This is a compilation from a number of studies, including randomized trials, whose findings differ from the conclusions in the WHI trials about Cardiovascular Risk.
based on the excellent review article: "Rise and Fall" of hormone therapy in postmenopausal women with cardiovascular disease Angela HEM Maas MD, Yvonne T Van der Schouw PhD,
Diederick E Grobbee MD PHD, Yolanda van der Graaf MD PhD,
Menopause, Vol.11, No. 2, 2004, p228-235
Effects of Hormones on Lipid and Vascular Physiology
Estrogens (ET)
Oral ET inhibits cholesterol synthesis in the liver
Oral ET inhibits LDL cholesterol oxidation and penetration into the vessel wall (necessary for plaque formation)
Oral ETincreases Triglycerides and VLDL cholesterol, with unclear clinical significance
Oral ET causes a two-fold rise in CRP, but the clinical significance of this is unclear
assumed that CRP levels promote vascular inflammation and plaque instability
Progestin has no affect on CRP level increase with estrogen (PEPI)
Transdermal estrogens improves lipoprotein parameters less than than oral (first pass effect)
Estrogen causes vasodilation by rapid activation (5-20min) of nitric oxide synthesis in endothelial cells
IV estrogen causes this in healthy women as well as women with atherosclerotic disease
PO estrogen appears to have same effect in animal models, but some trials fail to show an effect in women (see HERS, PHOREA trials)
Animal Studies (ET)
in monkeys ET inhibits vascular plaques after oopohorectomy (loss of hormones)
in monkeys, ET started after two years gave no vascular protection
in rats, with carotid intima damage, estrogen inhibits intima hyperplasia and smooth muscle proliferation (parts of plaque formation) only when given in the early stages of endothelial damage. After 3 days there was no benefit.
in pigs, percutaneous cardiac stents had lower rates of re-stenosis with decreased neointima proliferation when coated with 17beta estradiol
animal studies show protective effects of estrogen against the development of cardiac hypertrophy, which is increased in older women
Observational Studies of Hormone Therapy (HT)
generally indicate HT reduces cardiac risks by 35-50%
different preparations were used in the different studies with different dosing, so hard to compare
studies used different age groups, so hard to compare
support the hypothesis that estrogen has a beneficial effect in the early stages of atherosclerotic disease and vascular wall repair
support the hypothesis that longer exposure to endogenous estrogens protect against cardiovascular disease (CVD)
for each year's delay in the onset of menopause, the cardiovascular mortality decreases by 2%.
appear mediated by estrogen alpha and beta receptors
Framingham Heart Study (1976) and Nurses' Health Study (1987)
increase in cardiovascular disease in young women after bilateral oophorectomy (removal of ovaries which produce estrogen and progesterone), a risk that did not occur in women using hormone therapy (HT) after surgery.
Nurses' Health Study (HT 2001)
subgroup analysis shows a cardiac risk reduction of (-35%) among current HT users with up to 20 years of followup
subgroup analysis shows a cardiac risk increase in the first year only (+25%) , however no increase in mortality
After PTCA, elective percutaneous transluminal coronary angioplasty (1997)
current users of HT show fewer cardiovascular events (12% vs 35%)
current users of HT show better survival (93% vs 75%)
After Coronary Bypass surgery (1997)
chronic HT use was associated with significantly improved 5-year survival compared to never users
After Recent MI (2001)
starting Estrogen(ET) increased the incidence of unstable angina, death and reinfarction
compared to chronic or never users
attributed to proinflammatory and thrombogenic effects of ET
[ISLT] Dont start ERT until heart damage has been stabilized.
After First MI (2002), unopposed 17beta-estradiol had no effect on the frequency of reinfarction or cardiac death after two years of treatment, but the study had low power due to non-compliance.
Randomized Trials
CVHS trial
Cardiovascular Health Study (2001)
HT affected only arteries of healthy women
over age 80 had no effect on brachial artery flow
suggests that healthy endothelium responds to estrogens, damaged endothelium does not
suggests that estrogen may be more important in maintaing vascular health than in treating damage
EPAT trial
Estrogen and Prevention of Atherosclerosis Trial (2001)
showed that 17beta-estradiol slowed vascular intima thickening
Statins and Estrogens had equal, non-additive beneficial effects
ERA trial
Estrogen Replacement and atherosclerosis Trial (2000)
continuous CEE0.625mg with and without MPA2.5mg
no differences in coronary vessel diameter or clinical outcomes
postmenopausal for average 20 years
HERS trial
Heart and Estrogen/progestin Replacement Study (1998)
advanced mean age (67 years)
83% of participants were receiving aspirin or other antiplatelet agents at entry
33% were receiving beta-blockers, and 53% were receiving lipid-lowering drugs.
18% were receiving angiotensin-converting enzyme inhibitors
Women in the studywith more risk factors were less likely to be taking aspirin (P<0.001) and lipid-lowering drugs (P=0.006).
Coronary Events
No benefit of combined continuous CEE0.625mg/2.5mgMPA in preventing CHD after 4.1 years nor when extended to 6.7 years of follow-up (HERSII)
Increase of coronary events in the first year of treatment by 50%
Statins
No increase risk for women who were on Statin therapy (note EPAT trial results for Statins)
Statin baseline use reduced risk to no statistical significance (HR=1.34, 95%CI=0.63-2.86, p=0.45)
Statins prevent the rise in CRP levels caused by estrogen monotherapy
Aspirin had equal improvement to Estradiol for vascular intima in EPAT, so if on Aspirin might expect a reduced effect of Estrogen (non-additive) in HERS
Role of Aspirin not well defined in HERS
Assumption is that HT destabilizes plaques (increased lysis), and Statins stabilize plaques
Venous thromoboembolism (VTE)
VTE risk was higher in the hormone group(HR=2.7, CI=1.4-5.1, p= 0.003)
Statin or Aspirin
use wiped out increased VTE risk equally
Statins lowered rates of VTE by 50% with or without HT(HR=0.40, 95%CI=0.18-0.91 multivariate)
Aspirin lowered rates of VTE by 50%
VTE risk decreased over time (from HERSI to HERSII)
so non-significant difference in later years after more exposure
Other factorsincreased VTE risk more:
VTE was increased by lower-extremity fractures (HR=18.1,CI=5.4 to 60.4)
VTE was increased after nonsurgical hospitalization (HR=5.7, CI=3.0 to 10.8)
VTE was increased in the first 90 days after inpatient surgery (HR=4.9, CI=2.4 to 9.8)
VTE was increased by a diagnosis of cancer (HR=3.9, CI= 1.6 to 9.4)
[ISLT] need to control HRT studies for Aspirin, Statin and Estrogen exposure
PEPI trial
Postmenopausal Estrogen/Progestin Interventions Study (1999)
*****Oral Estrogen alone or in combination with Progestinnormalized lipoprotein levels to premenopausal levels
Medroxyprogesterone acetate (MPA) attenuated the improved lipid levels with estrogen (-75%)
but there were no detrimental effects from this attenuation
micronized progesterone also attenuated but less (-30%)
LDL levels decreased in all treatment groups
both continuous or cyclic therapy
Oral Estrogen increases CRP serum levels
MPA (medroxyprogesterone acetate) and micronized progesterone had no effect on CRP (continous or cyclic)
there were no changes in BP or insulin level between the groups
fibrinogen was slightly decreased in treatment groups
two-hour post challenge glucose increased in the CEE plus medroxyprogesterone acetate (cyclic and continuous) groups but was unchanged in CEE alone and CEE plus MP groups
Estrogen, with or without progestogen, was associated with a lower weight gain
PHOREA trial
Postmenopausal Hormone Replacement Against Atherosclerosis (2001)
48 week treatment with 17beta-estradiol with and without progestin
progressive increase of carotid intima was not slowed with any hormone treatment
Estrogen with or without progestin decreased LDL and Fibrinogen serum levels however (improvement)
WEST trial
Women's Estrogen for Stroke Trial (2001)
oral estrogen only (no progestin) given after ischemic stroke or TIA
mean age 71 years
mean follow-up of 2.8 years (short term study)
oral 17beta estradiol did not have a beneficial effect on transient ischemic attack or stroke
increase in recurrent stroke or mortality in first 6 months only (HR 2.3, 95%CI=1.1-5.0, with poorer outcomes)
findings at 2.8 yearslost statistical significance
Stroke or Death (HR=1.1, CI=0.8-1.4 NS)
Death alone (HR=1.2, CI=0.8-1.8 NS)
Non-fatal stroke (HR=1.0, CI=0.7-1.4 NS)
Fatal stroke (HR=2.9, CI=0.9-9.0 NS)
WHI trial
Women's Health Initiative (2002, 2004)
Women in this study were older, well past menopause, without hormones for many years before entering the study
showed a two fold increase in thromboembolic events
thromboembolic events for both PE and DVT combined
PE (Pulmonary Embolism) increase is non-significantleaving only DVT (Deep Vein Thrombosis) contribution when corrected for multiple testing
increase is in non-fatal events
would expect to see an increase in mortality with such an increase incidence of thromboembolic events
not controlled for Statin and Aspirin use, believed to counter VTE risk (more use in Placebo group identified)
contrast the Estrogen+Progestin and Estrogen Arms; note problems with statistical significance
indicates that early intervention is a factor in the prevention of atherosclerosis and endothelial damage
randomized initially to treatment group, but not well controlled as to actual treatment exposure and outcome group
WHI-OS trial
Women's Health Initiative Observational Study (nested case-control, still on-going)
HT significantly elevates CRP
HT does not elevate other inflammatory markers (interleukin-6)
Total levels of inflammatory biomarkers (not just CRP) seem to be important in predicting coronary risk
Suggests that other factors than HT are involved in inflammatory states that increase risk of early cardiovascualr events
Other Data
SERMS (Selective Estrogen Receptor Modulators)
treats osteoporosis
may reduce the incidence of breast cancer
decrease LDL, but no change in HDL, TRIG
decreased LipoproteinA, fibrinogen, homocysteine
no change in plasminogenactivator inhibitor-1, CRP
venous thromboembolism risk similar to oral estrogen
MORE trial
Multiple Outcomes of Raloxifene Evaluation trial (retrospective)
no early increase in first year, 40% reduction after 4 years of treatment
older population
RUH trial
Raloxifene Use for the Heart Randomization trial (randomized)
currently underway
References
"Rise and Fall" of hormone therapy in postmenopausal women with cardivascular disease, Angela HEM Maas MD, Yvonne T. Van der Schouw PhD, Diederick E Grobbee MD PHD, Yolanda van der Graaf MD PhD,
Menopause, Vol.11, No. 2, 2004 p228-235
Postmenopausal Hormone Therapy Increases Risk for Venous Thomboembolic Disease
The Heart and Estrogen/progestin Replacement Study, Deborah Grady, MD, MPH; Nanette K. Wenger, MD; David Herrington, MD, MHS; Steven Khan, MD; Curt Furberg, MD; Donald Hunninghake, MD; Eric Vittinghoff, PhD; and Stephen Hulley, MD, MPH, for the Heart and Estrogen/progestin replacement Study Research Group,
Annals of Internal Medicine, 2 May 2000, Vol 32, Issue 9, p689-696
Risk Factors and Secondary Prevention in Women with Heart Disease: The Heart and Estrogen/progestin Replacement Study, Eric Vittinghoff, PhD; Michael G. Shlipak, MD, MPH; Paul D. Varosy, MD; Curt D. Furberg, MD, PhD; Christine C. Ireland, MPH; Steven S. Khan, MD; Roger Blumenthal, MD; Elizabeth Barrett-Connor, MD; and Stephen Hulley, MD, MPH, for the Heart and Estrogen/progestin Replacement Study Research Group
Annals of Internal Medicine, 21 January 2003, Vol 138, Issue 2, p81-89
