A PRIMAVERA VEM AÍ… proferidas/Slides 2007/… · populações, e a confusão de riscos relativos com riscos absolutos! WHI and breast cancer Once again, it is apparent that the

A PRIMAVERA

VEM AÍ…

Aproveitem melhores tempos !

estamos hoje expostos a

vulcões de

estudos explosivos

que derramam as cinzas

das notícias erradas

sobre todo o Mundo…

como a conferência de

imprensa sobre o WHI:

com notícias muitíssimo

quentes…

e…, só mais tarde… a primeira

publicação do WHI (JAMA)…

Os manifestos panfletários…

Os seus manifestos panfletários não

foram transmitidos em primeira mão

aos responsáveis pela saúde das

mulheres. Ao contrário, comunicaram-

nos à Imprensa que os aceitou

erróneamente como verdadeiros e os

publicou em títulos de caixa alta !

Assim conseguiram gerar o pânico nas

populações, e a confusão de riscos

relativos com riscos absolutos!

WHI and breast cancer

Once again, it is apparent that the alarmist

reports that spread world-wide when the

first results of the WHI study were

published in 2002 were unjustified based

on the more recent further analyses,

particularly in peri- and early

postmenopausal women.

Press statement of IMS. April 11, 2006.

As encíclicas…

“O que é especialmente

preocupante acerca das

declarações e encíclicas das

prescrições é a aceitação cega da

infalibilidade do WHI e do MWS”

Sturdee D and MacLennan A –(Editorial) Should epidemiology, the media and

quangos determine clinical practice? Climacteric 2004;7:1-2

“Baseado no grupo de estudo do WHI, a

implementação dos resultados

para a clínica tem pouca base científica, se é que tem alguma…”

Adam Ostrzenski and Katarzyna M Ostrzenska. Am J Obst Gynecol

2005;193:1599-604

The women enrolled in WHI and HERS

initiated EPT more than a decade after

menopause on average, and the majority

of events that produced this pattern

occurred in older women.

March 2007 position statement of The North American

Menopause Society.Menopause 2007;14(2):1-17

Data from large studies such as the WHI and HERS should not be extrapolated to symptomatic postmenopausal women younger than 50 years of age who initiate HT at that time as these women were not

studied in those trials

March 2007 position statement of The North American Menopause Society.Menopause 2007;14(2):1-17

It is not possible to extrapolate

conclusions from the study of one

compound, dose, and route of

administration directly to another.



The WHI study was not designed, and therefore was not powered, to investigate the consequences of hormone therapy (HT) in women below 60 years of age.

Press statement of IMS. February 13, 2006.

e ….

os investigadores do WHI

não sabem interpretar os seus resultados…

a pesar de os apresentarem

como a verdade…

“O Estudo da Saúde das

Enfermeiras (NHS) e outros

semelhantes podem estar

correctos e o WHI estar

equivocado, ou vice-versa”

Rossouw J, 2003

”Pode suceder também que cada um deles esteja equivocado.

Talvez o estrogénio das pastilhas não seja a molécula em que nos devamos concentrar”

Rossouw J, 2003

“ Se os dois estudos estiverem certos

então pode ter sucedido que as

mulheres estudadas em ambos fossem

diferentes nalgum aspecto que os

investigadores não decifraram”.

Rossouw J, 2003

WHI

(Women´s Health Initiative)

O que é que mudou? por

Manuel Neves-e-Castro XII Jornadas Minhotas de Ginecologia

Março 2007

e-mail: [email protected]

NADA !

NADA!

e por quê?...

porque só agora é que a comunidade científica

percebeu

o que é o WHI e

o que não é o WHI…

desde há 4 anos…

a SPM soube e sabe ler o WHI !

e por isso se pode verificar que sempre estivemos na vanguarda da leitura correcta (que agora se confirma), nos concensos e artigos publicados !

http://www.spmenopausa.pt

http://www.spmenopausa.pt/

O que é que o WHI é ?

e

O que é que o WHI não é ?

O WHI não foi desenhado para

estudar o efeito da THM

• em mulheres menopáusicas sintomáticas

• durante os primeiros 10 anos após a

menopausa

WHI

• O WHI foi um estudo desenhado apenas para se verificar se a THM tinha efeitos protectores das doenças cardiovasculares:

- em mulheres sem os sintomas frequentes da pós-menopausa (afrontamentos, suores nocturnos, etc)

- com mais de 10 anos após a menopausa (a média de idades foi de 63 anos)

- submetidas a uma única terapêutica hormonal contínua (0,625mg de estrogéneos equinos conjugados e 2,5 mg de acetato de medroxiprogesterona) que não era ajustada em função da idade (até 80 anos!...) nem dos seus efeitos secundários !

Por que motivo se fez o estudo

WHI?

Para determinar o efeito a longo prazo dos tratamentos hormonais na:

prevenção de

doenças cardíacas e

fracturas do colo do fémur, e

possíveis aumentos de risco para

cancro da mama e

cancro do cólon.

Mensagem do Presidente do Estudo WHI

www.hormone.org

Press Statement IMS

The WHI study was not designed, and

therefore was not powered, to investigate the

consequences of hormone therapy (HT) in

women below 60 years of age. Therefore,

any attempt to present the results of the study

as indicating that HT may inflict damage to the

heart in general – a message that was accepted

by many medical societies and regulatory Authorities

is simply wrong and must be amended.

WHI

Que vantagens trouxe?

Uma chamada de atenção para

em termos gerais de THM

- se estudarem doses mais baixas do E e P

- se estudar o benefício/risco

a) das vias de administração

b) das moléculas de P e E usadas

c) da duração das THM

- se determinar qual a idade pós-menopáusica

segura para se iniciar uma THM

A forma como se interpretaram

os resultados em termos de:

- Risco Absoluto (RA ou AR)

- Risco Relativo (RR ou RR)

- Risco Atribuível (RAt ou AtR)

- Número Necessário para Causar Dano

(NNCD ou NNH)

A MENOPAUSA FOI ATACADA

POR UM

TERRORISTA HORMONAL !

O Terrorista

Hormonal

O Terrorista

Hormonal

Quero tomar

TH !

O Terrorista

Hormonal

Quero tomar

TH !

Mas alguns médicos dizem que

NÃO !...

Homem

woman

Homem

Mulher

WHI

O que se disse e ...

O que não se disse...

Quais foram as conclusões do WHI no que se refere a:

cancro da mama?

doenças cardiovasculares?

Efeito sobre o risco de

cancro da mama

WHI aumento do risco: RR 1.26 (CI 1.00-1.59); 26% aumento de risco

AR 0.38% vs 0.30% (ie, 38 vs 30 casos anualmente por

10.000 mulheres)

NÃO SIGNIFICATIVO !

HERS aumento do risco: RR 1.27 (CI 0.84-1.94); 27% aumento de risco


10.000 mulheres)


WHI (JAMA 2002;288:321-331)

Results: “the difference reaches “almost nominal

statistical significance” (i.e. not statistically different!)

Discussion: “the substantial risks for CVD and breast

cancer” (?!...) MNC/04

Se os resultados do WHI se

calcularem, por ano, como

NNT NNH

DCV 1428

ACV 1250

TEV 588

Cancro da mama 1250

Cancro de Cólon 1667

Fracturas osteoporóticas 227

(total)

Neves-e-Castro M. Menopause in crisis post-Women’s Health Initiative? A

view based on personal clinical experience. Human Reproduction 2003;18:2512-8

Women’s Health Initiative (WHI) per 1000 pts over 5 years

CHRT no HRT At Risk

Event

Coronary Heart Disease 17 13 +4

Stroke 13 9 +4

Pulmonary Embolism 8 4 +4

Invasive Breast Cancer 17 13 +4

Colorectal Cancer 5 8 -3

Hip Fracture 4 6 -2

Global Index 82 72

Then, why all this

noise?...

Mainly because the conclusions of

recent trials were severely

misinterpreted by the medical

professionals, the media and by the

women, themselves

MNC/05

Are Women in a crisis?

YES !

Why?

Because

We have a tendency to accept as valid

the headlines that circulate in the

media without having critically read the

full papers to which they refer

We are not able to explain to our

patients the meaning of those risks and

how small they are compared to other

risks to which they are expose MNC/05

To begin with, and

in the light of the present evidence,

doctors and women should be

reassured that the suggested HT’s for

the relief of symptoms in the

menopause

are safe and very effective !

Medicina Baseada na Evidência

e/ou

Evidência Baseada na Medicina

?

Manuel Neves-e-Castro

Medicina Baseada na Evidência

e/ou

Medicina Baseada na Inteligência

?

Lucas Viana Machado

Evidence informed practice (A Clínica Informada pela Evidência)

• It is clearly time to change “evidence based medicine” to “evidence informed practice”.

• I suggest the era of evidence informed rather than evidence based medicine has arrived

Glasziou P. Centre for Evidence-Based Medicine. University of

Oxford OX3 7LF. BMJ 2005;330:92

Evidence-Based Medicine implies that recommendations should be limited to the

women for whom the studies are relevant.



The practice of medicine is ultimately based on the interpretation at any one time of the entire body of evidence currently available.

March 2007 position statement of The North American Menopause

Society.Menopause 2007;14(2):1-17

e … eis um exemplo de um

CONTRA-SENSO…

Effects of conjugated Equine Estrogen in Postmenopausal Women

with Hysterectomy. JAMA, 2004;291:1701-1712

Stroke

“In women 50-59 years not taking HT,

ischemic stroke is expected to occur in

3 out of 1000 women during 5 years.

Five years use of HT would yield 1

additional case of stroke/ 1000 women”

EMAS Statement; 2004.

“Estamos afogados em informação

mas famintos de sabedoria”

John Naisbilt

O que é que parece ter mudado na interpretação dos resultados de

WHI?

No que se refere a:

–Cancro da mama?

–Doenças cardiovasculares?

O cérebro é como um

paraquedas…

ambos funcionam melhor

quando se abrem !

Lord Thomas Dewar

A Mortalidade Cardiovascular

é o dobro da

Mortalidade por Cancro da Mama

BENEFITS OF HORMONE THERAPY

In women less than 60 years old, recently menopausal and without prevalent cardiovascular disease, the initiation of HT does not cause early harm and may reduce cardiovascular morbidity and mortality.

Continuation of HT beyond the age of 60 should be decided as a part of the overall risk–benefit analysis.

IMS press statement, February 2007

Clinica Cardiovascular da Mulher

• 13% das mulheres com idade superior a 45

anos teve uma síndrome coronária aguda

• 55% da mortalidade na mulher é devido a

doença cardiovascular (cardíaca, cerebral)

• As mulheres, representam 62% da

mortalidade por Insuficiência Cardíaca

• A doença coronária na mulher pré-menopausa

é menos prevalente, mantendo-se assim

durante 10 a 15 anos até aos 70 anos, altura

em que iguala o homem

Hormone replacement therapy and risk

for coronary heart disease

Long-term HRT use is not associated

with increased risk for CHD in the CORA-study.

This research even supports the notion that HRT can

positively affect a number of risk factors like central

adiposity, insulin resistance and blood pressure.

HRT may even protect from CHD, but adverse lifestyle

habits like heavy smoking and a not sufficiently healthy

nutrition can offset the beneficial effects of HRT.

Windler E et al. Maturitas 2007 in press.

Hormones and the Heart

1 in 3 women will die from coronary heart disease (CHD) in the USA.

1 in 25 women will die from breast cancer

Fitzpatrick LA. JCEM 2003;88(12):5609-10

Causes of Death Among Women*

*Percentage of total deaths in 1999 among women aged 65 years and older.

Anderson RN. Natl Vital Stat Rep. 2001;49:1-13.

Heart Disease

Other Cancers

Other

Diabetes

Chronic Lower Respiratory

Disease

Cerebrovascular Disease

Breast Cancer 34%

10%

6%

3%

15%

28%

4%

NNH / Year (Number Needed to Harm)

(the reciprocal of the AtR, the atributable risk)

Coronary Heart Disease

WHI (RR 1.29) 1428

HERS (RR 0.99) 5000

Breast Cancer

WHI (RR 1.26) 1250

HERS (RR 1.27) 833

MNC

“Not everything that can

be counted counts;

and not everything that counts can be counted”

Albert Einstein

“HRT is associated with a

35% reduction in mortality

for women who suffered

myocardial infarction”.

Shlipack MG, Angeja B, Go AS, et al Circulation 2001;104:2300-2304

Doenças cardiovasculares (WHI )

O que estava oculto

- com terapêutica combinada (E+P)?

- com terapêutica só com E?

Younger Women May Receive Heart Protection From

Estrogen Therapy

In women ages 50-59 who had undergone a

hysterectomy, a significant protective effect of estrogen treatment, when both primary (heart attacks and heart attack death) and secondary (coronary artery bypass surgery, angioplasty, confirmed angina pectoris) cardiac endpoints were considered.

Dr. S. Mitchell Harman, director and president of Phoenix-based

Kronos Longevity Research Institute (KLRI) in Archives of Internal Medicine 2006;106:357-363

An update of the WHI Study !

WHI investigators reported (Feb 2006) a statistically significant (34%) lower risk for the combined endpoint of myocardial infarction (heart attack), coronary death, coronary revascularization and confirmed angina among women who were between the ages of 50 and 59 at the start of the study (RR 0.66; 95% CI 0.45-0.96).

Hsia J et al.Arch Intern Med 2006;166:357-363

Hsia J, Langer RD, Manson J et al. Conjugated equine estrogens and coronary heart

disease. Arch Int Med 2006;166:357-65





Press Statement IMS

The estrogen plus progestogen arm of the WHI

and the estrogen-alone arm actually showed that

HT does not

increase the risk of coronary heart disease in

the peri- and early menopause,

and may even carry beneficial effects.

Feb 2006

Hormonas

e

Cancro da Mama

Menopausal women and their

doctors are scared about the side

effects of HRT

mainly about breast cancer

MNC/05

Cancro da mama (WHI)

o que concluiu o WHI ?

o que estava oculto no WHI ?

WHI ...

A VERDADE !

O fluxo da Verdade

corre através dos seus

canais de enganos ...

Rabindarath Tagore,1911

POTENTIAL SERIOUS ADVERSE

EFFECTS OF HORMONE THERAPY

Women should be reassured that the possible risk of breast cancer associated with HT is small (less than 0.1% per annum).


POTENTIAL SERIOUS ADVERSE

EFFECTS OF HORMONE THERAPY

Data from the WHI and Nurses’ Health Study suggest that long-term estrogen-only administration for 7 and 15 years, respectively, does not increase the risk of breast cancer in American women.

Recent European observational studies suggest that risk may increase after 5 years.


Breast Cancer Risk in Postmenopausal

Women Using Estrogen-Only Therapy

Our nationwide study shows that the use of oral or transdermal estradiol for less than 5 years does not increase the risk of breast cancer, but such a risk appears with increasing duration of use in 2 to 3 extra cases of breast cancer per 1.000 women in 10 years of follow-up.

Lyytinen H et al. Obstetrics & Gynecology 2006;108(6):1354-1360

The EMAS 2006/2007 update on

clinical recommendations on

postmenopausal hormone therapy

To conclude from these new publications they

suggest the absence of increased risk of breast cancer using estrogen only therapy after short periods of time (less than 10 year). An increased risk may exist thereafter, however.

Gompel A et al. Maturitas 2007;56(2);227-9

Estrogen and progestogen use in peri-

and postmenopausal

women

In absolute terms, this increased risk was rare in the WHI, being 4 to 6 additional invasive cancers per 10,000 women per year who used EPT for 5 or more years.

March 2007 position statement of The North American Menopause Society.Menopause 2007;14(2):1-17

Cancro da Mama WHI

C.I. (1.00 – 1.59)

ARC 0.30% / 10.000 / yr

ART 0.38% / 10.000 / yr

RR 1.26 (26%)

Attributable Risk = 8/10.000 / yr

= 1/ 1.250 / yr

NNH = 1.250 / yr

MNC/04

Cancro da Mama HERS

C.I.(0,84-1.94)

ARC = 0,59% / 10.000 / yr

ART = 0,47% / 10.000 / yr

RR = 1.27 (27%)

Attributable Risk = 12 / 10.000 / yr

= 1 / 833 / yr

NNH = 833 / yr

MNC/04

Breast cancer and the use of HRT

Considering 10.000 women on the combination HRT then for each year there would be:

Seven additional cases of heart attacks

Eight cases of stroke,

Eight cases of pulmonary embolus,

Eight cases of invasive breast cancer,

Six fewer cases of hip fractures

Baum M. The Breast 2005;14-178-80

O Cancro da Mama

O risco de cancro da mama com os

E+P combinados contínuos é mínimo.

É necessário tratar 1250 mulheres

(NNH) durante 1 ano até que se

diagnostique 1 cancro da mama (o que

é equivalente ao risco relativo de 23%!)

Cancro da Mama

O Risco Relativo aumentado de Cancro da Mama com os estrogénios mais progestagénios durante 5, 6 anos é comparável ao aumento de risco de Cancro da Mama para uma mulher que consome uma bebida alcoólica por dia ou que tem um Indice de Massa Corporal de 24, em comparação com 22.

It must be emphasized that we are

talking about an increased incidence of

the disease, which does not

automatically translate into an increase

in deaths from the disease.

Baum M. The Breast 2005;14:178-80

Almost 2/3 of women now diagnosed with

breast cancer are likely to survive at least 20

years • Cancer Research UK researchers estimate that 64%

of women newly diagnosed with breast cancer in England and Wales will live for at least 20 years - compared with 44% in the early 1990s.

• More than 7 out of 10 women (72%) are now predicted to survive for at least 10 years, compared with 54% diagnosed in the early 1990s.

• Survival in women aged 50 to 69 - the age group in which breast cancer is most commonly diagnosed - was even better, with 80% predicted to live for at least 10 years while 72% survived to at least 20 years.

Prof. Michel Coleman, London School of Hygiene and Tropical Medicine told reports; Oct.10, 2005.

Source: Eurocare study

53.6 40.5 49.2 51.0 84.3 76.1 65.4 EUROPE

56.7 43.5 55.0 56.3 91.0 80.0 67.0 Switzerland

57.6 42.5 52.2 54.4 90.6 82.6 67.4 Sweden

57.1 43.9 55.0 55.8 89.8 78.0 65.5 Spain

47.0 31.2 34.8 38.8 70.0 67.4 48.8 Slovenia

N/A N/A 49.0 43.5 68.9 71.9 44.0 Portugal

40.5 25.2 26.3 28.7 57.9 63.1 38.6 Poland

54.9 40.0 51.4 53.6 88.4 77.2 62.1 Norway

55.7 42.7 51.9 54.0 87.7 78.2 68.4 Netherlands

N/A N/A 35.9 53.3 65.0 74.8 39.4 Malta

55.6 41.2 51.2 52.1 82.5 80.6 63.9 Italy

N/A N/A 45.9 55.2 90.9 79.6 76.2 Iceland

55.6 44.1 50.5 54.5 89.9 75.4 75.9 Germany

57.9 44.5 55.9 58.7 85.3 81.3 75.2 France

55.8 41.4 54.0 52.7 84.0 81.4 66.5 Finland

51.2 33.5 43.2 47.6 88.0 74.9 41.5 Denmark

46.0 32.3 38.1 36.4 78.1 64.0 50.1 Czech Rep.

57.9 47.5 N/A 58.4 88.2 75.4 83.6 Austria

47.3 34.7 40.1 36.5 79.1 69.5 48.8 WALES

49.5 35.6 45.3 47.2 90.1 72.3 53.6 SCOTLAND

50.8 37.1 45.7 46.2 85.6 73.6 53.8 ENGLAND

All (F) All (M) Colon (M) Colon (F) Skin* Breast Prostate

% of patients alive five years after diagnosis

European Cancer Survival

Extended use of estrogen for

10 years increases risks by 0,5%, and by

15 years increases risks by 0,9%

but..

upon cessation of HRT, the relative risk quickly returns to 1.0 !

Coombs N J, Taylor R, Wilcken N. and Boyages J. BMJ 2005;331:347-

349

Breast Cancer

• The diagnosis of a breast cancer after the initiation of a HRT (with a duration of less than 5 years) is only a proof of its growth stimulatory effect (not of its carcinogenic effect)

• Therefore, the reversal of the risk to 1 after the cessation of HRT confirms again only its growth promoting effect and denies a carcinogenic effect.

Dietel M., Lewis MA. and Shapiro S. Human Reproduction 2005;20:2052-60

Breast Cancer

• The doubling time of an initial cancer cell,

up to the diagnosis of a resultant 1cm

tumor, is most likely greater than 10 years.

• This is why many dormant cancer cells

may exist in a “normal” breast ! MNC/05

Occult Breast Cancer

Clinically occult in situ

BC’s are frequent in

young and middle-aged

women. Nielsen M et al-Br J Cancer 1987;56:814-9

Occult Breast Cancer

Breast malignancy was

found in 22 women

(20%)

Nielsen M et al-Br J Cancer 1987;56:814-9

Thus…

• Mammographies give more false

negative than false positive results !

• A “normal” mammography does not

exclude the presence of cancer cells

that may “explode” a few months later…

MNC/05

Estrogen replacement therapy in

patients with early breast cancer

The mortality rates from breast cancer for

the ERT users was 4.28% compared with

22.3% in the nonusers.

Natrajan PK and Gambrell RD. Am J Obstet Gynecol 2002;187:289-95

HRT in Breast Cancer Survivors: results:Matched Analysis

174 breast cancer cases taking estrogen

matched 4:1 controls with cancer not taking Estrogen.

Cases

(ERT/HRT)

Controls

(no ERT/HRT) recurrence 17/1000 30/1000

Br cancer

deaths

5/1000 16/1000

Total deaths 16/1000 30/1000

O’Meara et al, JNCI 2001

“Recurrent breast cancer was

found in 9% of HRT users and

15% of nonuser”.

O’Meara ES et al.JNCI 2001;93:754-761

Mortality following development of

breast cancer while using

oestrogen or oestrogen plus progestin:

W Chen, DB Petitti and AM Geiger.

British Journal of Cancer 2005;93:392–398

This study explored survival after

exposure to oestrogen or oestrogen

plus progestin at or in the year prior to

breast cancer diagnosis

oestrogen plus progestin users

had lower all-cause mortality

and breast cancer mortality

Chen W, Petitti DB and Geiger AM. British Journal of Cancer

2005; 93:392-398

Breast cancer survival after hormone

exposure

Overall survival after hormone

exposure

Breast Cancer

Estrogens and Progestagens

• No significant increases in risk was observed in users of estrogens used alone (RR 1.1; 95% CI=0.8-1.6) compared with non exposed women but it was greater in combination with oral progestagens (RR 1.3; CI 1.1-1.5)

• The risk was significantly greater (p <0.001)with HRT containing synthetic progestagens (RR 1.69; CI 1.5-1.9) than with HRT containing micronized progesterone (RR 1.0; CI 0.83-1.22)

Fournier A et al. Int J Cancer 2005;114:448-454

Fournier A et al. Breast Cancer Res Treat.2007,Feb 27 in press

Reduced hormone therapy use might be cause of steep decline in

breast cancer cases

A report presented December 14, 2006, at the 29th San Antonio Breast Cancer Symposium in Houston shows a 7% drop in US breast cancer rates. The analysis suggests a link between the decline in breast cancer and hormone therapy (HT) use.

December 2006 position statement of The North American Menopause Society

Recent declines in hormone therapy

utilization and breast cancer incidence:

clinical and population-based evidence

Clarke CA et all. Journal of Clinical Oncology 2006;24(33):e49-50

http://www.jco.org/content/vol24/issue33/images/large/zlj0330653400001.jpeg


breast cancer cases

Greatest decrease in breast cancer was in the number of ER+/PR+ breast cancers. There was little change in other breast cancers. The greatest decrease also occurred in the women aged 50 to 69, those most likely to be using HT.

Gass M. F.NAMS special issue released December 20,2006


breast cancer cases

Their data most likely reflect existing cancers just below the detection limit in 2002 that slowed or stopped their growing.



breast cancer cases

Another finding that is consistent with an effect

on preexisting tumors is the fact that not a single

study thus far has reported a risk increase for

noninvasive disease. If HT were initiating

(causing) new tumor formation, one would

expect to see an increase in in situ disease.


Analisemos então os

Riscos

Há riscos?

É indispensável que seja dada

informação sobre as diferenças entre

riscos relativos e riscos absolutos uma

vez que os primeiros são a principal causa

de desinformação e alarmismo, sendo os

favoritos dos media…

MNC/05

E então ...

Como saber

Qual é a verdade

e

Qual não é ?

Explain the risks in a way that is

understandable....

Compare the risks of HRT with other

better known risks....

MNC/05

Increase

incidence

Relative

risk Risk factor

+ 20% 1 : 1.2 Physical activity – activate : inactive

+ 60% 1 : 1.6 Serum lipids – normal : raised

+ 30% 1 : 1.3 Alcohol consumption-none:≥20 g daily

+ 30% 1 : 1.3 Hormone replacement-never:5 or

more yrs

+ 10% 1 : 1.1 Oral contraceptives – never user:ever user

+ 40% 1 : 1.4 Age at first birth – 20 yrs : 35 yrs

+ 30% 1 : 1.3 Parity – multiparous : nulliparous

+ 30% 1 : 1.3 Age at menarche – 14 yrs: 11 yrs

+ 100% 1 : 2.0 Age at menopause - 42yrs : 52 yrs

+ 150% 1 : 2.5 Body weight-normal weight : obesity

BREAST CANCER

R. Santen, 2004

Exemplos de Risco Absoluto, Risco Relativo, Risco Atribuível

• Se comprar um número da lotaria, terá 1 oportunidade em um milhão de ganhar. (risco absoluto).

• Se comprar cinco números da lotaria, a oportunidade será cinco vezes maior, ou simplesmente 5 em um milhão.

• As oportunidades de ganhar aumentam 5 vezes, (risco relativo).

• A diferença entre os dois riscos é de 4 em um milhão (risco atribuível)

Risco atribuível, ou de excesso (que é o mais importante para a clínica)

A diferença entre o risco de

base, subjacente, e o risco após

receber TH é denominada

risco atribuível, ou de excesso.

Não confunda…

Risco Relativo com

Risco Absoluto !

Intervalo de Confiança (C.I.)

Um C.I. de 95% significa que há 95% de

probabilidades de que os “valores

verdadeiros” da população estejam entre

os dois limites.

Se o C.I. cruza a linha de “diferença

nula” ao ponto de que o benefício se

converta num risco (i.e.1), pode concluir-

se que os resultados não são

estatísticamente significativos.

Manson J et al. Menopause2006;13(1):139.147

Linha de diferença nula

Linha de diferença nula Linha de diferença nula

Linha de diferença nula

Efeito sobre o risco de

cancro da mama

WHI aumento do risco: RR 1.26 (CI 1.00-1.59); 26% aumento de risco


10.000 mulheres)


HERS aumento do risco: RR 1.27 (CI 0.84-1.94); 27% aumento de risco


10.000 mulheres)


Ao ler estudos

Epidemiológicos POR FAVOR !

Não leiam só os títulos…

Não leiam só os resumos…

Há que ler os artigos completos!!

Devemos ser críticos!

Devemos construir os nossos próprios

conceitos!

MNC

Assessment of the

understanding of the risks and

benefits of hormone

replacement therapy (HRT) in

primary care physicians

Williams RS, Christie D and Sistrom C.

Am J. Obstet Gynecol 2005;193:551-6

Respondents that overestimate the

increase or decrease in risk were making

the error of confusing relative risk with

absolute risk difference.

There is a great need for physician

education about the attributable

risks and benefits of HRT MNC/05

Strategies to help patients

understand risks

Paling J. BMJ 2003;327:745-8

Risks of women medicated with E+P (5.2 years)

women

Risks of women medicated with E only (6.8 years)

women

Risks of Breast Cancer

according to different factors

Podem reduzir-se

os efeitos secundários ?

There are no really “safe”

biological active drugs...

There are only “safe” physicians !

Kaminetzy HA 1993

“Aquele que aprende

mas não pensa

está perdido.

O que pensa mas não aprende

é perigoso…

Confucius

mas…

se aprendermos e

pensarmos…

nem estaremos perdidos

nem seremos perigosos

para as nossas doentes pós-

menopáusicas

Wenger NK. Am J Geriatr Cardiol 2000;9:204-9

A práctica Clínica…

Conhecer

a doença que uma mulher tem

é tão importante como

conhecer

a mulher que tem a doença

William Osler

Os médicos devem dar a

informação

a mulher deve acatar a

sua decisão

Os médicos devem dar a

informação

a mulher deve fazer o

que decidiu

Qual é o melhor tratamento ? • As necessidades e preferências da mulher são

decisivas baseadas no conselho do médico

• Não deve esquecer-se que apesar de haver muitos tratamentos hormonais disponíveis não são no entanto indispensáveis

• Os médicos têm o dever de dar a sua melhor informação independente às suas doentes de modo a que elas possam fazer as escolhas acertadas e assim aderir aos tratamentos

• A mulher é quem toma a decisão se o médico não vir contraindicações

• Portanto o melhor tratamento é aquele que a mulher escolher

MNC

I personally believe that for the healthy

early post menopausal woman the long term

HT’s, other than relieving vasomotor

symptoms, may play an important role in

improving QoL and in the prevention of

CVD, osteoporosis and Alzheimer, under

surveillance.

Systemic (parenteral) estrogens, added when needed to vaginal progesterone or progestagen loaded IUD’s, may be very beneficial, largely overpassing minimal risks.

MNC/05

The conclusions of the WHI trial suggest

that the “safe “ woman (NNH between 600-

1000 women) to initiate HT is

- between 50-59 years of age

- with vasomotor symptoms

- less than 10 years after the menopause

- being treated with statins

- with a good lipid profile and

- with a Body Mass Index >25

Neves-e-Castro M. Human Reproduction 2003;18:2512-2518

E...

que tal com os

produtos

“naturais” ?...

Evitar que uma Mulher

beneficie de uma correcta terapêutica hormonal

na pós-menopausa

pelo receio de raros efeitos secundários

não me parece ser uma Medicina satisfatória…

M.Neves-e-Castro, 2000

O que é que temos

aprendido sobre a

Menopausa ?

“Each time we learn something new,

the astonishment comes from the

recognition that we were wrong before.

In truth, whenever we discover a new fact, it involves the elimination of old ones.

WE ARE ALWAYS, as it turns out, fundamentally IN ERROR.”

Lewis Thomas English Biologist (1913-1993)

As convicções são inimigos

mais perigosos da verdade do

que as mentiras

Friedrich Wilhelm Nietzsche

What has been learned from the

major observational studies and

clinical trials?

the first lesson

systematically administered progestagens may in part suppress some of the beneficial effects of estrogens and may also slightly increase the risk of breast cancer after treatments with duration greater than five years.

MNC/05



clinical trials?

the second lesson

estrogens, when given alone to

histerectomized women, did not appear to

minimally affect the risk for breast cancer

when compared with controls

MNC/05



clinical trials?

the third lesson

Metabolic effects of estrogens and

progestagens, as a whole, can differ

depending on the route of administration, i.e.

oral vs. parentheral, and on the combination of

both, in a sequential regimen or in continuous

combined administration. MNC/05



clinical trials?

the fourth lesson

Hormonal treatments are the first

choice for vasomotor symptom relief as

long as they are needed (on and off

assessment). They should not be used for

the secondary prevention of CVD, when

atheroma plaques are already present. MNC/05



clinical trials?

the fourth lesson (cont.)

Conversely, they may protect from CVD if started early during the transition into the post menopause.

Hormonal treatments are preventive of osteopenia and osteoporosis at any stage in life

MNC/05

The take-home message is:

(1)

Prescribe postmenopausal hormonal treatments when clinically indicated, if not contraindicated!

MNC/02


(2)

The prescription of long-term hormonal treatments must depend always on a benefit/risk analysis in comparison with other non-hormonal medications and strategies. MNC/02


(3)

No answers from ongoing clinical trials are indispensable to practice today a good Medicine !

MNC/02

BENEFITS OF HORMONE THERAPY

• HT remains the most effective therapy for vasomotor and estrogen-deficient urogenital symptoms.

• Quality of life and sexuality are key factors to be considered in the management of the aging individual.

• The administration of individualized HT (including androgenic preparations when appropriate) improves both sexuality and overall quality of life.


Recommendations on postmenopausal hormone therapy

• There are no reasons to place mandatory limitations on the length of treatment.

• Whether or not to continue therapy should be decided at the discretion of the well-informed hormone user and her health professional, dependent upon the specific goals and an objective estimation of benefits and an objective estimation of benefits and risks.


IMS reaction to recent breast cancer data

The use of hormones in early menopause and up to age 60 years has a very minor potential for harm, but may carry substantial benefits. Women should decide annually if they wish to continue

with treatment after consultation with their caregivers.

Press statement of IMS.December 19, 2006.

The new American way …

or …

a 180º rotation ! … MNC/05

NAMS position statement on

estrogen and progestagen use in

peri-and postmenopausal women

No single trial should be used to set

public health policy. The practice of

medicine must ultimately be based on the

interpretation of the entire body of

evidence currently available, given that

there will never be adequate clinical

trials to cover all populations,

eventualities, and regimens.

NAMS position statement on

estrogen and progestagen use in

peri-and postmenopausal women

Place no limit on ET/EPT treatment

duration, provided it is consistent with

treatment goals; if monitored regularly, no

stipulation is made regarding when to

reduce or stop therapy

Key Points:

NAMS March 2007

Position Statement

on Hormone Therapy

The North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society. Menopause 2007; In press.

Copyright 2007

HT and Vasomotor Symptoms

Treatment of moderate to severe vasomotor symptoms (ie, hot flashes, night sweats) remains primary indication for systemic ET/EPT

With few exceptions, every systemic ET/EPT product is government approved for this indication

Copyright 2007 NAMS position statement. Menopause 2007.

EPT and Breast Cancer Risk

Breast cancer risk increases with EPT use beyond 5 years

Increased absolute risk in WHI is viewed as rare (4-6 additional invasive cancers/10,000 women/yr when use EPT for ≥5 yrs)

(cont’d)


ET and Breast Cancer Risk (cont’d)

Women in WHI’s ET arm had 8 fewer cases of invasive breast cancer/10,000 women/yr of ET use

Available evidence suggests ET for <5 yr has little breast cancer risk impact

Limited observational data suggest ET for >15 yr may increase risk


3rd International Symposium of the

Portuguese Menopause Society In Celebration of the World Menopause Day

The Transatlantic Controversies - The State of the Art October 23, 2004 Fundação Engº António Almeida Oporto – Portugal

A equipe U.S.A.

1 2 3 4

1. R. Chlebowski 2.J.Rossow 3. R. Lobo 4. Th.Clarkson

A equipe Europeia

1. D.Barlow 2. H. Kuhl 4.P.Kenemans 4. A.Pines

1 2 3 4

As estrelas da Menopausa !

1 2 3 4

5 6 7 8 9 10 11 12

13

14 15

1.D.Barlow, 2.H.Kuhl, 3.P.Kenemans, 4.A.Pines, 5 F.Al-Azzawi, 6.J.Rossouw,

7.J.Stevenson, 8.R.Chlebowski, 9.S.Palacios, 10.Th.Clarkson, 11.M.Sousa,

12.M.Neves-e-Castro, 13.A.Genazzani, 14.J.Calaf, 15.R.Lobo

3rd International Symposium of the

Portuguese Menopause Society In Celebration of the World Menopause Day

The Transatla Algumas das

NCLUSÕES ntic Controversies - The State of

the Art October 23, 2004 Fundação Engº António Almeida Oporto – Portugal

CONCLUSÃO

KEEPS

Kronos Early Estrogen Prevention Study

estudo em curso em mulheres sintomáticas até 10 anos após a menopausa

Rexrode K and Manson J. Circulation 2007;115:820-2

ELITE

Early vs. Late Intervention Trial with Estradiol

estudo em curso

Não há melhor tratamento para

os sintomas do climatério do

que os tratamentos hormonais

•Se és um clínico tens que acreditar que

sabes o que ajuda os teus doentes.

Caso contrário não podes nem aconselhar

nem receitar.

•Porém, se és um cientista tens que ter incertezas: um cientista que deixa de fazer perguntas é um mau cientista…

George Pickering;”Physician and scientist” Br.Med.J. 1964;2:1615-9

UMA MULHER

no Outono da sua vida

merece um Verão de S.Martinho

em vez de um triste Inverno

Greenblatt

Como

concluir ?...

Este não é o fim, nem sequer o princípio do fim,

mas talvez seja

o fim do princípio ...

Winston Churchill

Esperando por mais...

IV Simpósio Internacional

da Sociedade Portuguesa de Menopausa

The Improvement of

Health and Disease Prevention

for the Mid-aged Woman:

The State of the Art

20 Outubro 2007

Lisboa . Portugal

Pestana Palace Hotel

visite o nosso website www.spmenopausa.pt em 4th International Symposium

Sociedade Portuguesa de Menopausa

Av. Almirante Reis nº 62 – 1º Esq.

1150-020 Lisboa - Portugal

Telf: (+351) 21 3174356 – (+351) 93 6016522 Fax: (+351) 21 3156658

e.mail: [email protected]

Hotel venue:

Pestana Palace – Hotel e Monumento Nacional

www.pestana.com

Participantes, até 31 Maio 2007:

Sócios da SPM e EMAS: € 200,00

Não - Sócios: € 250,00

Participantes, a partir de 31 Maio 2007:

Sócios da SPM e EMAS: € 250,00

Não - Sócios: € 300,00

Inscrições

Para mais informação:

que vão encontrar aqui !

http://www.spmenopausa.pt/

http://www.pestana.com/

IV Simpósio Internacional

da Sociedade Portuguesa de Menopausa Mário de Sousa – President e da SPM

Lisboa . Portugal, Pestana Palace Hotel, 20 Outubro 2007

The Improvement of Health and Disease

Prevention for the Mid-aged Woman:

The State of the Art Manuel Neves-e-Castro – Symposium Chairman

Speakers (confirmados):

D. Sturdee (UK): “The hot Flush”;

P.van der Weijer (NL): “Risks of HRT in the 50-59 year age group”;

R. Lobo (USA): “Metabolic Syndrome after menopause and the

role of hormones”

Anne Gompel (FR): “Hyperinsulinemia, obesity and the risk of breast

cancer”;

D. Herrington (USA): “Postmenopausal heart disease prevention: Why

the cardiologists have it all wrong?

J.C.Gallagher (USA): “The role of rank L in postmenopausal bone loss

and arthritis: Treatment options”;

F. Naftolin (USA): “Molecular factors in maintenance of the pelvic

floor in menopausal women”;

C.Castelo-Branco (SP): “Definition and diagnosis of sexuality in the 21rst

century: New horizons”

Chairmen: Lucas Viana Machado (Brasil) and Morris Notelovitz (USA) (Todas as sessões serão em Inglês)

terminei !... e…

este... já pode acordar…

Obrigado …

…por não terem ressonado !

Documents

A PRIMAVERA VEM AÍ… proferidas/Slides 2007/… · populações, e a confusão de riscos relativos com riscos absolutos! WHI and breast cancer Once again, it is apparent that the