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Does the Japanese Regulator ignore science?
Dementia Guidelines
Nocturia Guidelines
Guidelines for Low-dose Pills
CONTENTS （August 2019, Vol. 5, No. 14）

Editorial
Does the Japanese Regulator ignore science?

18

Review
Critical Assessment of Dementia Guidelines
Don't try to cure but communicate appropriately

19

Critical Assessment of Nocturia Guidelines
Non-pharmacological treatment is the best25

Critical Assessment of Guidelines for Low-dose pills
Thromboembolism may occur in 1 out of 37 high risk women28

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Editorial

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Does the Japanese Regulator ignore science?
Translated from the Editorial in Med Check(in Japanese) Jul 2019 ; 19 (75)

Human bone marrow-derived mesenchymal stem

to reduce the injury to spinal cord injury." It was also

cells ( trade name: Stemirac ) for spinal cord injury

published as a dissertation in a prestigious medical

were listed in the Japan’s National Health Insurance

journal (New Engl J Med 322: 1405, 1990), swaying

drug price list on February 26 through Preferential

over people’s minds. However, a critical reanalysis

Designation System. One intravenous injection

revealed that the efficacy was doubtful. In addition,

costs 14.95 million yen (140 thousand US dollars). In

there are many harmful reactions, such as delayed

the case of anti-influenza drug, Xofluza, which waswound healing and increased diabetes, and it is now

also listed through this system, at least a placebo-

believed that the therapy should not be used.

controlled randomized controlled trial ( RCT ) was
conducted. However, in the case of Stemirac, only

Before this high-dose steroid therapy was approved

one open trial including 13 patients was conductedin Japan, “pseudo” RCT ( an envelope method with nowithout untreated control.

strict randomization ) was conducted as a follow-up

The Nature advised the Ministry of Health, Labor

study (Otani K et al., Spine & Spinal Cord Journal 7:

and Welfare (MHLW) to "slow down" in its editorial in633, 1994). There was no difference between treated

the January 31, 2019 issue, but the MHLW ignoredand untreated ( placebo ) groups although "global

it.

improvement rating" was used to evaluate the result,a method which can be influenced by investigators’
All of the following criteria must be fulfilled

subjectivity. Then, an alternative endpoint “global

for the preliminary examination and designation;

efficacy rating” was used to create difference so that(1) the product should have a new mechanism of

the therapy would be approved. However, comparedaction, (2) the target medical condition is serious

to the process of Stemirac approval, it can be said thator life-threatening, (3) the product has extremely

the MHLW was still decent at that time.

high efficacy and safety, and (4) the sponsor should
develop the product rapidly and file an application inThis time, the Japanese Society for Regenerative

Japan ahead of the world. With regard to Stemirac,

Medicine released a statement to support the MHLW

the criteria 1, 2 and 4 are indeed satisfied, but thethat in the case of diseases with a small number ofcriterion 3 has not been proven yet. The efficacy

patients, it is difficult to arrange enough number ofis ambiguous as what is believed to be the effecttrial participants to confirm effectiveness statistically,of Stemirac might simply be the natural recovery

and it would take enormous time to do so. However,of spinal cord injury. Moreover, the risk of tumor

considering the epidemiological fact that about 5,000

development, which requires long-term follow-up, has

new spinal cord injuries occur each year in Japan, andnot been ruled out.

the fact that Otani et al. have registered 158 persons
in 15 months, this argument has no ground.

The MHLW should reflect on the history of
medications for spinal cord injury.

The MHLW should immediately withdraw theOn March 31, 1990, the New York Times publishedapproval of Stemirac and call for the implementation

an article introducing high-dose steroid therapy,of RCT. Japan’s scientific decency is now questioned.

stating "for the first time ever, a cure has been found

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Review
The 2019 annual theme: Criticism on treatment guidelines series (8)Guidelines for the Treatment of Dementia 2017
No drug is needed for management of dementia, but appropriate ways toattend to and communicate with persons with dementia are essential.
Synopsis from MedCheck 2019 (82): 34-35.
MedCheck Editorial Team

Summary● There are many drugs that may cause or worsen dementia, but there is no drug that prevents progression ofdementia, reduces behavioral and psychological symptoms of dementia (BPSD), prevents progression of disability, or
prevents institutionalization.
● There are currently four types of anti-dementia drugs approved in Japan and other countries, but in France, inAugust 2018, they were removed from health insurance coverage as they bring no benefit, but harm. As MedCheck
pointed out in 2007, they are not effective, but indeed very harmful. Do not prescribe or take the medication for
dementia.
● The symptoms of dementia are greatly affected by how caregivers attend to and communicate with the patients.
Persons with dementia would feel comfortable and their various symptoms would be largely mitigated when
Humanitude® is practiced. It is a multimodal comprehensive care methodology which incorporates eye contact,
verbal communication, and touch as its elements. .
● Japan's Guidelines for the Treatment of Dementia 2017 (GL2017) does not mention about medications that causedelirium or dementia, and does not introduce appropriate treatment and preventive methods for people withdementia nor non-pharmacologic treatments. GL2017 focuses on classification of the disease and pharmacologicaltreatment. Providing pharmacological treatments according to such guidelines should be avoided.

Keywords:
dementia, Alzheimer disease, dementia guidelines, dementia drugs, Aricept, exercise, cholesterol-lowering agent, statins, PPI,
anticholinergics, Humanitude®

After prescribing Aricept, nothing to do for dementia
This is a symbolic remark that represents Japanese"dementia guidelines" in simple words. It was tweeted by

Japanese Guidelines, they would not have anything to
do for dementia patients as no anti-dementia drugs arecovered by insurance.

a veteran doctor who understands dementia fairly well
[1].

2017 GL: Only diagnosis and pharmacological treatment

We h a ve a d d r e s s e d m a ny t i m e s t h e i s s u e o f

The revised guidelines for dementia 2017 [12] focusesmanagement or treatment of dementia [2-11], including

on early diagnosis,including BPSD, and pharmacologicalin our special issue on Dementia and Delirium No. 27

treatment. It recommends 4 drugs for dementia, such as[2]. Among the many articles, "France has delisted anti-

donepezil, and easy prescription of antipsychotics fordementia agents for reimbursement" [10] was really

BPSD without explaining about the risk of drug-induced

striking. Suppose doctors in France would follow theor drug-aggravated delirium and/or dementia.
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August 2019/ Vol.5 No.14 ・ Page 19

Review
Review
Drugs that cause or worsen delirium or dementia

We converted TSDD to exposure years and found theStatins: In chapter 4 of GL2017, statins are describedcorrelation coefficient with the onset of dementia was

as a preventive factor for dementia. It is based solely on

0.988 (p = 0.0001) for Alzheimer disease and 0.952 (p =a large number of observational studies that have not

0.003) for the dementia of all types (Figure). This means

been adjusted by initial cholesterol levels [9].

that it is possible to estimate that Alzheimer disease and

The Cochrane Study [13] found that the statins do not

all-type dementia would develop 4.2 times and 3.7 times

prevent dementia as a result of randomized controlled

more frequently, respectively, if rank 3 anticholinergics

trials (RCTs).

are used for 20 years. In addition, based on the data

The US Food and Drug Administration ( FDA ) [14]from other reports [18], the correlation between rank 2

revised the labels of statins in 2012 and warned of theor rank 3 anticholinergic agents and total dementia wasrisk of dementia, emphasizing the results of RCT thatsignificant. The risk level is estimated to be 2.7 if it isstatins cause dementia [15, 16]. The fact that the FDA has

continued for 20 years (see the web material for details).

revised the label should be taken seriously.
Nerve damage by statins is clearly observed in animal

Note: Note: There are many classification methods forexperiments, and it is certain that the drugs can cause

anticholinergic activity [17-19]. The latest review found 18

dementia.

classifications [20].

Anticholinergics: It has long been known that evenshort-term use of anticholinergics can cause memory

Animal studies also support the causal relationshiploss, attention deficit, delirium, and loss of consciousness.

between anticholinergics and the onset of dementia

In the epidemiological survey, the level of anticholinergic[21-24].

activity or the degree of clinical cognitive impairment,such as delirium, which the drugs may cause, is divided

PPI (proton pump inhibitor): PPI not only suppresses

into three categories (note), and the association with thegastric acid by proton pump inhibition of the gastriconset of dementia is reported [17-20]. The longer the use

mucosa, but also inhibits the proton pump (type V protonof potent anticholinergics is, the higher the incidencepump) of most cells in the body [25]. Therefore, it causesof Alzheimer disease and dementia of all types would

pneumonia and kidney disorder, and also interferes withbecome.

the function of nerve cells to reduce cognitive function

Gray et al. [17] converted rank 1 to 3 anticholinergics[11].

to standard daily dose ( SDD ) of rank 3 drugs to

There are three appropriate studies [26-28] that

determine the total exposure dose (TSDD), and reported

followed people who had used PPI for a long time (6-9the association with the dementia risk.

years) to determine the risk (hazard ratio) of developing

dementia. Overall, PPI increased dementia by 41%

Figure: Anticholinergic prescription years and risk of developing dementia (from the data in ref [17])A. Dementia (any type)

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August 2019/ Vol.5 No.14

B. Alzheimer disease( p <0.0001 ). Persons who originally had depression

judgment ability or poor problem-solving ability, but they

developed dementia 2.3 times [26] or 2.7 times [28]are very rich with emotions. However, their emotional

more frequently.

control is diminishing, so they tend to be more anxious,

Dementia Guidelines 2017 does not mention at all therisks of these agents that cause dementia.

be emotionally more vulnerable to trivial things, andget excited easily. If they are not properly attended,they might get hurt, excited and violent. Therefore, how

Antidementia agents do not prevent institutionalization

to attend to them and communicate with them is very

The methodology of a randomized controlled trial (RCT)

important. A specific example is introduced from a bookconducted for donepezil was very complex [29].
MMSE scores among people who could continue"Do not Take Dementia Drugs" [11] (see the box on page24).

taking medication without stopping for 12 weeks of run-

The basics of inappropriate interaction that should bein period after the start of the trial was higher by 0.93

avoided are summarized in Kitwood's "Malignant Social

points in donepezil group than those in placebo group.

Psychology" [31] (Table 1).

However, proportions of people who discontinued was

In addition, Humanitude ®, which was developed by

12.8% ( 36/282 ) in the donepezil group, while 6.4%

Gineste and Marescotti [32-35], is really important. It is(18/283) in the placebo group (odds ratio=2.2, p=0.01).

a multimodal comprehensive care methodology, which

Cognitive function of people who were withdrawn was

involves eye contact, verbal communication, and touch

not examined. There were 19 people in the placebo

as its elements [33]. Its 4 principles are summarized ingroup versus 40 people in the donepezil group who

Table 2 [1]. It is now widely practiced throughout thesuffered from serious unwanted effects in the 12

world, and Fukuoka City, Japan has incorporated it as a

weeks run-in period. This indicates that more people

part of its project [34].

experienced harm than benefit in the donepezil group.
The relative risk of entering institutional care in thedonepezil group compared with placebo was 0.97 (95%
CI 0.72–1.30; p=0.8). The relative risk of reaching theTable 1: Malignant Social Psychology by Kitwood [31]disability endpoint was 1.02 (0.72–1.45; p=0.9).
The proportion of patients with fatal outcome orserious adverse events was significantly higher in thedonepezil group ( 50.0% ) compared with that in theplacebo group (36.4%): odds ratio =1.75 (p = 0.001).
French regulators have warned of the risk of increased
mortality with galantamine use (0.3% placebo vs. 1.4%
galantamine) based on the results of two RCTs which wereconducted for two years [7]. At the time of approval ofquoted from ref [1]galantamine in Japan, these two RCTs were not includedin the examination report by the Japanese regulator [7].

Table 2: Principles of Humanitude ®

The odds ratio was 4.7 (p = 0.008, NNTH = 93), which was
calculated from the data of the published paper [30].
In France, drugs for dementia have been delisted fromreimbursement list because these data indicate no longterm benefit, but substantial harm.
Appropriate and inappropriate ways for attending to orcommunicating with people with dementia
People with dementia have impaired memory, poor

quoted from ref [1]

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August 2019/ Vol.5 No.14 ・ Page 21

Review
Review
How we interact and communicate with people with dementia is particularly important
Mr. X was 90 years old when he died. When hestaff when he felt cold outside and tried to get inside. If

was first institutionalized, he had neither incontinence,the staff had apologized then, he might not have gotten

hallucinations, delusions, nor violent behaviors. At

so angry.

night on day 68, as he was in bed with his glasses and

His doctor considered the phenomena such as

hearing aid on, a care staff tried to take them off after"anger" or "violence" seriously, prescribed 0.5 mg oftelling him that he should. Then, he angrily said "whatrisperidone (brand name Rispadar) to calm him andare you doing?" and he showed an action of attack withadded memantine (brand name Memary) thereafter.

his belt. When the care worker lowered his posture

However, his violence persisted when the staff did not

and apologized, using gestures with eye-contact, Mr. X

understand his intention, while he thanked them whenreplied with a smile saying, "I do not want to fight. I am

he was treated with respect and care. Parkinsonian

happy as you seem to understand me."symptoms, urinary and fecal incontinence emerged and

It is extremely important to understand the process incontinued as adverse reactions to risperidone. His bodywhich the man got angry, but became calm and smiledtemperature decreased and finally hypothermia as low

after the care staff dealt with him in an appropriate

as 30 ° C developed, followed by convulsions. He diedmanner.

a half year after he entered the institution. Hypothermia

In the morning on day 80, another care staff guided
Mr. X to go outside for a walk, but he tried to get inside

is one of the typical adverse reactions to risperidone,
which is described in the label.

because it was too cold there. But the staff closed thedoor and he could not get inside. Mr. X hit the staff's

The above is an excerpt from Ref [11]. Mr. X's

abdomen with his fist. Other staff came in to assist,

greatest misery was that when he got angry and violent,but failed to calm him down. In the afternoon, although

the medical professionals did not review the possible

his unrest continued, the staff took him out for a walk.

causes nor reconsider seriously the way in which the

However, during the walk, he did not follow the staff's

care staff interacted and communicated. Instead, they

advice and become violent against them. Mr. X waserroneously relied on drugs, which offered no benefit

angry because he thought he was interfered by thebut only harm.

Table 3 summarizes appropriate and inappropriate

We recommend non-pharmacological treatment

ways to attend to and communicate with people withincluding exercise. Some people may improve theirdementia based on "No need to cure dementia" [1] bycognitive function with drug therapy, but some may

Ueda, "Dementia changes 100% depending on how you

experience aggravation of behavioral and psychologicalinteract" [36] by Yoshida, and actual cases introduced insymptoms such as overexcitement, which may be morea book [11] and essays by Harumoto [2, 37].

difficult to care. Unfortunately, "dementia cannot be
cured pharmacologically".

In Practice:No need to cure. Consider only how to interact

In contrast, because persons with dementia may feel

Dementia Guidelines 2017 gives little emphasis onrelieved by the appropriate ways of interaction based onsuch non-pharmacologic care methods and only focuses

the three elements: eye contact, verbal communication,

on disease classification and pharmacological treatment.

and touch.

The prophylaxis methods of dementia are also
important. Be careful with your daily diet, exercise
properly, and ensure adequate sleeping time without
relying on sleeping pills.

We encourage you to review "what makes persons
with dementia anxious or angry.
We recommend you to learn Humanitude® and
improve eye contact, verbal communication, and touch.

If you or one of your family members develop

Through this methodology, you would surely find better

dementia, first of all, you should thoroughly check andstrategy to improve the care for persons with dementia.

avoid drugs that cause delirium and/or dementia.
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August 2019/ Vol.5 No.14

Table 3: Appropriate and inappropriate ways to interact and communicate with people with dementia

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References

21) Furukawa et al. Activation of acetylcholine receptors and microglia in hypoxic-

1) Ueda A, No need of cure for dementia, Nihonhyoronsha, 2014

PMID: 29695481

ischemic brain damage in newborn rats. Brain & Development 2013: 35 (7): 607-613

2) MedCheck editorial board,, dementia and delirium, MedCheck No. 27, 2007
3) Hama R, donepezil for dementia-is it effective or not? The Informed Prescriber
2007: 22 (6): 65-68.
4) MedCheck TIP editorial board, Yokukansan for dementia, MedCheckTIP, 2015: 15(62): 135-137
5) MedCheck TIP editorial board, Do not use memantine for dementia, MedCheck
TIP, 2016: 16 (63): 3-6
6) MedCheck TIP editorial board, Degrading medicines for Alzheimer disease (France),
MedCheckTIP, 2016: 16 (63): 7
7) MedCheck TIP editorial board, Long-term trial of donepezil and galantamine fordementia drugs MedCheck TIP, 2016: 16 (65): 60-61.
8) Hama R Critical appraisal of guidelines on dementia by The Japan NeurologicalSociety: non-pharmacological treatment focucing on exercise therapy. MedCheck TIP,
2016: 16 (68): 139-141
9) MedCheck TIP editorial board, Six typical harmful effects of statins, MedCheck
TIP, 2018: 18 (78): 88-90.
10) MedCheck TIP editorial board, drug for dementia out of insurance coverage inFrance, MedCheck TIP, 2018: 18 (80): 146.
11) Hama R, Do not take dementia drug, SB Creative, 201812) The Japanese Neurology Association, Guidelines for the Treatment of Dementia
Diseases 2017 https://www.neurology-jp.org/guidelinem/nintisyo_2017.html
13) FDA Drug Safety Communication: Important safety label changes to cholesterol
lowering statin drugs
https://www.fda.gov/Drugs/DrugSafety/ucm293101.htm
14) McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention ofdementia. Cochrane Database of Systematic Reviews 2016, Issue 1. Art. No.:
CD003160.
15) Muldoon MF, Barger SD, Ryan CM, Flory JD, Lehoczky JP, Matthews KA, Manuck
SB. Effects of lovastatin on cognitive function and psychological well-being. Am J
Med. 2000 May;108(7):538-46. PMID: 10806282
16) Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB. Randomized trial of theeffects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J
Med. 2004 Dec 1;117(11):823-9. PMID: 15589485
17)Gray SL, Anderson ML, Dublin S et al. Cumulative use of strong anticholinergics
and incident dementia: a prospective cohort study.
JAMA Intern Med. 2015 Mar;175（3）:401-7. PMID: 25621434
18) Richardson K, Fox C, Maidment I et al. Anticholinergic drugs and risk ofdementia: case-control study. BMJ. 2018;361:k1315. PMID:29695481
19) Durán CE Azermai M, Vander Stichele RH. The anticholinergic risk scale andanticholinergic adverse effects in older persons. Eur J Clin Pharmacol. 2013
Jul;69(7):1485-96. PMID: 23529548
20) Welsh TJ, van der Wardt V, Ojo G, Gordon AL, Gladman JRF. Anticholinergic
Drug Burden Tools/Scales and Adverse Outcomes in Different Clinical Settings: A
Systematic Review of Reviews. Drugs Aging. 2018 May 8. doi: 10.1007/s40266-0180549-z. PMID: 29736815

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22) Yoshiyama Y, Does Anticholinergics Enhance Neurodegeneration in Dementia:
Biochemical and Pathological Examinations Using a Model Mice (P301S Mutant Tau
Gene Transgenic Mice), Japanese journal of geriatric psychiatry , 2011: 22 (Suppl-3):
22523) Yoshiyama Y et al. Anticholinergics boost the pathological process ofneurodegeneration with increased inflammation in a tauopathy mouse model.
Neurobiol Dis. 2012 Jan;45（1）:329-36. PMID: 21889983 .
24) Yoshiyama et al. Does Anticholinergic Activity Affect Neuropathology?
Implication of Neuroinflammation in Alzheimer's Disease. Neurodegener Dis.
2015;15（3）:140-8. PMID: 26138491
25) Hama R, pneumonia with proton pump inhibitor (PPI), MedCheck TIP, 2017: 17(73): 114-116.
26) Haenisch B, von Holt K, Wiese B, Prokein J, Lange C, Ernst A, et al. Risk ofdementia in elderly patients with the use of proton pump inhibitors. Eur Arch
Psychiatry Clin Neurosci. (2015) 265: 419 –28.
27) Gomm W, von Holt K, Thomé F, Broich K, Maier W, Fink A, et al. Association of
proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims
data analysis. JAMA Neurol. (2016) 73: 410– 6.
28) Tai SY, Chien CY, Wu DC, Lin KD, Ho BL, Chang YH, et al. Risk of dementia fromproton pump inhibitors in Asian population: a nationwide cohort study in Taiwan.
PLoS ONE (2017) 12: e0171006 .
29) Courtney C, Farrell D, Gray R, et al (AD2000 Collaborative Group). Long-term
donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised
double-blind trial. Lancet. 2004: 363 (9427): 2105 -15. PMID: 15220031
30) Winblad B, Gauthier S, Scinto L et al (GAL-INT-11 / 18 Study Group). Safety andefficacy of galantamine in subjects with mild cognitive impairment. Neurology. 2008;
70 (22): 2024-35. PMID : 18322263
31) Kitwood T. Dialetical framework for dementia. Woods RT (ed.): Handbook of theclinical psychology of ageing. Pp 267-282, John Willey & Sons 1996 (quated fromreference 1)32) Gineste Y, Marescotti R. Humanitude Nurcing Care Methodology (cited from
Reference 1)33) Gineste Y, Marescotti R. Interest of the philosophy of humanitude in caring forpatients with Alzheimer's disease. Soins Gerontol. 2010: 85:26-7. PMID: 21137489(PubMed Abstract)34) Fukuoka City, Dementia Friendly City Project, http://100.city.fukuoka.lg.jp/
actions/1735) NHK TV program “Humanitude ®, Care methods for dementia-Eye contact, touchand talk, February 5, 2014 (quoted from reference 1)36) Yoshida K, Dementia changes 100% depending on your contact, IDP publication,
201737) Harumoto S, The best medicine is care: what I think after I get dementia (citedfrom reference 2 and 11)

Review

The 2019 annual theme: Criticism on treatment guidelines series (9)Nocturia: non-drug therapy is the best treatment
No drug can reduce sympoms
Synopsis from Med Check in Japanese March 2019 ; 19 (83):60-64
MedCheck Editorial Team

Summary● Nocturnal urinary frequency (nocturia) is a serious condition that lowers the quality of life (QOL), increases therisk of falling and fractures, and thus increases the mortality rate. It is one of the aging phenomena.
● In many cases, the cause of nighttime urinary frequency is nighttime polyuria, which is often caused by excessive
water intake, lifestyle problems such as a lack of exercise, medical conditions such as diabetes, and medications.
Fluid restriction and moderate exercise are more effective than drug therapy.
● The effects of anticholinergic agents and β3-agonists, which are used for treating so-called overactive bladder,
are minimal in treating nocturia, but they rather decrease the blood flow in the brain and cause brain dysfunction,
leading to dementia.
● Causal relations between nocturia and sleep disorders is an “eggs first or chickens first” issue. In either case,correct understanding of and non-pharmacological treatment for sleep disorders and nocturia are required.
Sleeping agents are not recommended in principle because they cause various harms.

Keywords:
frequent nocturia, Guidelines for nocturia, nocturnal urine passing, nocturnal polyuria, anticholinergics, beta-3 agonists, antidiuretic
hormone, sleep disorders, overactive bladder, prostatic hyperplasia

Introduction

urinates twice or more during the main sleep period

Japanese Guideline for nocturia is called "Guideline

lowers the quality of life (QOL), as, for instance, it would

for frequent nocturia" [1]. However, Internationalcause fatigue during the day. In addition, an examination

Continence Society defines nocturia as “waking to passof the data used in the recent meta-analysis [4] showedurine during the main sleep period" , without mentioningthat the total mortality rate for people who urinatedthe frequency of nocturia [2,3].

twice or more at night was higher by 22% compared

No studies have shown that a single nocturia episodewith people who urinated once or less at night. The

can be associated with an increase in all-cause mortality.

total mortality rate for people who urinated three times

There are several studies showing that two or more,or more was higher by 61% compared with that of all

especially three or more, nocturnal urinations are

subjects. This is not only because nocturnal urination

associated with an increase in all-cause mortality [4].

causes falls and fractures when patients get up to urinate

According to epidemiological surveys in Japan,

at night, but also because it is associated with a decline

the proportion of those who urinates at least once atin general brain functions and general physical functions.

night increases with age, and it is about 40% for men
and women in their 40s and over 80% in their 80s[5]. Nocturnal urinary frequency with which a patient

The bladder diary is the key to diagnosis
It is essential to have a detailed medical interview,
MED CHECK

August 2019/ Vol.5 No.14 ・ Page 25

Review
Reviewtaking systemic diseases, such as diabetes, into

polyuria is a physiological phenomenon due to theconsideration. In addition, doctors ask about the time todisappearance of this rhythm with age. This type of

go to bed and wakeup (old people often stay in the bed for a

nocturia can be prevented by restricting fluid intake

long time), bedroom environment, the room temperature,in the evening. In addition, moderate daytime exercise

access to the toilet etc. As for physical findings, it isis recommended as it increases brain blood flow andnecessary for diagnosis of fluid retention to check if

improves the secretion of antidiuretic hormone at night.

there is edema in the lower legs. Urinalysis is essential

The use of the antidiuretic hormone preparation

to determine if there is urinary sugar, diluted urine, or(desmopressin) as a drug therapy for this condition is not

urinary tract infections.

indicated and may cause hyponatremia.

After that, patients should complete a bladder diary
until their next hospital visit. A minimum of 24-hour

2. Bladder storage disorderconsecutive record is required. A bladder diary contains

Benign prostatic hyperplasia and/or overactive

not only the time and amount of urination, but also thebladder cause nocturia. According to a recent review,

intake of food, water and medicines. By doing this, thenone of the anticholinergic agents reduced the frequency

patient would be aware of the amount of fluid intake andof urination at night [14], although Japanese Guidelines

output, and the amount of intake of salt, caffeine andrecommend them for frequent nocturia [1].

alcohol. It will also motivate the patient to review his/herlifestyle, and will serve as a treatment.

3. Sleeping disorder
It is difficult to judge whether there is frequent urine

Three major causes

at night because there is sleep disorder, or vice versa,

1. Nocturnal polyuria

but in many cases both are experienced. If there is little

According to epidemiological surveys in Japan,

urine volume per urination during the daytime andnocturnal polyuria is the most common cause of nocturia

frequent urination, the patient may be awake at nightat night, accounting for 30 to 50% of all causes [5].

due to an urge to urinate. However, the frequency ofRestrict fluid intake because it is often due to excessive

urination is not high and urine volume per urination is

fluid intake. Although excessive dehydration is a risk

sufficient at night, nocturnal polyuria may be the cause.

factor for ischemic stroke and myocardial infarction,

If there is frequent urination in the daytime, urological

the result of a systematic review shows that there is no

consideration will be needed to determine if there is aevidence that excessive water intake leads to prevention

bladder storage disorder as described above.

of cerebral infarction and myocardial infarction [6].
Japanese Guidelines mention the effectiveness of
exercises for improving nocturia, such as walking,If polyuria is the cause, the cause of polyuria should
be investigated and a non-drug therapy should beconsidered.

dumbbell exercise, and squat as they return the fluid

Japanese Guidelines warn against easy prescribing

stored in the stroma into the blood vessel by muscle

hypnotics but at the same time they describe thepumping and also excrete it as sweat. But the guidelinescharacteristics of the drugs as ultra-short acting or

downgrades the evidence level as they are not base on

short acting suggesting that their blood concentrations

RCTs [1]. However there are some systematic reviews

decreases under the effective level by morning andof many RCTs that showed moderate exercise reduces

they have no hangover effect [1]. These descriptions

blood pressure [7,8]. Moreover 46 year follow-up cohort

practically recommend prescribing ultra-short acting

study shows that it prolongs life-span [9]. Intensity ofor short acting hypnotics. However hypnotics cause

optimal exercise is indicated by Duzel et al [10] or Aoyagi

tolerance, dependence, fall, depression, dementia or

et al [11] that were cited in Med Check [12,13].

impaired cognition, increase infection or even cancer andIn young people, at night, antidiuretic hormone

reduce life-span in total [15].

(vasopressin) is sufficiently secreted and nighttime urine

Moderate exercise that is effective in reducing thevolume decreases. Frequent urination with nighttime

frequency of nocturia is also effective in reducing

Page 26 ・ MED CHECK

August 2019/ Vol.5 No.14

sleeping disorders. We recommend non-pharmacologicalintervention including moderate exercise also forsleeping disorders.

References
1) The Japanese Continence Society. Practice Guidelines for Frequent Nocturia.
20092) Hashim H et al International Continence Society report on the terminology for
nocturia and nocturnal urinary tract function. Neurourol Urodyn 2019；38:499-508.
PMID:30644584
3) Everaert K et al. International Continence society consensus on diagnosis andtreatment of nocturia Neurouol Urodyn 2019;38:478-98. PMID: 30779378
4) Fan Y et al. Meta-analysis of nocturia and risk of all-cause mortality in adult
population. Int J Cardiol. 2015;195:120-2. PMID:26026926
5) Homma Y, et al (Neurogenic Bladder Society Committee) Epidemiologic survey oflower urinary tract symptoms in Japan. Urology. 2006 Sep;68(3):560-4. Epub 2006
Sep 18. PMID:16979726
6)Okamura K et al. "Can high fluid intake prevent cerebral and myocardial
infarction?" Systematic Review. J Jap Geriat Soc 2005; 42:557-63 (in Japanese withEnglish abstract) PMID:16248421.
7) Cornelissen VA et al. Impact of resistance training on blood pressure andother cardiovascular risk factors: a meta-analysis of randomized, controlled trials.
Hypertension 2011; 58:950-8. PMID: 21896934
8) Cornelissen VA et al. Exercise training for blood pressure: a systematic review andmeta-analysis. JAMA. 2013; 2: e004473 PMID: 23525435
9) Clausen JSR et al. Midlife cardiorespiratory fitness and the long-termrisk of mortality: 46 years of follow-up. J Am Coll Cardiol. 2018;72:987-95.
PMID:30139444
10) Duzel E et al. Can physical exercise in old age improve memory and hippocampal
function? Brain. 2016; 139(Pt 3):662-73. PMID:26912638
11) Aoyagi Y et al. Habitual physical activity and health-related quality of life inolder adults: interactions between the amount and intensity of activity (the Nakanojo
Study). Qual Life Res. 2010;19:333-8. PMID: 20084463
12) Hama R. Non-pharmacological treatment in dementia: Exercise is effective forboth treatment and prevention. Med Check TIP (in Japanese) 2016; 16(68):139-141.
13) Med Check Editorial team. Japanese Guidelines for dementia overemphasize
pharmacological treatment. Med Check 2019;19:84-89 (English version: p17-21 inthis issue）
14) Andersson KE et al. Pharmacotherapy for nocturia. Curr Urol Rep 2018; 19 (1):8
PMID: 29427214
15) Med Check Editorial team. Insomnia, Optimal Sleep Duration and Harm ofSleeping pills On Essential Points for Evaluating Hypnotics. Med Check in English
2017; 3(9):36-39.

MED CHECK

August 2019/ Vol.5 No.14 ・ Page 27

Review

The 2019 annual theme: Criticism on treatment guidelines series (10)Guidelines for Low-dose Pills (OC/LEP)

Thromboembolism may occur in 1 out of 37 high risk womenTranslated from Med Check in Japanese July 2019 ; 19 (84):83-88
MedCheck Editorial Team

Summary● Low-dose pill is a combination of two types of female hormones, namely estrogen (E) and progestin (P: luteinizing
hormone) at low dose (L).

● It has been used as an oral contraceptive at users’ own expense in Japan since 1998. In 2008, it was indicated for
improving symptoms of primary dysmenorrhea. Since then, it has been widely used by women aged 40 and over,whose risk of thrombosis is higher than the yonger women. Four-fifths of serious thrombosis that occurs when
taking low-dose pills is venous thrombosis.
● The use of low-dose pills particularly increases the risk of thrombosis by 12.6 times within 3 months after
commencement compared with the risk of non-users. Then, the risk slowly decreases, but even after a year, itremains 5-fold higher over a long period of time (5 years, 10 years). More than a half of thromboembolism occurs 7
years after the initiation of treatment. Therefore, even if no harm occurs in a short-term, it is never safe.
● One thromboembolism may occur in 330-110 women who are on low-dose pills for 10 years. The risk becomes
extremely high in women aged 40 or older. In women who initiated the medication at age 40 and continue thetreatment for 10 years, the incidence rate would become as high as 1 out of 74 women.
●Estrogen increases coagulation in both arteries and veins. If blood clots in the small arteries, blood pressure would
go up, and high blood pressure would promote blood clotting and the risk of venous thrombosis would be increased.
● If people with high blood pressure take low-dose pills, they are twice as likely to experience thrombosis ascompared with people with normal blood pressure. As compared with those with normal blood pressure who are
not on the medication, the risk would be 10-fold higher.
● The Guidelines of the Japan Obstetrics and Gynecology Association 2015, misrepresents “absolutecontraindications” and “relative contraindications” in the WHO guideline as “relative contraindications” and "usewith caution", respectively. It carelessly recommends the pills to people with high risk, such as those with high bloodpressure, obesity and migraine, and smokers.
Conclusion: The low-dose pill guideline is dangerous as it promotes careless use of the medication among people
with high risk.

Keywords:
low-dose pills, OC, LEP, deep vein thrombosis, pulmonary embolism, hypertension, contraception, dysmenorrhea, hypertension inpregnancy, Yaz, ethynyl estradiol, drospirenone

synthetic luteinizing hormone) at low dose (L). E and P are

Introduction
Low-dose contraceptive pill is a combination of an
estrogenic agent (E), ethynyl estradiol (EE) (usually lessthan 40

μ g, often 35

Page 28 ・ MED CHECKμ g), and a progestin agent (P:August 2019/ Vol.5 No.14

both female hormones. Low-dose pills were launched inJapan in 1999 as oral contraceptives (OC).

In 2008, a product of similar components, a low-

is experienced as an initial symptom. In either case,dose estrogen / progestin ( LEP ) combination, wasthrombus that has formed in a leg brakes off, reach theapproved for dysmenorrhea (Note 1), and is now widely

heart, pass through the right ventricle and extensively

used by women aged 40 years and older, who are more

obstructs the pulmonary artery. This may cause sudden

susceptible to thrombosis.

shortness of breath or dyspnea as oxygen cannot be

The Japanese Society of Obstetrics and Gynecology
published guidelines on low-dose pills in 1999 [1], 2005[2] and 2015 [3] (hereafter 1999 GL, 2005 GL, and 2015
GL, respectively).

In 2005 GL [2], warning was given quite carefully
by accurately quoting the World Health Organization's

taken in, leading to loss of consciousness and sudden
death.
US Foo d and Drug Administrat ion ( FDA ) uses
the term “thrombosis” referring mainly to venous
thromboembolism in its guidance for industry (2004[9],2017[10]).

(WHO) Medical Eligibility Criteria for Contraceptive Use

We believe that the usage of this term is important.

(WHO-GL) [4] in order to prevent serious harm of low-

When oral contraceptives were first introduced indose pills that may lead to death. However, in 2015 GL

Japan, some obstetrician/gynecologists enthusiastically[3], WHO-GL is quoted quite inaccurately, recommending

advocated the risk of thromboembolism caused by

the easy use of low-dose pills.

the drugs[11-13]. However, the same obstetrician/Let us see what have changed in the guideline and why
it is dangerous.

gynecologists recently changed their views and started
claiming that “thrombosis mentioned in the package
insert includes only arterial thrombosis, but not venous

Note1: Dysmenorrhea is uterine pain around the time of menses.
Pain may occur with menses or precede menses by 1 to 3 days. Pain
tends to peak 24 hours after onset of menses and subside after 2 to
3 days. It is usually sharp but may be cramping, throbbing, or a dull,
constant ache; it may radiate to the legs [5].

thrombosis” and “hypertension is not a risk factor forvenous thrombosis” [14] . As a result, 2015 GL has
incorporated their idea, and excluded hypertension as arisk factor for venous thromboembolism.
Note2: Venous thromboembolism does not refer toMeaning of terms 1:

thromboembolism near the surface of the skin, but deep

"Thrombosis" and "Thromboembolism"

venous thrombosis and pulmonary embolism.

Among many serious adverse reactions to low-dose
pills, it is "thrombosis" that relatively frequently occurs

Meaning of terms 2:

and can lead to sudden death. It can occur in both veins

Cases in which low-dose pills are contraindicatedand arteries. In Japan, about three-quarters to four-fifths

In WHO-GL [4], categories 3 and 4 mean "A conditionof thrombosis due to low-dose pills is venous thrombosis

where the theoretical or proven risks usually outweigh(Note 2) [6], and pulmonary embolism (so-called “economy

the advantages of using the method: risk outweighsclass syndrome” ), which often leads to sudden death,benefits" and "A condit ion which represents an

accounts for 40% of all venous thrombosis [7].

unacceptable health risk if the contraceptive method

Yaz combination tablet was approved for the treatment

is used: unacceptable health risk”, respectively, inof dysmenorrhea in 2008. Its package insert “warns” inboth of which "Do not use OC". Category 4 is absolutethe beginning that "the drug might cause thrombosis

contraindications, meaning that the drug should

which might follow a fatal course," in a red box [8]not be used in any conditions. Category 3 is relative

which is equivalent to to the black-box warnings in US.

contraindications, meaning that “Use of method not

It explains that sudden development of pain/swelling

usually recommended unless other more appropriate

in legs and/or shortness of breath are symptoms of

methods are not available or not acceptable” [4, 15, 16].

thrombosis that requires urgent treatment. “Sudden

While 2005 GL followed the criteria of the WHO-GL,

development of pain/swelling in legs” suggests that a2015 GL interpreted category 4, which originally means

thrombus has formed or thrombophlebitis has developed

absolute contraindications in the WHO-GL, as “OC/in deep veins. In some cases, no pain is felt, but dyspnea

LEP should not be prescribed in principle”. Moreover,
MED CHECK

August 2019/ Vol.5 No.14 ・ Page 29

2015GL interpreted category 3, which corresponds torelative contraindications in the WHO-GL, as “prescribe
carefully”. It explains as if the use of low-dose pills is thestandard.
Regarding blood pressure, according to the WHO
criteria, low-dose pills are contraindicated in patients
whose systolic blood pressure is 140-159 mmHg or
diastolic blood pressure is 90-99 mmHg when there arealternative treatment choices. In patients whose systolicblood pressure is over 160 mmHg or diastolic bloodpressure is over 100 mmHg, low-dose pills are absolutely
contraindicated.

that low-dose pills are “contraindicated” when otherappropriate methods are available. Therefore, alternativemeans of contraception, and preventive methods andtreatment for dysmenorrhea are important. While 2005
GL shows failure rates of various means of contraception
in Table, 2015 GL does not, emphasizing that lowdose pills are more effective than other means. Indeed,
the failure rate of contraceptive pills is low, and its
persistency rate is moderate. It is the most effective
method after sterilization among various choices ofcontraception. However, such a benefit would not
outweigh the high risk of sudden death. If the drug isrelatively contraindicated, it should be discontinued andMeans of contraception and treatment fordysmenorrhea other than low-dose pills
According to the WHO-GL, category 3 means
Figure 1: Risk of venous thromboembolism by duration of useof low-dose pills

other methods should be considered.
Non-drug therapies for prevention of dysmenorrhea
are to take sufficient rest and secure adequate sleep
time without depending on hypnotics as well as to havemoderate exercise regularly [16]. Then, reduce intake
of vegetable oils rich in linoleic acid, which turns into
arachidonic acid that causes inflammation. Instead,use oils rich in omega-3 fatty acid (Note 3) [5,17]. This
would help reduce the incidence of inflammation. As
for drug therapy, non-steroidal anti-inflammatory drugs(NSAIDs) are effective [5]. However, 2015 GL does not
mention anything about non-drug therapies and simply
recommends low-dose pills.
Note3: Arachidonic acid is transformed to prostaglandin
and leukotriene that are essential in inflammatory reaction.

Created by Med Check using data from Table 6 in ref [20],note high odds ratio continues after more than 5 years

Therefore, when it exists excessively, inflammation may be
induced. Oils rich in omega 3 fatty acid include EPA and
DHA in fish oil, and perilla seed oils, Shiso oil and linseed oil

Table: Failure rates of various contraception methods within
the first 1 year (conception rates)

among many vegetable oils [17].

Risk of thromboembolism with low-dose pills
When 2015 GL [3] and its commentary [18] discuss
the risk of thromboembolism with low-dose pills, theyemphasize the absolute risk. For instance, the risk ofvenous thromboembolism among non-pregnant womenis 1 to 5 persons in 10,000 person-years in non-low-dose
pill users, 3 to 9 persons in 10,000 person-years in usersof low-dose pills other than drospirenone containing
ones, and 10 persons in 10,000 person-years in*Ideal use: The chosen method is appropriately performed and continued.
**General use: The chosen method is generally performed, including occasionallyskipping the drug.

Page 30 ・ MED CHECK

drospirenone containing low-dose pill users, such as Yaz.
For pregnant women, thromboembolism may occur in 5
to 20 persons in 10,000 person-years. Within 12 weeks

August 2019/ Vol.5 No.14

after delivering a baby, it may occur in 40 to 65 persons

the risk diminishes after that. Thromboembolism thatin 10,000 person-years (announced by FDA [19]). Using

occurs after 5 or 10 years might not be recognized asthese data, 2015 GL and its commentary emphasize thatadverse reaction to low-dose pills, and thus might not be

the risk of thromboembolism is lower in low-dose pillreported.

users than in pregnant women and women after delivery.

Van Hylckama Vlieg et al. [20] conducted a large-scale

However, when the whole duration of pregnancy

case control study on venous thrombosis and pulmonary

and 12 weeks after giving birth are counted as one

embolism, involving non-pregnant, premenopausal

pregnancy/delivery, the risk of thromboembolism can bewomen. Based on the Table 1 in their study [20] whichcalculated to be 13 to 30 per 10,000 pregnancy/delivery.

shows odds ratio (OR) by duration of use. Odds ratio

In other words, 1 in 770-330 persons would develop

decreases over time; 12.6 within 3 months after initialthromboembolism during one pregnancy/delivery.

treatment, 8.3 between 3 and 6 months, 7.5 between 6

On the other hand, if low-dose pills are used for 4

months and 12 months, and 5.0 between 1 year and 2

years, thromboembolism may occur in 12-36 persons per

years. However, after 1 year, OR remained arround 5.0

10,000 persons (1 in 830 to 280 persons). The average

between 2 years and 5 years, and same level even after 5

duration of low-dose pill use by women who developed

years.

thromboembolism is 8 years in Europe and the U.S. (Thiswill be discussed more later).

Average duration of pill use was 8.3 years

In Japan, increasing number of women are expected

Van Hylckama Vlieg et al. [20] reported that among

to use the medication for a longer period. When low-

persons who developed venous thrombosis while taking

dose pills are used for 8 years as is the case in Europe

low-dose pills, duration of use was known in 1005

and the U.S., the risk of thromboembolism would become

persons. Over 80% of them were on the medication forequivalent to the risk when experiencing pregnancy/

more than a year, and over 60% of them were on thedelivery twice. When the medication is used for 10

medication for more than 5 years (Figure 2).

years and 20 years, the incidence rate would be 30-90

Suchon et al. [21] conducted a case control study,

persons in 10,000 persons (1 in 330-110 persons) andinvolving 968 venous thrombosis patients and 874

60-180 persons in 10,000 persons (1 in 170-56 persons),

controls whose ages were matched. The study showed

respectively. This is an extremely high incidence; morethat the average duration of pill use of women who

frequent than that after experiencing pregnancy/delivery

developed thromboembolism was 8.3 years (SD 7.4).

once.
Pregnancy and delivery carry some risks, but no matter

It is noteworthy that in the 2 large-scale case control
studies involving around 1000 participants each, over

how risky they are, there is no other means to have achild. In contrast, there are many alternative methods forcontraception and treatments for dysmenorrhea. They

Figure 2: Duration of pill use in women with thromboembolism

are incomparable.
The risk remains high after long-term use
The 2015 GL [3] and its commentary [18] emphasizethat thromboembolism occurs most frequently within
3 months after initial treatment. This is indeed true.
Furthermore, it is also true that the risk remains highafter 5 years among low-dose pill users compared with
non-users.
The problem in 2015 GL [3] and its commentary[18] is that they highlight reduction in the risk after
1 year, and this might create misunderstanding that

Created by Med Check using data from Table 6 in ref [20].
More than 60 % among women who developed venous thrombosis used
low-dose pills more than 5 years. Less than 20 % women used low-dose
pills less than one year.

MED CHECK

August 2019/ Vol.5 No.14 ・ Page 31

60 of the women who developed thrombosis with known

increases to 100 persons/100,000 person-years. Basedduration of use were on the medication for more thanon this rate, if the medication is initiated at age 40 and

5 years. In addition, the average duration of use wascontinued for 10 years, the cumulative incidence would

8 years, indicating the high risk even in the long-term

be 1400 persons/100,000 person-years or 1 in 74

users. In Japan, low-dose pills were approved in 1999,

persons. In hypertension complicating cases, it would be

and almost 20 years have passed since then. This means

doubled, and estimated 1 in 37 persons would developthat increasing number of women are on the medication

thromboembolism. Another report [23] also points out

for more than 5 years.

that the risk of venous thrombosis sharply increases

As mentioned above, when the duration exceedsby aging. Including both low-dose pill treated and non-

10 years, 1 in 330-110 persons would develop

treated women, when the incidence rate in age groupthromboembolism. The risk would become higher than

15-19 is compared with that in age groups 35-39, 40-44

that in women who experience 1 pregnancy/delivery

and 45-49, it increases by 4 times, 5.3 times and 6.6( 1 in 110-330 persons). This indicates that longer thetimes, respectively.

medication period is, higher the risk would become.
Low-dose pills double the incidence of hypertension
Hypertension caused by oral contraceptives has

Risk sharply increases after age 40
Nightingale et al. [22] conducted a follow-up study

already been reported in 1967 [24]. It was a high-on around 1 million person-years who were 15-49

dose pill at that time. One woman with normal blood

years old and were on low-dose pills between 1992

pressure experienced increase in blood pressure toand 1997. As a result, deep venous thrombosis was

180/120 mmHg after taking an oral contraceptive.

found in 395 women, and 43% of them was pulmonary

When the medication was discontinued, her blood

embolism. They reported the risk by age group. Figure 3

pressure was normalized, but when it was resumed, it

is reconstructed based on the data from the study.

went up to 160/100 mmHg. Another woman originally

The incidence rate was 30 persons/100,000 person-

had hypertension ( 150/90 mmHg ), and her blood

years in age group 15-19. It is 175 persons/100,000

pressure rose to 230/140, but returned to normal

person-years in age group 45-49; almost 6-fold increase.

after the medication was discontinued. Similar cases

In age group 30-39, it is about 50 persons/100,000

were reported later on. It was reported that among

person-years, but in age group 40-44, it sharply

high-dose pill users, 15.5-18% of them had developed
hypertension [25]. After that, another study reported
that systolic blood pressure and diastolic

Figure 3: Risk of venous thromboembolism in users of low-dose pills by age

blood pressure increased by average 6.4
mmHg and 2.7 mmHg in women who used
low-dose contraceptives ( ethynyl estradiol
30 μ g ), which is commonly used now,

while no hypertension occurred in women
who used progestin alone or IUD ( p<0.05)[26]. Therefore, there is no doubt that
hypertension is caused by oral contraceptives[26].
According to the most recent meta-analysis
Created by Med Check using data from Figure and text in ref [22]. Note sharp increasein thrombosis risk after age 40 in low-dose pills users. While the incidence rate is about[27], oral contraceptives, including those

50/100,000 person-years in age group 30-39, it is about 100/100,000 person-years inused in the past, increased blood pressure by

age group 40-44. In age group 45-49, it is 175/100,000 person-years. Based on this rate,

1.5 times. Based on cohort studies alone, it

if the medication is initiated at age 40 and continued for 10 years, the cumulative incidence
would be 1400 persons/100,000 person-years or 1 in 74 persons. In case of persons withdoubled blood pressure. Moreover, the risk

hypertension, the rate would be even doubled and would be as high as 1 in 37 persons.

of hypertension increased as duration of use

Page 32 ・ MED CHECK

August 2019/ Vol.5 No.14

became longer; 13% increase every 5 years.
Low-dose pills promote coagulation and increases blood

Figure 4: Risk of hypertension* on venous thromboembolism
stratified or adjusted by OC use.

pressure
In order to investigate the cause of hypertension afteradministration of low-dose pills and pregnancy-induced
hypertension, animal studies in which both estrogenand progestin are administered [28-30]. Since estrogenaffects coagulation system and promote coagulationin peripheral arterioles, particularly arterioles in theglomerulus leading to reduction of renal blood flow andhypertension. In addition to this, sodium retention causedby synthetic progestin may contribute to development ofhypertension. This is the likely mechanism (Note 4). It isreasonable that increased coagulation leads to not only

Created by Med Check using data from ref [22,31,32].
*: Hypertension include HIP (history of hypertension in pregnancy).
OC: oral contraceptives or low-dose pills

artery thrombosis, but also deep venous thrombosis andpulmonary embolism.

scale case-control study with two comparison groups [31]which examined the risk of hypertension on occurrence

Note4: Increased coagulation leads to vascular occlusionof thromboembolism by use of low-dose pills (or adjusted

and hypertension. This coincides well with a study thatby the use of low-dose pills) [22,31,32] were identified.

showed that epsilon aminocaproic acid [28] and tranexamic

According to a meta-analysis of the studies, hypertension

acid [30] cause nephrosclerosis by promoting intravascularwould double the risk of thromboembolism (Figure 4).

coagulation and occluding vessels in the kidneys, andincrease blood pressure. Epsilon aminocaproic acid is a
fibrinolysis inhibitor, which inhibits dissolving of clots.
The study also demonstrated that antithrombin III, which
suppresses formation of thrombus, inhibits this process [30].
Low-dose pills create hormonal condition similar to thatduring pregnancy. Therefore, women who are more likely todevelop increased coagulation would develop a condition
similar to pregnancy-induced hypertension. In other words,

Low-dose pills alone may increase the risk ofthromboembolism by 5 times. Therefore, when persons
with hypertension take the drugs, the risk increases
by about 10 times as compared with that in nonhypertensive persons without the pills.
In fact, it was reported that when a woman who had
hypertension during pregnancy took low-dose pills,
the risk of thromboembolism increased by 9.2 times asincreased coagulation causes occlusion in peripheralcompared with that in non-hypertensive persons without

arterioles, particularly vessels in the kidneys, leading to

the medication [31].

hypertension.

Eighty percent were venous thromboembolism
Hypertension increases the risk of thromboembolism

Sugiura et al.[5,6] assessed the risk of

The 2015 GL [3] states that hypertension is a risk

thromboembolism (by venous or arterial) related to low-

factor for artery thrombosis, such as myocardial

dose pill use using spontaneous reports recorded in theinfarction and cerebral infarction, but does not mention

Japanese Adverse Reaction database of Pharmaceuticals

at all that it is a risk factor for venous thrombosis.

and Medical Device Agency ( PMDA ) between April

However, in the package insert, low-dose pills are

2004 and December 2013. They assessed cases wherecontraindicated in “patients with hypertension” because

Yaz, Lunabell or Jemina, which were approved for“there is an increased risk of cardiovascular disorders

dysmenorrhea between 2005 and 2013, were used. They

including thrombosis”. The manufacturer clarified thatreported on 254 thromboembolism cases which could“thrombosis” includes "venous thrombosis". This agrees

be classified as venous or artery. Among them, 20.9%

with the US guidance for industry mentioned above.

(53 cases) was artery and about 80% was venous [5].

Two large-scale cohort studies [22, 32] and one large

This represents how dominant venous thromboembolism
MED CHECK

August 2019/ Vol.5 No.14 ・ Page 33

is in low-dose pill induced thromboembolism. Amongthe cases with venous thromboembolism, 40% hadcomplicating pulmonary embolism.

Conclusion
Low-dose pills are extremely dangerous agents asthey may cause thromboembolism in 1/100 persons

Arterial thrombosis accounts for 0% in age groupwhen they are used for 10 years. When the medication

10-19, 13% in age group 20-29, and over 20% in age

is initiated at age 40 and continued for 10 years, it mightgroup 30-39 and above, indicating increasing risk bycause thromboembolism in 1/74 persons. In persons

aging (Figure 5).

with hypertension, the incidence increases as high as
1/37 persons.

Yaz is particularly dangerous
Yaz is the first medicine introduced in Japan fortreating “dysmenorrhea” in 2008. It is about 8 times
likely to cause thromboembolism as compared withother low-dose pills [6] (Figure 6). At least 3 deaths were

The guidelines of the Japan Obstetrics and Gynecology
Association is misleading as it promotes the use of
dangerous low-dose pills as if they are safe.
Low-dose pills should not be casually used forcontraception nor dysmenorrhea.

reported within 3 years after it was launched. Other
reports also show that the risk increases by 1-3.3 times[34,35].

Figure 5: proportion of venous and arterial thrombosis in

Drospirenone, a progestine in Yaz and Yaz Flex has an

low-dose pills users by age

anti-androgenic potential[36]. It enhances estrogenic
potential of these products, although they contain
only 20 μ g of ethynylestradiol. High incidence ofthromboembolism by Yaz and Yaz Flex may be due toan anti-androgenic potential of drospirenone.
Yaz and Yaz Flex should not be used, and its approvalshould be withdrawn. The second generation oral
contraceptives are relatively safer for dysmenorrhea
among various generation of low-dose pills.

Figure 6: Incidence rate of thromboembolism by generation of low-dose pills (2009 ～ 2014 in Japan)
Generated by Med Check using the data in ref [6] p-ys: person-years
Vertical lines indicated 95% confidence interval of total incidence rateof thromboembolism. Note extremely high incidence rate in the usersof 4th generation low-dose pill (Yaz) which contain drospirenone
as progestin. High incidence of thromboembolism by Yaz may be
due to anti-androgenic property of drospirenone which enhances
estrogenisity of this product, although it contains only 20μg of
ethynylestradiol.
The 1st generation: EE (ethynylestradiol) 35 μ g ＋ norethisterone
brand name: Synphase, Lunabell, Frewell
The 2nd generation: EE 30-40 μ g ＋ levonorgestrel
brand name: Ange, Triquilar, Jemina (EE 20 μ g)
The 3rd generation: EE 30 μ g ＋ desogestrel
brand name: Favoir, Marvelon
The 4th generation: EE 20 μ g ＋ droespirenone
brand name: Yaz, Yaz Flex
Indication of underlined brand name is "dysmenorrhea".
Indication of Yax Flex is "improvement of pain complicated withendometriosis" in addition to "dysmenorrhea".

Page 34 ・ MED CHECK

August 2019/ Vol.5 No.14

References

21) Suchon et al. Risk factors for venous thromboembolism in women under

1）Japan Society of Obstetrics and Gynecology, About The Society, Guidelines

Thromb Haemost. 2016;115(1):135-42. PMID: 26290123

combined oral contraceptive. The PILl Genetic RIsk Monitoring (PILGRIM) Study.

Accessed Jan 5 2015 (not accecible on May 19 2019 http://www.jsog.or.jp/activity/
guideline_OC.html
2) Japan Society of Obstetrics and Gynecology ed. Guidelines for the use of low-dose
oral contraceptives (revised edition) December 2005
3) Japan Society of Obstetrics and Gynecology ed. Guidelines for the use of low-dose
oral contraceptives and low-dose combined estrogen-progestin products (OC・LEP
Guidelines) 2015.
4) World Health Organization(2004). Medical eligibility criteria for contraceptive use,
3rd ed. World Health Organization. https://apps.who.int/iris/handle/10665/42907
5) MSD Manual Professional. Gynecology and Obstetrics/dysmenorrhea
https://www.msdmanuals.com/professional/gynecology-and-obstetrics/menstrualabnormalities/dysmenorrhea
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hormone use in Japan、Heart 2016: 48: 826-831. (in Japanese)of combined oral contraceptives. Eur J Contracept Reprod Health Care. 2000; 5:265–274. PMID: 11245554
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ED

HECK

2019

Vol.5

No.14

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)
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