1. Terapeuticas hormonais
são ou não
Preventivas de DCV da mulher?
Manuel Neves-e-Castro
(Sociedade Portuguesa de Menopausa)
Janeiro 2002
2. White woman’s risk of death between
After all of 50 and 94 are:
the ages ...
“Only 20% of women who start
HRT seemfrom heart disease
31.0% to continue treatment
after 4 years”. breast cancer
2.8% from
2.8% from hip fracture
Pilon D, Castilloux A, Le Lorier J. Obstet Gynecol
Brinton LA, Schairer C. N Engl J Med.1997;336:1769-1775
2001;97:97-100.
3.
4.
5.
6.
7.
8.
9. Estrogens and Lipids
Favorable effects through the liver:
- inibition of lipoprotein lipase
- stimulation of the production of HDL –C
- stimulation of the synthesis of Apo-A¹
- stimulation of the uptake of LDL-C
- stimulation of the uptake of chylomicrons
- increased secretion of VLDL
- increased secretion of bile acids
- increased triglycerides (slight)
11. Lipid-lowering therapy promotes
clinically stable plaque
- Prolonged intensive lipid-lowering therapy is
associated with a markedly decreased lipid
content in carotid atherosclerotic plaques
- The clinical implication of this is that the low
plaque lipid composition would predict greater
plaque stability, and would thus reduce clinical
ischemic events such as myocardial infarction or
stroke.
Zhao X-Q et al. Arterioscler Thromb Vasc Biol 2001;21:1623-1629,1563-
1564 (October)
12.
13. Estrogens, Lipids and Vascular System
The majority of the positive effects on the
vascular system are non-lipid related
14.
15.
16.
17.
18.
19.
20. Estrogens and Vascular System
Estrogen may positively influence all the
steps involved in the formation of the
atherosclerotic plaque (accumulation of
cholesterol in the arterial wall, arterial
smooth muscle cell proliferation, platelet
aggregation, collagen and elastin
production)
21.
22.
23. “The HERS trial”
Letter to the Editor
Neves-e-Castro M.Climacteric 1999;2:59
24.
25. “On the basis of data from
randomized clinical trials,
hormone-replacement therapy
does not appear to reduce the risk
of cardiovascular events in
women with established coronary
heart disease”.
Manson JA, Martin KA
N Engl J Med.2001;345:34-40
26. “The Effect of Treatment with Estradiol
and Norethisterone Acetate on
Exercise Tolerance and on the
Frequency and Severity of Ischemic
Attacks in Postmenopausal Women
with Stable Angina Pectoris”.
Sanderson JE et al.J Cardiovasc Pharmacol 2001;38(3):372-383
27. Estrogens and Vascular System
“The total number of ischemic events/24 h
during ambulatory electrocardiographic
monitoring decreased by 0.82 events after
treatment compared with an increase in the
placebo group (0.94), a highly significant
difference (p=0.006)”.
Sanderson JE et al.J Cardiovasc Pharmacol 2001;38(3):372-383
28. “This particular combined hormone
replacement preparation may have a
beneficial effect on myocardial
ischemia in postmenopausal women
with established coronary disease”.
Sanderson JE et al.J Cardiovasc Pharmacol 2001;38(3):372-383
29. “Reduced risk of cardiovascular
events even within the first year of
HRT in a retrospective case-
control study of 1200 women with
myocardial infarction compared
with 5000 controls”.
Varas-Lorenzo C, Garcia-Rodriguez LA. Perez-Gutthann S, et al
Circulation 2000;101:2572-2578
30. “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
31. “CEE + MPA appeared to have a
more favorable effect in women
with high initial lipoprotein (a)
levels than in women with low
levels”.
Shlipack MG, Simon JA, Vittinghoff E, et al
JAMA 2000;283:1845-1852
32.
33. “The Nurse’s Health Study
investigation of primary prevention
indicates that hormone therapy
may be associated with coronary
benefits”.
Grodstein F, Manson JE, Colditz GA, et al. Ann Intern Med
2000;133:933-41
34. “Combined hormone replacement
therapy improves endothelial
function in healthy post-
menopausal women”.
Gužič-Salobir B, Keber I, Seljeflot I, et al
J Intern Med 2001;250:508-515
35. “When are observational studies
adequate evidence”?
Grady D. and Hulley SB. Ann Intern Med
2000;133:999-1001
36. “The Queen ... is naked!”
Critical Comment
Neves-e-Castro M..Maturitas 2001;38:235-237
37. “The HERS Study, as interpreted by
a practitioner, is nothing but a
phase III Study of a particular
product (0.625 mg of conjugated
equine estrogens plus 2.5 mg of
medroxyprogesterone acetate, in
one tablet daily)”.
Neves-e-Castro M. Maturitas 2001;38(3):235-237
38. “The protocol of the study does
not reflect good clinical
practice”.
Neves-e-Castro M. Maturitas 2001;38(3):235-237
39. “The higher rate (thrombotic
events) is probably a
consequence of the facts that
women involved in HERS were
older and had multiple risk
factors”.
Hulley S, Grady G, Bush T, et al. JAMA 1998;280:605-13
40. “HRT decreased or increased
atherothrombosis depending on
the presence of factor V Leiden
mutation”
Glueck CJ, Wang P, Fontaine RN, et al
Am J Cardiol 1999;84:549-554
41.
42. “Primary CHD occurred only in
172 of the 1380 women in the
hormone group and in 176 of the
1383 women in the placebo
group”.
Hulley S, Grady G, Bush T, et al. JAMA 1998;280:605-13
43. “For women who stopped taking HERS
medication, the risk of primary CHD
events was elevated in the first month
after stopping use of the medication”?!
ulley S, Grady G, Bush T, et al. JAMA 1998;280:605-13
44. “The RH comparing risk of the
primary CHD outcome in the
hormone and placebo group was
similar”.
Hulley S, Grady G, Bush T, et al. JAMA 1998;280:605-13
45. “Total mortality in the hormone
group was not significantly
different from that in the
placebo group (131 vs. 123
women)”.
Hulley S, Grady G, Bush T, et al. JAMA 1998;280:605-13
46. “HERS did not evaluate the effect of
estrogens plus progestin therapy, in
women without CHD, and it is not
known whether our findings apply
to healthy women. It is also not
known whether the use of different
progestin or of estrogens alone
would have been beneficial”.
Hulley S, Grady G, Bush T, et al. JAMA 1998;280:605-13
47. “The discrepancy between the
finding of HERS and the
observational studies may also
reflect important differences
between the study populations
and treatments”.
Hulley S, Grady G, Bush T, et al. JAMA 1998;280:605-13
48. “Perhaps post-menopausal
hormone therapy is beneficial in
women who have not yet
developed coronary disease but
not in women who already have
it”.
Grady D, Hulley SB. Ann Intern Med 2000;133:999-1001
49. “Numerous observational studies
have reported lower CHD rates in
postmenopausal women receiving
estrogen than in those who did not”.
“The strongest association was in
postmenopausal women with CHD;
estrogen users had 35% to 80%
fewer recurrent events than
nonusers”.
LaRosa JC-Circulation 2001;104:1688-1692
50. Vascular benefits of HRT limited to
women without atherosclerosis
“Estrogen may be more effective
for maintenance of vascular
health than it is for treatment of
established vascular disease”.
Herrington DM et al;Arterioscler Thromb Vasc Biol
2001;21:1867-1869,1955-1961
51. “Early intervention in the
progression of atherosclerosis,
especially at the start of
menopause, may be the key to
successful prevention of
cardiovascular disease with
HRT”.
Hodis HN, Mack WJ, Lobo RA, et al
Ann Intern Med. 2001;135:939-953
52. “The average rate of progression
of subclinical atherosclerosis was
slower in healthy postmenopausal
women taking unopposed ERT
with 17ß-estradiol than in women
taking placebo”.
Hodis HN, Mack WJ, Lobo RA, et al
Ann Intern Med. 2001;135:939-953
53.
54. “The risk for major coronary events
was lower among current users of
hormone therapy, including short-
term users, compared with never
users [(relative risk, 0.61 (95% CI,
0.52-0.71)]”.
Grodstein F. et al.Ann Intern Med 2000;133:933-41
55. “The findings of HERS should not
discourage the use of hormone
replacement therapy in the primary
prevention of cardiovascular
disease”.
Tolbert T. and Oparil S. Circulation 2001;103:620-2
56. Editorial
The time has come to stop letting the
HERS Tale Wag the Dogma
Michael E. Mendelson,; Richard H. Karas,
Circulation 2001;104:2256-2259
57. “We believe there has been
enormous overinterpretation and
misinterpretation of recent
clinical data (the HERS tale) with
regard to the efficacy of hormone
replacement therapy (HRT) in
preventing or diminishing the risk
of heart disease (the dogma)”.
58. “Hormone Replacement Threrapy
and Cardiovascular Disease”.
A Statement for Healthcare Professionals
From the American Heart Association.
Mosca L et al;Circulation.2001;104:499-503
59.
60. “Hormone Replacement Therapy and
Cardiovascular Disease”.
“There are insufficient data to suggest that
HRT should be initiated for the sole (?)
purpose of primary prevention on CVD”
(Circulation 2001)
61. “Hormone Replacement Therapy and
Cardiovascular Disease”.
The majority of data available to make clinical
recommendations are based on standard doses of
oral CEE/MPA. Evidence is insufficient to determine
whether different perparations, routes of delivery,
doses, or different progestins have a more favorable
or more adverse effect on clinical CVD end points”
(Circulation 2001)
62. “Hormone Replacement Therapy and
Cardiovascular Disease”.
“In conclusion, recommendations such as
these of the AHA (Circulation 2001),writen as they
are, may be less helpful than intended, both
for clinicians and women”.
Neves-e-Castro M.The ImaginaryWoman, Maturitas 2001;40:8-9
63.
64. “All medical interventions
should be individualised to the
specific woman’s age,
characteristics and needs”.
Genazzani AR, Gambacciani M. IMS Expert Workshop,
Climacteric 2000;3:233-240
65. The important issue, after all, is
not HRT.
What is important is the best
possible approach to preventive
medicine in a middle aged-
woman.
Neves-e-Castro M.(2000)
66. “It appears that half of the
benefits in the prevention of
cardiovascular diseases are not
hormone related”!
Mosca L, Grundy SM, Judelson D, et al. Circulation
1999;99:2480-4
68. “When hormone replacement
therapy is not possible”
Neves-e-Castro M in “The Management of the Menopause” The
Millennium Review 2000” Ed.John Studd; Parthenon, NY 2000
69. “Every discussion about the
Menopause (the Queen...) seems to
implicate that there is nothing but
HRT!”
Neves-e-Castro M. Maturitas 2001;38(3):235-237
72. The take home message
The prescription of long-term
hormonal treatments must depend
always on a benefit/risk analysis in
comparison with other non-hormonal
medications and strategies.
73. Preventing a woman from the
benefits of a sound
postmenopausal hormone
therapy because of the fear
of rare side effects does not
seem to be satisfactory
Medicine...
MNC 3/01
75. A Woman
in the autumn of her life
deserves an indian summer
rather than a winter of a discontent ...
Robert B Greenblatt
Editor's Notes
Suggested Main Points: 1) In women, the process of atherosclerosis begins early in life, and is possibly accelerated by the loss of estrogen at menopause. In this study, 2 measures of carotid atherosclerosis were examined by carotid ultrasound. 1 These parameters included intima-media thickness (IMT) and the presence of focal plaques. IMT has gained significant validity as an indicator of future cardiovascular events, both coronary and cerebrovascular. 2) The study population included premenopausal women who were 44 to 50 years of age as well as women who were 5 to 8 years beyond menopause. The data suggest that subclinical carotid atherosclerosis is present in relatively young women both before and after menopause. Given the fact that progression is associated with estrogen loss, it is important to effect lifestyle changes and therapeutic interventions that reduce cardiovascular risk. 3) The study also analyzed several risk factors for an independent association with the 2 parameters. The factors that were the strongest predictors follow: Predictors for intima-media thickness Predictors for focal plaques • Higher pulse pressure P <0.001 • Higher pulse pressure P = 0.028 • Triglycerides P <0.002 • Higher LDL P = 0.003 • Body mass index P <0.001 • Smoking P = 0.002 Reference: 1) Sutton-Tyrrell K, Lassila HC, Meilahn E, Bunker C, Matthews KA, Kuller LH. Carotid atherosclerosis in premenopausal and postmenopausal women and its association with risk factors measured after menopause. Stroke. 1998;29:1116-1121.
Suggested Main Points: 1) Demonstration that HRT may be effective primary prevention for CHD also comes from a recent study that used electron beam tomography as a measure of plaque volume. 1 Electron beam tomography is a noninvasive technique that can be used to measure coronary artery calcium. And although coronary artery calcium is a late manifestation of coronary atherosclerosis, it correlates with plaque volume. Reference: 1) McLaughlin VV, Hoff JA, Rich S. Relation between hormone replacement therapy in women and coronary artery disease estimated by electron beam tomography. Am Heart J. 1997;134:1115-1119.
Suggested Main Points: 1) Effect of HRT vs placebo on primary outcomes: 1 RR 95% CI Total CHD events 0.99 0.8-1.22 CHD deaths 1.24 0.87-1.75 Nonfatal MI 0.91 0.71-1.17 2) Women who were administered HRT had an increased risk of a second CHD event during the first year compared with those administered placebo. It should be noted that both of these groups had incidence rates below 5%, which was the rate used in designing the study to estimate the number of subjects needed for the predetermined statistical power. 3) A significant reduction in relative risk (RR) of a second CHD event from the first year to the fourth and fifth years with HRT was indicated by time trend analysis ( P = 0.009). 4) In the placebo group, the number of second CHD events was lower during the first year compared with the number in the remaining years of study. Reference: 1) Hulley S, Grady D, Bush T, et al for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605-613.
