M
C

ED

April

2018

Volume 4-The Informed Prescriber

N 10

HECK

o

Is the “Right-to-try” a “Right of Patient” ?
Who benefits from the guidelines?
Guidelines for influenza treatment in Japan is misleading
Do general health checks prolong lifespan?

CONTENTS （April 2018, Vol. 4, No. 10）

Editorial

Is the “Right-to-try” a “Right of Patient” ?

2ReviesWho benefits from the guidelines?

3

Guidelines for influenza treatment in Japan is misleading

6

Do general health checks prolong lifespan?

Page xvi ・ MED CHECK - TIP April 2018/ Vol.4 No.10

11

M
C

ED

-The Informed Prescriber

HECK

Editorial

Is the “Right-to-try” a “Right of Patient” ?
Translated from the Editorial in Med Check-TIP (in Japanese) Jan 2018 ; 18 (75)
Keywords:
randomized controlled trial, right-to-try, conditional early approval, real-world data, observational study

Randomized controlled trial ( RCT ) is a scientificmarket in Japan. Development of some cholesterol-

procedure necessary for ultimately determining

lowering agents was discontinued before approval.

efficacy and safety of a drug. A series of deregulation

The hypoglycemic agents approved after 2000 do notthat rocks it from the ground has begun in 2017.

reduce cardiovascular disease. Hence in the United

Before discussing it, let’s briefly review the history ofStates, a compromise was made to approve a productregulation of pharmaceuticals.

which at least showed non-inferiority to a placebo as aSince the global thalidomide disaster in early 1960's,

new valuable product. However, it may be very difficult

regulatory authorit ies in many countries haveto apply this method to any medicine.

established and applied a system in which new drugs

Hence a new idea, "the-right-to-try" law was

are approved by confirming the efficacy and safety bypromoted to allow patients to try unapproved agents

RCTs.

that completed Phase I. It passed through the Senate

Among them, the United States established thein the United States in August 2017 and has beenstrictest regulations, which required two RCTs for the

deliberated at the House as of February 2018. Even if aevidence of efficacy and safety. However, it has beendamage is caused by trial of an unapproved agent, thebecoming more difficult to provide them especiallycompany does not take responsibility. In other words,

since 1990’s when numerous new substances

it is a corporate responsibility avoidance measure thatwere discovered and invented due to advances inputs "right of patient" in front.

science and technology, and they were introduced as
pharmaceuticals.

In Japan, the same was made possible withoutchanging laws. The Ministry of Health, Labor andAlthough novel drugs such as antihypertensive

Welfare Division Chief 's notification on October 20,

agents have "action to lower blood pressure”, the effect2017 "Conditional Early Approval System" made earlyof prolonging the life span has not been proven by RCT

approval possible with a condition of confirming

except for a case of serious hypertension. Therefore, if

validation and safety by conducting observational

RCT proved that a certain disease such as heart diseasestudies with a small number of people after approval . It

or stroke is reduced by the substance, it is accepted

is adoption of an alchemic "drug approval" method thatas a medicine. Cholesterol lowering agents anddoes not require RCTs.

hypoglycemic agents are the other examples. Moreover,"Observational study" can never be a substitutederegulation was made: such that only one RCT isof randomized controlled trial. However regulators

required for approval of a new product. Most of theare now allowed to approve new products by using

medicines currently in use are the substances approved"Observational study" or what they call the "Real-by the deregulated requirements.

World Data". They say that "Real-World Data" need lessAmong many agents developed and approved after

resources with fewer patients’ data and less expense2000 by less strict regulations, some products arewhile RCTs need more resources with more patients’

excluded from health insurance in Europe due to theirdata and more expenses. With this unbelievable logic,

adverse effects or inefectiveness. One such example isthis procedure is being promoted.

aliskiren, an antihypertensive agent which increased
cardiovascular disease and death is still now on the

Page  ・ MED CHECK - TIP April 2018/ Vol.4 No.10

Such an outrageous act can never be accepted.

Review
Who benefits from the guidelines?
Translated from the Editorial in the issue 75 (Jan. 2018) as the introduction of the series:
Critical appraisal of the Japanese “Practice Guidelines”
Keywords:
practice guidelines, Antibiotic Guidelines, antihypertensive, strength of endpoints, overall survival, total
mortality, indirect surrogates, study design

This year, we would like to address the problems in clinicalhave been created in accordance with the Evidence-Basedpractice guidelines as our theme of the year. Guidelines are

Medicine. In these guidelines, many references are cited, thetools to guide how to perform medical practice appropriately.

recommendation level is determined and finally new drugs

In the early 1990s, we were impressed by the "Antibiotic

are recommended for use.

Guidelines" edited and published by Therapeutic Guidelines, anonprofit organization in Australia. It was made in the 1970s

Modern medical doctors may want to believe that theirin response to the emergence of resistant bacteria due totherapeutic skills are much more advanced than those of 30

overuse of antibiotics in the country.

or 50 years ago. But is this true?

The latest version of the "Antibiotic Guidelines" at that

New drugs strongly act on the body: A hypotensive agent

time was translated and published in 1999 by the Japansurely lowers blood pressure, a cholesterol lowering agent

Institute of Pharmacovigilance (now NPO Japan Institute ofsurely lowers cholesterol level and a hypoglycemic agent

Pharmacovigilance) because we thought that it would serve notsurely lowers blood sugar level. A neuraminidase inhibitor

only for medical professionals but also for patients. We invitedreliably inhibits neuraminidase of influenza virus.

Mary Heming, the editorial executive of the “Therapeutic

influenza vaccine using splits of influenza virus as an antigen

Guideline” as a guest speaker of the 2nd Pharmacovigilancesurely produces antibodies against them.

Seminar in 1999. This antibiotic guideline is excellent as

Various guidelines use these findings as evidence. They

it clearly distinguishes the diseases or conditions in which

explain as if scientific evidence is complete and recommend

antibiotics should be used from those in which antibiotics

new agents as useful drugs.

An

are not necessary based on scientific evidence. We learned
from her lecture how the guidelines were born (The Informed
Prescriber Oct. 1999).

This makes healthcare professionals believe these agentsare useful for their patients ( people ), and prescribe anddispense them for their patients (people).

It may be a desire of many people to live healthy, avoid
illness, and live long. For this purpose, one would consult a
medical doctor and seek medicines.

Will diseases be cured or complications be prevented if
blood pressure falls, cholesterol level goes down, and blood
glucose level decreases? Will this help us become healthy?

In modern science, the mechanism of the body is elucidated

What about possible serious harm caused by medicinesat the molecular level, human genetic information is preciselythat may shorten the life span? As recommended by the

elucidated, many receptors and their ligands (substances acting

guidelines, doctors prescribe antihypertensive agents,

on receptors) are discovered, and numerous potential newcholesterol lowering agents and hypoglycemic agents.

drugs are developed.

Pharmacists dispose them. Patients take medicines without
doubting the health professionals’ medical practice of good

Since 2000, many clinical practice guidelines haveintention.

been published in Japan as well. They are claimed to

MED CHECK - TIP April 2018/ Vol.4 No.10 ・ Page This series will critically examine guidelines based on the

drug: Is it a therapeutic advance?” in the ISDB Manualevidence of proper balance of benefit and harm of products

issued in 2005 (http://www.isdbweb.org/documents/uploads/

which are recommended by the guidelines. It will investigate

manual_full_text.pdf).

and appraise in depth some key products to prove thatthey are actually ineffective or harmful as these are often

In order to evaluate benefits and harm of a new product,

neglected by various guidelines made by so-called “experts”.

we consider the strength of endpoints as the most important

In this series, we evaluate new products in accordanceindicator to be assessed as shown in the Box 1 in thewith the instruction in the “Chapter 8 Reviewing a new

Chapter 8 of the ISDB Manual.

Strength of the evidence

From Chapter 8 of the ISDB Manual.
http://www.isdbweb.org/documents/uploads/manual_full_text.pdf

The strength of the evidence must be assessed by looking at the primary outcome measures used in thetrials and at other aspects of the design of the study. The outcome measures and the design and conduct ofrandomised controlled trials are often inadequate, and lead to unreliable or irrelevant conclusions. Therefore
careful appraisal of trial reports is needed to assess the reliability of the trial results.
When evaluating a treatment for a disease from which patients die, the most obvious and measurable
outcome is whether the treatment improves survival. However, even when ‘survival’ is the most appropriate
primary endpoint, very often in clinical trials a surrogate endpoint, such as transient symptomatic relief and/or
improvement of certain laboratory tests, is used instead. The reason for this is that it allows trials to be shorteror to require inclusion of fewer patients.
Another problem is the use of combined endpoints (e.g. definite myocardial infarction (MI) and death from MI(cause-specific morbidity and mortality)). A combined endpoint may miss important effects of treatment that

actually shorten overall survival and/or lead to other serious complications.5

The primary endpoint of realinterest for patients is death from all causes, with all serious events, such as cancer, included in the endpoint.
Box 1 shows a hierarchy of endpoints. The hierarchy is from the US National Cancer Institute and relates
to evaluation of treatments for cancer, but it can be adapted to other therapeutic areas too. Box 2 shows ahierarchy of study design.
These hierarchies do not include non-clinical evidence, which should also be considered in an evaluation –e.g. pharmacokinetic studies, dose-ranging studies, studies in healthy volunteers, toxicology (see Box 4 and theannexe at the end of this chapter).

Page  ・ MED CHECK - TIP April 2018/ Vol.4 No.10

Box 8.1 Strength of endpoints (ranked in descending order)

Source: Based on a hierarchy from the US National Cancer Institute web site (http://www.cancer.gov/cancertopics/pdq/levels-evidence-adult-treatment/)*a: Added by the manual’s editors, to make more applicable to other diseases and interventions.
*b: If “carefully assessed quality of life” is combined with overall survival, the combined endpoint could be classified as A-2.

Box 2. Hierarchy of study design

Source: Based on a hierarchy from Levels of Evidence and Grades of Recommendation by Centre for Evidence-Based Medicine, Institute of Health
Sciences, Oxford[www.cebm.net/levels_of_evidence.asp#notes]*a: All or none case-series (i.e. when all patients died before the treatment became available, but some now survive on it; or when some patients died before
treatment became available, but none now die on it, are classified as 1c).

MED CHECK - TIP April 2018/ Vol.4 No.10 ・ Page Review
Review
Annual theme of 2018: Critical appraisal of the practice guidelines (1)Guidelines for influenza treatment in Japan ismisleading
Translated from Med Check-TIP (in Japanese) Jan. 2018 ; 18 (75):10-12

Many doctors use practice guidelines made by various medical societies as "guidelines” for their clinical practice. However,guidelines may often be harmful for their patients. "Critical appraisal of the practice guidelines" is the annual theme of the year
2018. The first issue is about influenza management.

Summary
1. Anti-influenza agent is useless and harmful
In Japan, if you have influenza, you would see a doctor, and if a rapid test is positive, the doctor would prescribe aneuraminidase inhibitor such as Tamiflu. Experts of infectious diseases and policy makers recommend "early treatment withantiviral drugs". As a result, total prescriptions per capita of neuraminidase inhibitors in Japan is 1000 times or more than thatin the UK. Sudden death due to respiratory suppression or accidental death after abnormal behavior by Tamiflu still continues
to be reported.
Neuraminidase inhibitors do not inhibit the growth of viruses in human bodies, but they inhibit the hosts’ endogenous
neuraminidase and suppress their immunity. The reduction of symptoms after using neuraminidase inhibitors is only anapparent effect. They do not prevent severe condition and have no effect in decreasing hospitalization or death. They haves noeffect in preventing influenza virus infection either. These were confirmed by the Cochrane neuraminidase inhibitor team. On
the other hand, accidental deaths after abnormal behavior and sudden death due to respiratory suppression were reported
after Tamiflu use. Neuraminidase inhibitors especially Tamiflu should not be used.
2. Influenza vaccine is not recommended
The guidelines recommend that people should be vaccinated annually for the prevention of influenza. However, theJapanese influenza vaccine does not prevent infection because it does not make immunity for prevention of infection at the
mucosal surface of the nose and bronchus.
All observational studies that claim influenza vaccine to be effective are the results obtained by ignoring the usual healthconditions (healthy vaccinee effects or healthy user bias). A large-scale survey (Maebashi survey), which was not affected by thehealthy user bias, clearly showed that the influenza vaccine had no effect. This survey is most reliable. Moreover, the results ofa systematic review of randomized controlled trials showed that it was ineffective for the elderly who had used the same typeof vaccine as those in Japan.
In adults and children aged 16 to 65 years old, the efficacy was observed for the inactivated vaccines (not permitted in Japan).
However, as many as 70 persons should be treated to prevent influenza in only one person. Although harm is rare, it may cause
convulsions or Guillain-Barre syndrome, an intractable neurological disease. Influenza vaccine is not recommended.

Keywords:
influenza, guideline, Tamiflu, neuraminidase inhibitor, antiviral agent, abnormal behavior, sudden death, influenza
vaccine, split vaccine, inactivated vaccine, live attenuated vaccine, Maebashi City survey

Page  ・ MED CHECK - TIP April 2018/ Vol.4 No.10

1. Neuraminidase inhibitors

3. Even patients without concomitant diseases,--- antiviral drugs can be administered by the doctor.

Japanese guidelines recommend using themLet’s examine the 2011 proposals of The Japanese

As 1 to 3 are written before the fourth point “4. Most of

Association for Infectious Diseases [2] (JAID 2011), manual of

influenza infection is self-limiting with natural cure and

the Japan Physicians Association (JAPHA 17/18) [3], treatment

administration of anti-influenza drugs is not essential”, theguidelines of the Japan Pediatric Society [4] ( JPS 2017 ),true meaning of “Use of anti-viral agent is not essential' iscomprehensive measures by Ministry of Health, Labor andundermined and cannot be understood by the pediatricians.

Welfare [5] (MHLW 2017) and Q & A by MHLW (MHLW Q&A)
[6].

The MHLW recommends early consultation
MHLW recommends early consultation when one gets

Recommend drug use in all cases
The opinion described in the JAID 2011 [2], which was firstinfluenza as an answer to the question “What should I do with
influenza?” in the "MHLW Q & A". It explainspresented during the outbreak of influenza in 2009, shows a“(1) Consult a medical doctor as soon as possible if you

fundamental idea of the society.

feel sickly”
If you notice symptoms, they recommend to see a medical"As a general rule, ---- the biggest goal is to prevent

doctor as soon as possible. A neuraminidase inhibitor may

severity to reduce hospitalization and death by

be prescribed as recommended by the JAID 2011, " JAPHA

administration of neuraminidase inhibitors." "It is most

17/18" or "JPD 2017" if consulted. Thus, in reality there is noimportant that as much as possible, starting therapy withrestriction on the treatment of influenza in Japan.

anti-influenza drugs at the earliest stage of the disease in
all cases."

Most antivirals in the world are used in JapanAs a result, the number of prescriptions of neuraminidase

This recommendation emphasizes the importance of anti-

inhibitors per 1000 people in Japan is 50 times, 300 times,

influenza agents on the premise that “influenza gets severe”,

1,000 times, and 1,200 times higher than in that in France

neglecting the fact that "influenza is a self-limiting infection".

and Sweden, Italy, and UK, respectively. Numerous abnormal

It claims that "neuraminidase inhibitor" can "prevent severity

behaviors have been reported [7].

of influenza and recommends broad use of neuraminidase
inhibitors.

Virus does not decrease

As a result, "JAID 2011" [2] states that "using oseltamivir,

The general perception that neuraminidase inhibitors (NIs)raninamivir or zanamivir" is considered for most patientssuch as Tamiflu inhibits the growth of viruses and lightens

without any specific limitations.

symptoms is a typical misunderstanding. As explained in the

The JAPHA 17/18 presents almost the same idea as theserecommendations in JAID 2011.

figure, NIs interfere with the virus leaving the cells. In the US,
the label of oseltamivir does not state that Tamiflu suppresses
proliferation of virus in humans. Rather, there is definite

The JPS 2017 also recommends antiviral use
The recommendation of JPS 2017 is slightly different. It

evidence that symptomatic relief is independent of virus
growth suppression.

says “4. Most of influenza infection is self-limiting withnatural cure and administration of anti-influenza drugs is

Symptom relief is due to inhibition of human endogenous

not essential".

neuraminidase

However, before this sentence,

Respiratory syncytial ( RS ) virus causes pneumonia

1. Patients such as infants, having underlying diseases orwith a high mortality rate in infants. When Tamiflu waspatients with strong respiratory symptoms are at high risk

administered to mice infected with this RS viruses whichof severity.

had no neuraminidase, symptoms reduced, while virus load

2. In principle, it should be used within 48 hours after

increased.

onset, but it should be considered even after more than
48 hours have passed since onset.

The reason is that Tamiflu inhibits the function ofendogenous neuraminidase in animals and humans.

MED CHECK - TIP April 2018/ Vol.4 No.10 ・ Page Neuraminidase is deeply involved in immune systemof the neuraminidase inhibitor on symptomatic relief andand/or defense system. Inhibition of host’s endogenous

the mechanisms of the delayed reactions to Tamiflu suchneuraminidase by NIs suppresses its action leading not toas reduced antibody production are described in detail in afight against viruses. Hence the symptom relief is merely thereview article [11].

apparent effects of NIs and not the true beneficial effect for

Although there are opinions that recommend the use [12]the host. As a result, unwanted disorders may occur in various

based on a systematic review by a group other than Cochraneorgans such as renal disorders, diabetes and so on. Moreover,team, a paper that criticizes them has already been publishedthere is a potential danger that the symptoms worsen in the[13].

high risk persons of influenza.
Hospitalization did not reduce
A systematic review [8] of NIs by Cochrane team, in which

Ineffective for prevention
Because neuraminidase inhibitors do not reduce

I also participated and discussed, does not recommend NIs.

proliferation of influenza virus, they have no therapeutic

In the revision launched in June 2017, oseltamivir (Tamiflu)

effect other than apparent slight symptom relief. When they

was downgraded in the World Health Organization’s essential

were used for prophylaxis, no efficacy was demonstrated.

medicines list (EML) from the “core” to the “complementary”

Although a clinical trial for prophylaxis reported the efficacy,list. Although it was left for use by high risk persons, Tamiflu

it was merely manipulation of the data from RCTs [13].

would be deleted in the next revision [9].

Because Tamiflu reduces production of antibody against

Among four neuraminidase inhibitors available in

influenza and viral shedding in the respiratory tract, aJapan, Tamiflu is an extremely dangerous substance, as it

substantial number of patients with influenza infection

causes abnormal behaviors leading to accidental death andshowed false negative testing results by Tamiflu. These

suppresses respiration leading to sudden death [10]. The

phenomena made apparent reduction of influenza patients inpathogenesis of abnormal behaviors and sudden death is

the Tamiflu group compared with the placebo group.

clear and the association is causal [10]. The apparent effectFigure 1: Budding and release of influenza virus, neuraminidase(N) and hemagglutinin (H)The influenza virus germinates from a human respiratory cell (A, B), andfinally it is connected by a saccharide chain, a neuraminic acid, to humancells (C). When this is cut by neuraminidase, the virus separates fromthe cell (D and E). Tamiflu inhibits neuraminidase in the virus and keeps
the virus in (C) state, but it does not kill the virus. The symptoms slightly
reduce because the human endogenous neuraminidase is inhibited andthe immunity is weakened.

Figure 2: Live Influenza virus, inactivated whole virion
vaccine and split vaccine
The influenza vaccine in Japan is a vaccine made from theabove split parts H ( hemaglutinine ) and N ( neuraminidase ) ( G ).
Vaccines that are reported effective abroad are a live attenuatedvaccine or an inactivated vaccine using the whole virion (F). Split
parts actually form like petal by agglutination. http://www7a.
biglobe.ne.jp/SuzunokiCC/fluwa2.html

Page  ・ MED CHECK - TIP April 2018/ Vol.4 No.10

2. Influenza vaccine: ineffective and harmful
Vaccine claiming effectiveness is not available in Japan

compare a group of persons who did not have vaccine due todiseases and a group of persons who were vaccinated due togood health.

JPS 2017 states "influenza vaccine has been reported as

A series of observational studies ( cohort studies ) by

having efficacy preventing the onset of influenza and reducing

Maebashi City Medical Association of Gunma prefecture [17,the number of absent days at school” based on the Cochrane's

18] may be the only one large-scale survey comparing thesystematic review [14].

frequency of influenza-like fever between groups (cities) not

However, the vaccines that the systematic review reported

using the vaccine and groups (other cities) using the vaccine

are the "inactivated vaccine" or the "live attenuated vaccine"with similar usual health conditions. They surveyed tens ofof spray-type on nasal mucosa, both of which have neverthousands of people over two years and showed no difference

been approved in Japan. Because strong adjuvants are added,

between the vaccinated and unvaccinated groups. It is stillthese vaccines are more toxic than the split vaccine which is

the most reliable observational studies for the evaluation ofavailable in Japan.

effectiveness of subunit vaccine in the world.

Japanese split vaccine is ineffective and harmfulMore death reported in only one RCT

On the other hand, the vaccine used in Japan, as shown in

Govart's trial [19] is the only RCT which studied the efficacy

the figure on the previous page, is a collection of some partsof split vaccine, the same type of vaccine as the one used inof virus and is called “split vaccine” or “subunit vaccine”.

Japan, in suppressing symptoms in the elderly. According to

Antibodies that are produced by this vaccine are those forthe results, the vaccine had no efficacy for the reduction ofcleaning up the parts such as N (neuraminidase) and H

symptoms. Rather, there were six deaths in the vaccine group(hemaglutinine) dispersed in blood when the influenza virus

compared with three in the placebo group. Randomized

is broken by the action of fever and immunity (see the figure

controlled trials of split vaccines against children and non-on the previous page). In other words, antibodies produced byelderly adults only examine the rise of antibodies and none ofthe vaccine are "antibodies for cleaning up waste". Failurethem have examined symptomatic suppression effects.

to prevent invasion of influenza virus is also mentioned in"Ministry of Health, Labour and Welfare Q & A" [6].

In the Cochrane’s systematic review of the RCTs for adults

The vaccine may induce harms. Even if they are rare, it causes

under the age of 65 [20], only inactivated vaccines and live

Guillain-Barre syndrome, neurological intractable diseases

attenuated vaccines showed symptomatic effects. The number

such as narcolepsy, anaphylaxis and convulsions.

needed to treat to benefit was 70 showing only one person
escaped influenza when 70 persons were vaccinated. There is

No proof for reduction of "hospitalization and death"no effect of split vaccine used in Japan.

The reference paper [15] that the JPS 2017 claims as theevidence of "reduction of hospitalization due to influenza" is a

When you have influenza

case-control study. Moreover, it is never reliable because one

If you visit an outpatient clinic for consultation, thereof the most important confounding factors, "healthy vaccinee

may be sick people or patients with high risk or elderlies

effect or healthy user bias” was not adjusted.

in the waiting room. You may give your influenza to theseIn "HMLW Q & A" [16], “evidence” claiming 34% to 55%

people. No medical examination or medication is required

reduction of illness and 82% reduction of deaths is citedfor influenza, because it is a self-limiting infection with mild

based on the worst observational study which ignored

symptoms.

"healthy vaccinee effect or healthy user bias”.

Let's think that it is a good opportunity to take enoughrest and sleep with adequate nutrition and fluid. Only when

Healthy vaccinee bias of observational studies
Please imagine the situations in which one is inoculated

you have a severe headache disturbing your sleep, low doseparacetamol may be helpful. Let's just take a rest.

with a vaccine. If one has fever on the day for vaccination or

For your further reference, please see my books "Preventing

one has sickness from day to day, s/he will be refrained from

Encephalopathy Caused by Medicines" [21] and "Tamiflu isvaccination. Ignoring such a background, many observational

Harmful as Presumed" [22].

studies claiming the effectiveness of influenza vaccine

MED CHECK - TIP April 2018/ Vol.4 No.10 ・ Page References
1) Is general health check-up effective? English version of Med Check TIP, 2018: 3(10): 6-1011) Hama R. The mechanisms of delayed onset type adverse reactions to oseltamivir.
Infect Dis (Lond). 2016; 48 (9): 651-60.

2) The Japanese Association for Infectious Diseases "On indication of Anti-Influenza

https://www.tandfonline.com/doi/abs/10.1080/23744235.2016.1189592

Drugs (Revised Edition)" http://www.kansensho.or.jp/guidelines/110301soiv_teigen.

12) Watanabe Akira, a meta-analysis on the effectiveness of Tamiflu, treatment

html (in Japanese)
3) Japan Physicians Association, Influenza Research Group, Influenza Clinical
Practice Manual, 2017-2018 Season Edition (12th Edition) (in Japanese)
4) Japan Pediatric Society, Information on clinical practice of influenza etc. (in Japanese)
http://www.kansensho.or.jp/guidelines/110301soiv_teigen.html
5) Ministry of Health, Labor and Welfare, Comprehensive measures against influenza
in 2017(in Japanese) http://www.mhlw.go.jp/bunya/kenkou/influenza/index.html
6) Ministry of Health, Labor and Welfare, Influenza Q & A (in Japanese)
http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou01/qa.html
7) Med Check TIP editorial team, Tamiflu, abnormal behavior is multiplied by
16 times, Med Check TIP, 2018: 18 (1): 21 (in Japanese) http://npojip.org/
sokuho/170726.html
8) Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, et al. Neuraminidase
inhibitors for preventing and treating influenza in healthy adults and children.
Cochrane Database Syst Rev. 2014; 4: CD008965. http://cochranelibrary-wiley.
com/doi/10.1002/14651858.CD008965.pub4/epdf9) Web MedCheck. Tamiflu downgraded in the essential medicine list of the World
Health Organization (WHO). http://www.npojip.org/sokuho/170726.html (inJapanese)
10) Hama R et al, Bennett CL. The mechanisms of sudden-onset type adverse
reactions to oseltamivir. Acta Neurol Scand. 2017; 135 (2): 148-160
https://onlinelibrary.wiley.com/doi/full/10.1111/ane.12629

Page 10 ・ MED CHECK - TIP April 2018/ Vol.4 No.10

guidelines for anti-influenza drugs,
https://mrkun.m3.com/mt/onepoint/2711/view.htm?pageContext=opd1.0&sort=unread&mkep=list
13) Hama R, Jefferson T and Heneghan CJ. Cochrane team comments on ECDC
Opinion (draft), drug check TIP 2016 16 (65): 66-68
14) Jefferson T et al .: Vaccines for preventing influenza in healthy children.
Cochrane Database Syst. Rev., 2012 CD004879.
15) Talbot H. K et al .: Effectiveness of influenza vaccine for preventing laboratoryconfirmed influenza hospitalizations in adults Clin. Infect. Dis. 2013; 56 (12)1774-1777.
16) Kamiya Ji, Heisei 19 (1999) Emerging and reemerging infectious diseaseresearch project "Research on the effect of influenza vaccine17) Yugami S (Maebashi City Influenza Research Group): Influenza epidemics in nonvaccinated areas. 1987
18). Yamamoto S, Why influenza vaccine is ineffective, The Informed Prescriber
1987: 2 (10): 73-76 (in Japanese)
19) Govaert TM et al, The efficacy of influenza vaccination in elderly individuals.
JAMA. 1994; 272 (21): 1661-5.
20) Demicheli V et al, Vaccines for preventing influenza in healthy adults. Cochrane
Database of Systematic Reviews 2014, Issue 3. Art. No .: CD001269.
21) Hama R, Preventing encephalopathy induced by medicines, NPO japan Instituteof Pharmacovigilance, 200822) Hama R, Harmful Tamiflu as was presumed, Friday Publishing Ltd, 2008

Review
Review
Annual theme during 2018: a series of critical appraisal of practice guidelines (2)Do general health checks prolong lifespan?
Translated from Med Check-TIP (in Japanese) Mar. 2018 ; 18 (76):28-31

In this series of article, we discuss the efficacy and effectiveness of "general health checks" on all-cause mortality. Firstof all, in this issue, we examine randomized controlled trials (RCTs) and systematic review of them. Subsequently, we
will examine the practice guidelines on hypertension, cholesterol etc., which "general health checks" find frequently as
health problems or risk factors of major diseases such as ischemic heart diseases or stroke.

Summary● A Cochrane's systematic review of randomized controled trials (RCTs) examined the general health checks on all-cause
mortality for adults less than 65 years of age. After about nine years of follow-up, there were no differences on all-cause
mortality between the health checks group (74 per 1000 participants) compared with the control group (75 per 1000). No
difference was found by several subgroups and sensitivity analyses by various factors. There was no difference on mortality
rate from heart diseases or cancer either.
● Eight RCTs (12 cohorts) which examined the general health checks on all-cause mortality in 65 years or older were found.
Meta-analysis of them showed that mortality rate in the general health checks group increased by 30% compared with thecontrol group as a whole in 65 years or older (including 75 years or older). All-cause mortality increased by 62% in the age of 75
or older (odds ratio 1.62, p = 0.0002).
● In a Finish RCT with long term follow up, after general health checks for males with 38 to 54 years of age, low risk
participants were allocated into two groups; an intervention group who were treated intensively with various health problems
for five years or a control group without intervention. All-cause mortality after 18 years in the intervention group increasedby 54%, compared with that in the control group. There may be some problems in the measures of intervention after general
health checks.
● In Japan, there is no RCT that assessed the efficacy of general health checks on all-cause mortality, but there are many
surveys that support the results above. These will be discussed in detail in the next issue and thereafter.
Conclusion: General health checks do not prolong lifespan, and it seems that life expectancy shrinks on
the contrary, especially in the elderly aged 75 years or older. Advices for lifestyle and method of treatment
based on the current practice guidelines may be inadequate.

Keywords:
general health checks, special health examination, randomized controlled trial, death, health advice, medical
intervention, intensive treatment

Introduction"Special Health Examination" is a term used in the healthresults. You may be advised for taking medications in order tobe healthier and to live longer.

examination in order to find a specific disease such as “breast

The purpose is certainly good. However, it may really becancer screening” and “lung cancer screening”. In the "general

good if the general health checks actually help you live longer.

health checks", on the other hand, various examinations are

We have assessed various cancer screening examinations so

performed comprehensively. It may find risk factors that may

far in this bulletin. As a result, we concluded that occult bloodlead to future full-blown diseases. You may be intervened fortesting for colorectal cancer may be effective [1]. However,dietary habits, exercise, sleep, smoking, etc. according to thebased on the best evidence available we reported that most

MED CHECK - TIP April 2018/ Vol.4 No.10 ・ Page 11

cancer screenings including breast cancer screening [2,3],

lifestyles and receive medical care if necessary. As a result,uterine cancer screening [4], lung cancer screening [5] andyou have “no effect” on prolonging lifespan. It means thatprostate cancer screening [6] were ineffective.

everything ended in vain.

In the FORUM on MedCheck TIP No. 75, in response to
the questions from a reader, we preliminary wrote on the

Why it has no efficacy?

ineffectiveness of general health checks for elderly people.

Several limitations have been pointed out for this systematicThis time we will look at the efficacy of comprehensive

review [15]. For example, many of the included studies

general health checks for not only the elderly but also non-have been reported before the 1970's and antihypertensive

elderly people (less than 65 years old).

agents, cholesterol lowering agents, hypoglycemic agents arechanging with the times. However, in the review, the risks

A brief history of general health checks system in Japan
In Japan, complete medical checks began in the 1950’s. An
automated laboratory device (autoanalyzer) was developed andratios for all-cause mortality were reported separately before
and after 1980 with no differences: risk ratios were 0.99 and
1.03, respectively.

introduced in the general health checks in 1970 [7, 8], which

In addition, in the Cochrane review, they conductedenabled us to get laboratory test results within the day ofmany subgroup and sensitivity analyses: for example, withexamination. In 1982, Elderly Health Law was amended. Freeor without lifestyle interventions, by the number of healthmedical expense system for the elderly was abolished andchecks, by the length of follow-up period, by geographicalgeneral health check system was introduced for the citizens

location, with or without examination by physician, by theaged 40 years or older [9]. In 1994, the law was revised todegree of selection bias, performance bias and detection bias

strengthen general health check system for people aged 40

etc. In any subgroup and sensitivity analysis, the risk ratios

years or older [9].

were between 0.98 and 1.03 with no difference in all-cause
mortality.

Comparative trials on general health checks (1)No effect on mortality in non-elderly adults
A Cochrane systematic review that assessed the efficacy ofgeneral health checks [14] reported as follows:

Inter99, a latest RCT published in 2014 also shows that
there was no efficacy on prolonging lifespan by general healthchecks [16]. Health check group ( 11,629 participants ) andcontrol group (47,987 participants) were followed for about 10

The authors searched randomized controlled trials (RCTs)

years. Risk ratio for cardiovascular disease was 1.03, strokeof general health checks on mortality including all-cause

0.98, total death 1.00. These suggest that medical treatment

mortality comparing "general health check group" and control

using newly developed antihypertensive agents, cholesterolgroup without intervention in adults excluding the elderly.

lowering agents, hypoglycemic agents may not be able to

A total of 14 RCTs were found. Of these 9 RCTs reported all-prolong lifespan.

cause mortality. Total participants were 155,899 who were

There are some inadequate criticisms on the methods:

followed for about 9 years (median) and 11,940 deaths wereparticipants’ age was young, proportion of participants with

reported. All-cause mortality rate was 74/1000 in the healthrisk factors were low, less participants had general healthcheck group compared with 75/1000 in the control group.

checks, intervention did not always lead to improvement of

Risk ratio for all-cause mortality was 0.99 (95% CI: 0.95, 1.03).

lifestyle and not many examinees visited medical facilities [15].

Mortality rates from cardiovascular disease (risk ratio 1.03)
and cancer (1.01) were similar and showed no difference in

Deaths increased at 18 years after general health checks andthe mortality rate between both groups.

medical interventions

The purpose of general health checks is to find risk factors

Let's look at the results of a randomized controlled trial thatleading to full-blown diseases early; i.e. hypertension, lipid

Cochrane's review did not include, but followed participants

abnormality, hyperglycemia, etc. and correct lifestyle ifwith risk factors of cardiovascular disease for 18 years [17,necessary. If intervention to life styles were not successful18].

for improvement of risk factors, treatment by medicine may

This study was conducted in Finland. People who werebe considered. In other words, manpower and money were

between 38 and 54 years old from 1972 to 1973 wereconsumed, people consume time, move some distance to visit

eligible. The methods were different from the Cochrane’

medical facilities to receive health checks, try to improve theirs review in that all participants received general healthPage 12 ・ MED CHECK - TIP April 2018/ Vol.4 No.10

checks. People who had serious diseases such as myocardialgroup and control group without health checks and RCTs

infarction and stroke were excluded, and 1222 participants

aimed at elderly people aged 65 years or older were excluded

who were healthy or at least one risk factors such as

from the review. Therefore, we examined 10 trials [19-28]

hypertension, high cholesterol, smoking, obesity for ischemicthat were excluded from the review. There may be more trials

heart diseases were randomely allocated to intervention

other than these, but this time it is the results of the analysis

group or control group.

of them.

Participants of control group (n=610) had no intervention

Among the 10 RCTs, two [27, 28] were excluded fromexcept those with diastolic blood pressure exceeding 110

the analysis because data on all-cause mortality was not

mmHg who were advised to consult a doctor. On the otherreported. As a result, 12 cohort in eight papers [19-26] which

hand, 612 participants in the intervention group were advised

reported data on all-cause mortality after general healthon lifestyle such as diet and smoking. If blood pressure orchecks comparing with non-health checks after follow-up forcholesterol level did not improve, antihypertensive agent

approximately 2 years or more. These papers were published(thiazide or β blocker) or cholesterol lowering agent (fibrate orafter 1990 [20-26] but one in 1979 [19].

probucol) was prescribed. The target value of blood pressure

Data on all-cause mortality were meta-analysed andwas less than 140/90 and the target value of total cholesterol

combined odds ratios and their 95% confidence interval

was 260 mg / dL (Note 1). After five years of intervention, the(95%CI) were calculated by random effect model (DerSimonian-

average blood pressure decreased from 148/96 to 138/88

Laird) for participants of 65 years old or older and for thoseand the total cholesterol level decreased from about 275 mg/

75 years old or older (Note 2).

dL to 260 mg/dL.

In total, among 12,711 participants followed for about

In the control group, the blood pressure was decreased

two years or more, 996 died. In the elderly as a whole (65from 146/94 to 142/91 and the total cholesterol levelyears old or older), the odds of total death increased by 30%

remained the same level at 270 mg/dL.

compared with those who did not receive general health

After 18 years, 95 died in the intervention group while
only 65 died in the control group. Odds ratio is 1.54 (95%checks (Figure A+B): combined odds ratio=1.30 (95% CI = 1.00,
1.69, P = 0.0527, I 2 = 65.2%)

confidence interval 1.10 to 2.16, p=0.0117 ). More than twice

There were no significant differences for the cohort of 65

cardiovascular diseases were observed in the intervention

years or older (excluding the cohort with the age of 75 years orgroup compared with the control group. Although advice

older), but the results were inconsistent (I2 = 72 %) containing

for smoking cessation was also done, the results were

results with a significant decrease and a significant increase

disappointing.

in the mortality rate (Figure A).

Employers are obligated to do "health checks at workplace"

Combined odd ratio of seven cohorts from 4 trials targeting

which almost all employees receive in Japan. According tothose 75 years or older [23-26] showed 62% increase of all-the results of health checks, lifestyle intervention such as

cause mortality in health check groups than control groupdiet or exercise may be given. Unless the level of indicator(Figure B) with no inconsistency (I2 = 0 %).

for health would be “improved”, it may be attributed to the

There were 6 RCTs (7 cohorts) for 2 years of follow-up, 2

lack of personal effort. However, this Finnish study clearly

RCTs (5 cohorts) for 3 years of follow-up. There was one RCTshows that aggressive intervention including treatment with[20] which followed for four years, but we used the data for

medicines may worsen and shorten their lifespan, although

the two-year follow-up period because of the least attritioninterventions were given with "goodwill" after general healthbias.

checks.
Note2: "65 years or older" includes not only the participants
Note1: Target level of total cholesterol at the time the healthof 65 to 74 years old but also "65 years old or older including

checks was conducted.

75 years or older”, if it cannot exclude “75 years or older".

Comparative trials on general health checks (2)Death increased in the elderly

Japanese studies also suggest harm of medical interventions
There is no RCT that assessed the efficacy of general health

The Cochrane Review [14] is a systematic review ofchecks in Japan, but there are several studies that may berandomized controlled trials (RCTs) comparing health checkup

helpful for assessing it. For example, a cohort study called

MED CHECK - TIP April 2018/ Vol.4 No.10 ・ Page 13

NIPPON-DATA is one of them. From these data, you can see

Conclusions

that the independence after 15 years is lowered by use of

It is concluded that general health checks do more harm

anti-hypertensive treatment. In a randomized controlled trial

than good for the elderly 65 years or older, especially 75

called JATOS, strict anti-hypertensive treatment may cause

years or older. It seems that general health checks may doharm for health, including possible shortening of lifespanmore harm than good even for the non-elderly adults younger

than mild treatment. There are some other studies showing

than 65 year old. At least it can be said that benefit does notsimilar results [12].

exceed harm.

After all, general health checks, even though some

It seems that advice for lifestyle to improve risk factors ofabnormalities or risk factors were found, subsequentmajor diseases and medical intervention after general healthintervention by current knowledge or common sense inchecks rather than the checks itself may harm the health ofmodern medical science may do more harm to people thanthose who received checks, even though they were done by

good. It is especially true for the elderly aged 65 years or“good will”. It may rather be "unnecessary meddling".

older. It may indicate that if people suddenly change their

Considering that the substantial human resources,

way of lifestyle, or take a new medicine, lifespan may be

expenses, time are required for general health checks, cost

shortened rather than prolonged. In this point, practiceeffective balance is poor. If you want to live healthy and long,guidelines for individual diseases may be deeply involved. We

it may be appropriate not to receive general health checks

will examine the practice guidelines for individual diseases atand not to visit a doctor unless you have or feel substantial

the next issue and thereafter.

abnormal symptoms with potential risk of your life.

Figure: Meta-analysis results of health checks on all-cause mortality

Overall elderly (65~) : combined odds ratio 1.30 (95% CI = 1.00, 1.69, P = 0.0527, I 2 = 65.2%)
65 years old or older excluding 75 years old or older: combined odds ratio 1.09 (95% CI = 0.78, 1.53, P = 0.61, I 2 = 70.2%)
75 years old or older: combined odds ratio 1.62 (95% CI = 1.25, 2.10, P = 0.0002, I 2 = 0%)
Stuck (1) and (2) are low risk groups, and (3) and (4) are high risk groups

Page 14 ・ MED CHECK - TIP April 2018/ Vol.4 No.10

https://www.ncbi.nlm.nih.gov/pubmed/1870247

References
1) Tanida N, Prevention and Treatment of Colorectal Cancer. MedCheck 2006: 6 (21):2-15.
2) Prescrire team, whether to screen breast cancer by mammography (Part 1).
MedCheckTIP. 2016: 16 (63): 21-23. (Translated from Presscrire Int.)
3) Prescrire team, same (Part 2, Part 3) MedCheckTIP. 2016: 16 (66): 92-95.
4) Screening does not reduce cervical cancer death. MedCheck TIP. 2017: 17 (71):54-57. MEDCHECKTIP in English 2017: 3 (8): 16-20
http://npojip.org/english/MedCheck/Med% 20Check-TIP% 2008-08-17.pdf
5) Oshima A, prevention of lung cancer and prevention of tobacco related diseases.
MedCheck 2006: 6 (22): 2-9.
6) Kimoto Y. Prostate cancer can not be prevented by screening. MedCheck 2005: 5(20): 2-12.
7) Iwatsuka T, The history and current state of comprehensive general health checks
in Japan, Jananese J Health Checks 1994: 21 (4): 370-376.

TA. Mortality in participants and non-participants of a multifactorial prevention
study of cardiovascular diseases: a 28 year follow up of the Helsinki Businessmen
Study. Br Heart J 1995: 74: 449-454. Https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC484055/
19) Tulloch AJ, Moore V. A randomized controlled trial of geriatric screening andsurveillance in general practice. J R Coll Gen Pract. 1979 Dec; 29 (209): 733-40.
PMID: 536982
Am J Public Health. 1995 Mar; 8520) German PS, Burton LC, Shapiro S, Steinwachs DM, Tsuji I, Paglia MJ, Damiano
AM. 3): 379-86. PMID: 7892923
21) Morrissey JP, Harris RP, Kincade-Norburn J, McLaughlin C, Garrett JM, Jackman
AM, et al. Medicare reimbursement for preventive care. Changes in performance ofservices, quality of life, and health care costs. Apr; 33 (4): 315-31. PMID: 7731275
22) Williams SJ, Elder JP, Seidman RL, Mayer JA. Preventive services in a Medicare

https://www.jstage.jst.go.jp/article/jhep1985/21/4/21_4_370/_pdf
8) Miyashita M, Relationship of The Japan Society of Complete Medical Checks andthe Japan Society of General Health Checks. Complete Medical Checks 2013: 28(1): 5-6.

managed care environment. J Community Health. 1997 Dec; 22 (6): 417-34. PMID:
9403400
23) Patrick DL, Grembowski D, Durham M, Beresford SA, Diehr P, Ehreth J, et al. Costand outcomes of Medicare reimbursement for HMO preventive services. Healthhttps://www.jstage.jst.go.jp/article/ningendock/28/1/28_5/_pdf
9) Ministry of Health, Labor and Welfare, White paper of Health, Labor and Welfare(2008 Ed) Chapter 1, Transition of Measures concerning Health in Japan
http://www.mhlw.go.jp/wp/hakusyo/kousei/14/dl/1-01 .pdf

Care Financ Rev. 1999 Summer; 20 (4): 25-43 .PMID: 11482123
24) Büla CJ, Bérod AC, Stuck AE, Alessi CA, Aronow HU, Santos-Eggimann B, etal.
Effectiveness of preventive in-home geriatric assessment in well functioning,community-dwelling older people: secondary analysis of a randomized trial. J Am

10) National Health and Nutrition Survey

Geriatr Soc. 1999 Apr; 47 (4): 389-95. PMID: 10203111

http://www.mhlw.go.jp/bunya/kenkou/kenkou_eiyou_chousa.html

25) Stuck AE, Minder CE, Peter-Wüst L, Gillmann G, Egli C, Kesselring A, et al. A11) MedCheck, feature "Hypertension": 2001: No.2
12) MedCheck, feature "hypertension" part 1 (2010: No38) and part 2 (2010: No39):13) MedCheck, feature "Metabolic syndrome" 2006: No. 2414) Krogsbøll LT, Jørgensen KJ, Grønhøj Larsen C, Gøtzsche PC. General healthchecks in adults for reducing morbidity and mortality from disease. Cochrane
Database of Systematic Reviews 2012, Issue 10. Art. No .: CD009009
15) Sekizawa Y, will general health checks reduce mortality rate? Reduce medical
expenses?

randomized trial of in-home visits for disability prevention in community-dwellingolder people at low and high risk for nursing home admission. Arch Intern Med.
2000 Apr 10; 160 (7): 977-86. PMID: 10761963
26) Phelan EA, Balderson B, Levine M, Erro JH, Jordan L, Grothaus L, et al. Delivering
effective primary care to older adults: a randomized, controlled trial of the senior
resource team at group health cooperative. J Am Geriatr Soc. 2007 Nov; 55 (11):1748-56. PMID: 17979898
27) Schweitzer SO, Atchison KA, Lubben JE, Mayer-Oakes SA, De Jong FJ, Matthias

https://www.rieti.go.jp/jp/columns/a01_0455.html
16) Jørgensen, T., et al., "Effect of screening and lifestyle counseling on incidence ofischaemic heart disease in general population: Inter99 randomized trial." BMJ,
2014. 348: g 3617.
17) Strandberg TE, Salomaa VV, Naukkarinen VA, Vanhanen HT, Sarna SJ,
Miettinen TA Long-term mortality after 5-year multifactorial primary prevention ofcardiovascular diseases in middle-aged men.JAMA 1991: 266: 1225-1229.

MC18) Strandberg TE, Salomaa VV, Vanhanen HT, Naukkarinen VA, Sarna SJ, Miettinen

RE. Health promotion and disease prevention for older adults: opportunity forchange or preaching to the converted? Am J Prev Med. 1994 Jul-Aug ; 10 (4):223-9. PMID: 7803065
28) Eekhof J, De Bock G, Schaapveld K, Springer M. Effects of screening for disorders
among the elderly: an intervention study in general practice. Fam Pract. 2000 Aug;
17 (4): 329-33. PMID: 10934182

ED

HECK

The Informed Prescriber
2018

Vol.4

No.10

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

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
Information Technology (IT): KURODA, Akira (Systems Engineer)
Copyright NPOJIP
www.npojip.org
Registered address:#702, Ueshio 5-1-20, Tennouji,
Osaka JAPANE-mail: npojip@mbr.nifty.com

MED CHECK - TIP April 2018/ Vol.4 No.10 ・ Page 15