The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. part 1: comparison of therapeutic efficacy
The Timing Hypothesis and Hormone Replacement Therapy:A Paradigm Shift in the Primary Prevention of Coronary HeartDisease in Women. Part 1: Comparison of Therapeutic Efficacy
Howard N. Hodis, MD,*†‡ and Wendy J. Mack, PhD*‡
:The long-held belief that outcome data from interven-
Sex-Specific Primary Prevention Therapy: Statins and
tion trials in men are generalizable to women has cre-
ated the framework in which the primary prevention ofcoronary heart disease (CHD) in women is viewed, but
3-hydroxy-3-methylglutaryl coenzyme A reductase
over the past decade, data have accumulated to refute
such a supposition of generalizability. These lines ofevidence concern the sex-specific efficacy of CHD pri-
Statins are the most commonly used medications for
mary prevention therapies and timing of postmeno-
lipid lowering and for the primary prevention of CHD
pausal hormone replacement therapy (HRT) initiation
in women and men. The prevailing belief is that statins
according to age and time since menopause as modifiers
reduce CHD events and mortality under primary and sec-
of efficacy and risk. Although the standard primary pre-
ondary prevention conditions in women and men. How-
vention therapies of statins and aspirin reduce CHD in
ever, careful examination of randomized control trial
men, neither therapy reduces CHD and, more impor-
(RCT) data does not provide clear evidence that statins
tantly, mortality in women under primary prevention
reduce CHD events or total mortality in women under pri-
CHD and mortality in primary prevention when it is
In the first large meta-analysis of RCTs of statin ther-
initiated in women who are younger than 60 or are
apy in which primary (six RCTs; n = 11,435 women) and
less than 10 years since menopause. Herein, the efficacy
secondary (eight RCTs; n = 8,272 women) CHD preven-
of the commonly used therapies for the primary preven-
tion trials were analyzed separately in women, the data
tion of CHD in women, statins, aspirin, and postmeno-
support a significant reduction in CHD events (hazard
pausal HRT is discussed. The comparative risks of
ratio (HR) = 0.80; 95% confidence interval (CI) = 0.71–
these therapies will be discussed in Part 2 of this series.
0.91) but not in total mortality (HR = 1.00, 95%
CI = 0.77–1.29) in women under secondary preventionconditions, although neither CHD events (HR = 0.89,
95% CI = 0.69–1.09) nor total mortality (HR = 0.95,
95% CI = 0.62–1.46) was reduced in women under pri-
In the first sex-specific meta-analysis to analyze pri-
mary CHD prevention trials independently from secondaryprevention trials, statin therapy reduced CHD in men butnot in women under primary prevention conditions,2 evenwith inclusion of the Management of Elevated Cholesterolin the Primary Prevention Group of Adult Japanese(MEGA) trial in which 5,356 women were enrolled and
From the *Atherosclerosis Research Unit, University of Southern
followed for more than 5 years.3 Statin therapy did not
California, Los Angeles, California; †Department of Medicine, Keck
significantly reduce total mortality in women or men under
School of Medicine, University of Southern California, Los Angeles,
primary prevention conditions (Table 1).2 These results
California; and ‡Department of Preventive Medicine, Keck School ofMedicine, University of Southern California, Los Angeles, California.
were confirmed in another sex-specific meta-analysis ofstatins and CHD prevention4 (Table 1) that included
Address correspondence to Howard N. Hodis, Harry J. Bauer andDorothy Bauer Rawlins Professor of Cardiology, Atherosclerosis Research
RCTs conducted in individuals with diabetes mellitus with-
Unit, Keck School of Medicine, University of Southern California, 2250
out a history of cardiovascular disease (CVD), as well as
Alcazar Street, CSC 132, Los Angeles, CA 90033. E-mail: athero@usc.edu
in MEGA and the Justification for the Use of Statins in
2013, Copyright the AuthorsJournal compilation 2013, The American Geriatrics Society
trials does not alter the conclusion that statin therapy has
Table 1. Comparison of Statin Therapy on Coronary
a null effect on CHD events and total mortality in primary
Heart Disease and Total Mortality in Primary Preven-
The sex-specific efficacy of primary prevention of CHD
reported for statins is concordant with that of aspirin ther-
apy.8 In meta-analyses of primary CHD prevention trials,
aspirin significantly reduced MI by approximately 32%
with a null effect on stroke in men, whereas in women,
aspirin had a null effect on MI but significantly reduced
ischemic stroke by approximately 17%.8,9 In women and
men, aspirin therapy has a null effect on total mortality
under primary CHD prevention conditions. Consistent
with statin therapy, the null effect of aspirin therapy on
CHD extends to high-risk women with diabetes mellitus
without a history of CVD. In the Japanese Primary Preven-
tion of Atherosclerosis with Aspirin for Diabetes (JPAD)
trial, the largest RCT of aspirin therapy and primary CHD
prevention in individuals aged 30 to 85 with type 2 diabe-tes mellitus (1,152 women), the effect of aspirin therapy
HR = hazard ratio; CI = confidence interval.
on CHD was null relative to placebo (relative risk(RR) = 0.88, 95% CI = 0.53–1.44) after a median treat-
Prevention: An Intervention Trial Evaluating Rosuvastatin
ment of 4.4 years.10 The consistency across individual pri-
(JUPITER), another primary CHD prevention RCT with a
mary CHD prevention trials and sex-specific meta-analyses
large cohort of 6,801 women.5 Even though this meta-
show no evidence that aspirin therapy reduces CHD events
analysis included a greater number of women at greater
or total mortality in women without preexisting CVD,
risk for CHD than the previous meta-analyses, the risk
including those with diabetes mellitus who are at high risk
reduction reported for CHD in women was statistically
of CHD. The sex-specific nature of CVD benefits restricted
nonsignificant, and total mortality was no different than in
to men under primary prevention conditions is seen with
other interventions such as angiotensin-converting enzyme
As the consistency across individual primary CHD
inhibitor therapy, with men having less CVD and mortal-
prevention trials and sex-specific meta-analyses shows,
there is no clear evidence that statins reduce CHD eventsor total mortality in women without preexisting CVD. Theone possible exception is JUPITER in which the primary
Timing of Initiation of Postmenopausal HRT
trial endpoint for CHD was lower (HR = 0.54, 95%CI = 0.37–0.80)5 in women but JUPITER was stopped
early, after a median follow-up of 1.9 years, and it is
Over the last decade, cumulated data from RCTs of HRT
unclear whether findings from JUPITER were due to the
clearly demonstrate two distinct populations of women
unique characteristics of the cohort (women aged 60
who respond differentially to HRT according to timing of
with low-density lipoprotein cholesterol <130 mg/dL and
HRT initiation relative to age and time since menopause.13
high-sensitivity C-reactive protein 2 mg/dL),5 the trial
Specifically, CHD events and total mortality benefits occur
biases and flaws6,7 or to the subjective nature of certain
when HRT is initiated in younger women (<60) in close
components of the primary endpoint.5 The JUPITER pri-
proximity to menopause (<10 years since menopause) and
mary cardiovascular endpoint was a composite comprising
a null and possible adverse effect when initiated in older
“hard endpoints” (nonfatal myocardial infarction (MI),
women ( 60) remote from menopause (>20 years since
nonfatal stroke, or confirmed death resulting from cardio-
menopause).13 The beneficial effect of HRT on CHD
vascular causes) and “soft endpoints,” whose occurrence
according to timing of HRT initiation has been shown in a
rely on medical decisions (arterial revascularization or hos-
large meta-analysis of 23 RCTs with 191,340 women-
pitalization for unstable angina pectoris). In men, all of
years of follow-up.14 When analyzed over all ages and in
the hard and soft components of the composite primary
women who initiate HRT when aged 60 and older or
endpoint were significantly lower in the rosuvastatin than
more than 10 years after menopause, the effect of HRT on
in the placebo arm. In women, only the soft endpoints
CHD is null. In women who initiate HRT when younger
(revascularizations and hospitalizations) were significantly
than 60 or less than 10 years since menopause, the risk of
lower and clearly drove the primary endpoint to statistical
CHD is statistically significantly 32% less than with
significance because none of the hard endpoints in the
placebo (Figure 1). The magnitude of CHD reduction for
women differed significantly (P > .10) between the rosu-
women younger than 60 or less than 10 years since meno-
vastatin and placebo arms.5 Total mortality was not statis-
pause when randomized to HRT is similar to observational
tically different between the rosuvastatin and placebo arms
studies of populations of women who initiated HRT at the
in women (P = .12) or men (P = .08).5 Including JUPITER
in meta-analyses along with other primary prevention
THE TIMING HYPOTHESIS AND PREVENTION IN WOMEN
A Coronary Heart Disease
The 11-year WHI CEE trial follow-up (7 years of
randomized treatment and 4 years of postintervention fol-
0.99 (0.88-1.11)
low-up) showed that women aged 50 to 59 given CEE had a
>60 years old >10 years since menopause, 1.03 (0.91-1.16)
CI = 0.38–0.90), total MI (HR = 0.54, 95% CI = 0.34–
<60 years old
0.86), and total mortality (HR = 0.73, 95% CI = 0.53–
<10 years since menopause, 0.68 (0.48-0.96)
1.00) than with placebo. Compared with women aged 60 to69 and 70 to 79, the
P-value for interaction was statistically
Relative Risk (95% CI) B Total Mortality
P = .04, respectively18), indicating that the CEE effect onthese outcomes differs according to age. Invasive breast can-
0.98 (0.87-1.18)
cer was statistically significantly 23% lower (HR = 0.77,
>60 years old,
95% CI = 0.62–0.95) in women who received CEE than
Mean age = 66 years 1.03 (0.91-1.16)
with placebo regardless of age at randomization.18
<60 years old,
Of immense importance to understanding early initia-
Mean age = 54 years 0.61 (0.39-0.95)
tion of HRT, long-term use, and clinical outcomes inhealthy young women is the Danish Osteoporosis Preven-
tion Study (DOPS)19, the only prospective longitudinal
Relative Risk (95% CI)
randomized trial designed to examine clinical outcomes in
Figure 1. (A) Relative risks (RRs) and 95% confidence inter-
women who were specifically a priori randomized to HRT
vals (CIs) for coronary heart disease events associated with
in the perimenopausal or early postmenopausal period.
hormone replacement therapy (HRT) from a meta-analysis of
DOPS included 1,006 women who were on average
23 randomized controlled trials (RCTs) in 39,049 women
50 years old (range 45–58) and 7 months postmenopausal
(followed for 191,340 women-years). Results are shown for
when randomized for 10 years to oral 17b-estradiol plus
all ages and for women aged 60 and older or more than
sequential norethisterone acetate or to an untreated group.
10 years after menopause or younger than 60 years old or less
Hysterectomized women received oral 17b-estradiol 2 mg
than 10 years after menopause when randomized and HRT
daily. After randomized treatment, the women were fol-
initiated. (B) RRs and 95% CIs for total mortality associated
lowed for another 6 years for a total follow-up of
with HRT from a meta-analysis of 30 RCTs in 26,708
16 years. After 10 years of randomized treatment, the
women (followed for 119,118 women-years). Results are
composite primary trial endpoint of mortality, MI, or
shown for all ages and for women aged 60 and older or more
than 10 years after menopause or younger than 60 years old
(HR = 0.48, 95% CI = 0.27–0.89), and total mortality
or less than 10 years after menopause when randomized and
was 43% (HR = 0.57, 95% CI = 0.30–1.08) lower in the
HRT group than in the control group. After a total fol-low-up of 16 years, the composite primary trial endpointremained significantly 49% lower (HR = 0.61, 95%
The Women’s Health Initiative (WHI) trial data also
CI = 0.39–0.94) and total mortality was 34% (HR = 0.66,
support the “timing” hypothesis, showing significant
95% CI = 0.41–1.08) lower in the women originally ran-
trends of an HRT effect on CHD according to time since
domized to HRT than in those randomized to the control
menopause.17 Women randomized to conjugated equine
group. There were no statistically significant differences in
estrogen (CEE) less than 10 years after menopause had a
incident breast cancer, stroke, or venous thromboembolism
52% lower risk of CHD than with placebo (HR = 0.48,
between treatment groups in DOPS. DOPS results are sim-
95% CI = 0.20–1.17), whereas women who were 10 to
ilar to the 11-year WHI CEE trial follow-up data of the
19 years since menopause (HR = 0.96, 95% CI = 0.64–
women aged 50 to 59 when randomized to CEE18 and to
1.44) and 20 or more years since menopause (HR = 1.12,
the 32% lower CHD14 and 39% lower total mortality20
95% CI = 0.86–1.46) showed no benefit of CEE on CHD.
shown in meta-analyses of RCTs of women younger than
Women randomized to CEE plus medroxyprogesterone
60 or less than 10 years since menopause with HRT than
acetate (MPA) within 10 years after menopause had a
12% lower risk of CHD than with placebo (HR = 0.88,95% CI = 0.54–1.43), whereas women 10 to 19 years
after menopause (HR = 1.23, 95% CI = 0.85–1.77) and
Although the risks and benefits of HRT continue to be
20 or more years after menopause (HR = 1.66, 95%
debated, postmenopausal HRT is the only primary preven-
CI = 1.14–2.41) showed no benefit and possibly a greater
tion therapy in women that has been demonstrated to
risk with CEE plus MPA than with placebo. With both tri-
reduce total mortality and extend life.13 The beneficial
als combined, women randomized to CEE and CEE plus
effect of HRT on total mortality according to age was
MPA within 10 years of menopause had a 24% lower risk
shown in a large meta-analysis of 30 RCTs with 119,118
of CHD than with placebo (HR = 0.76, 95% CI = 0.50–
women-years of follow-up.20 When analyzed across all ages
1.16), whereas women 10 to 19 years since menopause
and in women aged 60 and older when initiating HRT, the
(HR = 1.10, 95% CI = 0.84–1.45) and 20 or more years
effect on total mortality was null, whereas there was signi-
ficant 39% lower total mortality in women younger than
showed no benefit and a possibly greater risk of CEE and
60 (mean age 54) when with HRT than with placebo
CEE plus MPA on CHD than with placebo.
(Figure 1), a difference similar to that fond in observational
quality-adjusted life years (QALYs) at a cost of $2,438 per
studies. Age at HRT initiation in women in observational
QALY gained.22 Net gains gradually increase with treat-
studies and age of younger women randomized to RCTs
ment durations of 5 to 30 years, and results for younger
examined in the meta-analysis was similar.15,16
women are robust to all sensitivity analyses, with HRT
Similar to CHD trends, total mortality in WHI was
remaining highly cost effective. At $2,438 per QALY
30% lower with CEE plus MPA and CEE therapies than
gained, these data indicate that HRT is a highly cost-effec-
with placebo in women aged 50 to 59 when randomized.17
tive strategy for improving quality-adjusted life. Alterna-
Women randomized to CEE when younger than 60 had a
tively, there is a smaller net gain of 0.11 QALYs at a cost of
29% lower risk of total mortality than with placebo
$27,953 per QALY gained for 65-year-old postmenopausal
(HR = 0.71, 95% CI = 0.46–1.11), whereas women aged
women initiating HRT.22 Cost effectiveness ratios of less
60 to 69 (HR = 1.02, 95% CI = 0.64–1.44) and 70 to 79
than $50,000 per QALY are considered worthwhile, those
(HR = 1.20, 95% CI = 0.93–1.56) showed no effect of
less than $5,000 per QALY gained are considered highly
CEE on total mortality. Women randomized to CEE plus
cost effective, and a cost-effectiveness ratio greater than
MPA when younger than 60 had a 31% lower risk of total
$100,000 per QALY is considered unattractive.23
mortality than with placebo (HR = 0.69, 95% CI = 0.44–1.07), whereas women aged 60 to 69 (HR = 1.09, 95%
CI = 0.83–1.44) and 70 to 79 (HR = 1.06, 95% CI = 0.80
–1.41) showed no benefit of CEE plus MPA on total mor-
The cumulated data and their implication for women’s
tality. In both trials combined, women randomized to CEE
health in the primary prevention of CHD have become
plus MPA or CEE when younger than 60 had a statisti-
clearer over the past decade as the sex-specificity of statins
cally significant 30% lower risk of total mortality than
and aspirin and timing of initiation of HRT as modifiers of
with placebo (HR = 0.70, 95% CI = 0.51–0.96), whereas
efficacy and risk in women have become more fully eluci-
women aged 60 to 69 (HR = 1.05, 95% CI = 0.87–1.26)
dated. The data clearly show that standard primary CHD
and 70 to 79 (HR = 1.14, 95% CI = 0.94–1.37) showed
prevention therapies that are presumably efficacious in men
no benefit of CEE and CEE plus MPA on total mortality.
(statins and aspirin) do not statistically significantly reduce
To address the risks and benefits of HRT, a Bayesian
CHD events or total mortality in women.
meta-analysis was conducted using RCTs and observa-
Data are consistent in showing that, when initiated in
tional studies to evaluate the effect of HRT on total mor-
women younger than 60 or less than 10 years after meno-
tality in postmenopausal women younger than 60 who
pause, HRT reduces CHD events and total mortality,
initiated HRT in close proximity to menopause.21 Results
extends life, and is highly cost effective. The risks associ-
from this meta-analysis using 19 RCTs with 16,283
ated with HRT, such as breast cancer, are considered rare
women (mean age 54.5) followed for 83,043 women-years
(<1 event per 10,000 women treated per year) (see Part 2).
over 5.1 years (range 1–6.8 years) showed total mortality
The evidence-based data are large and consistent across
approximately 40 observational studies and meta-analyses
(CrI) = 0.52–0.96) in women randomized to HRT than in
encompassing 20 to 30 RCTs. In addition, the type and
those who received placebo. Using pooled data from eight
magnitude of risks associated with the standard primary
prospective observational studies in which 212,717 women
CHD prevention therapies are similar to those associated
were followed for 2,935,495 patient-years over a mean of
13.8 years (range 6–22 years), total mortality was 22%
Although the data are clear in showing sex-specific
(RR = 0.78, 95% CrI = 0.69–0.90) lower in HRT users
benefits restricted to men under primary prevention condi-
than in nonusers.21 Total mortality was 28% (RR = 0.72,
tions with statin and aspirin therapy,2–5 the old paradigm
95% CrI = 0.62–0.82) lower with the RCT and prospec-
that “what works in men must work in women” continues
tive observational data combined. Results from this study
to be promulgated as evidence-based data indicating the
indicate a convergence of evidence from several sources
fallacy of this paradigm are ignored. Data supporting the
that support a beneficial effect of HRT on total mortality
use of statin and aspirin therapy for a significant reduction
in women who initiate HRT in close proximity to meno-
in CHD events and total mortality under primary preven-
pause. Results from this meta-analysis also indicate that
tion conditions for women are lacking (Table 2). The data
RCTs and observational studies are similar, each with a
consistently support that, when initiated in women youn-
total mortality reduction of approximately 25%, similar to
ger than 60 or less than 10 years after menopause, HRT
the 10-year randomized trial follow-up (43% lower total
reduces CHD and total mortality (Table 2). The statisti-
mortality) and 16-year total follow-up (34% lower total
cally significantly greater risk of diabetes mellitus, risk of
mortality) of DOPS,19 the 11-year follow-up of WHI CEE
breast cancer similar to that with CEE plus MPA therapy,
(27% lower total mortality),18 and the significant 30%
and potential for the increase in new cancer cases in older
lower (HR = 0.70, 95% CI = 0.51–0.96) total mortality
persons24 associated with statin therapy have important
shown in postmenopausal women younger than 60 with
implications for the balance of benefit and risk of statin
HRT than with placebo in the WHI trials.17
therapy under primary prevention conditions in whichindividual RCTs and meta-analyses show no benefit in
reducing CHD events or total mortality in women (seePart 2). In light of the accumulating data and safety label
A cost-effectiveness analysis indicates that, compared with
changes to include warnings of diabetes and cognitive
no therapy, HRT given to postmenopausal women in their
impairment that the Food and Drug Administration
50s for 5 to 30 years results in a substantial increase of 1.5
THE TIMING HYPOTHESIS AND PREVENTION IN WOMEN
Comparison of the Effect of Initiation of Hormone Replacement Therapy in Young Postmenopausal
Women with that of Statin and Aspirin Therapy on Coronary Heart Disease and Total Mortality in PrimaryPrevention
aInitiation in women younger than 60 or less than 10 years after menopause.
requires,25 the use of statin therapy for the primary pre-
age of 50 and an average of 7 months after menopause,
vention of CHD in men has also been questioned.6,26
DOPS provides strong evidence of the long-term efficacy
DOPS, the only prospective longitudinal randomized
and safety of HRT for reducing CHD and total mortality.
trial conducted specifically in women younger than 60
Inconsistencies in presentation and interpretation of HRT
(average age 50) and less than 10 years after menopause
data has created great confusion for healthcare providers
(average 7 months), provides direct and compelling evi-
and patients alike, culminating in the call for an indepen-
dence for up to 16 years that the benefits of prevention of
dent commission to evaluate the interpretation and dissem-
chronic diseases outweigh the risks.19 Women included in
ination of the evidence-based data in relation to public
DOPS specifically represent women studied in previous
observational studies, and hence, DOPS is the only ran-
The totality of evidence indicates that the benefits of
domized trial to appropriately test the “estrogen cardio-
the initiation of HRT at or near menopause outweigh the
protective” hypothesis in the same population of women
risks, with the weight of evidence supporting downstream
in which this hypothesis was generated. In addition, few
prevention of morbidity and mortality. Healthcare provid-
prevention therapies other than HRT have been studied
ers and patients can be confident in applying the cumula-
under randomized conditions for 10 years.
tive data in making clinical decisions concerning chronic
Timing of initiation of primary prevention therapy
disease prevention, keeping in mind that any prevention
appears to have significant biological and clinical conse-
strategy must be personalized. Cumulative data provide
quences for women. The timing of initiation of primary
not only strong evidence of the beneficial effects of HRT
prevention therapies provides opportunity for reduction of
when initiated in women in close proximity to menopause,
CHD events and total mortality throughout the postmeno-
but also reassurance of their safety.
pausal period and forges a new paradigm in the primaryprevention of CHD in women. It is important to rethink
the appropriate clinical application of the evidence-based
Funded in part by National Institutes of Health, National
data: reduction of CHD events and total mortality in
Institute on Aging Grant R01AG-024154.
women who initiate HRT when younger than 60 or less
Conflict of Interest: The editor in chief has reviewed
than 10 years after menopause versus no reduction of
the conflict of interest checklist provided by the authors
CHD events or total mortality with statin and aspirin ther-
and has determined that the authors have no financial or
apy (Table 2). Women aged 60 and older or more than
any other kind of personal conflicts with this paper.
10 years after menopause have likely missed the window
Author Contributions: Both authors took part in all
of opportunity for benefit from HRT and should probably
not initiate HRT for the primary prevention of CHD.
In conclusion, a large body of RCT data converges
with results from observational studies, animal studies,and basic science supporting that HRT health outcomes
vary according to age or time since menopause. Focused in
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GENERAL REGULATIONS Code Ref: FP 2.1 GR FRUIT AND VEGETABLES Version: 2.1-Oct04 Annex: ENGLISH VERSION 7. ANNEX 7.8: EUREPGAP PRODUCT CROP LIST (This Annex forms part of the EUREPGAP General Regulations Fruit & Vegetables and may be referred to by other EUREPGAP documentation.) achras zapota coconuts potatoes aloe vera coriander prickly pears courgette
Preventive medications In addition to a healthy lifestyle, preventive medications can help people avoid many illnesses and conditions. A consumer-directed health (CDH) plan that includespreventive medications can help support the goal ofongoing good health. This list provides examples of your plan’s preventivemedications by drug category. This is not an all-inclusive list. Coverage prior t