. Of the 19 trials, PROBE method waspressures were 142 vs. 144 and diastolic pressures wereused in 10 trials, but this method has fundamental flaws.

78 vs.79. These differences look minimal, but are notParticipants with unfavourable events or end-points inonly statistically significant (0.004 and 0.009 respectively)

the intervention group can be withdrawn before thebut also may affect the outcomes favourably for intensive

blinded end-point assessment. A typical example of suchgroup (Note). Moreover, the paper does not mention if

problem can be found in the Japanese MEGA study on

the differences are significant or not. In addition, thecholesterol-lowering agents (pravastatin or brand nameproportions of male patients were 61% vs. 65% ( p =Mevalotin ) [17]. Although the study reported that the

0.0008 ). This difference was also favourable for the

all-cause mortality rate in the Mevalotin group showed

intensive group.

tendency to decrease, the overall survival rate was

However, the primary outcome was not significantly

significantly lower in the Mevalotin group than in the

different. Only cerebral hemorrhage was significantly

control group. This paradoxical results occurred because

decreased (HR = 0.37: 0.15-0.95, p = 0.03), but total deaththe Mevalotin group had significantly more withdrawals

rather increased (intensive group 106/1501 vs. 101/1519,

than non-Mevalotin control group [18].

HR = 1.03: 0.79-1.35) [19].

Most subjects had complications
Out of 19 RCTs which 2019 GL is based on, 5 trials
involved diabetic patients. The other 5 were for patientswith renal disease, 2 trials were for hypertension patientswith history of mild cerebral infarction (lacuna infarction)

Note: Statistical significance can be tested based on thenumber of subjects (1501 vs. 1519 persons), average bloodpressure, and standard deviation ( 19 vs. 19). Difference inproportions of sex was tested by chi-square statistics.

Contradictions among SPRINT trial resultsor those with cardiovascular diseases, and 3 trials were

Although, we did not find clear bias among baseline

for elderly patients. There were only 4 trials involving

characteristics in the SPRINT trial [10], which ispeople without specific illnesses or non-elderly adults.

considered as the pivotal evidence, we found major

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December 2019/ Vol.5 No.15

contradictions in the results.

in e-GFR ) or rather less renal impairment ( long term

In the serious adverse event section, acute renal

dialysis ) occurred in the intensive group than in the

injury or acute renal failure listed in the medical record

standard group in patients with chronic kidney diseases

occurred overwhelmingly more frequently in the(CKD) at baseline. These findings in the outcome also

intensive group (193/4678) as compared with the mild

contradict with the fact that 3.5 times more renalgroup (117/4683) (p = 0.00001) (Figure 1).

impairment ( 30% decrease in e-GFR ) occurred in theOn the other hand in the outcome section, nodifference (composite renal outcome and ≧ 50％ reduction

intensive group (3.8%) than in the standard group (1.1%)
in patients without CKD at baseline (Figure 2).

Data independent of trial show renal injury in intensive group

A hospital discharge summary is coded independent of the clinical trial, while data for GFRs are collected for the clinical trial ( ‡ and underlined).
Hence hospital discharge summary data may be more reliable. Intensive treatment causes 1.7times more acute kidney injury and/or renal failure ( →）.

Major contradictions in outcomes and between adverse events

Renal impairment occurs more in intensive group than standard group in patients without CKD at baseline, while no difference or rather lessrenal impairment in intensive group in patients with CKD at baseline. It is difficult to explain the reasons for such contradicting results.

MED CHECK

December 2019/ Vol.5 No.15 ・ Page 41

Review
Review
These contradictions cannot be explained by medical

trials of Diovan (valsartan) [21,22], which were retracted

common sense. However, a hospital discharge summary

after fabrication of data came to light in Japan (see pageis coded independent of the clinical trial, while data for

48 in this issue).

GFRs are collected for the clinical trial.
Because data coded independent of the clinical trial
may be more reliable than the data collected as theObservational studies show intensive lowering increasemortality.

clinical trial, increase of acute renal injury or acute renal

To date, long-term cohort studies conducted in

failure based on the hospital discharge summary may be

Japan have shown that total mortality rate [23,24] andmore reliable. Hence we consider that the overall results

death from cancer [24] are higher in people who usedof SPRINT trial indicate that intensive treatment causes

antihypertensive drugs as compared with those without

more kidney injury and/or renal failure.

the medication. The risk is particularly high in people

A Chinese report by Wei et al. [20] showed impossible

whose systolic blood pressure is below 120 [25].

result. It reported that after the 4-year follow-up, theIn a recent cohort study, JACC study that followed

number of death from cardiovascular diseases in theabout 28,000 people without cardiovascular disease,intensive group is about half of that in the mild groupcancer, or renal disorder, the risk of death may be(Figure 3). A similar type of result was reported in thehigher by 30% in antihypertensive users with lowest

Report by Wei and Kyoto Heart study

A: Intensive treatment compared with the standard treatment decreased cardiovascular (CV) mortality by 50.3% (p = 0.002) with 25 and 50 CV
deaths respectively. It is extremely unnatural for a study with only 360 participants for each group to achieve such remarkable results of efficacy
with high significance. However, it may be possible that such a result could be obtained if participants with good prognosis in the standard
treatment group were withdrawn. The results recall that of Kyoto Heart Study [22] which was retracted due to manipulation and/or fabrication ofdata ( B and C). Verification is required! !

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December 2019/ Vol.5 No.15

risk (130-139/80-85) than in non-users with the highest

Comparison of mortality risk ratio by baseline blood

blood pressure (above 160/100) [26]. The risk was 2.2

pressure: treated vs not treated with anti-hypertensive agentstimes and 3 times higher in antihypertensive users
whose blood pressure was below 130/85 and 120/80,
respectively, than in non-users whose blood pressure
was above 160/100 (Figure 4).
Conclusion
Most of the trials which 2019 GL referred to as
evidence for the target level of below 130/80 areflawed and unreliable. Therefore, the guidelines are notcredible. It is dangerous to manage hypertension basedon the guidelines. Do not follow them.

Reconstructed by MedCheck team from the data in ref [26].
The risks of death from cardiovascular disease in the untreated groups
were calculated based on the hazard ratio adjusted for 7 risk factors
including sex and age compared with that of 130-139/85-89 (reference)group by recalculating when hazard ratio of the highest blood pressuregroup is 1.0. The risks of the treated groups were calculated based on thehazard ratio adjusted for 7 risk factors including sex and age comparedwith that of reference group by multiplying the ratio (treated/untreated)of reference groups' crude mortality from cardiovascular disease.

References
1) Med Check Team. Do general health checks prolong lifespan?,MedCheck TIP(in English) 2018：4(10)：11-15.
https://www.npojip.org/english/MedCheck/Med% 20Check-TIP% 2010-05-09.pdf
2) Med Check Team. Japanese Guideline for Hypertension is for disease mongering、
MedCheck TIP (in English) 2018：4（11）：20-23https://www.npojip.org/english/MedCheck/Med% 20Check-TIP% 2011-08-29.pdf
3) Japanese Society of Hypertension. Guidelines for the management ofHypertension 2014 (in Japanese)
https://www.jpnsh.jp/data/jsh2014/jsh2014v1_1.pdf
4) Japanese Society of Hypertension. Guidelines for the management of Hypertension
2019 (in Japanese) Life Science publishing Co Ltd.
5) Hansson L, et al.; HOT Study Group. Effects of intensive blood pressure
lowering and low-dose aspirin in patients with hypertension: principal results ofthe Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998; 351:
1755-1762. PMID:9635947
6) Hama R、Intensive lowering blood pressure increase deaths-From HOT and JATE
studies. The Informed Prescriber 2001: 16(6):55-58 (in Japanese).
7) Wlielton PK, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AG5/APbA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Managementof High Blood Pressure in Adults: A Report of the American College of Cardiology/
American Heart Association Task Force on Clinical Practice Guidelines.
Hypertension. 2018; 71: e13-e115. PMID: 29133356 (Erratum in Hypertension.
2018; 71: e140-e144. PMID: 29743247)
8) Williams B, et al.; Authors/Task Force Members:. 2018 ESC/ESH Guidelines for the
management of arterial hypertension: The Task Force for the management ofarterial hypertension of the European Society of Cardiology and the European

The Informed Prescriber 2010: 25(7):97-101 (in Japanese).
14) Veterans Administration Cooperative Study Group on Antihypertensive Agents.
Effects of treatment on morbidity in hypertension: Results in patients with diastolicblood pressures averaging 115 through 129 mm Hg, JAMA 1967: 202:1028-1034,
15) Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild
hypertension. Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.:
CD006742
16) Saiz LC, Gorricho J, Garjón J, Celaya MC, Erviti J, Leache L. Blood pressure targets
for the treatment of people with hypertension and cardiovascular disease.
Cochrane Database Syst Rev. 2018 Jul 20;7:CD010315. PMID:30027631
17) Nakamura H, et al (MEGA Study Group) Primary prevention of cardiovasculardisease with pravastatin in Japan (MEGA Study): a prospective randomised
controlled trial. Lancet. 2006 Sep 30;368(9542):1155-63. PMID: 17011942
18) Hama R and Sakaguchi K. Pravastatin (Mevalotin) reduces survaival The
Informed Prescribe 2006: 21(8/9):84-86
19) Benavente OR, et at; SPS3 Study Group. Blood-pressure targets in patients withrecent lacunar stroke: the SPS3 randomised trial Lancet. 2013; 382: 507-515.
PMID: 23726159
20) Wei Y, et al. Effects of intensive antihypertensive treatment on Chinese
hypertensive patients older than 70 years. J Clin Hypertens(Greenwich). 2013; 15:420-427. PMID:23730991
21) Mochizuki S, Dahlof B, Shimizu M, et al, for the Jikei Heart Study group. Valsartan
in a Japanese population with hypertension and other cardiovascular disease (Jikei
Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality
study. Lancet 2007; 369: 1431–39. PMID: 17467513
22) Sawada T, Yamada H, Dahlof B, Matsubara H, for the KYOTO HEART Study

Society of Hypertension: The Task Force for the management of arterialGroup. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive

hypertension of the European Society of Cardiology and the European Society ofpatients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J 2009;

Hypertension. J Hypertens. 2018; 36: 1953- 2041. PMID: 30234752
9) Sakima A, et aL The Optimal Blood Pressure Targets for Patients with
Hypertension: A Systematic Review and Meta-analysis. 2019 Apr;42(4):483-495.
PMID:30948822
10) SPRINT Research Group. A Randomized Trial of Intensive versus Standard BloodPressure Control. N Engl J Med. 2015; 373:2103-2116. PMID: 26551272
11) ISDB, Starting or strengthening a Drug Bulletin: a practical manual: Chapter 8
Reviewing a new drug: Is it a therapeutic advance?
12) Sipahi I, Debanne SM, Rowland DY et al. Angiotensin receptor blockade and

30: 2461–69. PMID: 19723695
23) Ueshima H et al. Report in 1995 of the National Integrated Project for
Prospective Observation of Non-communicable Disease and Its Trends in the Aged
(NIPPON DATA) 1980 (in Japanese).
24) Irie F, Iso H et al. Prediction of mortality from findings of annual health checkups
utility for health care programs. Nihon Koshu Eisei Zasshi. 2001;48(2): 95-108 (inJapanese). PMID: 11268626
25) Hama R Do not lower blood pressure by medicines Kadokawa 2005
26) Yamagishi K, Sawachi S, Tamakoshi A, Iso H; JACC Study Group. Blood pressure

risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol. 2010

levels and risk of cardiovascular disease mortality among Japanese men andJul;11(7):627-36PMID:20542468

women: the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC

13) Hama R. Angiotensin receptor blocker (ARB) and increase of cancer and sepsis.

Study). J Hypertens. 2019 Jul;37(7):1366-1371.PMID:30882600

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December 2019/ Vol.5 No.15 ・ Page 43

Review

The 2019 annual theme: Criticism on treatment guidelines series (11) Part 2

NICE (UK) Recommends Treatment if Blood
Pressure is 160/100 or overThe most appropriate guidelines revised in August, 2019

Synopsis from Med Check in Japanese November 2019 ; 19 (86):128-130
Med Check Editorial Team

Summary●In the previous issue, we introduced that the guidelines in U.S. and Europe were revised to lower the target bloodpressure below 130 mmHg (hereafter, mmHg is omitted). These guidelines were all created by medical associations
which share the mutual interests with pharmaceutical companies.
●There are other guidelines for management of hypertension in the U.S. and Europe. As of now, the mostappropriate standard is the guidance of National Institute for Health and Care Excellence (NICE) in the U.K., followedby the one created by the U.S. Eighth Joint National Committee (JNC-8). Unlike most medical associations, these twoorganizations have minimal conflict of interests with the industry.
●NICE recommends the use of antihypertensive drugs only when blood pressure remains 160/100 or over after
lifestyle advises. Its basic standard is to lower blood pressure below 160/100. This is consistent with the results of
two Cochrane reviews. The U.S. JNC-8 targets below 150/90 for people aged 60 years and older. For people aged
under 60 years or those with diabetes and chronic kidney disorders, it basically recommends the target bloodpressure below 140/90.
●The latest guidance on management of hypertension by NICE was revised on August 28th, 2019. Therefore, it has
taken the result of SPRINT, which was published in 2015, into account as well.
Conclusion: No antihypertensive drug treatment is needed unless blood pressure is over 160/100.

Keywords:
hypertension, guideline, target blood pressure, NICE, JNC-8, Cochrane review, conflict of interest

Cochrane's systematic reviews and meta-analysis of

Introduction
In our latest article [1] we criticised the Japaneseplacebo-controlled RCTs [6] reported that the treatment

guidelines for management of hypertension revised inby antihypertensive drugs in mild hypertension

2019 ( 2019 GL ) [2]. We explained that the 2019 GL( 140-150/90-99 ) does not reduce total death andfollowed the hypertension guidelines created by somec a r d i o v a s c u l a r d i s e a s e s . M o r e o ve r i t i n c r e a s e smedical associations in the U.S. [3] and Europe [4] which

discontinuation of the treatment due to adverse events

aim at lowering the target blood pressure below 130

by almost 5 times as compared with placebo.

mmHg in response to the result of SPRINT [5]. However,Another Co chrane review [7], which analyzed

there are other guidelines which are more reliable than

individual patient data from a study comparing intensive

such strict guidelines [3,4].

and mild lowering groups, showed no decrease in total

As we referred in the latest article [1], one of the
Page 44 ・ MED CHECK

December 2019/ Vol.5 No.15

death and cardiovascular diseases.

The hypertension guideline of NICE [8,9] is consistent
with the findings of these reviews [6,7].

80 with mild hypertension ( Stage 1) who has damage
in the target organ (risk factor for cardiovascular disease).

The 8th guideline of the Joint National Committee

However, in those with mild hypertension who has[10,11] led by the U.S. National Institute of Health (NIH)no risk factor, there is no evidence to prove benefit ofalso proposes a relatively appropriate standard. Thisantihypertensive drug treatment.

article will examine them in detail.

The Cochrane review [6] evaluated 4 randomized
controlled trials for antihypertensive drug treatment

U.K. NICE: Classification of hypertension, risk factors andin patients with mild hypertension (systolic BP

target blood pressure140-159 or diastolic BP 90-99) who have no establishedThe latest guidance of NICE was published in 2011 [8],cardiovascular disease at baseline. After 4-5 years ofand was renewed on August 28th, 2019 while no change

the treatment, comparison with placebo showed no

was made in the main part.

significant difference in each endpoint: overall mortality

Its target for antihypertensive treatment follows
the principle of the treatment before 1999, whichrate ( n=8912, RR = 0.85, 95% CI:0.63, 1.15.) , coronary

is to use ant ihypertensive drugs only when the1.57）, stroke (RR = 0.51, 95%CI:0.24, 1.08) and total

blood pressure remains higher than 160/100 in theartery disease（ n = 7080, RR = 1.12, 95 % CI:0.80,

absence of particular risk factor after appropriate non-cardiovascular event (RR = 0.97（95%CI: 0.72, 1.32）.

pharmacological interventions or lifestyle advises.

were unknown in a subgroup of patients with mild

The data on those withdrawals due to adverse events

hypertension. However, data are available for patients
NICE classifies hypertension as follows

with mild and moderate hypertension combined (n =Stage 1 ( mild hypertension ): clinic blood pressure is

17,354), and more withdrawals occurred in the treatment

140/90 or higher and subsequent ambulatory bloodpressure monitoring (ABPM) daytime average or homegroup (RR = 4.80, 95%CI:4.14,5.57, absolute risk increased

blood pressure monitoring ( HBPM ) average blood

The conclusion of the Cochrane review is consistentby 8.9% over 5 years: Note) .

pressure is 135/85 or higher.

with that of NICE CG127 which states that no evidence

Stage 2 (moderate hypertension): clinic blood pressure

support the benefit of antihypertensive drug treatment

is 160/100 or higher and subsequent ABPM daytime

in patients with mild hypertension who has no risk factor

average or HBPM average blood pressure is 150/95 orfor cardiovascular disease.

higher.
Stage 3 ( severe hypertension ): clinic systolic bloodpressure is 180 or higher or clinic diastolic bloodpressure is 110 or higher.

Note: The increase of absolute risk by 8.9% indicates that 1
out of 11 patients who used antihypertensive medication
discontinued the treatment and dropped out due to adverse
events.

The following organ damages are listed for determining

The U.S. JNC-8 was created by committee members withwhether to start antihypertensive medication or not.

no conflict of interest

Target Organs: damage to organs such as the heart,

The committee members of JNC-8 consist of 17

brain, kidneys and eyes. Examples are left ventricularexperts who specialize in hypertension, primary care

hypertrophy, chronic kidney disease, hypertensive

including geriatrics, cardiology, nephrology, nursing,

retinopathy, and increased urine albumin:creatinine

pharmacology, clinical trials, evidence-based medicine,ratio.

epidemiology, informatics and the development andimplementation of clinical guidelines in systems of care

No advantage in using antihypertensives in mild

who were selected from more than 400 nominees. Unlike

hypertension

JNC-7 (2003), all the members are obliged to disclose

The NICE guidance recommends to start

their conflict of interest with pharmaceutical companies

antihypertensive drug treatment with adults aged underwhich are involved in development and marketing of
MED CHECK

December 2019/ Vol.5 No.15 ・ Page 45

Review
Review
antihypertensive drugs. Among the 17 members, 4 (24%)

pressure for those aged under 30 years. Therefore, for

had conflict of interest. Those with conflicts were allowed

those aged under 60 years, the committee recommends

to participate in discussions as long as they declared

to maintain blood pressure below 140/90 ( Expert

their relationships, but they recused themselves from

opinion).

voting on evidence statements and recommendations4) Likewise, the committee recommends below 140/90

relevant to their relationships or conflicts [10].

for patients with diabetes or chronic kidney disease

Bakris told "JNC-8 is not just JNC-7 “Retooled” or(Expert opinion).

“Repainted”, but Imploded and Reconstructed" [11].
American College of Physicians supports JNC-8
The main basis for NICE was the double blinded

American College of Cardiology (ACC) and American

randomized placebo controlled trials and the meta-

Heart Association (AHA), which share mutual interest

analysis of them. In addition, JNC-8 also referred towith pharmaceutical companies, do not support JNC-8

unblinded RCTs such as HOT which compared groups

and have created their own guidelines, recommending towith different target blood pressure levels.

lower blood pressure below 130/80 [3].
On the other hand, American College of Physician (ACP)

Target 150/90 for people aged 60 years and older
JNC-8 recommends as follows:
1) In the general population aged 60 years or older,and American Academy of Family Physicians (AAFP) havedeclared their support for JNC-8, but not for ACC/AHA
guideline [12,13].

initiate pharmacologic treatment to lower blood pressure(BP) at systolic blood pressure (SBP) of 150 mmHg or

Conclusion

higher or diastolic blood pressure (DBP) of 90mmHg or

As of now, among the guidelines published by public

higher and treat to a goal SBP lower than 150mmHg andinstitutions, the British NICE offers the most appropriate

goal DBP lower than 90mmHg. Strong Recommendation

guidance which recommends to start antihypertensive(Grade A).

drug treatment for blood pressure over 160/100 (Table).

2) Evidence for lowering diastolic blood pressure below

The guidelines created by medical associations in

90 in general population aged 30-59 is available.

Japan, U.S. and Europe, which have major conflict of3) However, there is no sufficient evidence regarding

interest with the industry, recommend the target blood

the target systolic blood pressure for general populationpressure of 130/80. However, this has not scientificaged under 60 years or the target diastolic bloodbasis, and thus should not be followed.

NICE：National Institute of Health andCare Excellence,
JNC: Joint National Committee.
ACP: American College of Physician,
AAFP:American Academy of Family
Physicians,
ACC: American College of Cardiology,
AHA: American Heart Association,
ESC: European Society of Cardiology,
ESH: European Society of Hypertension
10 year risk of ASCVD: 10-year risk ofatherosclerotic cardio vascular diseases

Page 46 ・ MED CHECK

December 2019/ Vol.5 No.15

References
1) Med Check Team. Scientific evidence of hypertension Guideline 2019 is poor.
Med Check in English 2019：5(15)：38-43.
2) Japanese Society of Hypertension. Guidelines for the management of Hypertension
2019 (in Japanese) Life Science publishing Co Ltd.
3) Whelton PK, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AG5/APbA/ASH/ASPC/NMA/PCNA
Guideline for the Prevention, Detection, Evaluation, and Management of High Blood
Pressure in Adults: A Report of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines. Hypertension. 2018; 71: e13e115. PMID: 29133356
4) Williams B, et al.; Authors/Task Force Members:. 2018 ESC/ESH Guidelines for the
management of arterial hypertension: The Task Force for the management ofarterial hypertension of the European Society of Cardiology and the European
Society of Hypertension: The Task Force for the management of arterial hypertensionof the European Society of Cardiology and the European Society of Hypertension.
J Hypertens. 2018; 36: 1953- 2041. PMID: 30234752
5) SPRINT Research Group. A Randomized Trial of Intensive versus Standard BloodPressure Control. N Engl J Med. 2015; 373:2103-2116. PMID: 26551272
6) Diao D, Wright JM, Cundiff DK et al. Pharmacotherapy for mild hypertension.
Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD006742
7) Saiz LC, Gorricho J, Garjón J, Celaya MC, Erviti J, Leache L. Blood pressure targets
for the treatment of people with hypertension and cardiovascular disease.
Cochrane Database Syst Rev. 2018 Jul 20;7:CD010315. PMID:30027631
8) NICE, Hypertension in adults: diagnosis and management [CG127] https://www.
nice.org.uk/guidance/CG127/uptake
9) NICE, Hypertension in adults: diagnosis and management [NG136] https://www.
nice.org.uk/guidance/ng136
10) James PA, Oparil S, Carter BL et al. 2014 evidence-based guideline for the
management of high blood pressure in adults: report from the panel members
appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-20. PMID:24352797
11)Bakris GL Changes in Guideline Trends and Applications in Practice: JNC 2013https://pdfs.semanticscholar.org/3dc1/93e89a453f0ce5df8d607ee64a915b2cad18.pdf12) Qaseem A, Wilt TJ, Rich R, Humphrey LL, Frost J, Forciea MA; Clinical
Guidelines Committee of the American College of Physicians and the Commission
on Health of the Public and Science of the American Academy of Family Physicians.
Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older toHigher Versus Lower Blood Pressure Targets: A Clinical Practice Guideline From
the American College of Physicians and the American Academy of Family
Physicians. Ann Intern Med. 2017 Mar 21;166(6):430-437. PMID: 28135725
Epub 2017 Jan 17. Erratum in: Ann Intern Med. 2018 Apr 3;168(7):530-532.
13) AAFP, AAFP Decides to Not Endorse AHA/ACC Hypertension Guideline, Academy
Continues to Endorse JNC8 Guideline, December 12, 2017https://www.aafp.org/news/health-of-the-public/20171212notendorseaha-accgdlne.html

MED CHECK

December 2019/ Vol.5 No.15 ・ Page 47

Review
Neglect of Correcting Scientific Fraud:
Ruling over Diovan Scandal
Med Check Editorial TeamOn November 19, 2018, the Tokyo High Court

who played a key role in data manipulation and/or

made a ruling over a case of clinical trial involving an

fabrication were acquitted [2,3]. The judgment clearlyantihypertensive valsartan, the so-called Diovan case [1].

recognized that researchers from the Kyoto Prefectural

Diovan (generic name valsartan) is an antihypertensive

University of Medicine, in addition to the above-

agent classified as an angiotensin receptor blockage

mentioned defendants, were deeply involved in the(ARB). Defendants, Nobuo Shirahashi ( former Novartis

manipulation and/or fabrication of data in a clinical trial

Pharma employee, mentioned in the papers only as acalled "Kyoto Heart Study" [4] (Figure 1-4).

statistician) and Novartis Pharma Co., Ltd. based in Japan,

Blood pressures are exactly the same in both groups including thebaseline and follow up period. Standard deviations are also exactly thesame in both groups.

The subject of the trial was exclusively the Kyoto Heart
Study [4] led by doctors at Kyoto Prefectural Universityof Medicine, but similar clinical trials were conducted at
Jikei University [5], Chiba University, Shiga University

Note that Mr. Shirahashi is described as an academic statistician in Jikei
Heart Study.
Primary endpoint reduced nearly one half, although the baselinecharacteristics and the follow up blood pressures are exactly the same inboth groups. Primary endpoint: mainly stroke, TIA, and angina pectoris.

Page 48 ・ MED CHECK

December 2019/ Vol.5 No.15

However, the law at the time of 2009, when the

The subject of the trial was exclusively the Kyoto Heart“research paper” in question was published, did not

Study [4] led by doctors at Kyoto Prefectural University

stipulate any regulation to penalize researchers’ scientificof Medicine, but similar clinical trials were conducted at

misconduct in medical research. The only legal basis is

Jikei University [5], Chiba University, Shiga University

the prohibition on “false or exaggerated advertising”.

of Medical Science, and Nagoya University. The data

It is a law that prohibits advertising, describing, orin these studies were forged and altered in the same

disseminating false or exaggerated articles that may

way as those in the Kyoto Heart Study. As a result, total

be misunderstood as guarantees of the efficacy and/or

12 documents were published in English peer-review

effectiveness of medicines.

journals as “academic papers”, but all of them were laterIn the judgment, “advertising” is defined by threecriteria: (1) that it targets an unspecified large number ofpeople, (2) on specific medicines, and (3) it is used as ameans to attract customers.
The judgment included medical professionals such as

retracted due to the manipulated and/or fabricated data
(Appendix).
If such scientific frauds are not judged as crimes,
scientific misconducts by pharmaceutical companies
and researchers will be out of control.

doctors as customers. Based on the three criteria, theThe penal provisions of the Clinical Research Law

judgment concluded that the retracted articles werethat was legislated after this scandal are extremely

not “advertisement” and were not used as a means ofpoor. They would not prevent scientific fraud and/or

attracting customers, because they were peer-reviewed

crime by pharmaceutical companies and academic

academic papers although they included false description

researchers.

on a specific medicine, targeting an unspecified large
number of people.
However, the fact that the articles were retracted
from English peer-reviewed journals due to manipulated

References

and/or fabricated data clearly shows that they were not1）The Japan Times. Editorial "Lessons from the Diovan scandal" Jan 14, 2014.

scientific. Hence it should be concluded that they werediovan-scandal/#.XcoEQDP7Tb0

merely advertisement with false statements, aiming at

https://www.japantimes.co.jp/opinion/2014/01/14/editorials/lessons-from-the2)Hama R. Web Med Check No 178 https://www.npojip.org/sokuho/181118.html(in Japanese)

attracting customers. A peer-reviewed academic paper3)Hama R. Web MedCheck No 179 https://www.npojip.org/sokuho/181121.html

that shows efficacy and safety of a medicine has great4) Sawada T, Yamada H, Dahlof B, Matsubara H, for the KYOTO HEART Study Group.

advertising effects and influence doctors (customers forwith high cardiovascular risks: KYOTO HEART Study. Eur Heart J 2009; 30: 2461–69.

pharmaceutical companies). That's why the defendants

created false documents as “academic” papers.
Defendants printed a large number of false documents(in Japanese)
Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients
PMID: 19723695
5) Mochizuki S, Dahlof B, Shimizu M, et al, for the Jikei Heart Study group. Valsartan
in a Japanese population with hypertension and other cardiovascular disease (Jikei
Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study.
Lancet 2007; 369: 1431–39. PMID: 17467513

as academic papers and distributed them to doctors.
They used them to promote sales and prescriptions. The
strategy worked well and contributed to maintaining
annual sales of over 100 billion yen (nearly one billion
U.S. dollars or one billion Euros) for many years. In otherwords, these documents are nothing but “advertising”,
and are exactly “false or exaggerated article” defined by
the law. Therefore, even with the prohibition provision of“false or exaggerated advertisement” at that time, it waspossible to make more just decision. However neither the
district court nor the high court understood the actual
situation, and the criminals were acquitted by a mere
theory.
MED CHECK

December 2019/ Vol.5 No.15 ・ Page 49

Adverse Reactions
Tamiflu: Deaths after Abnormal Behaviour among
Teenagers Revisited:
Probably related to the removal of contraindications
Translated from Med Check (in Japanese) Jan 2020 ; 20(87):12
Rokuro Hama

Keywords:
oseltamivir, removal of contraindications, teenagers, abnormal behaviour, death, suicide

The Ministry of Health, Labor and Welfare (MHLW)
has concluded that there is no causal relationshipbetween Tamiflu use and abnormal behaviour [1, 2],
and revised the package insert in August 2018 to lift
Red Box Warnings with relative contraindications ofTamiflu in children aged 10 to 19. A newspaper [4]reported that the MHLW’s committee had reviewed
42 cases with serious abnormal behaviours such as
running or jumping as adverse events during thewinter season (2018/19) [3].
The frequencies of serious abnormal behaviours

m: million prescriptions

or deaths after abnormal behaviour by kind of drug
are unknown from the newspaper report. In addition,other drugs (odds ratio 119.2, p <0.0001) (See 2018/19 in

it was reported that a junior high school student died

the Figure 1). When meta-analysis is performed for thein the afternoon on December 10, 2019 after taking anlast three years, the risk is about 65 times higher thananti-influenza drug for influenza. However, the name ofthat of other drugs (Figure 1).

the drug was not specified [5]. Isn't Tamiflu really related
to abnormal behaviour? Let's examine it.

Increased reports may be related to the removal ofcontraindication

The risk of death after abnormal behaviour is 120 times
higher with Tamiflu than with other drugs

The estimated number of prescriptions for Tamiflu
for children aged 10 to 19 has remained similar in the

According to the MHLW's data [3], the numbers oflast three seasons, at 100,000, 78,000 and 122,000,

anti-influenza prescriptions for children aged 10 torespectively. However, the number of deaths after

19 in the 2018/19 season were 122,000 for Tamiflu,

abnormal behaviour has been increasing: 0, 2, and 4. It

and 1.616 million for other drugs including Xofluza,

should be noted here that this is related to the move for

Inavir, Relenza and Rapiacta. Among them, 4 fatal cases

lifting contraindications. .

after abnormal behaviours or suicide were reported in

Just before the 2017/18 season, the move rapidly

patients prescribed with Tamiflu (1 in 30,000), while 0 in

became active. For example, the Japanese Society ofpatients with other drugs. Statistically, the risk of Tamiflu

Pediatrics published a guideline for the treatment ofis estimated to be about 120 times higher than that ofinfluenza in 2017/18, saying that it was necessary toPage 50 ・ MED CHECK

December 2019/ Vol.5 No.15

Tamiflu induces 10 times more serious
abnormal behaviours
If you compare the proportion ofserious abnormal behaviour reports per
million prescriptions in the past threeseasons by age (0-9 years, 10-19 years , 20
years old and above) between Tamiflu andinhalers (Relenza and Inavir), the risk of
Tamiflu is always higher than that of theinhalers in all ages and all three seasons(Figure 2). Overall, the risk of Tamiflu is
10 times higher than that of the inhalers
Proportions of reported serious abnormal behaviour cases per million prescriptions were(odds ratio 10.02, p <0.0001) (Figure 3).

higher among Tamiflu users than among inhaler users in all seasons and all age groups.
Inhaler antivirals: Relenza (zanamivir) and Inavir (laninamivir)

Epidemiological studies and animal
experiments show causal relationships

consider administration of Tamiflu by notifying the

As we have previously described in detail [7], Tamiflu

adverse event including abnormal behaviours, if theuse and abnormal behaviours or sudden deaths arepatient had respiratory diseases or milk allergy, andfirmly related based on evidence from various levels

neither zanamivir nor laninamivir could be used. This isof studies including clinical case series, clinical study

a sort of message, implying "Tamiflu can be prescribedreports, epidemiological studies, animal toxicity studies

for teens".

and studies on mechanisms of action including receptor

In addition, in 2018, the MHLW completely denied theor enzyme levels.

causal relationship and contraindication was removed

Don't be misled by the MHLW's trick to cover up thefrom the package insert, so the doctor was held liable

truth. You should look at the data cautiously to avoid

even if a teenager who received prescription died after

making wrong judgement.

abnormal behaviour. It has become easier for doctors toreport fatal cases.

References: see p54

Odds of reported serious abnormal behaviour were significantly higher among Tamiflu users thanamong inhaler users in 6 out of 9 strata. Combined odds ratio is 10.02 (p<0.0001).
Inhaler antivirals: Relenza (zanamivir) and Inavir (laninamivir)

MED CHECK

December 2019/ Vol.5 No.15 ・ Page 51

Adverse Reactions
High Risk of Death from Tamiflu and Xofluza
Serious toxicity necessitating suspension of its use
Translated from Med Check (in Japanese) Jan 2020 ; 20(87):13
Rokuro Hama
Keywords:
oseltamivir, baloxavir, sudden death, death from infection, diarrhea, melena, neuraminidase inhibition, endonuclease inhibition

We have reported on the risk of bleeding [8],admission. Her condition worsened the next day, andresistance, bacterial pneumonia, melena, and serious

she was complicated with DIC (disseminated intravasculararrhythmia [9] associated with Xofluza. In this article, we

coagulation) and died 9 days after taking the drug due toanalyze the adverse reaction reports with fatal outcomes

multiple organ failure. The doctor reported "positive" fordisclosed by MHLW [3]. We also present some typicalcausality with Xofluza.

fatal case reports after Xofluza use.
Case 3 (Sudden death): A male in his 70s without heart
Case 1 (Sepsis with multiple organ failure): A healthy man

disease consulted for sore throat, joint pain, cough andin his 40s consulted 6 hours after onset of influenza

sputum. He was diagnosed with influenza A by rapid

symptoms. He was diagnosed with influenza due totesting. He took Xofluza 40mg. On the next day, his fever

typical symptoms such as high fever and chills, and took

continued and he was treated symptomatically. Three

Xofluza 40mg. After resting in bed with fever for 2 days,

days later, his family member went to his room to checkhe was transported to emergency room and hospitalized.

on him as he had not gotten up and found him dead,Blood culture revealed pneumococcus. He was intubatedlying down beside his bed. He was diagnosed with "acuteand ventilated for multiple organ failure with septicemia

cardiac death" by the post-mortem examination. The

and rhabdomyolysis, but he died three days later. The

doctor reported "positive" for causality with Xofluza.

doctor reported "positive" for causality with Xofluza.
High risk of death from Tamiflu and Xofluza use
Case 2 (Sepsis with multiple organ failure): A woman in her
90s who had been prescribed with various
medications, including an antihypertensive:(losartan), donepezil, diuretics (furosemide andspironolactone), raloxifen and vitamin D, hada fever of 37.8°C and was prescribed with
Xofluza 40 mg for a diagnosis of influenza
A. Her temperature went down 2 days
after taking Xofluza, but she revisited due
to an increased respiratory rate at night.
Pneumonia or heart failure was suspected
and she was transferred to another hospital.
She was hospitalized because pneumonia
was suspected by chest X-rays. She had
hepatic and renal insufficiency at the time ofPage 52 ・ MED CHECK

December 2019/ Vol.5 No.15

Inhaler antivirals: Relenza (zanamivir) and Inavir (laninamivir)

In 2018/19 influenza season, no death case wasalthough it is well-known that Xofluza inhibits cap-

reported among 2.94 million users of inhalers (Relenza

dependent endonuclease which is specific to influenza

and Inavir ). On the other hand 14 death cases fromvirus [12].

adverse reaction were reported out of 2.57 million

Endonuclease activity is essential for cell division and

Tamiflu users and 37 death cases out of 4.27 million

cell proliferation to maintain normal tissues and tissue

Xofluza users. One died out of 180,000 Tamiflu users

repair in case of injury [13]. Xofluza may inhibit theseand one died out of 120,000 Xofluza users. The number

important processes for protection of human body.

of death cases per million prescriptions in the age 10-19

In particular, in the intestinal tract where Xofluza maygroup was 33 deaths for Tamiflu (all deaths occurred after

accumulate, it suppresses the function and regeneration

abnormal behaviour). For patients aged over 20, 6 died outof the intestinal epithelium, inhibits water absorption toof 1 million Tamiflu users and 12 died out of 1 million

cause diarrhea, damages the intestinal epithelium and

Xofluza users. The risk of death for Tamiflu users and for

induces melena. It may cause translocation of intestinal

Xofluza users were 33 times and 52 times higher thanbacteria into blood stream and cause sepsis withthat for users of inhaler antivirals, respectively (Figure

bacteremia, multiple organ failure and septic shock.

and see MedCheck Web No. 181 [10]).

In fact, a woman in her 20s who was diagnosed with
influenza by testing without complication developed

Sudden death and sepsis due to Tamiflu and Xofluza use

diarrhea every 30 minutes from the night after taking

During the three seasons since 2016/17, among 26

Xofluza 40 mg, Later, she found her stool mixed withdeaths reported as adverse reactions to Tamiflu, 8 diedblood and on the next day bloody stool was confirmed byafter abnormal behaviour, 6 died suddenly, and 4 died ofa doctor. She recovered 6 days later [14].

sepsis.

It is reported that secondary bacterial pneumonia

Of the 39 deaths reported to date for Xofluza, 37 were

occurred in 33.3% of Xofluza users, while it wasaged over 20, and 25 were aged over 70. Among 33

observed in only 2% of Tamiflu users who visited andeath cases for which we could speculate the cause of

emergency facility [15]. The risk was 25 times greater

death, 16 were sudden deaths including sudden loss offor Xofluza than for Tamiflu (P <0.0001) [9].

consciousness or respiratory arrest, and 14 had severe

The mechanism of sudden death in Xofluza users

infections such as pneumonia, sepsis with multiple organ

may also be related to the inhibition of endogenous

failure. In addition, although among 35 cases in which

endonucleases and impaired nerve and/or heart function.

causal relationship was reported, physicians identified
positive causality in 33 cases, the MHLW denied
causality in all cases, explaining " causality cannot be
assessed due to a lack of information etc."

In practiceInfluenza is a self-limiting infection which is cured
spontaneously. Antivirals are not required. Adequate restand hydration are the best treatments. High-risk people,

Mechanisms of death are related to the action of thesuch as the elderly, diabetics and patients with impaireddrug

kidney function are at greater risk of death from harm

Tamiflu itself enters into the brain and causes
abnormal behaviour, suppresses respiration, leadingof Xofluza or Tamiflu. Hence neither Xofluza nor Tamiflu
should be used. Do not use these agents for influenza.

to sudden death [7]. It inhibits not only neuraminidaseof the influenza virus, but also human's endogenous

References: see p54

neuraminidase, and reduces symptoms of influenza
and simultaneously suppresses immunity, exacerbating
infections, impairing renal function and inducing or
worsening diabetes [11].
On the other hand, possibility of inhibiting endogenous
endonuclease in the human body cannot be ruled out

MED CHECK

December 2019/ Vol.5 No.15 ・ Page 53

References for the articles "Death After Abnormal Behaviour
among Teenagers Revisited (p50-51) and " High Risk of Deathfrom Tamiflu and Xofluza" (p52-53)
1）MHLW Committee on the safety of pharmaceuticals
https://www.mhlw.go.jp/stf/shingi/shingi-yakuji_127869.html Dossier for theCommittee 2018.5.16 (in Japanese)2) ibid Dossier for the Committee 2018.7.13 (in Japanese)3) ibid Dossier for the Committee 2019.10.29 (in Japanese)4) Yomiuri Newspaper "42 Abnormal behaviours after flu infection、2019.10.30 (inJapanese)
5) Japan Today, Boy falls to death from apartment while under treatment for flu
2019.12.11
https://japantoday.com/category/national/junior-high-school-boy-falls-to-deathfrom-apartment-while-under-treatment-for-flu
6) Hama R Tamiflu: Death after abnormal behaviour among teenagers again. Web
MedCheck No180 (2019.11.15）(in Japanese)
https://www.npojip.org/sokuho/191115.html (Free)
7) Hama R, Bennett C. The mechanisms of sudden-onset type adverse reactions tooseltamivir. Acta Neurol Scand. 2017;135(2):148-160.
https://onlinelibrary.wiley.com/doi/full/10.1111/ane.12629 (free)8) Nakanishi T and Hama R. Hemorrhage caused by anti-influenza viral "Xofluza".
MedCheck 2019：19（83)：56-57 (in Japanese)
9) Hama R. Adverse Reactions to Xofluza: Tolerance, pneumonia, sudden death andHemorrhage MedCheck. 2019：19（86)：131 (in Japanese)
10) Hama R. High risk of death from Tamiflu and Xofluza. Web MedCheck
No181(2019.12.15）(in Japanese)
https://www.npojip.org/sokuho/191215.html (Free)
11) Hama R. The mechanisms of delayed-onset type adverse reactions to oseltamivir.
Infect Dis (Lond). 2016;48(9):651-60.
https://www.tandfonline.com/doi/full/10.1080/23744235.2016.1189592 (Free)
12) Furuichi Y、Bulletin of RNA Japan https://www.rnaj.org/newsletters/item/
614-furuichi-1213) Kiyonari S. 5th Endonuclease https://www.sbj.or.jp/wp-content/uploads/ file/sbj/9109/9109_biomedia_4.pdf
14) Yamagishi T. A survey on the secondary bacterial pneumonia after influenza infection.
Presentation at the 47th annual scientific meeting of the Japanese Society for Acute
Medicine (2019.10.02 to 04）

M
C

ED

HECK

2019

Vol.5

No.15

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

Page 54 ・ MED CHECK

December 2019/ Vol.5 No.15

Advisors:HONZAWA,Tatsuo (MD[GP]); KIM,Mieko(Pharmacist);
MUKAI, Junji (Pharmacist); SEGAWA,Yusuke; SUMIDA, Sachie(MD[Dermatologist]); TERAOKA, Akio (Pharmacist) ; TOI, Chihiro(Pharmacist); UMEDA, Tadahito (MD[psychiatrist])
Editorial Officers: SAKAGUCHI, Keiko
Production Team: UMEKI, Yukiko; SAKAGUCHI, Keiko; MATSUMOTO, Koji
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