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INCORPORATED

Important Fax MessagePlease Deliver Immediately

To:

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From:

Michelle Warren, MDColumbia Univ College of P & S

February 8, 2005

Karen Mittleman

Fax:

Time:

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9:15 AM EST

609-524-2315609-497-2304

Number of pages (including cover sheet): 17

Re: Outline

Dear Michelle:

Attached is an extended outline for the manuscript we discussed earlier thisweek. When reviewing it. please keep in mind which audience this should beideally addressed to and thus, what journal you would like to submit it to. Thatwill help expedite the development of the manuscript.

I'll be in the office on Monday but Will then be taking off for the holidays. You caneither send your comments to the outline by fax to the number above with yoursuggestions for the target journal, or you can let me know by voicemail or e-mailwhen you will be in your office after the holidays for me to contact you.

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DWRITE 072376

How Generalizable Are the Effects of Estrogen? A Comparative Review of HormoneTherapy Products

I. IntroductionA. Recently, the hormone therapy (HT) arm of the Women's Health InitiatIve (WHI) was

stopped early because the results suggested that the health risks exceeded the healthbenefits over an average of 52 years of follow-up (Wnting Group for the Women'sHealth Initiative Investigators, 2002). Because the regimen used in the trial wascontinuous combined conjugated equine estrogens (CEE, 0 625 mg) plusmedroxyprogesterone acetate (MPA, 2,5 mg), some have suggested that thIS study maybe applicable only to this specific regimen (Stevenson et aL 2002).

B. ThIs paper reviews the research data from postmenopausal HT products containingdifferent types of estrogens and progestins and using different regimens with regard tothe major risks and benefits, including those reported in the WHI trial.

C. Because estrogen therapy (ET) has been available smce 1942, there IS a vast literaturepublished on both ET and HT. This review is ltmited to clinical trials published overthe last 15 years (1987-2002), but includes meta-analyses or review papers that haveevaluated the ltterature prior to 1987. This approach ensures that the climcal studiesinclude doses that are currently standard or lower.

D. Based on the eVIdence avaIlable, the potential nsks of breast cancer and cardIOvasculardisease with HT use should be weighed against its beneficial impact on menopausalsymptoms, osteoporosis, and colon cancer, regardless of the type of estrogen orprogestin or route of administration. Whether lower doses ofHT wi11Improve therisk:benefit ratio remains to be determined.

II. Breast CancerA. Over 70 studies have evaluated the risk ofbreast cancer associated with the use of any

type ofpostmenopausal ETIHT. Prior to the WHI findings, the majority of eVIdencewas derived from observational studies: these studies. in total. suggested equivocalfindings (Bush et aI., 2001).1. In the WHI study using CEE&fPA (Writing Group for the Women's Health

Initiative Investigators, 2002), the risk for the overall population emerged after 4years of HT use; however, the Increased risk in WHI was observed only in thesubset of women who used postmenopausal HT before entry into the study.

2. Several observational studies provided data regarding the effect of other estrogenson the risk ofbreast cancer and reveal a similar risk (Hedblad et aI., 2002; Henrichet aI, 1998; Magnusson et aL, 1999; Manjer et aI., 2001; Ng et aL 1997: Olsson etaI., 2001; Persson et al., 1996; Persson et aI., 1997; Persson et aI., 1999; Souranderet aL 1998; Tavani et aL 1997).

3. The strongest evidence that the risk on breast cancer is similar among differenttypes of estrogens is provided by the Collaborative Group on Hormonal Factors In

Breast Cancer (Collaborative Group on Hormonal Factors in Breast Cancer, 1997).a) The CollaboratIve Group reanalysis suggests that the RR ofbreast cancer

increases 1% to 3% for each year ofuse (Collaborative Group on HormonalFactors in Breast Cancer, 1997).

b) In the Collaborative Group reanalySIS, the authors stated the RR ofbreast cancer

__1-

DWRITE 072377

did not vary according to the type or dose of estrogen used (CollaborativeGroup on Hormonal Factors in Breast Cancer, 19(7).

B. Several European studies, mainly from Scandinavia, have evaluated primarily 17~­

estradiol and the RR of breast cancer.1. Five studies reported an increased risk with ever-use ofET/HT (Hedblad et aI.,

2002~ Magnusson et aI., 1999~ Manjer et aI., 2001; Olsson et aI., 2001; Persson etaI., 1996).

Z. Four studies reported no increased risk with ever-use (Henrich et al., 1998~ Perssonet al., 1997; Persson et aI., 1999; Tavani et aI., 1997).a) Two of these did report an increased risk with increased duration (Persson et aI.,

1997~ Persson et aI., 1999).b) Two reported an increased risk with subset analyses (Hennch et aI., 1998;

Tavani et aI., 1997).3. One study that reported no increased risk suhsequently reported increased risk in

the same cohort in a later publication (Persson et aI., 1996; Persson et aI., 1999),4. Only 2 smaller studies (Ng et aL 1997~ Sourander et aL 1998) did not report any

finding of mcreased nsk.

III. StrokeA At least 4 randomIzed placebo-controlled tnals (Hemngton et aI., 2000; Hulley et aI.,

1998; Viscoli et aL 2001; Writing Group for the Women's Health InitiativeInvestigators, 2002), one meta-analysIs (Nelson et aI., 2002), and many observationalstudies have reported the effects ofpostrnenopausal ET/HT on stroke (Angeja et aI.,2001; Beard et aI., 1995; Bushnell et aI" 2001; Cauley et aI., 1997; Finucane et al..1993; Folsom et aI., 1995; Fung et aI., 1999; Grodstein et aI., 1997; Grodstem et aI.,1999; Grodstein et aL 2000; Henderson et al., 1991, Lemaitre et aI., 2002; O'Keefe etaI., 1997; Paganini-Hill et aI., 2001; Pedersen et aI., 1997; Petitti et aI., 1998; Rodriguezet at., 2001; Shlipak et aI., 2001; Sourander et aI., 1998; Stampfer et aI., 1991).

B. A recent meta-analysis (Nelson et aI., 2002) pooled results from 9 observational studies(Fmucane et aI., 1993; Fung et aI., 1999; Grodstein et aI., 2000; Pedersen et aI., 1997;Petitti et aL 1998; Pfeffer et aI., 1978; Sourander et aI., 1998; Thompson et aI., 1989;Wilson et aI., 1985). The relative risk for overall stroke incidence was increased anlOngever users (RR, 1.12; 95% CI, 1.01-1.23); the RR was elevated for thromboembolicstroke (RR, 1.20; 95% CI, 1.01-1.40), but not for subarachnoid or intracerebral stroke(Nelson et aI., 2002).

C. While the majority ofprevious studies did not observe an increased risk of strokeassociated with postmenopausal ETIHT, more recent evidence supports a smallincreased RR (Goldstem et aI., 2001).1. In the WHI trial ofprimary prevention. the overall hazard ratio for stroke (fatal and

nonfatal) was 1.41 (95% nominal CI, 1.07-1.85), after an average of5 2 years offollow-up (Writing Group for the Women's Health Initiative Investigators, 2002).The increased risk of stroke appeared in year 2 and persisted to the end ofthe study.When separated mto fatal or nonfatal events, CEEIMPA users had an mcreased nskfor nonfatal stroke. but not for fatal stroke.

2. Two secondary prevention trials that randomized women to CEE/MPA the HeartEstrogen Replacement Study (HERS and HERS II) (Grady et aI., 2002; Hulley et

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DWRITE 072378

aI., 2002; Simon et aI., 2001) and the Estrogen Replacement and Atherosclerosis(ERA) trial (Herrington et aL, 2000)--reported nonsignificant mcreased risks forany stroke.

3. The recent Women's Estrogen for Stroke Trial (WEST) is the only randomized,placebo-controlled trial (n = 664; mean age, 71 years), evaluating the effects of17~-estradiolon stroke (Viscoli et al., 2001). This study reported an increased riskof stroke (RR, 2.30; 95% confidence interval [CI], 1.1-5.0) in the first 6 months oftherapy.

D. In studies that have evaluated predommantly estrogens other than CEE, 2 studiesmcluded a vanety of dIfferent estrogens (Pedersen et aI., 1997; Thompson et aI., 1989),and one appeared to include only formulations containing 17~-estradiol (Sourander etaI., 1998).1. Thompson and colleagues assessed the effects of 76 different ET/HT regimens used

in the United Kingdom on the risk of stroke and MI (Thompson et aL, 1989) Sixtypercent of the recorded prescriptions in this case-control study were wntten forestropipate, ethinyl estradioVmethyltestosterone, CEE. norethisterone.dlethylstilboestrol, and ethinyl estradIOl.

2. Pedersen and colleagues also evaluated the effects of ET/HT on the risk of strokesubtypes in a Danish case-control study (1422 cases and 3171 controls) (Pedersen etaI., 1997). A variety of different hormone regImens and preparatIOns were mc1uded(tablets. patches. and preparations for injections).

3. A Fmnish cohort study exammed the effects ofET/HT on morbidity and mortalityfrom stoke lSourander et al., 1998). Current estrogen users (n = 988) received 17~­

estradiol (mean daily dose, 1.4h mg) at baseline; 139 women used a progestin.E. There appears to be a dose-related effect on the risk of stroke. In the large,

observational trial, the Nurses' Health Study, the RR of stroke was increasedSIgnificantly among women who took CEE 0.625 mg/d (RR = 1.35; 95% C1, 1.08-1.68)or those who took CEE ~1.25 mg/d (RR = 1.63; 95% C1. 1.18-2,26); however. therewas no assOCIated increase in stroke for CEE 0.3 mg/d (RR = 0.54; 95% CI, 0.28-1 06[based on only 9 cases]) (Grodstein et aI., 2000).

F. While the data specific to non-CEE containing postmenopausal HT and stroke arelimited, they are consistent with the total data evaluatmg the nsk of stroke WIth ETIHT.

IV. Venous ThromboembolismA. Prior to WH1, a number of studies (randomized and observational) examined the risk of

venous thromboembolic events (VTE, deep venous thrombosis [DVT] or pulmonaryembolism [PE]) WIth postmenopausal ETIHT.1. The hazard ratio (RR) for VTE in the WHI trial was 2.11 (nominal 95% CI, 1.58­

2.82).2. In conjunction with the US Preventive Services Task Force, Miller and colleagues

•

(Miller et aI., 2002) calculated a summary risk estimate for VTE based on a meta-analysis of 12 studies that used a variety ofET/HT products and doses (BostonCollaborative Drug Surveillance Program, 1974; Daly et aI., 1996; Daly et aI.,1996; Devor et aI., 1992; Grodstein et aI., 1996; Herrington et aI., 2000; Hoibraatenet al., 1999; Hulleyet aI., 1998; Jick et aI., 1996; Perez Gutthann et aI., 1997;Varas-Lorenzo et aI., 1998; Writing Group for the PEPI TriaL 1995). These studies

_.3_

DWRITE 072379

mcluded the randomized controlled HERS (Hulley et aI., 1998), ERA (Herringtonet a1.. 2000), and Postmenopausal Estrogen/Progestin Intervention (PEPD (WritingGroup for the PEPI Trial, 1995) trials, all of which used CEEIMPA. In the Nurses'Health Study CGrodstein et aI., 1996), CEE with or without MFA was the primaryHT reported. Current use of postmenopausal ET/HT was associated with a 2-foldincreased risk ofVTE (RR, 2.14; 95% CI, 1.64-2.81).

3. Individual studies reporting an increased risk ofVTE with ET/HT regimens otherthan CEEIMPA had similar findmgs (Daly et aI., 1996; Hoibraaten et aI., 1<:)99; Jicket a1.. 1996; Perez Gutthann et aI., 1997; Varas-Lorenzo et aI., 1998).a) In a case-control study conducted in the UK., Daly and colleagues (Daly et a1..

1996) analyzed 103 cases (69 with DVT, 39 WIth PE) and 178 controls; 44women in each group were currently using estrogen products that included oralCEE, 17~-estradiolor estradIOl valerate, piperazine estrone sulphate, andtransdermal estradiol. Approximately half of the hormone users in each groupalso used a progestm, although the type was not specified. The authors indicatedthere were no significant differences in the risk of VTE between oral andtransdennal ET/HT.

b) In a large population-based case-control study in the UK. (n = 347,253) (PerezGutthann et a1.. 1997), no difference in risk was determined for estrogen aloneor combined WIth progestin, transdermal vs oral regimens, nor for low vs highdose therapy.

c) Risks of similar magnitude have been reported in an Italian population cohortstudy, m WhICh 79% used transdermal estradIol (Varas-Lorenzo et aI., 1998).

d) In a population-based case-control study in Norway, a total of 176 cases and352 matched controls were analyzed (Hoibraaten et aI., 1999). The authorsnoted that only ET/HT products contaming estradIOl were used, but differentprogestins, and both oral and transdermal routes of administration, werereported.

B. The evidence indicates an increased risk of VTE associated with postmenopausal HT.Relative risks for venous thromhoembolic events have been reported in the approximaterange of2.0 to 3.0, with the greatest risk seen within the first 2 years of use.

C The data regarding risk ofVTE and postmenopausal HT with estrogens other than CEEare consistent with the lIterature for all ET/HT. Therefore, the potential risk ofVTEshould be considered when prescribing any postmenopausal HT product.

V. Coronary Heart DiseaseA. While the vast majority ofpublished observational studies reported a 30% to 50%

lower mCIdence of CHD among postmenopausal ET/HT users (Grady et aI., 1992:Grodstein et aI., 2000; Hernandez Avila et aI., 1990), recent randomIzed clmical trials(Clarke et aI., 2002; ESPRIT team, 2002; Hulley et a1.. 1998; Viscoli et aI., 2001;Writing Group for the Women's Health Initiative Investigators, 20(2) have failed toshow that ET/HT prevent or treat CHD.1. Two of the largest randomized clinical trials to evaluate CHD risk with HT use. the

WHI (Writing Group for the Women's Health Initiative Investigators, 2002) and theHERS (Hulley et aI., 1998), used continuous combined CEE 0.625 mglMPA 2.5mg. Events were highest dunng the first year oftherapy.

- -- - - - - - - -____4

DWRITE 072380

1. Two smaller randomized clinical trials, the Papworth HRT Atherosclerosis Study(PHASE) (Clarke et aI., 2002) and WEST(Viscoli et aI., 2001) used different formsofHT containing 1713-estradioI.a) In the PHASE Study, a small, 4-year secondary prevention trial (n = 255), event

rates were hIghest in the first 2 years (Clarke et aI., 2002).b) Similar findings were noted in the WEST, in which CHD was a secondary

outcome in older (average age, 71 years) postmenopausal women (n = 6(4) witha recent stroke who were randomized to 1713-estradiol (1 mg/d) or placebo foran average of2.8 years (Viscoli et aI., 2001).

3. Recent data from the oEStrogen in the Prevention of ReInfarction Tnal (ESPRIT)indicated that 2 mg/d of estradiol valerate did not prevent reinfarction or cardiacdeath compared WIth placebo (ESPRIT team, 2002).

B. Similar trends for women with established CHD were found in posthoc analyses ofseveral prospective observational cohorts that w;:ed a variety ofETIHT formulations(Alexander et aI., 2001; Grodstein et aI., 2001; Heckbert et aI., 2001).1. Heckbert and colleagues evaluated recurrent CHD in 981 women who had survived

an initial MI using data from the Group Health Cooperative, a health maintenanceorganization (Heckbert et aI., 2001 ).a) Unopposed estrogens (most common were esterified estrogens [70% of oral

estrogen use] and CEE [28% of oral estrogen use]) were used 67% of the totaltime. Combined estrogen-progestin was used 33% of the time, with MPAVIrtually the only progestm used.

2. Retrospective analysis of the Coumadin Aspirin Reinfarction Study (CARS)database resulted in an HR of lA4 (95% CI, 1.05-1.99) forrecurrent first yearevents ofcardiac death, MI, or unstable angina m postmenopausal women whowere new users ofET/HT compared with never users (Alexander et aI., 2001).

3. In an analySIS of 2489 women with CHD from the Nurses' Health Study, a RR of1.25 (95% CI, 0.78-2.00) was noted for women who mitiated postmenopausalETIHT within 1 year of an MI, and RRs of0.55 (95% CI, 0.13-2.27) and 0.38 (95%CI, 0.22-0.66) were observed for the second and subsequent years ofuse,respectively. compared with nonusers (Grodstein et aI., 2001).

C. One explanation for the difference between the epidemiologic data and the randomizedtrial data is a potential bias effect. A recent meta-analysis that included studIes rated asgood or fair quality found that among the observational studies that adjusted forsocioeconomIC status (SES), there was no association between any postmenopausalestrogen/progestin therapy use and CHD events (RR, 0.88; 95% CI, 0.64-1.21)(Humphreyet aI., 2002).

D. There is no randomized clinical trial evidence that the use of postmenopausal HT withestrogens other than CEE results in a different risk of CHD than HT containing CEE.1. It has been recommended by the AHA that estrogens as a class should no longer be

prescribed to women with CVD for the purposes ofpreventing cardiac events(Mosca et aI., 2001).

E. The risk of CHD should be conSIdered when prescnbing postmenopausal HT products,regardless of the type of estrogen or progestin used. the route of administration, or theregImen.

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DWRITE 072381

VI. Menopausal SymptomsA. Incidence and Effects of Menopausal Symptoms

1. Hot flushes are the most common symptom ofthe peri- and post-menopause,affecting 68% to 93% of women (Freedman, 2000; Thompson et al., 1973).

2. Ln addition to increasing hot flushes, the menopausal transition is associated withincreased complaints of vaginal dryness, pain dunng intercourse, imtabihty,depressed mood, and sleep disorders (Dennerstein et aL 2000; Gold et al., 2000;Maartens et a1., 2001). These changes are the primary reason that women initiate orcontinue HT (Newton et a1., 1997).

3. Hot flushes and the physiologic events that accompany them are part of a complexsequence of events that affect overall quality ofhfe (QOL) for pen- andpostmenopausal women.

B. Effects of HT1. Vasomotor Symptoms

a) Recent literature on the efficacy and safety ofETIHT for treatment ofvasomotor symptoms includes over 40 randomized controlled clinical trials.These trials evaluated several estrogen compounds for efficacy in treatingvasomotor symptoms, including conjugated equine estrogens (CEE) both aloneand in combination with a progestin, oral estradiOl, transdennal estradiOl,esterified estrogens, estradiol valerate, synthetic conjugated estrogen, estriol,and estrone sulfate.

b) In the studies that used the standard dose of 0.625 CEE (Archer et a1., 1992;Good et a1., 1999; Gordon et a1., 1995; Greendale et a1., 1998; Hilditch et aL1996; Huber et a1., 2002; Kokcu et a1., :2.000; LUCIano et al., 1993; Pomel, 1996;Scharfet a1., 1997; Siseles et aL 1995: Strickler et aL 2000; Studd et a1., 1995;Utlan et a1., 2001), decreases in frequency and severity ofhot flushes weresignificant compared to placebo. The addition of a progestin does not negateestrogen efficacy on hot flushes relief (Utian et al., 2001).

c) Similar improvement of vasomotor symptoms has also been shown with otheroral (Marslew et aL 1992: Meuwissen et a1., 2001; Notelovitz et a1., 2000;Rebar et a1., 2000; Rozenberg et a1., 2001; Saure et a1., 2000; Simon et a1., 1999;Speroffet a1., 2000; Stadberg et a1., 1996; Sulak et a1., 1999) and transdermal(Pome! et a1., 1995; Rozenbaum et a1., 1996; Studd et aL 1995; Utian et a1.,1999) estrogen treatments III randomized controlled tnals. In one comparativel2-week trial, oral CEE 0.625 mg and transdermal estradiol (50 Ilg daily)provided similar symptom relief (Studd et a1., 1995).

d) A dose-response has been reported with oral estrogens (both CEE andestradiol), which tends to disappear when a progestin (either MPA or NETA) iscombined (Notelovitz et al., 2000; Speroff et a1., 2000; Utian et a1., 2001). In theWomen's HOPE study, Utian and colleagues noted that lower doses ofMPA(1.5 mg) combined WIth lower doses of CEE (0.45 mg or 0.3 mg) were alsoeffective for the relief of vasomotor symptoms (Utian et al., 2001).

2. QOLa) Only a few QOL studies have been placebo-controlled studIes, and they

generally enrolled small samples with short duration of use.b) A randomized, placebo-controlled study involving 242 women found that

DWRITE 072382

health-related QOL and well-being improved after 12 weeks of 50 Ilg/dayoftransdermal estradiol compared with placeho (Wiklund et aI., 1993). Similarresults have been found with oral estrogens, CEE or estradiol, standard or low­dose formulations, whether or not combined with a progestin (Baerug et aI.,1998; Derman et aI., 1995; Rebar et aI., 2000). Little difference exists betweensequential and continuous regimens, in particular on the menstrual domain ofWHQ (Ulrich et aI., 1997).

3. Sleep and Mooda) Estrogen-induced improvements in sleep were associated with alleviation of

vasomotor, somatic, and mood symptoms (Polo-Kantola et aI., 1998). Similarpositive impact of estrogens on sleep has been reported in other studies (Keefeet aI., 1999; Scharf et aI., 2000; Strickler et aI., 2000; Wiklund et aI., 1992) butnot all (Purdie et at, 1995).

b) ET has been associated with positive effect on fatigue/energy, and depressivemood only m symptomatic women (CagnacCl et aI., 1997; Hlatky et al., 2002)A positive effect of estrogens has been reported in two small pilot studiesenrolling depressive postmenopausal women (Carranza-Lira et aI., 1999;Schmidt et aI., 2000). However, no positive effect of estrogens on mood hasbeen reported in demented women (Kyomen et al., 1997; Mulnard et aI., 2000;Wang et aI., 2000).

4. Sexual Functiona) A meta-analysis of 10 placebo-controlled trials demonstrated that estrogens

(oral, transdermal, and vagmally admmistered) are more effective than placebofor the measured variables ofpatient symptoms, dyspareunia, vaginal pH,cytologiC findmgs, and physician assessment (Cardozo et aI, 1998).

VII. OsteoporosisA. Incidence and Effects of Osteoporosis

1. 30 million women age 50 years or older in the United States have low bone massand, of these, 8 million have osteoporosis (National Osteoporosis Foundation,2002). Halfof all postmenopausal women Will have an osteoporosis-related fractureduring their lives (Melton et aI., 1992).

2. Bone loss is most rapid in the years nnmedmtely following menopause, whencirculating estradiol levels drop precipitously (Nilas et aI., 1989; Slemenda et aI.,1987; Slemenda et aI., 199fl).

3. Low bone mineral density (BMD) is the smgle best predictor of fracture nsk mpostmenopausal women (Kanis, 1997).

B. Effects ofHT on OsteoporosisApproximately 50 studies were considered in this analysis. The majority of the studieswere randomized and placebo controlled; however, several meta-analyses andobservational trials were also mcluded.1. Bone Mineral Density

a) Oral CEEIMPA, mcluding lower doses, has a positive effect on BMD in thelumbar spine, forearm, and hip, based on the findings of several randomized,placebo-controlled trials (Lindsay et aI., 2002; Writing Group for the PEPITrial, 1996) as well as a recent meta-analysis (Wells et aI., 2002).

7

DWRITE 072383

b) Increases in spine and hip BMD have also been documented with ethinylestradiol combined with norethindrone acetate (NETA) (Speroff et aI., 1996).

c) Transdermal estradiol has also been shown to increase BMD in a randomizedclimcal trial (Studd et aI., 1996).

2. Fracture Riska) The CEEIMPA component of the WHI (Writmg Group for the Women's Health

Initiative Investigators, 2002) is by far the largest randomized, placebo­controlled trial to date evaluating fracture risk. After a mean follow-up period of5.2 years, significant reductions in the hip, vertebral, and total fractures wereobserved with CEEIMPA.

b) One small trial randomIzed clmical tnal (n = 75) reported a reduced risk ofvertebral fractures with 100 Ilg/d of transdermal 1713-estradiol (Lufkin et aI.,1992).

c) The decrease in fracture risk with postmenopausal HT has been demonstrated mseveral large observational studies, including the Framingham Study and theStudy of OsteoporotIc Fractures (SOF) (Cauley et aI., 1995; Kiel et aI., 1987).

d) The data do not suggest a difference in effect on BMD among variousformulations ofpostmenopausal ETIHT. However, there is "orne suggestionfrom the Women's HOPE study that combination estrogen/progestin therapymay produce greater increases in BMD than estrogen-only therapy (Lindsay etaI., 2002).

e) Data from the ORAG meta-analysis, which included randomized clinical trials-other than the WHI, did not suggest differences between variouspostmenopausal HT combinations (Wells et aI., 2002).

VIII. Colorectal CancerA. Data from the WHT randomized clinical trial indicated a reduction in RR ofcolorectal

cancer with CEEIMPA use (hazard ratio = O.h3; 95% [confidence interval] CI, 0.43­0.92). These data are consistent with observatIOnal studIes.

R Meta-analyses by Hebert-Croteau in 1998(Hebert-Croteau. 1998) and Grodstein andcolleagues in 1999(Grodstein et aI, 1999) evaluated 20 and 18 studies, respectively

C. The overall RR of0.85 (95% CT, 0.73-0.99) for colon cancer reported by H6bert­Croteau( Hebert-Croteau, 1998) was similar to that found by Grodstein et al(Grodsteinet aI., 1999) for colon cancer (RR = 0.80; 95% CI, 0.74-0.86); the summary RR forcolorectal cancer was 0.66 (95% CL 0.59-0.74).

IX. ConclusionA. The risks for breast cancer, VTE, and stroke are apparent in all ETIHT products.B. Although the CHD data speCIfic to other estrogens are limited, the data clearly do not

support an absence of risk.C. Potential risks ofbreast cancer and CVD should be considered when prescribing

postmenopausal HT products, regardless ofthe type of estrogen or progestin, route ofadmini"tration, or regimen.

DWRITE 072384

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AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY

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DWRITE 072395

INCORPORATED

Important Fax MessagePlease Deliver Immediately

To:

Date:

From:

Michelle P. Warren, MDCenter for Menopause, HormonalDisorders and Women's Health

February 7,2005

Karen D. Mittleman, PhD

Fax:

Time:

Phone:Fax:E-mail:

212-879-2658

11:10 AM EST

609-524-2315609-497-2304kmittle@dwrite.com

Number of pages (including cover sheet): 44

Re: Draft Manuscript

Dear Dr. Warren:

Attached is the draft of the paper based on the outline we discussed in January.I've sent this via e-mail to you also" After you've had a chance to review it, pleasecontact me and we can diSCUSS the best way to handle changes.

Hope you are well in these turbulent times!

Best regards,

Karen D. Mittleman, PhD

Attachment

189 WALL STREET, PRINCETON, NEW JERSEY 08540.609/924-1116. FAX: 609/497-2304

DWRITE 072140

May 19, 2003

Amy S. Marren, MDDIrector, Women's HealthcareWyeth PharmaceuticalsGlobal Medical Communications150 N, Radnor-Chester RoadRoom 1104St. DavIds, PA 19087

Dear Amy:

Enclosed is a copy of the draft that was sent to Michelle Warren on May 16th, Please

share the paper with Mary Send!. I hope you understand my concern about having toomany copies circulated.

Please don't hesitate to call me at (609) 524-2315 if you have any questlons or concerns.

Regards,

Karen D. Mittleman, PhDSenior Medical Writer

KDM/apEnclosure

DWRITE 072141

,'

A Comparative Review of the Risks and Benefits of

Hormone Replacement Therapy Regimens

Michelle P. Warren, MD

Department of Obstetrics and Gynecology

Columbia University College ofPhysicians and Surgeons

New York. New York

Address for reprints:

Michelle P. Warren, MD

Professor of Obstetncs. Gynecology and Medicme

Sloane Hospital for Women

Columbia-Presbyterian Medical Center

16 East 60th Street

New York, NY 10022

Tel.: (212) 326-8548

Fax: (212) 326-8547

E-mail: mpwl@columbiaedu

DWRITE 072462

EXHIBIT

M1J1[3

Condensation

Reviews clinical studies investigating different types and regimens ofhorrnone

replacement therapy to assess the "generalizability" ofthe results ofthe Women's Health

InitIatIve.

2

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3

Abstract

The Women's Health Initiative (WHI), a large, randomized, placebo-controlled trial,

investigated the effect of conjugated equine estrogens combined with medroxyprogesterone

acetate on specific potential long-term benefits and risks. This paper reviews the clinical studies

mveshgating different types and regimens of estrogens combined with progestins m order to

assess how applicable the results ofthe WHI are to hormone replacement therapy (HRT)

regimens in general_ Studies reviewed were limited to randomized clinical trials and

observational studies published over the last 15 years (1987-2002). as well as meta-analyses and

reviews that may have included the literature before 1987. The increased risks for venous

thromboembolism, stroke, coronary heart disease, and breast cancer that were identified In the

WHI trial have also been reported with postmenopausal hormone therapies containing a variety

of estrogen and progestin products. The beneficial effects noted in the WHI with respect to

reductions in fractures and colorectal cancer have not been evaluated in large, randomized

controlled trials using different estrogen/progestin combinations; however, observational trials

using a variety of estrogen or hormone replacement therapy (ERTIHRT) products and

randomized clinical studies evaluating bone mineral density, an excellent predictor of fracture

risk, with different ERTIHRT regimens would suggest that results would be similar to those

found in the WH!. Although the relief ofmenopausal symptoms, the primary reason women seek

treatment. was not included in the overall benefit/risk analysis of the WHI, numerous tnals

suggest that all therapies are effective. Overall. these data indicate that the benefit/risk analysis

reported in the WHI can be generalized to all postmenopausal HRT products.

Key Words: benefit, risk, hormone therapy, estrogen and progestin preparations.

DWRITE 072464

4

Introduction

The honnone replacement therapy (HRT) ann ofthe Women's Health Initiative (WIll),

which included 16,608 postmenopausal women aged 50-79 years (mean age, 63 years) with an

intact uterus at baseline. was stopped early-after an average of5.2 years of follow-up-because

the results suggested that the health risks exceeded the health benefits.] Since the regimen used

in the trial was continuous combined conjugated equine estrogens (eEE, 0.625 mg) plus

medroxyprogesterone acetate (MPA, 2.5 mg), some have suggested that the findings from tills

study may be applicable only to this specific regimen.2 ,3

To assess this hypothesis. this paper reviews clinical studies investigating different types

and regimens of estrogens in combination with progestins with regard to the major risks and

benefits, includmg those reported in the WHI tnal. Studies were limited to randomized clInical

trials and observational studies published over the last 15 years (1987-2002), as well as meta­

analyses and reviews that may have included the literature before 1987. An attempt was made to

include only those studies that clearly identified the use ofHRT rather than estrogen replacement

therapy (ERT) or a combination ofERT and HRT. Cases where this was not possible are noted,

For each ofthe outcomes below. the WIll findings are discussed followed by the clinical

evidence on different types ofHRT.

Documented risks ofHRT

Breast cancer. Recent studies of the effects of various regimens ofERT and HRT on

breast cancer are summarized in Table 1 The WHI IS the first randomized, placebo-controlled

trial to evaluate the effect of HRT (specifically CEEIMPA) on the incidence ofinvasive breast

cancer. The investigators reported an overall hazard ratio (HR\ of 1.26 (nominal 95% confidence

DWRITE 072465

mterval [eI]. 1.00-1.59) after an average of5.2 years offollow-up.l The increase was marginally

significant and emerged after 4 years ofHRT use. When prior use ofHRT was considered in a

subgroup analysis. an increased risk ofbreast cancer was observed only in the subset ofwomen

who used HRT before entering the study: the HR was 1.06 (95% CI, 0.81-1.38) among never

users; 2.13 (95% CL 1.15-3.94) for women with <5 years ofprior use; 4.61 (95% CI. 1.01-21.02)

for women with 5-10 years ofprior use; and 1.81 (95% CI, 0.60-5.43) for women with 10 years

ofprior use.· These data proVIde valuable mformatlon for clirncians who often see patients With

symptomatic complaints early in the menopause and suggest that a prolonged exposure may be

necessary before a small increase in risk is seen.

Before the WHI. the relative risk (RR) ofbreast cancer with ERT or HRT use was

evaluated mover 70 observational studIes. Although an increased nsk ofbreast cancer With

either ERT or HRT has been questioned based on the lack ofconsistency among studies.4,5 the

1997 Collaborative Group on Hormonal Factors in Breast Cancer reanalysis of the worldwide

data from 51 epidemiology studiesb reported findings that were somewhat consistent with those

seen in the WHI. For all studies combined (approximately 12% ofwomen who documented

hormonal constItuents used HRT) an RR of 1.14 (8E, 0.03; P = .00001) was noted with ever use

ofERTIHRT.6 The RR ofbreast cancer did not vary according to the type or dose ofestrogen

used and there was no evidence ofmarked differences between ERT or HRT preparations. In

their subanalysis of the type ofpreparation used. the RR ofbreast cancer in current users ofHRT

or progestins alone for <5 years was 1.15 (8E. 0.19; significance not reported). Because lIttle

Information was available about use of any HRT regnnen for a long period oftime, the authors

could not make reliable conclusions about the effects ofdifferent regimens on breast cancer risk.

The authors also reported that current use ofERT for <5 years was not associated with an

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6

increased risk ofbreast cancer (RR, 0.99; SE, 0.08); these findings are in accord WIth those of

the WHI. in that the ERT ann ofthe WIll continues.

A number ofobservational studies published since the Collaborative Group reanalysis

evaluated the RR ofbreast cancer with HRT, specifically defined as a combination ofestrogens

and progestins. Several reported no signIficant mcrease in RR ofbreast cancer with HRT use.7•

11

For those studies in which an increase in RR ofbreast cancer with HRT use was Identified, I~·~O

the types and regimens of the hormones used are discussed below.

An increased risk ofbreast cancer was observed in Swedish women using HRT. 12•14

Magnusson and colleagues l1 investigated breast cancer risk in a population-based case-eontrol

study ofwomen 50 to 74 years. The odds ratIo (OR) for ever use ofHRT containing "medlum­

potency estrogens" (mostly oral 2 mg 17~-estradiol) and any progestm was 1.63 (95% CI, 1.37­

1.94), with a trend toward an increased risk with duratIon of use (OR, 1.07 per year of use; 95%

CL 1.02-1.11). Ever use ofHRTwith progestins derived from progesterone (e.g., MPA) was not

assocIated with an increased risk ofbreast cancer (OR, l.l·t 95% CI. 0.69-1.881. nor was there

an increased risk with duration ofuse (OR, 0.95 per year of use: 95% CI. 0.80-1.14). In contrast.

ever use ofprogestins denved from testosterone (e.g., noretrnsterone acetate [NETA]) was

associated with an increased risk (OR, 1.68; 95% CI, 1.39-2.031 that was influenced by duration

(OR, 1.08 per year ofuse; 95% CI, 1.03-1.13). When only HRT regimens using testosterone­

derived progestins were evaluated. the risk ofbreast cancer with ever use ofeither cyclic (OR.

1.48; 95% CI, 1.08-2.04) or continuous (OR, 1.41; 95% CI, 1.09-1.83) regimens was increased;

however. an increase with mcreasing duration of use was only seen for the continuous regimen

(OR, 1.19 per year ofuse; 95% CI, 1.09-1.31). The potential differenc·es in breast cancer risk

with different progestins have been attributed to the greater increase in inSUlin-like growth factor

DWRITE 072467

7

1 actIvity with more androgenic progestins.zl

Persson and colleagues13 assessed the risk ofbreast cancer in a cohort of 11.231 Swedish

women prescribed ERTIHRT (median age of65 years) using a record linkage with the National

Swedish Cancer Registry. In women who reported using "medium-potency estrogens" (48%

used 17j3-estradiol, 15.2% used CEE. 36.8% used mixed estrogens) plus progestins (45%

testosterone-derived [250 Ilg levonorgestrel or 1 mg NETA]. 55% progesterone-derived [5 mg or

10 mg MPA]). the RR(adjusted for age. follow-up time. age at first full-term pregnancy. body

mass index [BMl], education. and menopausal age/status) was not increased with HRT use for 1

to 6 years (RR, 1.4; 95% CL 0.9-2.3); however. an mcreased nsk ofbreast cancer was noted with

;26 years ofHRT use (RR. 1.7; 95% CI. 1.1-2.6). In an earher study using the same cohort (n =

22.597. mean age of 54.5 years at cohort entry III 1983). Persson et a1.14 reported standardized

incidence ratios (SIRS) for breast cancer in 5.573 women who used 2 mg 17j3-estradiol plus

cyclic 250 Jlg levonorgestrel. The authors observed a time-dependent moderate risk with this

HRT regimen. The SIRs increased from 1.1 (95% CI, 0.8-1.5) with <5 years of follow-up to 1.3

(95% CI. 1.0-1.7) after 5 to 9 years of follow-up. and further increased to 1.4 (95% CI. 1.1-1.8)

after ;210 years.

Recently. Olsson et al 20 reported the results of a population-based cohort study among

29.508 women selected from southern Sweden. The participants were followed for 10 years to

determine whether different types ofHRT and differences In duration of use resulted III

differences in risk ofbreast cancer. ApprOXImately 3.700 women had used HRT. After

potentially confounding variables were adjusted for. users oflong-term. continuous-combined

HRT had a significantly higher risk ofbreast cancer compared to never users (RR, 4.60; 95% CI,

2.39-8.84). Nonsignificant elevated risks were seen for long-term sequential HRT (RR, 2.23;

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8

95% CI. 0.90-5.56). gestagen-only therapy (HR. 3.74; 95% CI. 0.94-14.97), and estriol-only use

(RR, 1.89; 95% CI. 0.81-4.39). The greatest risks were seen with use ofcontInuous-combined

and gestagen-only therapy 48 months or longer- No increased risks were seen in women after 5

years ofnonuse. Estradiol-alone therapy did not significantly increase the breast cancer risk. The

authors do not state which specific estrogens or progestins were used in the combination

therapies. Whether the type ofprogestogen influences the nsk profile is unclear.

Five studies conducted In the United States also reported an increased RR for breast

cancer with current use ofHRT!S-IQ Two of these were regional case-control studies16,1Q and the

others were multicenter. population-based. case-control studies.1S.17.18

Ross and colleagueslQ

evaluated the effect ofHRT on breast cancer risk in women (1897

cases. 1637 controls) aged 55-72 years and hvmg in Los Angeles County. CalIfornia.

Combination therapy was most commonly prescribed sequentially. and CEE 0.625 mg and MPA

(no dose reported) was used by the majority ofwornen. Breast cancer risk increased with

increasing duration ofHRT use (OR per 5 years ofuse. 1.24; 95% CL 1.07-1.45; P = .005).

When sequential and continuous HRT were evaluated individually. only the OR per 5 years of

sequential HRT use was sigmficant(OR, 1.38; 95% CL 1.13-1.68; P= .0015); however, the

differences between regimens were not significant. Chen et al.16 reported similar findings in a

nested case-control study (1995 case, 692 controls) ofpostmenopausal women aged 50-74 years

emolled in the Group Health Cooperative ofPuget Sound. Current use oforal HRT (the type of

estrogen or progestin was not identified) was associated with an increased nsk ofbreast cancer

(OR. 1.49; 95% CI. 1.04-2.12). The OR for breast cancer in women who used HRT during the 5­

year period that ended at I year before diagnosis was 1.61 (95% CI. 1.03-2.50). Risk was

similarly increased in sequential and continuous combined HRT.

DWRITE 072469

9

Schairer and colleagues17 evaluated the risk ofbreast cancer with HRT (primarily

CEEIMPA) in a cohort study of46,355 women (mean age at follow-up, 58 years) from the

Breast Cancer Detection DemonstratIon Project. The RR ofbreast cancer With ever use or

current use ofHRTwas 1.3 (95°/0 CI, 1.0-1.6) and 1.4 (95% CI, 1.1-1.9), respectively. Based on

a linear excess risk model, the authors noted a significant trend (P = .01) for a duration effect

with HRT (RR increased by 0.08 for each year ofHRT use: 95% CI, 0.02-0.16). although the

effect was only significant for women with a BMI :Q4.4 kg/m2•

In a multicenter study conducted in Massachusetts, New Hampshire, and Wisconsin,

5298 postmenopausal women (ages 50-79 years) with a new diagnosis of invasive breast cancer

and 5571 controls were evaluated. ls Ever use ofHRT (primarily CEE and MPA) was associated

with an increased RR ofbreast cancer (RR, 1.43; 95% CI, 1.18-1.74); no differences in risk were

noted between sequential (progestin added <10 days/cycle) or continuous (progestin added >21

days/cycle). In a report that followed the WHI findings, Weiss and colleaguesl8 evaluated the

effect ofHRT regimens (type of estrogens or progestins was not reported) on breast cancer nsk

In women (4575 cases, 4682 controls), aged 35-64 years, participating in the Women's

Contraceptive and Reproductive Experiences Study, which was conducted in Atlanta, Detroit,

Los Angeles. Philadelphia.. and Seattle. Odds ratios for breast cancer risk with short-term use «2

years) ofany combined HRT regimen was not increased. Current use ofHRT for 2:5 years was

associated with an increased risk (OR, 1.37; 95% CI, 1.06-1.77), although the increase was

confined to continuous combined HRT.

In summary, the fmdmgs of the WHI that longer-duration CEEIMPA is associated with

an increased RR ofbreast cancer are consistent with other studies using similar products as well

DWRITE 072470

10

as studies conducted in Europe where different estrogen and progestin products are more

common.

Cardiovascular outcomes

Veno/ls thromboembolic events

Table II summarizes recent studies ofthe effects ofvarious regimens ofERT and HRT

on cardIOvascular outcomes. The potential risk of venous thromboembolic events (VTEs). deep

venous thrombosis (DVT), or pulmonary embolIsm (PE) WIth ERTIHRT IS well recognized. In

the HRT arm of the WIll trial, the increased HR for VTEs was 2.11 (nominal 95% CI. 1.58­

2.82).1 It should be noted this population included a small number ofwomen with a history of

VTE; when the authors analyzed this subset ofwomen., the HR for future VTE with HRT was

4.90 (95% CI. 0.58-41.06).

Before the WHI. a number ofstudies (randomized and observational) examined VTE

risk- In conjunction with the US Preventive Services Task Force. Miller and colleagues22

calculated a summary risk estimate for VTE based on a meta-analysis of 12 studies that used a

variety ofERTIHRT products and doses.23-34 The meta-analysis revealed that current use of

postmenopausal ERTIHRTwas associated with a twofold increased nsk ofVTEs (RR. 2.14;

95% Cl1.64-2.81). In the studies that examined duration ofuse. the highest RRs were observed

within the first 2 years; the summary RR for year I in these studies was 3.49 (95% CI, 2.33­

5.59\.

These studies included three randomized controlled trials. the Heart and

Estrogen/progestIn Replacement Study (HERS)23 and the Estrogen Replacement and

Atherosclerosis (ERA) trial.24 both secondary prevention trials. and the primary prevention

Postmenopausal EstrogenlProgestin Interventions (PEPD trial.2S all ofwhich used continuous

DWRITE 072471

11

combined 0.625 mg CEE plus 2.5 mg MPA. fu the HERS (n =2763) and the ERA trial (n =

309). the average age ofthe women studied was >65 years.23,24 The relative hazard (RH) of

VTEs with HRT use over a mean of4.1 years in HERS was 2.89 (95% CI, 1.50-5.58)23; in the

ERA trial, the authors noted a small number ofevents over the average 3.1 years of follow-up,

with no differences observed between HRT users and placebo.~4 In the PEPI tnal, 875 healthy

postmenopausal women (mean age =56 years) were randomized to placebo, CEE 0.625 mg, or

CEE combined with either continuous MPA 2.5 mg, cyclic MPA 10 mg (12 days/month), or

micronized progestin (MP) 200 mg (12 dayslmonth).2S A total of 10 participants in the active

treatment groups and none in the placebo group experienced VTEs; no differences were noted

between ERTIHRT groups. Oral CEE With or without MPA was also the primary type of

ERTIHRT reportedly used in the Nurses' Health Study, an observational study ofover 112,593

women aged 30-55 years in 1976.31 The authors noted that current use ofpostmenopausal

hormones, primarily ERT in this report, resulted in an increased risk ofprimary PE (RR, Z.I;

95% CI, 1.2-3.8).

Studies reporting an mcreased nsk ofVTE with ERTIHRT regimens other than

CEEIMPA had similar findings 26-30 fu a case-control study ofwomen aged 45-64 years

conducted in the United Kingdom. Daly and colleagues2b analyzed 103 cases (69 with DVT, 39

with PE) and 178 controls; 44 women in each group were currently using estrogen products that

included oral eEE, 1713-estradiol or estradiol valerate, piperazine estrone sulphate, and

transdermal estradiol. Approximately halfofthe hormone users in each group also used a

progestm (type was not specified), and tlbolone was considered HRT. The adjusted OR for VTE

m current HRT users compared with nonusers was 3 5 (95% CI, 1.8-7.0). The authors indicated

there were no significant differences in the risk ofVTE between ERT and HRT, oral and

DWRITE 072472

11

transdennal therapy. or between lower-dose (equivalent to CEE 0 625 mg. 1713-estradiol 1 mg. or

transdennal delivery of 17J3-estradiol 50 ~g per 24 h) or higher-dose (equivalent to CEE 1.25

mg. 17J3-estradioI2 mg, or transdermal delIvery of1713-estradlOl 100 ~g per 24 h) preparatIons.

In a large. population-based. case-control study in the United KIngdom In =347.253

women. 50-79 years).27 the adjusted OR for VTE in current HRT users was 2.1 (95% CI. 1.4­

3.2). The increased risk was restricted to first-year users; the adjusted ORs for VTE were 4.6

(95% CI. 2.5-8.4). 3.0 (95% CI. 1.4-6.5). and 1.1 (95% CI, 0.6-2.1) in current users for 1 to 6

months. 6 months to 1 year. and> I year. respectively. No difference in nsk was observed for

estrogen alone or combmed With progestin. transdennal vs. oral regimens. or for lower-dose

(equivalent to CEE 0.625 mg or transdermal delivery of 17J3-estradiol 25 ~g or 50 ~g per 24 h)

vs. higher-dose (equivalent to CEE 1.25 mg or transdermal delivery of 17J3-estradiol I00 ~g per

24 h) therapy.

A similar overall risk ofVTE (OR. 2.3; 95% CI, 1.0-5.3) was reported in an Italian

population cohort study of265.431 women aged 45-79 years. in which 79% reported use of

transdermal estradio1.28 As noted in previous studies. the increased risk appeared restricted to the

first year of use (OR. 2.9; 95% CI. l.2-6.9) and. although data were linuted, a lugher VTE risk

was noted ill women who usedHRT (OR. 5.0; 95% CI.I.5-16.7) compared with ERT (OR. 1.4;

95% CI, 0.4-4.6).

In a population-based case-control study ofwomen aged 45-70 years in Norway.

Hoibraaten and colleagues analyzed the risk ofVTE in a total of 176 cases and 352 matched

controls using hospital charts from a period of 6 years.30 The authors noted that only ERTIHRT

products contaimng estradiol were used. but different progestins and both oral and transdermal

routes of administration were reported. The adjusted OR for VTE in current users ofHRTwas

DWRITE 072473

13

not sigmficantly increased (OR, 1.22; 95% Cl 0.76-1.94); however, an increased risk ofVTE

was noted during the first year of use (OR., 3.54; 95% CI, 1.54-8.29).

The overall evidence supports an increased risk of VTE associated with postmenopausal

ERTIHRT. Relative risks for VTEs range between 2.0 to 3.0, with the greatest risk seen within

the first I to 2 years ofuse. The data regarding risk ofVTE and postmenopausal ERTIHRT are

consistent for all types of estrogens and progestins.

Stroke

At least four randomized placebo-controlled trials,I,23.24.35 one meta-analysis,36 and many

observational studies31-56 have reported the effects ofpostmenopausal ERTIHRT on stroke. A

recent meta-analysis conducted for the US Preventative Services Task Force36 pooled results

from 9 observational studies41.44.49.s2.54.55.51-SQ that were rated fair to good in quality with respect

to internal valtdlty. The summary RR for overall stroke incidence was increased among ever

users (RR, 1.12; 95% CI, 1.01-1.23); the authors noted no differences between current, ever, and

past users. In subanalyses, the RR was elevated with HRT for thromboembolic stroke (RR. 1.20;

95% CL 1.01-1.40). but not for subarachnoid or intracerebral stroke.36

In the HRT arm of the WHI trial, the overall HR for stroke (fatal and nonfatal) was 1.41

(nommal 95% CI, 1.07-1.85) after an average of 5.2 years offollow-up.1 When separated into

fatal or nonfatal events. CEEIMPA users had an increased risk for nonfatal stroke (HR 1.50;

nominal 95% CI, 1.08-2.08) but not for fatal stroke (HR 1.18: nominal 95% Cl 0.58-2.50). The

increased risk ofstroke in HRT users appeared in year 2 (HR, 1.71) and persisted through year 5

(HR., 1.87). In a recent subanalysis from this trial, HRT was associated With an Increased risk for

ischemic stroke (HR =1.44; 95% CI, 1.09-1.90), but not for hemorrhagic stroke (HR =0.82;

95% CI. 0.43_1.56).60 In contrast to the WHI, no increased risk for any stroke was noted in the

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secondary prevention tnals that randomized women to CEE 0.625 mgIMPA 2.5 mg-HERS and

HERS II (an open-label, 2.7-year extension of the HERS )6H>3 and the ERA tnal.~4

The Women's Estrogen for Stroke Trial (WEST) is the only randomized, placebo­

controlled trial evaluating the effects of 1713-estradiol on stroke.35 A total of664 postmenopausal

women (mean age =71 years) who recently had an ischemic or transient ischemic stroke

received placebo or 1713-estradiol 1 mg. Women with a uterus received an annual 12-day course

ofMPA 5 mg. An increased RRofany stroke (RR, 2.30; 95% CI, U-5.0) was observed in the

ERT group within the first 6 months of therapy, although no significant differences were noted

between treatment groups In either nonfatal (RR, 1.0; 95% CI, 0.7-1.4) or fatal stroke (RR, 2.9;

95% CI, 0.9-9.0) for the overall study (mean follow-up of2.8 years).

In other studies that evaluated estrogens other than CEE, three included a variety of

different estrogens38.S4,S8 and one appeared to include only formulations containing 1713­

estradiol.ss Thompson and colleagues assessed the effects of 76 different ERTfHRT regimens on

the risk of stroke and MI in women aged 45 to 69 years who were seen at 83 general practices in

the United Kingdom.S8 Sixty percent of the recorded prescriptions in this case-control study were

wntten for estropipate, ethmyl estradioVmethyltestosterone, CEE, norethisterone,

diethylstilboestrol, and ethinyl estradiol. Based on data from 109 cases and 174 controls, the

authors reported no increase in the risk of stroke for either estrogens alone. progestins alone. or

combined HRT products.

In a Danish case-control study, Pedersen et al.S4 evaluated the risk ofstroke subtypes in

women aged 45-64 years who had a nonfatal stroke durmg 1990-1992 (1422 cases and 3171

controls). A variety ofdifferent hormone regimens and preparations (tablets, patches, and

preparations for injections) were included in the analysis. No associations were observed

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between the use ofERT or HRT and the risk of subarachnoid hemorrhage, intracerebral

hemorrhage. or thromboembolic infarction. For transIent ischemic attacks. the current use of

ERT (OR. 2.11; 95% CI. 1.41-317) but not HRT (OR, 1.25; 95% CI, 0.86-1.82) was associated

with an increased RR. Using the US National Registry of Myocardial Infarction-3 database (n =

114.724 women ~55 years\. Angeja and colleagues38 evaluated the impact ofHRT use on the

risk of in-hospital hemorrhagic and ischemic stroke after an acute Ml For the 7353 women

(mean age, 71 years) who were currently using any estrogen. progestin. or estrogen-progestin for

reasons other than contraceptIon, the adjusted RRs for ischemic stroke were 0.89 (95% CL 0.66­

1.81) and 0.88 (95% CI. 0.58-1.35) for hemorrhagic stroke.

A Finnish cohort study eXanJined the effects ofERTIHRT on morbidity and mortality

from stroke in 7944 women who were born between 1923 and 1939 (aged 57 to 6* at the

initiation of follow up).55 Current estrogen users (n = 988) received 1713-estradiol (mean daily

dose. 1.46 mg) at baseline; 139 women used a progestin. The adjusted RR for stroke morbidity

(RR. 0.86; 95% CI. 0.42-1.75) or mortality (RR. 0.16; 95% CI. 0.02-1.18) was not significantly

influenced by current ERTIHRT use. although the authors noted that the reductIon in stroke

mortality was ofborderline significance (P = .049). These data were based on only 10 cases of

stroke. one ofwhich was fatal.

There may be a dose-related effect ofestrogens on the risk ofstroke. In the 20-year

follow-up report from the Nurses' Health Study (n = 70,533). the RR of stroke was increased

significantly among women who took CEE 0.625 mg (RR, 1.35; 95% CI. 1.08-1.68) or those

who took CEE ~1.25 mg (RR. 1.63; 95% CI, 1.18-2.26); however, there was no associated

increase in stroke for CEE 0.3 mg (RR, 0.54; 95% CI, 0.28-1.06 [based on only 9 cases)).52

While the data for the risk of stroke specific to postmenopausal HRT containing

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estrogens and progestins other than CEE and MPA are limited. they are consistent with the total

data evaluating the risk ofstroke with ERTIHRT.

Corollary heart disease

The majority ofpublished observational studies using a variety ofpostmenopausal

hormone therapy products reported a 30% to 50% lower incidence ofCHD among ERTIHRT

users.52 ,(>4,05 In a recent meta-analysis using studies rated as fair or good in quality, Humphrey

and colleaguesoo reported a summary RR for CHD of0.80 (95% CI. 0.64-0.78) among current

users ofERTIHRT. However. when the authors evaluated only those studies that reported

adjusting for socioeconomic status. the reduction in RR for CHD was no longer significant

(summaryRR. 0.97; 95% CI. 0.82-1.16).

Data from recent randomized clinical trials have failed to show that ERT/HRT is

protective against primary or secondary CHD.1.23,35,07,08 As noted preVIOusly. the primary

prevention WHI trial I and the secondary prevention HERS23 investigated the effect of continuous

combined CEE 0.625 mglMPA 2.5 mg on CHD in postmenopausal women who were on average

63 and 67 years. respectively. In the WHI. the investigators reported an HR of 1.29 (95% CI,

1.02-1.63) for CHD (nonfatal and fatal MII.1 The mcrease in the risk ofCHD in the HRT group

was greatest in year 1 (HR, 1.78). This potential trend ofthe risk of an early event was also

evident inHERS.23 The increase in risk of recurrent CHD in year 1 (RH. 1.52; 95% CI. 1.01­

2.29) decreased with continued HRT use (P = .009 for trend in log RHI.leading to an overall

null rmding for the effect ofHRT on the risk ofCHD events (RH. 0.99; 95% cr. 0.80-1.22) over

the average follow up of4.1 years.

Three additional randomized clinical trials (If secondary prevention of CHD. the

Papworth HRT Atherosclerosis Study (PHASE),07 the oEStrogen in the Prevention of

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ReInfarction Trial (ESPRIT).b8 and the WESr5 used different forms ofERTIHRT containing

estradiol. The PHASE is a randomized. open-label. blind end-point trial of255 postmenopausal

(average age, 67 years) with angiographically proven ischemic heart disease who received

transdermal ERT (n =58), transdermal HRT (n =76), or no treatment (n =121) for an average of

30.8 months.67 Neither the type of estrogens or progestins used nor treatment doses was reported.

Hospitalizations for unstable angina, nonfatal MI, and CHD death were the main outcomes

measured. Over the 4-year trial, the event rate ratio with transdermal ERTIHRT was 1.29 (95%

CI, 0.84-1.95), with no differences observed between the ERT and HRT groups. The authors

noted that the most frequently observed events were hospitalizations for unstable angina; these

occurred mamly wlthm the first 2 years ofrecruitment to the trial.

In the WEST, CHD was a secondary outcome in older (average age, 71 years)

postmenopausal women (n = 664) with a recent stroke who were randomized to 17~-estradiol 1

mg (n =337) or placebo (n =327) for an average of 2.8 years.35 These authors reported the RR

for any cardiac event (nonfatal or fatal) with ERT use was 1.1 (95% CI, 0.6-1.9); for nonfatal

MI. the RR was 1.2 (95% CI. 0.5-2.5). Recent data from the ESPRIT indicated that estradiol

valerate 2 mg also did not prevent reinfarction or cardiac death compared with placebo.b8In this

trial, 1017 postmenopausal women, aged 50-69 years, who had survived a first MI received ERT

(n =513) or placebo (n = 504) for 2 years. The event rate ratio for either reinfarction or cardiac

death with ERT was 0.99 (95% CI. 0.70-1.41). In contrast to previous studies, the authors

reported that the RR ofcardiac death with ERT was lowest durmg the first 3 months after

entering the trial (RR. 0.33; 95% CI, 0.11-1.01).

This trend for risk of early events with ERTIHRT in women with established CHD was

also noted in post hoc analyses ofprospective observational cohorts that used a variety of

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fommlations.bq

-71 Heckbert and colleagues evaluated recunent CHD in 981 women (mean age,

67.8 years) who had survived an initial MI using data from the Group Health Cooperative, a

health maintenance organization in Washington State.6Q Unopposed estrogens (most common

were esterified estrogens [70% of oral estrogen use] and CEE [28% oforal estrogen use]) were

used 67% of the total time; combined estrogen-progestm was used 33% ofthe time, With MPA

virtually the only progestin used. The overall adjusted RH for recurrent MI or CHD death was

not influenced by ERTIHRT use (RH, 0.96; 95% CI, 0.62-1.50); however, there was a suggestion

ofan increased risk within the first 60 days of initiation or re-initiation of therapy (RH, 2.16;

95% CI, 0.94-4.95), followed by a reduction in risk with use ofERTIHRT for >1 year (RH, 0.76;

95% CI, 0.42-1.36).

SimIlar findings were reported in an analysis of2489 women with CHD from the Nurses'

Health Study.70 Women who initiated postmenopausal ERTIHRT (primarily CEE with or

without MPAl within 1 year of an MI had an RR for CHD events of 1.25 (95% CI, 0.78-2.00);

for the second and subsequent years of use, the RRs were 0.55 (95% CI, 0.13-2.27) and 0.38

(95% CI, 0.22-0.66), respectively. In a retrospective analYSis ofwomen ~50 years from the

Coumadin Aspirin Reinfarction Study (CARS) database, the HR for recurrent first-year events of

cardiac death, MI, or unstable angma was 1.44 (95% CI, 1.05-1.99) for new users ofERTIHRT

(median age, 58 years) compared with never users (median age, 67 years).71 The types and

dosages ofhormones were not reported. In addition, the authors noted that new users ofERT (n

= 70) had a 48% occurrence of the composite end point compared With 23% in new users of

HRT (n = 26; P= .014). However, there were few MIs and no deaths among the new users of

ERTIHRT; thus the abihty to detect real differences was reduced.

In addition to the incidence ofCHD, Humphrey and colleaguesbb evaluated ERTIHRT

DWRITE 072479

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use and the risk ofCHD mortality in their meta-analysis of5 observational studies42 ,46.55.72.73 that

were rated as fair or good in quality. These studies included the use of ERTIHRT contammg

pnmanly CEE and MPA4t> as well as regimens pnmanly contaming 1713-estradioI.55 Current use

ofERTIHRT was associated with a reduced risk ofCHD mortality (summary RR, 0.62; 95% CL

040-0.90). although any use ofERTIHRT (including current. past. or ever use) was not

associated with a significant reduction in CHD mortality risk (summary RR. 0.74; 95% CI. 0.36­

1.45).

Potential beneficial effects ofERTIHRT use were also found for in-hospital survival after

MI based on the subset of 114,724 women ~55 years participating in the National RegiStry of

Myocardial Infarction-3 descnbed above.38.40 Shhpak and colleagues40 reported an adjusted OR

of0.65 (95% CI. 0.59-0.72). indicating an improved rate ofsurvival in current users ofHRT

(defined as the use ofestrogen. progestin, or estrogen/progestin for reasons other than

contraception). This benefit was observed for all age groups (55-64. 65-74. 75-84. and >84

years). with the reduction in the adjusted OR for CHD mortality greatest for the youngest group

ofwomen (OR. 0.54; 95% CI, 0,41-0.71).

Additional data from coronary artery bypass patients suggest that estrogen may have

benefits in relation to vascular injury. Nussmeier et al.74 conducted a retrospective analysis of the

records of4259 patients aged ~55 years who underwent primary elective isolated coronary artery

bypass surgery at Texas Heart Institute in Houston. Women (n = 1161) who were using

ERTIHRT at hospital administration (n = 256) had significantly less in-hospital mortality

compared to women who were not (P < .005). Eighty-five percent ofthe honnone therapy users

were taking CEE or estradiol alone; the rest were taking CEE and MPA

In summary. the early increased risk ofCHD incidence with CEE/MPA that was

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20

observed in the WHI1 and HERS23 has been documented more recently in both randomized

clinical trialsb1 and retrospective analyses ofobservational cohort studies that investigated

ERT/HRT products containing a variety ofestrogens and progestins.hQ•11 The potential reduction

in nsk ofCHD mortality seen In observatIOnal studies using various ERTIHRT

products4IJ ,42,46,55,n,13 has not been documented in randomized climcal stuches using either

CEEIMPA1,23 or ERTIHRT predominantly containing estradioL35,61.68

Documented Benefits of HRT

Osteoporosis

Fracture risk

Until the WHI trial, there were no large, randomized clinical trials designed to evaluate

the use ofHRT on fracture risk. After a mean follow-up of 5.2 years, the WHI investigators

reported significant reductions in hip (HR, 0.66; nominal 95% CI, 0.45-0.98), vertebral (HR,

0.66; nOlD1nal 95% CL 0.44-0.98), and total fractures (HR, 0.76; nOlD1nal 95% CI, 0.69-0.85)

with CEEIMPA.I The WHI is also the first trial to show reductions in risk of fracture in women

who were not defined as "at risk" for osteoporosis.15 Based on a preliminary analysis. about

2.1 % women in the 50 to 64 age group and about 9.4% women in the 65- to 79-year age group

were osteoporotic according to the baseline BMD measurement.76 Recently, Wells et aL77

conducted a meta-analysis of 7 randomized chmcal trials,23,78-83 not including the WHI, that

reported the RR ofvertebral and nonvertebral fractures with different fonus ofERTIHRT

(including oral CEE with or without MPA, NETA, estradiol valerate, micronized 1713-estradiol

and transdermal I 7~-estradiol). The summary or weighted RRs were 0 66 (95% CI, 041-1.07)

for vertebral fractures and 0.87 (95% CI, 0.71-1.09) for nonvertebral fractures. When the WHI

DWRITE 072481

21

was later included in the summary estimate for nonvertebral fractures, the reduction in RR was

0.78 (95% CI. 0.64_0.96).84

The decrease in fracture risk with postmenopausal ERT/HRT has been demonstrated in

several large observational studies, including the Framingham Heart Studl5 and the Study of

Osteoporotic Fractures (SOF).86In the Frammgham study, 2873 women who were aged 30 to 62

years at the time ofthe first examination (1948-1951 ) were included in the analysis; 60% (n =

1720) were living at the time the fracture data were examined (1983-1985).85 For those women

who reported use of estrogens (CEE was primarily used) within the past 2 years, the RR ofhip

fracture, adjusted for age and weight, was reduced (RR, 0.34; 95% CI, 0.12-0.98). The SOF, a

prospective study of 9704 women ~65 years, evaluated the effects ofdifferent types oforal ERT

and HRT on wrist and all nonvertebral fraCtureS.86 The current use ofHRT resulted ill reductIons

in the adjusted RRs for both wrist (RR, 0.31; 95% CL 0.11-0.84) and all nonvertebral fractures

(RR, 0.51; 95% CI, 0.33-0.78); these were similar to the reductions seen with ERT use.

BOlle milleral dellsity

Since low bone mineral density (BMD) is the single best predictor of fracture risk in

postmenopausal women,87 BMD has been used to evaluate the efficacy of antiresorptive agents

for postmenopausal osteoporosis. Three large. randomized clinical trials using CEEIMPA,

including lower doses, have documented beneficial effects on lumbar spine and hip BMD.88.89 In

the 3-year PEPl trial described previously. both spine and hip BMD increased approximately 5%

and 2%, respectively. In the 2-year Women's Health, Osteoporosis, Progestin, Estrogen

(Women's HOPE) trIal of 749 postmenopausal women (average age, 52 years), significant

increases in spine and hip BMD from baseline were observed with CEE 0 625 mg/MPA 2.5 mg,

as well as with lower doses containing CEE 0.45 and 0.3 mg with MPA 1.5 mg.89

Increases

DWRITE 072482

22

ranged from 1.7% to 3.5% for spine BMD and from 1.9% to 2.6% for hip BMD for the lower

and higher CEEIMPA doses. respectively.

In their systematic review of 57 studIes. Wells and colleagues evaluated a number of

randomized clinical trials that used a variety ofERTIHRT products other than CEEIMPA.77

These studies included oral regimens containing ethinyl estradIol. NETA. estradiol valerate. 17P­

estradiol. mestranol. gestranol. estrone sulfate. MP, or nylestriol. and transdermal or cream

regimens containing 17p-estradiol. The weighted mean difference in spine BMD with ERTIHRT

compared with controls after 2 years for all studies combined was 6.76% (95% CI, 5.63%­

7.89%). For hip (femoral neck site) BMD. the weighted mean difference between ERTIHRT and

control groups was 4.11% (95% CI. 3.45%-4.80%) after 2 years oftreatrnent. The authors did

not find a difference in effect on BMD among VarIOUS formulations ofpostmenopausal

ERTIHRT.

HRT has also been shown to decrease biochemical markers ofbone turnover that are

correlated with an increase in BMD. In two large placebo-controlled trials oftransdermal 1713­

estradiol combined cyclically with dydrogesterone. Delmas et al.90 found that the increase in

BMD seen with HRT could be monitored by measuring such markers as C-telopeptide oftype I

collagen. In the Women's HOPE study. standard and lower doses ofcontmuous combined

CEEIMPA SIgnIficantly reduced serum osteocalcin and urinary cross-linked N-telopeptides of

type I collagen. biochemical markers ofbone formation and bone resorption. respectively.89

The WHI findings confirm that HRT continues to be an important therapy for preventing

osteoporosis. Although large. randomized trials of fracture risk with HRT products other than

CEEIMPA are lackmg. BMD is increased With a variety ofERTIHRT products. In addition.

lower doses ofERTIHRT increase BMD; however, whether lower doses ofERTIHRT also

DWRITE 072483

23

reduce fracture nsk requires further research.

Colorectal cancer. Before the WHI, the data on the RR ofcolon cancer 3fId ERTIHRT

had been derived from primarily from observational studies In the WHI, a reduction in the risk

of colorectal cancer was observed with CEEIMPA use (HR, 0.63; nominal 95% CL 0.43-0.92)

over an average of 5.2 years.! These beneficial findings are consistent with those reported in

meta-analyses by H6bert-Croteau91 and Grodstein et a1.92 that summarized data from studies

conducted in several countries that used a variety ofERT/HRT products. The overall RR for

colon c3flcer of0.85 (95% CI, 0 73-0 99) reported by Hebert-CroteauQI was similar to that

reported by Grodstein et al.Q2 for colon c3flcer (RR. 0.80: 95% CI. 0.74-0.86): these authors

noted a summaryRR for colorectal c3flcer of0.66 (95% CI, 0.59-0.74).

Although the only large. r3fldomized clInical tnal to report a reductlon in colorectal

cancernsk with HRT used oral CEE O.625/MPA 2.5 mg} the fact that these findings are similar

to those noted in observational studies that included a variety ofERTIHRT products would

suggest that postmenopausal women will benefit regardless of the type ofERTIHRT regimen

used. The mechanisms behind this benefit are yet to be deterrmned; the role of estrogen receptors

in the colonic epithelium is bemg investlgated.Q3

Menopausal symptoms. One of the primary concerns related to the overall risklbenefit

analysis ofHRT in the WHI was the fact that the importance ofthe relief ofmenopausal

symptoms was not considered and that women with severe menopausal symptoms were excluded

from the study. Since most women initiate HRT for symptom relief, interpretation ofthe findmgs

from WHI may be affected by clInical practice.

Incidence alld effects ofmellopausal symptoms

Hot flushes are the most common symptom of the peri- and postmenopause, affecting

DWRITE 072484

24

68%94 to 93% ofwomen.95 In addition to increasing hot flushes. the menopausal transition is

associated with increased complaints ofvaginal dryness. pain during intercourse. irritability.

depressed mood, and sleep disorders.%·98Hot flushes and the physiologic events that accompany

them are part of a complex sequence of events that affect overall quality oflife (Qoq for peri­

and postmenopausal women.

Reliefofmel/opal/sal symptoms

Recent literature on the efficacy and safety ofERTIHRT for treatment of vasomotor

symptoms includes over 40 randomized controlled clinical trials. These trials evaluated several

estrogen compounds alone in various delivery systems and in combination with a variety of

progestins.

Decreases in frequency and severity ofhot flushes compared to placebo have been shown

in a variety ofstudies that used the standard dose ofCEE 0.615.99-112 as well as those involving

lower doses.99 The additlon of a progestm does not negate estrogen efficacy for reliefofhot

flushes, and may even enhance efficacy with lower doses.99

Similar improvement ofvasomotor symptoms has also been shown in randomized

controlled trials with other estrogens. including both oral113·\22 and transdennaII12.12J-125

regimens. In one comparative 12-week trial of104 postmenopausal women (average age, 52

years), oral eEE 0.615 mg and transdermal estradIol 50 Jlglday proVIded sImIlar symptom

relief. 112

A dose-response has been reported with oral estrogens (17J3-estradiol or CEE), which

tends to disappear when a progestm (NETA or MPA) is added.Go.lI701l8 In the Women's HOPE

study, lItian and colleagues noted that lower doses ofMPA (1.5 mg) combined with lower doses

ofCEE (0,45 mg or 0.3 mg) were also effective for the reliefofvasomotor syrnptoms.99

DWRITE 072485

25

A meta-analysis of 10 placebo-controlled trials demonstrated that a variety of estrogens

(estriol, l7~-estradiol, and CEE) administered by oral, transdennal, or vaginal routes were all

effective in the treatment ofsigns and symptoms of urogenital atrophy, including dyspareunia. m

In the Women's HOPE study. the vaginal maturation index, a measure of vaginal atrophy, was

similarly improved with standard and lower doses of oral CEE and MPA.'19

Quality of life. Only a few studies designed to evaluate the effects ofERTIHRT on QOL

have been placebo-controlled, and they generally enrolled small samples with short duration of

use. A randomized. placebo-controlled study involving 242 women (mean age, ",53 years) found

that health-related QOL and well-being improved after 12 weeks of 50 I!glday of transdennal

estradiol compared with placebo.127 Similar results have been found with standard- or lower-dose

formulations of estrogens (esterified estrogens, 17~-estradiol, or CEE) whether combined with a

progestin or not. 12Q,1 28-130

Recently. the WHI investigators reported their findings for QOL measures at baseline and

1 year for all women. and after 3 years in a subset ofl511 women. 13J Only about 17% ofthe

women enrolled in WHI were <5 years since menopause, a time when menopausal symptoms are

most severe and may affect their quality oflife. m After 1 year of treatment, HRT was associated

with significant benefits in self-reported sleep disturbances, physical functioning, and body pain;

in contrast. no differences were noted in measures ofsocial functioning. mental health. and

sexual satisfaction. The benefits noted in year 1 were not found after 3 years of treatment. In the

574 symptomatic women. 50 to 54 years of age, only sleep disturbances were improved after 1

year of treatment. It should be noted that the scales used in the WHI were not those

conventionally used to evaluate postmenopausal women, and there was only one self-report

question on sexuality in women whose partner status was unknown.

DWRITE 072486

26

Sleep and mood. Improvements in sleep were associated with alleviation ofvasomotor.

somatic, and mood symptoms in a randomized crossover study of 63 postmenopausal women

(mean age, 56 years) administered transdermal estradiol either by gel or patch. lJ3 Similar

positive impact on sleep has been reported in other studies104,134-136 that used a variety of

ERTIHRT products (oral CEE, 1713-estradiol, MPA, and NETA. or transdennal1713­

estradiollNETA).

Estrogen replacement therapylHRT has been associated with a positive effect on

fatigue/energy and depressive mood in symptomatic women in randomized clinical trials137,m

that used oral CEE with either MPA or norgestrel, and in a prospective study that used

transdennal estradiol with either NETA or dydrogesterone.1JQ With the exception ofthe

HERS,IJ7 the average age of the women investigated was :;;55 years. The women in the HERS

with flushing symptoms were younger (63 vs. 67 years) and nearer to their last menstrual cycle

(13.7 vs. 18.7 years) than those Without symptoms.1J7 In their trial of33 postmenopausal women

(mean age, 54.3 years), Purdie et al 138 reported that the improvement in anxiety and depression

with 12 weeks oforal CEE 0.625 mg plus cyclic norgestrel 0.15 mg was not accompanied by

improvements in sleep quality. In contrast. neither measures of energy and fatigue nor depression

were improved in the WHI trial.13I

A positive effect ofERT (either CEE or 1713-estradIol) has been reported m two small

pilot studies enrolling depreSSive postmenopausal women aged 41-56 years.140,141 In contrast,

oral CEE does not have a benefiCial impact on mood in older women (mean ages ranged from 73

to 84 years) with dementia. 14!.144 These data support the beneficial effects ofdifferent ERTIHRT

products on menopausal symptoms. Although not all studies have demonstrated an improvement

DWRITE 072487

27

in QOL, sleep, or mood, those studies that have reported improvements have Included a vanety

ofERTIHRT regimens.

In the recently published Women's Health Initiative Memory Study (WHIMS) 145

involving a subset of 7,480 non-demented women, 4,532 participants were randomized to either

combInation HRT (0.625 mg CEE plus 2.5 mg ofMPA) or placebo daily. Because the primary

outcome was the incidence ofAlzheimer's disease and dementia, recruitment was lImited to

women over the age of65 years. Thus the mean age of the population was slightly over 70 years

when HRT was initiated. The principal finding ofthis report was an increased incidence of

dementia in women on HRT (45 vs. 22 events per 10,000 person-years), resulting in an HR of

2.05 (95% cr, 1.21-3.48). Although thIs outcome would not have been anticipated 10 years ago,

it is consistent with the results obtained from the Cache County Studyl4b publIshed in the JOIln/al

ofthe American Medical AssociatiOll last year. The women in the Cache study had a mean age of

74. Previous HRT use, or use for greater than 10 years, was associated with decreased risk.

whereas current use ofless than 10 years was associated with increased risk. This suggests that

imtIatIon of therapy late in lIfe is not protective and may increase nsk. Numerous observational

studies have suggested a protective effect when honnones were initiated at the time of

menopause, suggesting that there may be a critical time for initiation oftherapy in order to

produce this effect.14b.148 Most of these observational studies do not give accurate infonnation

regarding the type ofhonnone preparation used.

The second WHIMS report showed non-significant differences in cognitIve dechne,

although there was a trend toward lower scores in the treated group.149 Another recent report

from the WHI showed a slight increase in strokes (31 %)bO compatible with the principal WHI

DWRITE 072488

28

report. The latter finding does ratse the issue of possible microvascular events occurring in

susceptible older women leading to dementia,

Conclusion

This review evaluates the literature amassed on the risks and benefits ofpostmenopausal

hormones that have been highhghted by the recent findmgs from the WHI. I Although some have

suggested that the data reported in the WHI cannot be generalized to other HRT therapies.2 the

evidence presented in this paper suggests that both the risks and benefits associated with CEE

0.625 mgIMPA 2.5 mg have been identified in studies that used other estrogens (e.g.• oral ethinyl

estradiol. 1713-estradiol. estradiol valerate. piperazine estrone sulphate. estriol. or transdermal

1713-estradiol) and other progestins (e.g.• oral NETA. levonorgestrel. norgestrel. or transdermal

norethisterone. and dydrogesterone). Although recent findings with lower doses ofHRT have

suggested the benefits of standard doses are intact. whether lower doses WIll minlffiize the risks

seen with standard doses remams to be determmed.

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29

Acknowledgments

I would like to thank Amy S. Marren, MD, and Mary Sendi, RPh, for assistance in

searching the literature and developing the tables for this article. I am also grateful to Karen D.

Mittleman, PhD, and Stephen M. Parker, ELS, for their editorial assistance.

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Table I. Studies of effects of estrogen or hormone therapies on risk ofbreast cancer

Study!Country

Therapies Studied Study DesignJSubjects

Effect of Hormone Therapy on Breast CancerRisk

No significant effect ofERT or ERTIHRT on fISk.regardless of duration of use, time since last use, typeof hormone therapy, type of estrogen, or dose of CEE

Case-control studyCases: n = 109 (26.6"0 used

ERT)Controls: n = 545 (19.6°. used

ERT)Age ~45 yrs

P~pulatlon bas~ case-~o~tr~I'--6~·'e~Ij"HRT us~: - ---Cases: n = 1897 (54°0 used 1·5 years: OR 1.11

HRT) >5-10years ORI.SIControls: n = 1637 (52° 0used >10 years: OR 1.51

HRT) Per 5 years ofuse: OR 1.24'Ages 55-72 yrs Overall ERT use

>15 years OR 1.24 (less than 15 years: all OR:::1.02)

Per 5 years of use: OR l. 06By HRT regltnen:

Sequential: per year ofuse OR 1.38+Cominuous: per year ofuse OR 1.09

For both in situ and invasive'breast cancerAny HRT, current use: OR 1 52Any HRT, past use: OR 150Any HRT use: OR 1.54Non-CEE use' OR 186CEE use OR 1.49ERT only use: OR 1 66HRT only use: OR 1.02Use for <5 years: OR 1 55

____ . __ . -:::-- _. ._ _ Use ~l!~~1y~rs: OR.1_§L____ _ _Populatlon-based case-control Mean duration ofuse: 90 months for white women,

study 63 montlIs for blackCases: n =384Controls: n = 420Ages 20-74 yrs

CEENon-CEEERTHRT

ERTProgestin onlyHRTCEE $0.625 rugCEE >0.625 mgTransdermal estrogenCEE were used by 73%; 14°,'0 usedCEE and "other estrogens"Th-;-ri"py-~';;~-mairiiy--EItT:'~06i5

CEE most popular dose

Combined therapy most commonlysequential. With MPA mostcommon progestin

us

Moorman PG, et alAm J Public Health, 2000

us

us

CEEorCEEfMPA

Henrich JB, et ai.J elm Epltfemlol, 1998

Ross RK, et ai,J Natl Callcer lllst, 2000

51

Table I. Studies of effects of estrogen or honnone therapies on risk ofbreast cancer (continued)Studyl Therapies Studied Study Designl Effect of Hormone Therapy on Breast Cancer

Country SUbjects Risk

Schairer C, et 011JAMA,2000

US

Writing Group for the WHI.IAMA,2002

US

38". ofpemon years: estrogen-onlyuse

4°. E+P only use42~" with no hormone useCEE primary estrogen usedMPA primary progestin used

CEE 0.625/MPA 2.5 mgld

Retrospective cohort: n =46,355 women l473,687person years I

Cases: n = 2082Mean age = 58 yrsMean follow-up=IO.2 years

Randomized, placebo-controlled tnal

AclJve bi.: n = 8506Placebo: n = 8102Ages 50-79 yrs

Ever-use E only' RR 1.1- 805 cases/196,666 person­years

Ever-use E+P only: RR 1.3- 101cases/179,401person-years

Current HRT use: RR 1.4' (Nott? significant only IfBMI was <24 4)

Current ERT use: RR I 1

Duration ofuse:RR mcreases by 0.01 for eacn years ofERTRR mcreases by 0.08 for eacn years of HRT use

Duration smce last HRT use:1-2 years: RR 1 2>2-4: RR 12>4-6: RR 0 6>6 RRO.6

Duration slDce last ERT use:1-2 years: RR 1 4'>2-4: RR 12>4-6: RR 0,9>6 RR l.l

Data m study on disease stage and tumor IuslOlogyOverall HR: I 26 after an average of 5.2 yrs follow­

up

Subgroup analysis among women who used HRTbefore the study:

Tne HR was increased only in women who usedHRT before the study:

2.13' for women with <5 years of prior use4.61' for women with 5-10 years of prior useI.81 for women with 10 years of prior use1.06 among never users

52

Table I. Studies of effects of estrogen or hormone therapies on risk of breast cancer (continued)Studyl Therapies Studied Stud)' Design! Effect of Hormone Therapy on Breast Cancer

Country Subjects Risk

Newcomb PA, et al.Cancer Epidellliol Biolllarkels

Prev, 2002

us

l7p-estradiol

ERT (79°0 used CEEIHRT l86° 0 used MPA)

Multicenter case-control studyCases n = 5298 (1~71 HRT

users. 3827 non-users)Controls n= 5571 (I~39 HRT

users, 4132 non-users)Ages 50- 79 yrs

Average duration ofERT use cases lOJ yrs, controls9.2 yrs

Average duration ofHRT use: cases 4.2 yrs, controls~.5 yrs

Ever-use ofERT: RR I 23­Ever-use ofHRT: RR 1 ~3·

Current ERT use: RR \.25+Current HRT use: 1.39-Ever-use of contInuous combmed HRT' RR 1.5~·

Ever-use ofsequennal HRT, RR 1.57DurationofERTuse RR 1.0lperyear-ERT use <5 years' RR 1.07; >5 years RR I.3~·Duration ofHRT use: RR I. M per year·HRT use <5 years: RR 1.32·; >5 years RR 1.50·Time since HRT last use:

<5 years RR 1.7110-19 years: RR2.38

Time since last ERT use:<5 years RR 1.76·5-9 years: RR 1.2210-19 years: RR 1.12~O years RR 1.0~

Persson I. et al./nl J Cancer, 1996

Sweden'Soui-and~d::eiat" -- _m_.Lancet, 1998

Fmland

Mainly 17p-estradiol

17p-estradlol

. ·--·Cohort'study- ETIHT: SlR 1.3-Total: n = 22,579 1-4 years: SIR 1.1Cases: n = 63~ 5-9 years: SIR 1.3

10+ years: 1 ~.

---Cohortstudy' -.-- --- . -'£'1'00: RR0.57'Total: n = 79~

Cases: n = 100

S3

Table I. Studies of effects of estrogen or hormone therapies on risk ofbreast cancer (continued)Studyl Therapies Studied Study Design! Effect of Hormone Therapy on Breast Canc:er

Country Subjects Risk

Sweden :=- ---,- -:-=-ET or HT, c:omponents not spedfied

------._----------_._---------

Magnusson C, et aLIn! J Cancer, 1999

SwedenPersson I, et alCancer Causes Control, 1999

Mainly 17p-estradiol

Mawy 17p-estradiol

Case-control studyCases n = 3345Controls; n = 3454

Cohort studyTotal: n = 10,472Cases: n = 198

ET: OR 1.94·HT: OR 1.63·Per year ofET use: OR I 03Per year ofHT use: OR 1.07'ETIHT: SIR 1.2HT: 1-6 years: RR lA, >6 years RR 1.7·ET: 1-6 years: RR 1.0; >6 years: RR 1.1

Case-control studyCases: n = 1031 (24°0 HRT

use IControls n = 919l27°~ HRT

use)Women <55 yrs

ReanalysisCases n = 17,949Controls: n = 35,916

ERTHRTComponents not identified

UnspecIfied no variation in rIskaccordmg to type of estrogen used

WorldWIde

Ever-use ofHRT RR 0.89ERT use RR 0.70·HRT use: RR 0.99Duranon ofHRT use:

<3 yrs: RR 0.863-5 yrs: RR 1.00~6 yrs. RR 0.85

Duranon since last use:<I yrs: RR 0.91~I yrs: RR 0.82

ERTiHRT'RR l.i-i·lSE, o.ofi; ;;;:00001; for everuse

RR ofbreast cancer m current users ofHRTorprogestins alone for <5 yrs 1.15 (SE. 0.19)

Current use of ERT for <5 yrs: RR. 0.99; SE. 0.08Per year of use: RR 1.023 . .

Ng E-H:etai:-' --------.. - ETIHT, othenvi'5e unspecified'---- Case-control study-- .--- --ETllff OR 0.54 -------

Callc~r. 1997 Cases. n = 204Controls: n = 882

Collaborative Group on'Hormomil'Factors in Breast Cancerl.ancet, 1997

US

Brinton LA, et al.Menopause, 1998

China

54

Table I. Studies of effects of estrogen or hormone therapies on risk ofbreast cancer (continued)Studyl Therapies Studied Study Designl Effect of Hormone Therapy on Breast Caneer

Country Subjects RIsk

Persson I, et alInt J Cancer, 1997

Sweden

Tavani A, et alCancer Epid."",io! Biomarkers

Prel',I997

Hal}'Sellers TA, et alAnllllltern Med, 1997

us

Manjer J, et allilt J Cancer, 2001

ETIHT, otherwIse unspeCIfied

ETIHT. otherwIse unspecified

"HRT'; no mformation onformulations

ETIHT. otherwise unspecified

Case-control studyCases; n = 435Controls: n = 1740

Case-control studyCases; n = 5984Controls: n = 5504

Prospecnve cohort study41,837 women, 55-69 yrs

Cohort studyTotal; n = 5865Cases; n= 141

ETfHT: OR 1.11-2 years: OR 0.93-5 years: OR l.06-10 years OR 0,911+ years: OR 2.1 +ETIHT: OR 1-2<60months OR 1.2>60 months. OR 1.3

Past users,,5 yrs ofHRT use RR = 1.04(95% CI not given)>5 yrs ofHRT use RR = 0,89(95"'0 CI not given}

Current users25 yrs: RR = 1.34>5 yrs: RR = L17

Interaction between family history and HRT use wasnot slgmficant P>0.2ETIHT: RR I 66+

SwedenOlss~n H, et al.Br J Cancer, 200 1

ETIHT:;;therwl~';~-sp-ec-i-fie-d-.----coJi~~tstudy _u, ----­

Total: n = 29,508Cases' n = 434

ETIHT: SIR 1.35+1-48 months: HR 13648+ months: HR 1.80+

Sweden'Hedbiad B, et afu ----- --,-' ETIHT, otberwise-umpeci'fied

Scand J Public Healtil, 2002

Sweden

Cohort studyTotal: n = 5721Cases n = 141

ETIHT: RR 152'

55

Table I. Studies of effects of estrogen or honnone therapies on risk. ofbreast cancer (continued)Study! Therapies Studied Studl'Design! Effect of Hormone Therapy on Breast Cancer

Country Subjects Risk

Multicenter, population-based,case-control

4575 cases. 4682 controls35-64 yrs

Nested case-control study1995 case. 692 conlrols50-74 yrs

HRT regimens (type of estrogens orprogestins was not reported)

ERTOral contmuous combmed HRTOral sequential HRTThe type of estrogen or progestinwas not identified

Estrogens or progestms used 10 thecombmatlon tlleraples were notidentIfied

US

Sweden

Weiss LK, et al.Obstet Gynecol. 200!

US

CIlen C-l., et .11.JAMA.,2002

OR for breast cancer <2 years' use of any combmedHRT regimen was not increased

Current use ofHRT for;;:5 years: OR, 1.37 (95~0 CI.1-06-177)

This mcrease \\las confined to continuous combinedHRT

Current use of oral HRT. continuous combined orsequential: OR, 1-49"

Use of CC or sequential HRT for;89 months inrecent 5 yrsc OR, 1.61"

Use ofCe HRT for ;;:20 months in recent 5 yrs: OR,1.85

Use of sequential HRT for;;:36 months 10 recent 5

- Olsson Hi. et al. - -_. '--COOtlnuous ~ombi;;ed-IiRT---- Population-based-cohort" stUdy - u~~ ~~~:-;:rn.:continuous.combine"d HRT···· ---CQ/leer.2003 Sequential HRT 29,508 women compared to never users (women w! a natural

Gestagens only Approximately 3.700 women menopause) HR, 4 60·Estramolonly had used HRT Long-term sequential HRT: HR, 2.23Estriol only 25-65 yrs Gestagen-only therapy: HR, 3.74

Estriol-only use: RR, 1-89Greatest risks were seen With use ofcontinuous­

combined and gestagen-only therapy ;;:48 monthsNo mcreased risks were seen ID women after 5 years

ofnonuseEstradiol-alone therapy dId not Significantly increase

tne breast cancer risk·sigmficant (i e .950• Cl did not include I). ERr - estrogen-only replacement therapy; HR = hazard ratio; HRT - estrogen plus progestin replacement therapy;OR =odds ratio; RR =relative risk; SIR =standard incidence ratio.

~;u=imo......~...en

56

Table II. Studies of effects of estrogen or hormone therapies on cardiovascular disease outcomesStudyl Therapies Studied Study Designl

Country SubjechEffect of Hormone Therapy on Cardio\'Bscular

Disease Risk

Events rates in estrogen users were 47 6/10000Primary end points: four womenmeasures of cardiovascular risk._._ ... J~.=5.IQ..forestr~gen~~~..

~i!!-ImCl......Nen..........

. CEE and/or CEE/MPA

I.Wntmg Group for the PEPITrialJAMA,I995

us

Hulley S. et al.JAM.4, 1998 (HERS IJAM.4, 20021HERS il)

US

CEE 0.625 mg, CEE combined With eithercontinuous MPA 2.5 mg, cycbc MFA 10 mg (12days/month), or micronIZed progestin eMF) 200mg (12 days/month)

CEE 0.625 mgIMP A 2S mg

Randomized, placebo­controlled study

875 healthy, postmenopausalwomen

Mean age: 56 1 yrs

HERS randomized, blinded.placebo-controlled; HRT =1380, placebo = 1383 Pl'vlWwith coronary disease

HERS II: open-labelobservational foHow-up study;HRT = 1156, placebo = 1165

Mean age: 67 yrs

Mean age at last Jlll'nstrualperiod 49 yrs

Mean duration of disease eventsurveillance = 6.8 years,includmg 2.7 years in HERS II

VTE10/682 VTE events occurred among the 4 estrogentreatment groups (of which 6 were superficIalthrombopWebitis)

0/165 occurred in the placebo group (P > .2)

Total thromboembolic eventsHERS (4.1 years): RH ofVTEs WIth HRT use over

a mean of4.1 years: 2.89+HERS IIll.7 years): RH = lAO with HRTTotal 16. 8 years): 49 HRT vs. 24 placebo,

RH=2.08+; 31 more VTE's per 10,000 womenlyrDVTHERS (4.1 years); RH = 2.82+HERS IT (2.7 years): RH=U3Total (68 years). RH 1.98+PEHERS (4.1 years); RH 2.78HERS 1I (2.7 years): RH 3.03Totale6.8 years): RH 2.86+; 13 more PE's per10,000 womenlyrCHDIncrease in risk of recurrent CHD m year 1, RH =152+Decreased risk with continued HRT use eP = 009for trend in log RH)Overall null finding for the effect ofHRT on thensk ofCHD events lRH. 0.99) over the averagefollow-up of 4.1 years

57

Table II. Studies of effects of estrogen or honnone therapies on cardiovascular disease outcomes (continued)Studyl Therapies Studied Study Design! Effect of Hormone Therapy on Cardiovascular

Country Sublects Disease RtskGrodstein F. et al. eEE 0 625 mg. CEE 1.25 mg. or eEE 0-3 mg Follow-up study RR for strokeArm Inlt!n1 MeLI, 2000 CEE 0625 mg: RR = 1.35·(Nurses' Health Study) N = 70,533 CEE I 25 mg: RR = 1.63·

CEE 0.3 mg: RR=O.54

~::u~mo"'"Nen-.CO

USHemngton D, et al.NEJM,2000

us

Alexander KP, et al.JAm Coil CarJIOl, 2001(Coumadin AspmnRemfarclion Study)

us

CEE 0 625 mg, CEE 0.ti251MPA 2.5 mg

Predommantly oral CEE; also HRT (27 5°. orusers)

Randomized. double-blind,placebo-controlled study

Mean of 3.2 years

PostmenopausallVomen Wlthcoronary disease, N = 309 IN=248 for angiography)

Mean age: 65.8 yrs

Retrospective observationalcohort IN = (857) wi a recentMI

Never users: n = 1333Praor/Current users: n =413New users: n = III

Mean age:Never used HRT: 67 yrsHRT users 58.5 yrs

All-cause mortality was sunilar in the 3 treatmentgroups IP = 0.128): placebo, 5.7%; estrogen alone,8~ 0; estrogen + MPA, 2.9%

CHD mortality was slDrilar in the J treatmentgroups (P= 0.651: placebo, 2.9~o; CEE alone, 4·0,CEE + MPA, 19~0

Incidence of CHD events was simIlar in 3 treatmentgroups lP - 0.69): placebo, 32.4%; CEE alone,29~o; CEE + MPA, 28.2°.

PE: increased risk with ERT lRR, 2 I·)"RR-ofdeathIMIIWlstable"ang;Iia for newusers oC-'HRT: 1.44·RR for HRT users was lower (RR =0.56·) thanERT usersUnstable angina among new users of HRT ID the I"6 moo RR = 1.88·Prior/current and new HRT compared to never userswere more likely to undergo cardiac catheterizationand duect PTCA (P < .01)New users had more unstable angina compared tonever users (P = 00I )

58

Table n. Studies of effects of estrogen or honnone therapies on cardiovascular disease outcomes (continued)Study/ Therapies Studied Stud)' Designl Effect ofHormone Therapy on Cardiovascular

Country Subjects Disease Risk

DVT: HR =2.07·; 13 more DVT's per 10,0001V0menlyr

Stroke (fatal and nonfatal): HR - IAI' after anaverage of5.2 years offollow-up

PEe HR = 2.13 (nCI 1.39-3.25, aCI 0.99-4.56); 8more PE's per 10,000 women I yr

16,608 healthyposbnenopausal women (HRT= 8,506, placebo = 8,102)

Mean age: 63Range: 50-79Average 5.2 year follow-up

us

Wntmg Group for the CEE 0 625 mglMPA 2.5 mg Prospective, randomized, VTE: HR = 2.11·; 18 more VTE's per 10,000Women's Health Initiative controlled trial 1V0menlyrInvesbgatorsJAMA,2002

CEE/MPA users had an mcreased risk for nonfatalstroke, HR = I. 50· but not for fatal stroke, HR =I 18

CIID (fatal and nonfatal MI). HR = 1 29·

17~-e5tradiol

MortabtyTotal mortabty lowest mthe current user group(p < .001)Cardiovascular mortality significantly lower inthe current user group (RR 0 21") compared topast and never usersCV morbidity for current users vs. nel'er users:RR 1.07CAD morbidity for current users vs. neverusers: RR 1.05

Adjusted RRStroke morbidIty RR = 0.86 (p = 0.0*9)Stroke mortality: RR =0.16Not sigrnficantly influenced by currentERTIHRTuseThese data were based on only LO cases ofstroke, one of which was fatal

Current estrogen users (n = 988) received 17~­

estradiol (mean daily dose, lA6 mg) at baseline.139 women used a progestin

Fmland

Sour~d~rC~-_ .. -oestradIOCiireandose1.46 n;g-------- -Observaltonal study

Lal/cet, 1998 N = 79*421% of non-hysterectomized women also used a Never users mean age: 60.9 yrsprogestin Former users mean age: 61.0

yrsCurrent users mean age: 59.9yrs

~::::jmo.....~....CD

59

Table II. Studies ofeffects of estrogen or hormone therapies on cardiovascular disease outcomes (continued)Stud)'!

CountryHoibraalen E, el al.rhronrb Htlemosl, 1999

Oslo, Norway

Therapies Studied

Only estradiol HRT producls were used(oralltransdermal), some with gestagen

Study Design!Subjects

Population-based case-controlCases = 176 (average age59.3)Controls= 352 (average age59.21

Effed of Hormone Therapy on CardiovascularDisease Risk

VTE: current use ofHRT. adjusted OR -1.22

VTE, stratificabon for bme of HRT exposure,compared to non-use:

<I year 3.54*>1 year 0.66

RR ofcardiac death with ERT was lowest duringthe first 3 months of study

RR=033

Average rale ratio of MI. cannac death, orhospitalizallon for unstable angina o\'er 4 }'l"s: I 29

Event rate ratio with ERTRemfarction: 0.99Cardiac death: 0.99

No difference In evenl rale between ERT and HRT

Mean age: 71 yrs

Women wilhprimary orsecondary diagnosis ofDVTIPE or olher venousthrombosIsRandomized.double-b1ijj"([-"· RRofdeathornonfaialstroke: Ii" ------. -.--placebo-controlled study RR of fatal stroke: 2.9

RR of death from CVD: 0.8RR of nonfatal stroke 1.0RR of any stroke: 1.1RR of nonfatal Ml I.2RR ofany stroke at 6 moo 2.3*RR of any cardiac event (nonfatal or falall wilhERT:Il

N = 1017 (PMW who hadsurvived a rust MI)

ERTn=513Placebo' n = 504

N = 664 PMW with a recentischemic stroke or TIA: HRT:n=337.placebo n=327

Ages 50-69 yrs

Oral 17~-estradioll mgld or placebo

--------,- .------ - ----=-----,----o~

Transdermal 17~-estradiol with or Without Randomized trialnoretlnsterone n = 255 with heart dISease

ERT n= 58HRT n=76

Controls: n = 121Mean age:

HRT, 66.3 yrsControl 67 yrs

'Oral estradiol valerate------- ---Randomize-d;Placebo-controlled tnal

ESPRJTteamLallcel, 2002

Clarke SC, el a!.BlGa. 2002 (PHASEI

UK

UK

us

~=im~NenNo

60

Table II. Studies of effects orestrogen or honnone therapies on cardiovascular disease outcomes (continued)Studyl Therapies Studied Study Design! Effect of Hormone Therapy on Cardiovascular

Country Subjects DlseaseRlskERT or HRT, variousregimens or componentsnot speclnedThompson SG, et a I.J Eprdemiol CommllnltyHet111h,1989

UK

Grodstein F. et al.NEJM, 1996 (Nurses'Health StudYl

60'lo of the recorded prescriptions in tillS studywere \Vlltten for estropipate, ethinylestradloVmethyltestosterone, CEE,noretmsterone, diethylstilboestrol, and ethinylestradiol

Hormone type not specified

Case-control study

n = 603 cases with stroke orMIn = 1206 controls

Ages: ..5-69 yrs

Prospective observattonal

N = 59,337 PMW

Stroke and MI:>I HRT prescription: RR 1.36·Only I ~D of the cases were usmg HRT at thetime of the eventRisk of stroke and MI with use lP = .09);

1-3 months: RR = 2.1"4-6 months: RR = 1.097-12months RR= 1.0613-24 months RR = 1.14>24 months: RR = 1.19

RR of stroke and MI m pattents receivingprogestogens alone: 1.90

Estimated RR = 5.27 for fatal events (P =,08)Estimated RR = 1...6 for non-fatal el'ents lP=08)

No type ofHRT use was significantly associatedwith the risk of stroke and MI, independently ofpotential confoundersMajor ClID was reduced in the HRT groupcompared to never users (RR =0 45·'

~::u::::jmCI""lNenN....

usAge: 30-55 years at inclusion No CHD benefit was seen in past HRT users

No associanon ofHRT and the mCldence of strokewas observed

61

Table n. Studies ofeffects of estrogen or honnone therapies on cardiovascular disease outcomes <continued)Studyl Therapies Studied Study Deslgnl Effect of Hormone Therapy on Cardiovascular

Country Subjects Disease RiskDaly E, et al. Mulltple estrogen products: CEE. Case-control study \lTELancet. 1996 estradiol/estradiol valerate, piperazme estrone ERT, OR = 3.2"

sulphate, transdennal estradiol preparaltons Cases = 103 HRT, OR = 5.3"UK Controls = 178 Risk With current use ofHRT:

Relative to non-users: OR 3.5·Average age: 53 9 yrs Relative to never users: OR 3.6"

Use for 1-12 months. OR =6,7·Use for 13-36 months, OR = 404·Use for 37-60 months. OR = 1.9Use for 2:61 months. OR = Z1

No significant differences in the risk ofVTE among\'arious therapies

62

Table U. Studies ofeffects of estrogen or honnone therapies on cardiovascular disease outcomes (continued)Stud)" Therapies Studied Study Design! Effect of Hormone Therapy on Cardiovascular

Country Subjects Disease Risk

Age adJusled RR for recurrent major coronarydIsease was 0.56' for current vs never users

For transient ischemic attacks. the current use ofERT (OR, 2.11") but not HR.T (OR, 1-25) wasassocialed Wlth an increased RR

Pedersen AT, et aL UnspecIfied ERT/HRT; oral, mjected. or patch Case-control study Current use, Ischenuc stroke~

Lancet, 1997 ERT: OR = Ll6n=1422cases HRT:OR=I.17Never use ofHRT: n = 484Former use ofHRT: n = 156Current use of unopposed

oestrogen: n = 73Current u~e of combined

reglll1ens n = 133n = 3171 control~

Denmark

Ages 45-64 yrs Recurrent CHD events among wornen with currentuse of <1 year compared WIth never-users: RR =1.25Slgmficant <P =.0021 decrease m risk withmcreasmg duration of curtent useLonger-lerm users compared to never users, RR fora second major coronary event 0.38'

10,000 postmenopausal women 60-75 yearsreceiving HRT, 420 additional recurrent cases ofCHD/year With short-term use. and 1,040 fewercases/year after long-Ierm use

~::u::jmo....NenNW

Short-term users compared to long-term users, riskfor recurrent coronary event: RR ~ 2.10After long-term use, nsk of recurrent coronaryevents: RR =0.50'SlgOificant lP =.02) trend ofdecrea~ingnsk forrecurrent coronary events with increasing durationofHRT

Table II. Studies ofeffects of estrogen or honnone therapies on cardiovascular disease outcomes (continued)

VTEERT.OR= 1.9HRT, OR = 2.2+RIsk wlth current use ofHRT. OR. 2 1+

Use for 1-6 months, OR = 4.6+Use for 6-12 months. OR = 3.0+Use for >12 months, OR = I I

No differences between regimens

Effect of Hormone Therapy on CardiovascularDisease Risk

Current or past use ofHRT reduced the nsk ofMI:Current: RR = 0.70+Past RR = 0 74+

Study DesignlSubjects

Ages: 50-79 yrs

Cases = 292Controls = 10,000

Case-control studyMultiple estrogen products: oral CEE,transdermal estradiol. estradlOlllnplant, otheroral unspecified HRT

Thnapies Studied

Estrogen alone or combined with progestin.transdermal vs oral regimens; low-dose(equivalent to CEE 0.625 mg or transdermaldelivery of 17p-estradlOl 25 mg or 50 mg per 24h) vs high-dose (equivalent to CEE US mg ortransdermal delivery of 1713-estradiol 100 mg.p~r.~i!!lthe!~~y __ ... . _..n. • ._. • __

ERTIHRT (not otherwise speCified) Case-control study in PMWWith confirmed fatal ornonfatal MI

Heckbert SR, et al.Arch Intern Aled, 1997

UK

Perez Gutthann S, et al.BMJ,1997

us

Stud)"Country

Cases: n = 850Controls: n =1974

Longer duration of use ofHRT asSOCIated with alarger reduction in nsk

ERT/HRT had been used atany time by 27°° of the casesand by 35°° of the controls

ERTIHRT was currently usedby 19.8°0 of the cases and by27.6° 0 of the controls

Risk for nonfatal MI according to duration ofestrogen among the women currently usmg estrogenwas

RR = 1.02 (>0 to <1.8 yrs)

RR = 0.79 (1.8 to <4.! yrs)RR = 0.63 (4.2 to <8.2 yrs)RR = 0.61 ( 28.2 yrS)

Varas-loreiJZ"o-C~et-aI. -- - -MultiPle-HRT-p~oduCb ~-nl CEE. -tiimdennalAm J Epldemiol. 1998 estradlol, other Ul19pecified regunens

Italy 79~ ° reported use of transdermal estradlOl

Average age: 69 yrs

Case-control study

Cases = 171Controls = 232

Ages: 45-79 yrs

Women who had discontinued the use ofestrogenrecently (wlthin 8 months [0.7 years] of the indexdate I, had a slightly htgher risk for Ml lOR 143)than those who discontinued estrogen use 0.7 to 2.7years before the index date

- -OR2.3 ofviE----RiskofVTE

ERT.OR= 1.4HRT, OR = 5.0·Use for 1 month to 1 year, OR = 2 9+

Use for >1 year, OR = 0 0

Table II. StudIes ofeffects of estrogen or hormone therapies on cardiovascular disease outcomes (contmued)Studyl Therapies Studied Study Designl Effect of Hormone Therapy on Cardiovascular

Country Subjects Disease RiskAngeja BG, et al. Estrogen, progestrn, estrogen-progestin for Prospective cohort Adjusted RR for ischenuc stroke 0,89J Am Coli CarJIO/, 2001 reasons other than contraception Adjusted RR for hemorrhagic stroke: 0.88

usN = 7353 current ERTIHRTusers

Mean age: 71 yrs- _. --- Pop~lait';-~as~d~~hort-- - -- -Mu1ti;ariat~~ad.i~tedRH for recUrrent Mi -ordeath

from CHD, current use ofHRT, 0.96

------------- --------- --------------.Heckbert SR, et al. ERT used 67°;' of the time, HRT 33°0

~;;u::::jmo.....NenNen

Arch Intern Mild, 2001

us

Esterified estrogens used 70~u of the time, eEE28~o

MPA was the progestin in virtually all cases

N = 981 survivors of an MIWithoutHRT: 2913person-yearsWith HRT: 686 person­yearsTotal follow-up: 3599person-years

Avcrage age: 67 8 yrs

Adjusted RH of recurrent coronary e\'ents:<60 days ofstartmg therapy: RH =2 1660 to 365 days: RH = 0.92>365 days: RH = 0.76

Adjusted RH of recurrent events during the I" yearstartlllg HRT: 1 30

Age-adjusted RH for eEE use compared Withesreritied estrogen use: 1.35

Overall adjusted RH for recurrent MI or CHD deathwas not mfluenced by ERTIHRT use (RH, 096)There was a suggestion ofan increased risk ~lthin

the flIst 60 days of initiation or re-mitiatlon oftherapy(RH, 2.16), followed by a reduction m nskwith use ofERTIHRT tor >1 year (RH, 0.76)

65

Table II, Studies ofeffects of estrogen or hormone therapies on cardiovascular disease outcomes (continued)Studyl Therapies Studied Study Design! Effect of Hormone Therapy on Cardiovascular

Country Subjects Disease RIskGrodstein F, et a!. Oral CEE wi or wlout progestin; oral 1713- Prospecti~e observational Major CHD, HRT users vs never-users· RR 0 65·Ann Intern AleJ, 2001 estradiol; transdermal: estrogen; other (not cohort IN = 2489) wi prevIous Current use for:(Nurses' Health Study) specified) Ml or atherosclerosis <: I yr RR = 1.25

Never users 38.6°0 1-1.9 yrs: RR = 0.55US Past users: 32.4°" 22 yrs: RR = 0.38

Current users 19.0".

Prospective

Age range: 57.4-60 yrs

Estrogen, progestin. or estrogen!progeslm forreaSOlLS other than contraception

Age adjusted RR = 0.56" for recurrent majorcoronary disease for current users vs never usersRecurrent CHD events among women with cunentuse of <1 year compared WIth never-users: RR 1.25Longer-term users compared to nel'er users, RR fora second major coronary event: 0.38-Short-term users compared to long term users, riskfor recurrent coronary event: RR = 2.10After long-term use, risk ofrecunent coronaryevents: RR = 0.50-SlgnificantlP = .02) trend of decreasmg risk forrecurrent coronary el'enls with increasing durationofHRTAdjusted OR of 0.65" mdlcating improved rate ofsumval In current HRT users ofall age groups

N =114,724 women~5 yrs Greatest reduction for CHD mortality for youngestWIth a confirmed MI group of women 155-64 yrsl: OR = 0.54-

ERTIHRT fonnulations- V"ati~d-from·studYt~--- --~feta.a~~lysls-ofEnghsh--------· vri -- - ------ . -.__ w _

study language studies via Medline RR wI cunent HRT use (overall) = 2.14"11966-2000), HealthSTAR RR in flCst year (6 case-control) =3.49·(1975-2000), Cochrane RR after 1Zmonths (6 case-control) = 1.91-Library databases, & reterence Pooled RR (studies excluding CAD) = Z,73"hsls ofkey articles Pooled RR (studIes including CAD) = 3.32+

Basehne nsk of VTE = 1.3 per 10,000 women peryearAbsolute rate i = L5 VTE events per 10,000women per year

International

Sh1lpak MG, et alCIrculation, 2001

US-MilieiJ, et a-I---- --Ann Intem MeJ, 2002

66

Table II. Studies ofeffects of estrogen or honnone therapies on cardiovascular disease outcomes (continued)Study1

CountryNelson HD. et aLJAAfA,2002

International

Humphrey 11. et alAnll Intel n Aled, 2002

Internallonal

Nussmeler NA. et alJ Thorac CardlOvasc SlIIg.2002

us

Therapies Studied

Unspecified ERTIHRT

Estrogen +1- progestin

ERTIHRT

8500 taking CEE or estradiol alone; rest were

taking CEE and MPA

Study DesignlSubjects

Meta-analysIs of key articles(\996-2001), evaluated thebenefits and harms ofHRT forpnmary prevention ofCVD.tIuomboembolism,osteoporosIs. etc,

Total N not repo rtedMedline and Cochranedatabase search from 1966 toDecember 2000 for studies ofpnrnary prevention (CVD orCAD)

Retrospecuve analySIS

N = 4259 records ofpatientsaged 55 yrs who underwentprimary elective, isolatedcoronary artery byPass surgery

Ertect of Hormone Therap)' on Cardio\'ascularDisease Risk

Ever use, overall stroke: RR - 1.12"Monality for all groups:

CVD: RR=0,75CHD: RR=0.74

Incidence for all groups: CVD: RR = 1.28CHD: RR = 0.88

current use'ofEin'lfllU was associated with areduced risk of CHD mortality (sununary RR,0.62·)

Mortality with any HRT use:CVD: RR - 0.75CAD: RR=O.74

Incidence with any use'CVD: RR = 1.28CAD: RR = 0.87

Summary RR for CHD of 0.80+ among currentusers ofERTIHRTHowever, when the authors evaluated only thosestudies that reported adjusting for SOClOeconormcstatus, the reduction in RR for Gm was no longersigmficant (summary RR, 0.97)Women using ERTIHRT at hospital adnumstrationhad sigmficantly less In-hospital mortality comparedto women who were not (P < .005)

~;0:::jmo.....NenN.....

~ - Significant (J.e., confidence mterval does not mclude I) ERT - estrogen-only replacement therapy, HR - hazard ratio; HRT - estrogen plus progestinreplacement therapy, OR = odds ratio; RR = relative risk.

August 22. 2003

Sandra Perrine. Managing EditorAmerican JOllmal ofObstetrics and Gynecology965 W. Hackberry CourtChandler. AZ 85148

Dear Ms Perrine'

Thank you for the opportunity to publish my manuscript. "A Comparative Review of the Risks andBenefits ofHormone Replacement Therapy Regimens" (Manuscript # E03-l194) in your prestigiousJournal. The comments TreceIved are as follows:

Reviewer #3:References: #57: Framingham should have a capital "F."Thave capitalized this accordingly.

#76 The state ofMaryland is abbreviated MD.Tbeheve that "MD" is only used in postal addresses. and so I have kept "Md" here.

#147 and 148 have PMID numbers which are not needed.I have removed these.

#149 only lists the first author; in multi-authored papers the first six authors should be listed.I have corrected thts.

# 60 and ISO are the same reference.I have removed reference #150

Tables: Table n should have the header changed from "Effect of Hormone Therapy on BreastCancer Risk" to "Cardiovascular Disease Risk" or a comparable outcome to reOect the title ofthe Table.I have corrected this accordingly.

I am grateful to thts reVIewer for poroling out these errors. I have also made some small editorialchanges to the last two pages of the paper.

I hope that these revisions will permit publication Please contact me if you require any othermatenals for my resubmission.

Sincerely,

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EXHIBIT

fI/1ltiY

MIchelle P. Warren. MJ)

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American Journal of Obstetm:s and Gynecology (2004) 1110, 1141-67

ELSEVIER

AMERICAN JOURNAL

'1OBSTETRICS

GYNECOLOGY

AJOG REVIEW

A comparative review of the risks and benefits ofhormone replacement therapy regimens

Michelle P. Warren, MD*

Department of Obstetrzcs and Gynecology, Columbw Utl/vcrsity College of Physicians and Surgeons, Nell' York, NY

Received for publIcatIon July 7,2003; revISed August 26, 2003; accepted September 15, 2003

KEY WORDSBenefitRiskHormone replacement

therapyEstrogenProgestm

The Women's Health InttlatIVe (a large, randomIzed, placebo-controlled tnaO investIgated the ef­fect of conjugated equme estrogens combmed WIth medroxyprQgesterone acetate on speCIfic 1'0­tentIallong-term benefits and flSks A reVIeW of the clImcal studIes that have InvestIgated dIfferenttypes and regImens of estrogens combmed With progestms was conducted to assess how applIca­ble the results of the Women's Health ImtIatIve are to hormone replacement therapy regImens mgeneraL The studies that were revIewed were Hmlted to randomized clmlcal tnals and observa­tIOnal studies that have been publIshed over the l'lst 15 years (1987-2002) and to meta-analysesand revIews that may have mcluded the lIterature before 1987, The Increased nsh for venousthromboemboHsm, stroke, coronary heart dIsease, and breast cancer that were IdentIfied In theWomen's Health ImtIatIve tnal have also been reported WIth postmenopausal hormone therapIesthat contam a vanety of estrogen and pwgestm products The benefiCIal effects that were noted III

the Women's Health Imtlatlve. WIth respect to reductIOns In fractures and colorectal cancer, havenot been evaluated In large, randomIzed controlled tnals that use dIfferent estrogen(progestIncombInatIOns; however, observatIonal tnals that used a vanety of estrogen or hormone replace­ment therapy products and randomIzed chmcal studIes that evaluated bone mmeral densIty (anexcellent predictor of fracture nsk) WIth dtlferent estrogen/hormone replacement therapy regi­mens would suggest that results would be SImIlar to those found In the Women's Health ImtIatIveAlthough the rehef of menopausal symptoms, the pnmary reason women seek treatment, was notIncluded m the overall benefit/fISk analySIS of the Women's Health ImtIatlve, numerous tnals sug­gest that all therapIes are effectjve Overall, these data mdlCate that the benefit/nsk analySIS thatwas reported m the Women's Health ImUatlve can be generalIzed to all postmenopausal hormonereplacement therapy products\fl 2004 ElseVIer Inc, All nghts reserved,

"Dr. Michelle Warren IS a consultant for Wyeth, Solvay and MerckPharmaCEUtICals and has research support from Grtho, Berlex, Pfizerand Merck PharmaceutIcals"

* Repnnt requesls' MIchelle P Warren, MD. Professor ofObstetncs, Gynecology .md MediCine, Sloane Hospital for Women,Columbla-Presbytenan Medical Center, 16 East 60th St, New York,NY 10022

E-matl mpw II,ii'columbla edu

0002-9378/$ - see front matter @ 2004 ElsevJer Inc All nghts reserveddoUO 1016(J aJog 2003 Oll 033

The hormone replacement therapy (HRT) arm of theWomen's Health Imtlatlve (WHI), which mcluded16,608 postmenopausal women aged 50 to 79 years(mean age, 63 years) With an intact uterus at baseline,was stopped early (after an average of 52 years of fol­lOW-Up exammahons) because the results suggested thatthe health nsks exceeded the health benefits, I Becausethe regimen that was used in the tnal was contmuous­combmed conjugated equme estrogens (CEE, 0,625

DWRITE 072596

1142

mg) plus medroxyprogesterone acetate (MPA, ~,S mg).some mvestIgators have suggested that the findmgs fromthis study may be apphcable only to this specific regl-

, 1men,- -

To assess thIs hypothesIs. we revIewed chmcal studIesthat investigated ditTerent types and regimens of estro­gens m combmatIon with progestms. with regard tothe major rISks and henefit~. includmg those nsks andbenefits that were reported m the WHI tnal StudIeswere lImIted to randomIzed clInIcal tnals and observa­tIonal studIes that had been publIshed over the last 15years (1987-2002) and to meta-analyses and reviews thatmay have Included the hterature before 1987, An at­tempt was made to Include only those studies thatclearly IdentIfied the use of HRT rather than estrogenreplacement therapy (ERT) or a combInatIOn of ERTand HRT Cases In whIch thIS was not pOSSIble arenoted, For each of the outcomes, the WHI findmgsare dIscussed and followed by the c1mical evidence ondIfferent types of HRT

Documented risks of HRT

Breast cancer

Recent studies of the effects of vanous regImens of ERTand HRT on breast cancer are summanzed m Table IThe WHI was the first randomIzed. placebo-controlledtrial to evaluate the effect of HRT (specifically CEE/MPA) on the mCldence of mvaslve breast cancer. The m­vestigators reported an overall hazard ratio (HR) of I ,~6(nommaI9S% CI, 1,00-1, S9) after an average of S.~ yearsoffollow-up, I The mcreasewas marginally significant andemerged after 4 years of HRT use, When prevIOus use ofHRTwas consIdered m a subgroup analysis. an increasedrIsk of breast cancer was observed onlv in the subset of-women who used HRT before entenng the study, TheHR was 106 (95% CI, 0,81-1.38) among never users.2 13 (95% CI. I 15-394) for women with < 5 years ofpre­VIOUS u~e, 4 61 (95% CI. 1 01-21 02) for women With 5 toIO years ofprevl0ususe. and 181 (95% CI, 0 60-5 43) forwomen WIth 10 years ofprevIOUS use 1 These data prOVIdevaluable mformatIon for clInICIans who often see patientsWIth symptomatic complamts early in the menopause andsuggest that a prolonged exposure may be necessary be­fore a small increase m nsk IS seen.

Before the WHI. the relative nsk (RR) of breast can­cer wIth ERT or HRT use was evaluated in >70 obser­vatIonal studies, Although an increased rISk of breastcancer with eIther ERT or HRT has been questIonedon the basis of the lack of consistency among studIes.4

5

the 1997 CollaboratIve Group on Hormonal Factors mBreast Cancer reanalvsls of the worldwide data from 51

•

epidemIOlogIC studlesb reported findings that were some-what conSIstent wIth those findmgs that were seen m theWHI For all studle... combmed (approxImately 12% of

Warren

women who documented hormonal constItuents re­ceIved HRT). an RR of Ll4 (SE, 003. P = ,00001)was noted WIth ever-use of ERTfHRT6 The RR ofbreast cancer dId not vary accordmg to the type or doseof estrogen that was used. and there was no evidence ofmarked dlfference~hetween ERT or HRT preparatIonsIn their subanalySlS of the type of preparatIon that wasused, the RR of breast cancer m current users of HRTor progestms alone for < 5 years was 1.15 (SE. 0 19: sIg­nIficance not reported) Because lIttle informatIOn wasavaIlable about the use of any HRT regimen for a longperiod of tIme. the authors could not make rehable con­clUSIOns about the effects of dIfferent regimens on breastcancer fisk The authors also reported that the currentuse of ERT for < 5 years was not associated WIth an in­creased risk of breast cancer (RR, 0,99, SE. 0,08). thesefindmgs are in accord WIth the findmgs of the WHI. inthat the ERT arm of the WHI contmues,

A number of observational studIes that were pub­lIshed after the CollaboratIve Group reanalySIS evalu­ated the RR of breast cancer WIth HRT. speCIficallydefined as a combmatIon of estrogens and progestms,Several studIes reported no slgmficant mcrease in RRof brea"t cancer With HRT use 7-11 For those studIesm whICh an mcrease m RR of breast cancer WIth HRTuse was IdentIfied. 1:-:0 the types and regImens of thehormones used are dIscussed later

An Increased nsk of breast cancer was observed mSwedish women who receIved HRT 12-14 Magnussonet al ll InvestIgated breast cancer rIsk m a populatIon-basedcase-controlled study of women 50 to 74 years old, Theodds ratIo (OR) for ever-use of HRT that contaInS "me­dIUm-potency estrogens" (mostly oral ~ mg 1713-estra­dlOl) and any progestIn was 1.63 (95% CI. 137-194).WIth a trend toward an mcreased nsk WIth duratIOn ofuse (OR, 1.07 per year of use, 95% CI, 1.02-LI I)Ever-use of HRT WIth progestms that were denved fromprogesterone (eg. MPA) was not assOCIated WIth an in­creased nsk of breast cancer (OR. LI4; 95% CI, 0,69­I 88), nor was there an mcreased nsk with duration ofuse (OR, 095 per year of use, 95% CI, 0,80-1 14) Incontrast. ever-use of prngestms that were denved fromtestosterone (eg. norethl~terone acetate [NETA]) was as­SOCIated WIth an mcreased nsk (OR. 1 68: 95% CI, 1 39­203) that was mfiuenced by duratIon (OR. I 08 per yearof use; 95% CI, 103-113). When only HRT regImensthat used testosterone-denved progestms were evaluated.the nsk of breast cancer WIth ever-use of eIther cyclIc(OR, 1,48; 95% CI, 1.08-1,04) or continuous (OR, 1.41,95% CI, 1.09-1.83) regImens was Increased; however, anincrease with Increasing duratIon of use was seen only forthe contmuous regimen (OR, 1.19 per year of use. 95%CI, 109-1.31), The potentIal dIfferences in breast cancernsk with different progestms have been attributed to thegreater increase m msulm-lIke growth factor 1 actIvIty withmore androgenIC progestms,'1

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Table I Studies of effects of ERT or HRT on risk of breast cancer

Study/country Therapies studIed Study desIgn/subJects

CEE or CEE/MPAHenrich et alB/ CEE Case-control study

United States

1143

Effect of HRT on breast cancer risk

For both in situ and invasive breast cancer:

Moorman et al9/

Umted States

Ross et al19/

United States

Schaner et al17/

United States

Non-CEEERT

HRT

ERT

Progestm only

HRTCEE <0.625 mgCEE >0.625 mgTransdermal estrogen CEE

were used by 73%; 14%used CEE and "otherestrogens"

Therapy was mainly ERT;<0.625 CEE mostpopular dose

Combined therapy mostcommonly sequential,with MPA most commonprogestin

38% of person years:estrogen-only use

4% estrogen + progestinonly use

42% with no hormone use

CEE primary estrogen usedMPA pnmary progestin

used

Cases: 109 (26.6"10 used ERT)Controlsubjeets: 545 (19.6%

used ERT)Age, 2::45 y

Population-based case­controlled study

Cases: 384

Control subjects: 420Ages, 20-74 y

Population-based case­controlled

Cases: 1897 (54% used HRT)

Control subjects: 1637 (52%used HRT)

Ages, 55-72 y

Retrospective cohort: 46,355women (473,687 person-y)

Cases: 2082

Mean age, 58 y

Mean follow-up, 10.2 y

Any HRT, current use: OR, 1.52Any HRT, past use: OR, L50

Any HRT use' OR, 1.54Non-CEE use: OR, 1.86CEE use: OR, 1.49ERT only use: OR, 1.66HRT only use; OR, 1.02Use for <5 y: OR, 1.55Use for ~ y: OR, 1.61Mean duration of use: 90 mo for white women, 63

rna for black womenNo Slgmficant effect of ERT or ERT/HRT on nsk,

regardless of duration of use. time since lastuse, type of hormone therapy, type ofestrogen, or dose of CEE

Overall HRT use:

1-5 y: OR, 1.11

>5-10 y: OR. 1.51

>10 y: OR, 1.51Per 5 y of use; OR, 1.24*Overall ERT use:>15 years OR, 1.24 « 15 y: all OR, ~ 1.02)Per 5 y of use: OR, 1.06By HRT regimen:Sequential: per year of use OR. 1.38*Continuous: per year of use OR, 1.09Ever-use estrogen only: RR, 1.1-805 cases/

196,666 person-yEver-use estrogen + progestin only: RR, 1.3-101

cases!179,401 person-yCurrent HRT use: RR, 1.4* (Note: significant only

if BMI was < 24.4)Current ERT use: RR. L1

Duration of use:RR increases by 0,01 for each year of ERTRR increases by 0.08 for each year of HRT useDuration since last HRT use:1-2 y RR, 1.2

(Continued on nevt poqe)

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1144

Table I (contmued)

Study/country Therapies studied

Writing Group for CEE 0.625/MPA 2.5 mg/dthe WHI1

/

United States

Newcomb et aL15/ ERT (79% used CEE)

United StatesHRT (86"10 used MPA)

1713-estradioLPersson et aL141 MainLy 1713-estradioL

Sweden

Sourander 17B-estradiolet aL55/FinLand

Study design/subjects

Randomized. pLacebo­controLLed triaL

Active therapy: 8506

PLacebo: 8102Ages, 50-79 y

MuLtlcenter case-controLLedstudy

Cases: 5298 (1471 HRT users,3827 non-users)

Control subjects: 5571 (1439HRT users, 4132 non-users)

Ages, 50-79 y

Cohort study

TotaL' 22,579Cases: 634

Cohort study

TotaL: 7944Cases: 100

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Effect of HRT on breast cancer risk

>2-4 y: RR, 1.2>4-6 y: RR, 0.6>6 y: RR, 0.6Duration since last ERT use:1-2 y: RR, 1.4*>2-4 y' RR, 1.2>4-6 y: RR. 0.9>6 y: RR. 1.1Data in study on disease stage and tumor

histoLogic condition

OveraLL HR: 1.26 after an average of 5.2 y folLow­up

Subgroup anaLysis among women who used HRTbefore the study:

The HR was increased onLy in women who usedHRT before the study:

2.13* for women with < 5 Yof previous use4.61* for women with 5-10 y of previous use1.81 for women with 10 y of previous use1.06 among never usersAverage durabon of ERT use: cases 10.1 y. controL

subjects 9.2 yAverage duration of HRT use: cases 4.2 y, controL

subjects 4.5 yEver-use of ERT: RR, 1.23*

Ever-use of HRT: RR, 1.43*Current ERT use: RR, 1.25*Current HRT use: RR. 1.39*Ever-use of continuous combined HRT; RR, 1.54*Ever-use of sequentiaL HRT; RR. 1.57Duration of ERT use; RR, 1.02 per year*ERT use < 5 y: RR, 1.07; >5 y RR, 1.34*Duration of HRT use: RR, 1.04 per year*HRT use < 5 y: RR. 1.32*; >5 Y RR, 1.50*Time since HRT Last use:<5y:RR,17110-19 y: RR. 2.38Time since Last ERT use:<5 y: RR, 1.76*5-9 y; RR, 1.2210-19 y: RR, 1.12> 20 y: RR, 1.04

ERT/HRT: SIR, 13*

1-4 y: SIR. 1.15-9 y: SIR, 1.310+ y: SIR, 1.4+ERT/HRT: RR, 0.57

(Con/Jnued on next /Joae)

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Table I (continued)

Study/country

Magnussonet al12/Sweden

Persson et alB,ISweden

ERT or HRT,components notspecifiedBrinton et al7

/

Umted States

Collaborati veGroup onHormonalFactors inBreastCancer61worldWlde

Ng et al13b/China

Persson et alll/Sweden

Tavani et al13CjItaly

Sellers et al10/

United States

TherapIes studIed

Mainly 1713-estradiol

Mainly 17B-estradiol

ERT

HRTComponents not identified

Unspecified: No variationin risk according totype of estrogen used

ET/HT, otherwiseunspecified

ET/HT. otherwIseunspecified

ET/HT, otherwIseunspecified

HRT; no information onformulations

Study desIgn/subjects

Case-control study

Cases: 3345Control subjects: 3454

Cohort study

Total. 10,472Cases: 198

Case-controlled study

Cases: 1031 (24% HRT use)Control subjects: 919 (27%

HRT use)Women <55 y

Reanalysis

Cases: 17,949

Control subjects: 35,916

Case-control study

Cases: 204Control subjects· 882Case-control study

Cases: 435Control subjects: 1740

Case-control study

Cases: 5984Control subjects: 5504Prospective cohort study:

41,837 women, 55-69 y

1145

Effect of HRT on breast cancer risk

ET: OR, 1.94*

HT: OR, 1.63*Per year of ET use: OR, 1.03Per year of HT use' OR, 1.07*ET/HT: SIR, 1.2

HT: 1-6 y: RR, 1.4; >6 'I: RR, 1.7*ET: 1-6 y: RR, 1.0; >6 'I: RR, 1.1

Ever-use of HRT: RR, 0.89

ERT use: RR, 0.70*HRT use: RR, 0,99

Duration of HRT use:< 3 'I: RR, 0.863-5 'I: RR, 1.00>6 y: RR, 085Duration since last use:< 1 'I: RR, 0.91> 1 y: RR, 0.82ERT/HRT: RR, 1.14* (SE, 0.03; P=.OOOOl) for

ever-use

RR of breast cancer in current users of HRT orprogestins alone for <5 y. 1.15 (SE, 0.19)

Current use of ERT for < 5 'I: RR, 0.99; SE, 0.08Per year of use: RR, 1.023ET/HT: OR, 0.54

ET/HT: OR. 1.1

1-2 'I: OR, 0.93-5 y: OR, 1,06-10 y: OR, 0.911+ y: OR, 2.1*ET/HT: OR, 1.2

< 60 mo: OR. 1.2>60 mo: OR, 1.3Past users

:::;. 5 Yof HRT use: RR, 1.04 (95% CI not given)>5 y of HRT use: RR, 0,89 (95% CI not given)Current users>5 y: RR, 134

(Continued on next page)

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1146

Table I (continued)

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Study/country Therapies studIed Study des1gn/subjects Effect of HRT on breast cancer risk

Manjer et aL13d/ ET/HT, otherwise Co hort study

Sweden unspecifiedTotal: 5865Cases: 141

Olsson et al13• / ET/HT, otherwise Cohort studySweden unspecified

Total; 29,508Cases: 434

Hedblad et al13f/ ET/HT. otherwise Cohort study

Sweden unspecifiedTotal: 5721Cases: 141

WeIss et all8/ HRT regimens (type of MuLticenter. popuLation-Umted States estrogens or progestlns based, case-controlled

was not reported)

Chen et al16/

United States

Olsson et allO/

Sweden

ERT

Oral contmuous combmedHRT

Oral sequentIal HRT

The type of estrogen orprogestin was notidentified

Continuous combined HRT

SequentIal HRTGestagens only

EstradioL onlyEstriol only

Estrogens or progestinsused in thecombination therapIeswere not identified

4575 cases, 4682 controlsubjects

Age: 35-64 y

Nested case-controlled study

1995 case, 692 controlsubjects

Age: 50-74 y

Population-based cohortstudy

29,508 womenApproximately 3700 women

had used HRTAge: 25-65 y

>5 y: RR. 1.17Interaction between family history and HRT use

was not sigmficant P > .2ET/HT: RR. 1.66·

ET/HT' SIR, 135*

1-48 mo: HR. 1.3648+ mo: HR. 1.80*ET/HT; RR, 1.52*

OR for breast cancer <2-y use of any combmedHRT regImen was not Increased

Current use of HRT for ~ 5 y; OR, 1,37 (95% cr.1.O6-1.77)

This Increase was confined to continuouscombined HRT

Current use of oral HRT. continuous combined orsequential: OR. 1.49*

Use of continuous combmed or sequentIal HRT for> 39 ma in recent 5 y: OR, 1.61*

Use of continuous combined HRT for ~20 mo inrecent 5 y: OR. 1.85

Use of sequential HRT for ~ 36 mo in recent 5 y:OR. 1.62*

Users of long-term. continuous-combined HRTcompared to never-users (women w/-a naturalmenopause)" HR, 4 60*

Long-term sequentIal HRT: HR. 2.23Gestagen-only therapy: HR, 3.74

Estriol-only use: RR. 1.89Greatest risks were seen WIth use of continuous­

combined and gestagen-only therapy > 48 moNo increased risks were seen in women after 5 y of

nonuse

Estradiol-alone therapy did not increase thebreast cancer risk significantly

SIR, Standard incidence ratio.* Significant (ie, 95"10 CI did not meLude 1)_ SIR = standard mCldence ratio,

Persson et all Ja used a record Illlkage with the NationalSwedish Cancer RegIstry to assess the rIsk ofbreast cancerIII a cohort of 11.231 SwedIsh women (medIan age, 65yearsl for whom ERT/HRT had been preSCrIbed, Inwomen who reported uSlllg "medIUm-potency estrogens"(48% used l71l-estradlOl; 15.2% used CEE: 36,8% usedmIxed estrogens) plus progestms (45% testosterone-de-

rIved [250 l1g levonorgestrel or I mg NETA], 55% proges­terone-derived [5 mg or 10 mg MPA]), the RR (adjustedfor age, follow-up time, age at first full-term pregnancy.body mass index, educatIOn, and menopausal age/status)was not increased WIth HRT use for 1 to 6 years (RR. 14;95% CI. 09-23), however, an increased risk of breastcancer was noted WIth >6 years of HRT use (RR. 1.7;

DWRITE 072601

Warren

95% CI, 1.1-2,6), In an earlier study that used the same co­hort(n = 22,597, mean age of54,5 years at cohort entry In1983), Persson et al '4 reported standardized incIdence ra­tIos for breast cancer In 5573 women who receIved 2 mg1713-estradiol plus cyclIc 250 llg levonorgestreL The au­thors observed a time-dependent moderate risk wIth thIsHRT regimen, The standardIzed incidence ratIos In­creased from 1 1 195% CI, 08-15) wIth <5 years offol­low-up to I 3 (95% CI, 1 0-1 7) after 5 to 9 years offollow-up and furtht:r Increased to 14 (Q5% CI, 11-18)after > 10 years

Recently, Olsson et afo reported the results of a popu­latIon-based cohort study among 29,508 women whowere selected from southern S\vedell, The partIcipantswere followed for 10 years to determIne whether dIfferenttypes of HRT and dIfferences In duratIon of use resultedIn dIfferences In nsk of breast cancer ApproXImately3700 women had received HRT After potentIally con­foundIng variables were adjusted for, users of long-term,contInuous-combIned HRThad a slgmficantly hIgher riskof breast cancer compared with never-users (HR. 4,60;95% CI. 2,39-884) NonSIgnIficant elevated rIsks wereseen for long-term sequentIal HRT (HR, 223, 95%CI, 090-556), gestagen-only therapy (HR, 374; 95%CI, 094-1497), and estrIol-only use (RR, 1 89, Q5% CI,0, l\ 1-4.3Q). The greatest rIsks were seen WIth use ofcontIn­uous-combIned and gestagen-only therapy 48 months orlonger, No Increased rIsks were seen in women after 5years of nonuse, EstradIOl-alone therapy dId not Increasethe breast cancer risk slgmficantly, The authors do notstate whIch speCIfic estrogens or progestms were used inthe combination ther.:lpies, Whether the type of progesto­gen influences the nsk profile IS unclear.

Five studIes that were conducted in the UnIted Statesalso reported an mcreased RR for breast cancer WIth thecurrent use of HRT !5-IQ Two of these studIes were re­gIOnal case-controlled studles.lh,IQ and the other 3 stud­ies were multIcenter, population-based, case-controlledstudIes 15,1718

Ross et all!) evaluated the effect flf HRT on hreastcancer rIsk III women (18Q7 cases, 1637 control suhJects)aged 55 to 72 years and hVIng In Los Angeles County,CahfornIa, CombInatIon therapy most commonly wasprescnbed sequentIally, and CEE 0625 mg and MPA(no dose reported) was used by most of the women,Breast cancer rIsk Increased \vlth IncreasIng duratIOnof HRT use (OR per 5 years of use, 1.24; 95% CI,1.07-1 A5, P = ,005), When sequentIal and continuousHRT were evaluated individually, only the OR per 5years of sequential HRT use was signIficant (OR, 1.38,95% CI, U3-1.68, P = ,0015), however, the differencesbetween regimens were not slgmficant Chen et 011 16 re­ported simIlar findings In a nested case-controlled study(1995 cases, 692 control subJects I of postmenopausalwomen aged 50 to 74 years who were enrolled In theGroup Health CooperatIve of Puget Sound Current

1147

use of oral HRT (the type of estrogen or progestInwas not Identified) was aSSOCIated with an Increased rISkof breast cancer (OR, 149. 95% CI, 1,04-2, 12L The ORfor breast cancer In women who received HRT dUrIngthe 5-year period that ended at 1 year before dIagnOSIswas 161 (95% CI, 103-250) RIsk was Increased SImI­larly III sequential and cnntmuous cnmhIned HRT

Schauer et .11 17 evaluated the rIsk of breast cancerWIth HRT (prImarIly CEE/MPAj In a cohort study of46,355 women (mean age at follow-up, 58 years) fromthe Breast Cancer DetectIOn DemonstratIon ProjectThe RR of breast cancer with ever-use and current useof HRT was U (95% CI, 1.0-1.6) and 14 (95% CI,1. 1-1.9), respectIvely, On the basis of a linear excess nskmodel, the authors noted a sigmficant trend (P =01)for a duratIon effect WIth HRT (RR Illcreased by 008for each year of HRT use, 95% CI, 0,02-0.16), althoughthe effect was SIgnIficant only for women wIth a bodymass Index of < 24,4 kg/m2

In a multicenter studY that was conducted III Massa-•

chusetts, New Hampshire, and Wisconsin. 5298 post-menopausal women (ages 50-79 years) wIth a newdIagnOSIs of InVaSIVe breast cancer and 5571 controlsuhJects were evaluated 15 Ever-use of HRT (pnmanlyCEE and MPA) was aSSOCIated WIth an Increased RRof breast cancer (RR, 143; 95% CI, 118-174); no dIf­ferences In rIsk were noted between sequentIal (progestInadded < 10 days/cycle) or contInuous (progestIn added>21 days/cycle), In a report that followed the WHI find­Ings, Weiss et al lx evaluated the effect of HRT regImens(type of estrogens or progestins was not reported) onbreast cancer rIsk in women (4575 cases, 4682 controlsubjects), aged 35 to 64 years, who were partIcIpatIngin the Women's ContraceptIve and Reproductive Expe­flences Study, whIch was conducted In Atlanta, DetrOIt,Los Angeles, PhIladelphIa, and Seattle, DRs for breastcancer nsk wIth short-term use «2 years) of any com­bIned HRT regimen was not Increased, Current use ofHRT for ~ 5 years was associated WIth an increased rISk(OR, 1 37; 95 % CI, 106-1 77), although the Increasewas confined to contInUOUS combIned HRT

In summary, the findmgs of the WHI that longer-du­ratIon CEE/MPA IS aSSOCIated WIth an Increased RR ofbreast cancer are consIstent WIth other studIes that usedSImIlar products and WIth studIes that were conducted InEurope where dIfferent estrogen and progestIn productsare more common,

Cardiovascular outcomes

Venous thromboembolic eventsTable II gives a summary of recent studIes of the effectsof vanous regImens ofERT and HRT on cardIOvascularoutcomes, The potentIal rIsk of venous thromboembolicevents (VTEs), deep venous thrombOSIS, or pulmonaryembolism WIth ERT/HRT is well recogmzed, In the

DWRITE 072602

1148

Table II Studies of effects of ERT or HRT on cardiovascuLar disease outcomes

Study/country Therapies studied Study design/subjects

Warren

Effect of HRT on cardiovascuLar disease risk

CEE and/or CEE/MPAWriting Group for the PEPI

TriaL25/United States

HuLLey et aL23,62/

Umted States

CEE 0.625 mg, CEEcombmed wlth eithercontinuous MPA 2.5mg, cyclic MPA 10 my(12 d/mo, ormicronized progesti n(MP) 200 my (12 days/month)

CEE 0.625 mg/MPA 2.5 mg

Randomized. pLacebo­controLLed study

875 heaLthy,postmenopausaL women

Mean age, 56.1 y

Primary end points: 4measures ofcardi avascuLar risk

HERS: randomized,bLinded, pLacebo­controLLed; HRT =

1380; pLacebo = 1383postmenopausaLwomen with coronarydisease

HERS II: open-LabeLobservationaL foLLow-upstudy; HRT = 1156,pLacebo = 1165

Mean age: 67 yMean age at Last

menstruaL period: 49 yMean duration of disease

event surveillance =6.8y includmg 2.7 y inHERS II

VTE10/682 events occurred among the 4 estrogen

treatment groups (of which 6 were superficiaLthromboph Lebitis)

0/165 events occurred in the placebo group(P >.2)

Event rates in estrogen users were 47.6/10000women

HR, 5.10 for estrogen users

TotaL thromboemboLic events

HERS (4.1 y): RH of VTEs with HRT use overa mean of 4.1 y, 2.89*

HERS II (2.7 y): RH, 1.40 I.\Ilth HRTTotaL (6_8 y): 49 HRT vs 24 pLacebo; RH, 2.08*;

31 more VTEs per 10.000 women/yDVT

Grodstein et aL52/

United StatesCEE 0.625 mg, or CEE 0.3 FoLLow-up study

mgN=70,533

HERS (4.1 y): RH. 2.82*HERS II (2.7 y): RH, 1.23TotaL (6-8 y): RH, L98*PEHERS (4.1 y): RH. 2.78HERS II (2.7 y): RH, 3.03TotaL (6.8 y); RH, 2.86*; 13 more PEs per

10,000 women/yCHDIncrease in risk of recurrent CHD in year 1; RH,

1.52*Decreased nsk with contmued HRT use (P= .009

for trend 10 Log RH)OveraLL nuLL finding for the effect of HRT on the

risk of CHD events (RH, 0.99) over theaverage foLLow-up of 4.1 y

RR for stroke

CEE 0.625 mg: RR, 135*CEE 1.25 mg: RR, 1.63*CEE 0 3 mg: RR, 0.54

(Continued on next page)

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Table II (continued)

Study/country

Herrington et al24/

United States

Alexander et at7 l/

United States

Therapies studied

CEE 0.625 mg, CEE 0,625/MPA 2.5 mg

Predominantly oral CEE;also HRT (27.5% orusers)

Study design/subjects

Randomized, double­blind, placebo­controlled study

Mean follow-up: 3.2 y

Postmenopausal womenwith coronary disease.309 (N = 248 forangiography)

Mean age: 65.8 yRetrospective

observational cohort(N =1857) w/a recentMyocardIal infarctIon

Never-users: 1333

Previous/current users;413

New users: 111

Mean age:Never used HRT: 67 y

1149

Effect of HRT on cardIOvascular d1sease nsk

All-cause mortality rate was similar in the 3treatment groups (P=,128):placebo, 5.7%;estrogen alone, 8"10; estrogen + MPA, 2.9%

CHD mortality rate was similar in the 3treatment groups (P =.65): placebo, 2_9%:CEE alone, 4°10; CEE + MPA, 19%

InCIdence of CHD events was slmllar In 3treatment groups (P=.69): placebo, 32.4%,CEE alone, 29%; CEE + MPA, 28.2%

PE: increased risk with ERT (RR, 2.1*)RR of death/myocardial/unstable angina for

new users of HRT, 1.44*

RR for HRT users was lower (RR, 0.56*) than ERTusers

Unstable angina among new users of HRT In thefirst 6 rna: RR, 1.88*

PrevIOus/current and new HRT compared tonever-users were more liKely to undergocardiac catheterization and directpercutaneous translummal coronaryanglOplasty (P< .01)

New users had more unstable angina comparedto never-users (P= .001)

Writing Group for theWomen's HealthInitiativeInvestigators l

/

Umted States

HRT users; 58,5 yCEE 0.625 mg/MPA 2.5 mg Prospective, randomized,

controlled trial

16,608 healthypostmenopausal women(HRT =8506;placebo =8102)

Mean age: 63 y

Range: 50-79 Y

Average follow-up: 5.2 y

VTE: HR, 2.11*; 18 more VTEs per 10,000women/y

DVT: HR. 2.07*; 13 more DVTs per 10,000women/y

PE: HR, 2.13 (nC!, 1.39-3.25; aCI, 0.99-456): 8more PEs per 10,000 women/y

Stroke (fatal and nonfatal): HR, 1-41* after anaverage of 5.2 y of follow-up

CEE/MPA users had an Increased risk fornonfatal stroke: HR, 1.50*; but not for fatalstroke: HR, =1.18

CHD (fatal and nonfatal MI): HR, 1.29*

17~-estradiol

Sourander et al55/

FinlandEstradiol, mean dose

1.46 mg21% of women with no

hysterectomy also useda progestin

Current estrogen users(n =988) receIVed 176­estradiol (mean dailydose, 1.46 mg) atbaseline; 139 womenused a progesti n

Observational study

N=7944

Never users mean age:60.9 y

Mortality rate

Total mortabty rate lowest in the current usergroup (P<.OOl)

Cardiovascular mortality rate significant lowerin the current user group (RR, 0.21*)compared to past and never users

(Continued on next voge)

DWRITE 072604

1150

Table II (continued)

Study/country

Hoibraaten et al30/

Norway

Viscoli et al35/

United States

Clarke et al67/

United Kingdom

ESPRIT team68/

United Kingdom

Therapies studied

Only estradiol HRTproducts were used(oral/transdermal);some with gestagen

Oral 1713-estradiol 1 mg/d or placebo

Transdermal 17~-estradlOl

with or withoutnorethlsterone

Oral estradiol valerate

Study design/subjects

Former users mean age:6LO y

Current users mean age:59.9 y

Population-based case­controlled Cases = 176(average age, 59,3 y)

Control subjects = 352(average age, 59.2 y)

Women WIth pnmary orsecondary dla9nosis ofdeep venousthrombosis/pulmonaryembolism or othervenous thrombosis

Randomized, double­blind, placebo­controlled study

N= 664 Postmenopausalwomen Wlth a recentischemic stroke ortranSlent IschemICattack: HRT, 337:placebo, 327

Mean age: 71 y

Randomized tnal

p= 255 with heart disease

ERT: 58HRT: 76Control subjects: 121Mean age'HRT: 663 yControl subjects: 67 y

Randomized, placebo-controlled trial

N= 1017 post menopausalwomen who hadsurvived a firstmyocardial infarction)

ERT, 513Placebo: 504

Ages: 50-69 Y

Warren

Effect of HRT on cardiovascular disease risk

CardIOvascular morbidity for current users vsnever users: RR, L07

Coronary artery disease morbIdIty for currentusers vs never users: RR, 1.05

Adjusted RRStroke morbidity: RR, 0.86 (P= .049)Stroke mortality: RR, 0.16Not significantly influenced by current ERT/HRT

useThese data were based on only 10 cases of

stroke, one of whIch was fatal

VTE: current use of HRT: adjusted OR, 1.22

VTE, stratification for time of HRT exposure,compared to non-use:

< 1 y, 354*> 1 y, 0.66

RR of death or nonfatal stroke, 1.1

RR of fatal stroke, 2.9RR of death from cardiovascular disease, 0.8RR of nonfatal stroke, 1 0RR of any stroke, LlRR of nonfatal myocardIal infarction, L2RR of any stroke at 6 mo, 2.3*RR of any cardiac event (nonfatal or fatal) with

ERT, 1.1

Average rate ratio of myocardIal infarction,cardiac death, or hospitalization for unstableangina over 4 y 1.29

No difference in event rate between ERT andHRT

Event rate ratio with ERT

Remfarctlon: 0,99

Cardiac death: 0.99RR of cardiac death with ERT was lowest during

the first 3 months of study: RR, 0.33

(Contrnued on nelf/: page)

DWRITE 072605

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Table II (continued)

Study/country

ERT or HRT, various•regImens or

components notspecIfied

Thompson et al58)

United Kingdom

Grodstein et al46)

United States

Pedersen et al54/

Denmark

Therapies studied

60% of the recordedprescn ptlOns m th1sstudy were written forestropipate, ethinylestradioL!methyltestosterone,CEE, norethisterone,diethylsti lboestrol, andethinyl estradiol

Hormone type notspecified

Unspecified ERT/HRT;oral, InJected, orpatch

Study desIgn/subJects

Case-controllpd study

N= 603 cases with strokeor myocardIal infarctIOn

N= 1206 control subjects

Ages: 45-69 Y

Prospective observational

N= 59,337postmenopausal women

Age: 30-55 y at inclusion

Case-controlled study

N= 1422 casesNever use of HRT: 484Former use of HRT: 156

Current use of unopposedestrogen' 73

Current use of combinedregi mens: 133

N= 3171 control subjectsAges: 45-64 y

1151

Effect of HRT on cardiovascular disease nsk

Stroke and MI:

> 1 HRT prescription: RR, 1,36*Only 1% of the cases were Using HRT at the time

of the eventRisk of stroke and myocardial infarction with

use (P= .09):1-3 mo: RR, 2.144-6 mo: RR, 1.097-12 mo: RR, 1.0613-24 mo: RR, 1 14>24 rna: RR, 119RR of stroke and myocardIal InfarctIOn m

patients receiVing progestogens alone: 1.90Estimated RR, 5.27 for fatal events (P=.08)Estimated RR, 1.46 for non-fatal events

(P=.08)No type of HRT use was significantly associated

with the risk of stroke and myocardialinfarction, independently of potentialconfounders

Major CHD was reduced m the HRT groupcompared to never users (RR, 0.45*)

No coronary heart disease benefit was seen inpast HRT users

No association of HRT and the incidence ofstroke was observed

Current use: Ischemic stroke

ERT: OR, 1.16HRT: OR, 1.17For transient ischemIC attacks, the current Use

of ERT (OR, 2.11*) but not HRT (OR, 1.25)was associated Wlth an increased RR

Age adjusted RR for recurrent major coronarydIsease was 0.56* for current vs never users

Recurrent CHD events among women withcurrent use of < 1 Ycompared with never­users: RR, 1.25

(Contrnued on neKt /Jaqe)

DWRITE 072606

1152 Warren

Table II (continued)

Study/country Therapies studied Study design/subjects Effect of HRT on cardiovascular disease risk

Average age: 53.9 y

Cases = 103Control subjects = 178

Multi ple estrogen Case-control studyproducts: oral CEE,transdermal estradioLestradiol implant, otheroral unspec1fied HRT

Multiple estrogen Case-control studyproducts: CEE,estradial/estradiolvalerate, piperazineestrone sulphate,transdermal estradlolpreparations

(Continued on neKt page)

ERT: OR. 3.2*HRT: OR, 5.3*Risk with current use of HRT;Relative to nonusers: OR, 3.5*Relative to never users: OR, 3.6"Use for 1-12 rna: OR, 6.7*Use for 13-36 mo: OR, 4.4"Use for 37-60 rna: OR, 1-9Use for > 61 mo: OR. 2.1No significant differences in the risk of VTE

among various therapiesVTE

ERT: OR, 1.9HRT; OR. 2.2*Risk with current use of HRT: OR, 2.1"Use for 1-6 mo: DR 4.6"

Sigmficant (P= .002) decrease in nsw wlthincreaSing duration of current use

Longer-term users com pared to never uses: RRfor a second major coronary event, 0.38*

10,000 postmenopausal women 60-75 yreceiving HRT, 420 additional recurrent casesof coronary heart disease/y with short-termuse, and 1040 fewer cases/y after long-termuse

Short-term users compared to long-term users,nsk for recurrent coronary event: RR, 2.10

After long-term use, risk of recurrent coronaryevents: RR, 0.50"

Significant (p= .02) trend of decreasing nsk forrecurrent coronary events with increasingduration of HRT

VTE

Cases = 292Control subjects = 10,000Ages: 50-79 yEstrogen alone or

combined withprogestin, transdermalvs oral regimens; low­dose (eqUivalent to CEE0.625 mg ortransdermal dellVery of1713-estradlOl25 mg or50 mg per 24 h) vshigh-dose (equivalentto CEE 1.25 mg ortransdermal delivery of1713-estradiollOO mgper 24 h) therapy

Daly et al33/

United Kingdom

Perez Gutthann et all7/

United Kingdom

DWRITE 072607

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Table II (continued)

Study/country

Heckbert et al69/

United States

Varas-Lorenzo et al28/

Italy

Angeja et al3B/

United States

Hec~bert et al69/

Umted States

Therapies studied

ERT/HRT (not otherwisespedfied)

Multiple HRT products:oral CEE, transdermalestradIOL, otherunspecified regi mens

79% reported use oftransdermal estradiol

Estrogen, progestin,estrogen-progestin forreasons other thancontraception

ERT used 67% of the t1me,HRT 33%

Esterified estrogensused 70% of the time,CEE 28%

Study design/subjects

Case-control study inpostmenopausal womenwith confirmed fatal ornonfatal myocardialinfarction

Cases: 850

Control subjects. 1974ERT/HRT had been used at

any time by 27% of thecases and by 35"10 ofthecontrol subjects

ERT/HRT was currentlyused by 19.8% ofthecases and by 27.6% ofthe control subjects

Average age: 69 y

Case-control study

Cases=l71Control subjects = 232

Ages: 45-79 Y

Prospective cohort

N=7353 current ERT/HRTusers

Mean age: 71 yPopulanon-based cohort

N= 981 survivors of anmyocardial infarctionWithout HRT: 2913person-y

1153

Effect of HRT on cardiovascular disease risk

Use for 6-12 rna: OR, 3.0*Use for >12 rna: OR, 1 1No differences between regimens

Current or past use of HRT reduced the risk ofMI:

Current· RR, 0 70*Past: RR. 0.74*Longer duration of use of HRT associated with

a larger reduction in risk

Risk for nonfatal myocardial infarctIOnaccording to duration of estrogen among thewomen currently usi ng estrogen

RR, 1.02 (>0 to <1.8 y)RR. 0.79 (1.8 to < 4.2 y)

RR, 0.63 (4.2 to < 8.2 y)RR, 0.61 (> 8.2 y)Women who had discontinued the use of

estrogen recently (Wlthin 8 mo [0.7 y] oftheindex date) had a sllght nsk for myocardIalmfarction (OR, 1.43) than those whodiscontinued estrogen use 0.7 to 2.7 y beforethe indeil date

OR, 2.3 of VTE

Risk of VTE:ERT: OR, 1.4HRT: OR, 5.0*

Use for 1 rna to 1 y: OR, 2.9*Use for> 1 y: OR, 0.0

Adjusted RR for ischemic stroke, 0.89

Adjusted RR for hemorrhagic stro~e, 0.88

Multivariate-adjusted RH for recurrentmyocardial infarction or death from CHD(current use of HRT), 0.96

(Continued on nert paqe)

DWRITE 072608

1154

Table II (continued)

Study/country

Grodstein et al70/

Umted States

Shlipak et al"O/United States

M

MIller et al~"/International

TherapIes studied

MPA was the progestinin virtually all cases

Oral CEE w/ or w/outprogestin: oral 17~­

estradiol; transdermal:estrogen; other (notspeCIfied)

Estrogen, progestin, orestrogen/progestin forreasons other thancontraceptIon

ERT/HRT: formulationsvaried from study tostudy

Study design/subjects

With HRT: 686 person-y

Total follow-up: 3599person-y

Average age' 67.8 Y

Prospective observationalcohort (N = 2489) wiprelflOUS myocardialinfarction oratherosclerOSIS

Never users: 38.6%Past users: 32.4%Current users: 29.0%Age range: 57.4-60 Y

Prospective

N= 114.724 women > 55Ywith a co nfi rmedmyocardIal mfarction

Meta-analysis of Englishlanguage studies viaMedline (1966-2000),HealthSTAR (1975­2000), Cochrane Librarydatabases, & referencelists of key articles

Warren

Effect of HRT on cardIOvascular dlsease risk

Adjusted RH of recurrent coronary events:<60 d of starting therapy: RH, 2.1660-365 d: RH, 0.92

>365 d: RH, 0.76Adjusted RH of recurrent events during the first

year starting HRT, 1.30Age-adjusted RH for CEE use compared with

estenfied estrogen use: 1.35Overall adjusted RH for recurrent myocardial

infarction or Coronary heart disease deathwas not mfluenced by ERT/HRT use (RH,0.96)

There was a suggestion of an increased riskWlthin the first 60 days of mitiation orreinitiation of therapy (RH. 2.16), followedby a reductIon In nsk with use of ERT/HRT for>1 y (RH, 0.76)

Major CHD, HRT users vs never-users: RR, 0.65*

Current use for:< 1 y: RR, 1.251-1.9 y: RR, 0.55~ 2 y: RR, 0.38Age adjusted RR, 0.56* for recurrent major

coronary disease for current users vs neverusers

Recurrent Coronary heart disease events amongwomen Wlth current use of < 1 Y comparedwith never-users: RR, 1.25

Longer-term users compared to never users, RRfor a second major coronary event, 0.38*

Short-term users compared to long-term users,risk for recurrent coronary event: RR, 2.10

After long-term use, risk of recurrent coronaryevents: RR, 0.50*

Slgmficant (p= ,02) trend of decreasing nsk forrecurrent coronary events with increasingduration of HRT

Adjusted OR of 0.65* that indicates improvedrate of survival in current HRT users of all agegroups

Greatest reduction for Coronary heart diseasemortality rate for youngest group of women(55-64 y): OR, 0.54*

VTE

([onlJnued on neJrl; page)

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Table II (continued)

1155

Study/country

Nelson et aL36/

InternationaL

Humphrey et aL66/

InternationaL

Nussmeler et aL74/

United States

TherapIes studIed

Unspecified ERTIH RT

Estrogen + progestin

ERT/HRT

85% receiving CEE orestradiol alone; restwere receivi ng CEEand MPA

Study desIgn/subJects

Meta-anaLysis of keyarticles (1996-2001),evaluated the benefitsand harms of HRT forprimary preventIon ofCardiovascuLar disease.thromboemboLism.osteoporosis, etc.

TotaL N not reportedMedLine and Cochrane

database search from1966 to December ;WOOfor studies of primaryprevention(Cardiovascular diseaseor Coronary arterydisease)

Retrospective analysis

N= 4259 records ofpatients aged 55 y whounderwent primaryelective, isolatedcoronary artery bypasssurgery

Effect of HRT on cardIOvascuLar dlsease risk

RR w/ current HRT use (overall), 2.14­RR in first year (6 case-control), 3.49*RR after 12 months (6 case-controL), 1.91*PooLed RR (studies excluding Coronary artery

disease), 2073*PooLed RR (studies includIng Coronary artery

dIsease), 3-32*Baselme nsk of VTE. 1.3 per 10.000 women per

yearAbsolute rate t, 1.5 VTE events per 10,000

women per yearEver use; overaLL stroke: RR, 1.12*

MortaLity rate for aLL groups:CardiovascuLar disease: RR. 0.75Coronary heart dIsease: RR. 0.74Incidence for all groups: CardIovascular dlsease:

RR, 1 28Coronary heart dIsease: RR. 0.88Current use of ERT(HRT was associated with

a reduced risk of Coronary heart diseasedeath (summary RR, 0.62*)

MortaLity rate with any HRT use;CardiovascuLar disease: RR, 0.75Coronary artery disease: RR. 0,74Incidence with any use:Cardiovascular disease: RR, 1.28Coronary artery disease: RR, 0.87Summary RR for Coronary heart dIsease of 0,80*

among current users of ERT/HRTHowever. when the authors evaLuated onLy

those studies that reported adjusting forsOCloeconomic status. the reduction in RR forCoronary heart disease was no longersignificant (summary RR, 0.97)

Women using ERT/HRT at hospitaLadministration had slgmficantLy Less 10­

hospItaL deaths compared to women I.\lhowere not (P<.005)

* = signtficant (i e.. confidence intervaL does not include 1).

DWRITE 072610

1156

HRT arm of the WHI tnal, the mcreased HR for VTEswas 2,11 (nommal 95% CI, 1,58-2,82), I It should benoted thIS population included a small number ofwomen with a hIstory of VTE; when the authors ana­lyzed this subset of women, the HR for future VTE wIthHRT was 490 (95% CI, 058-41 06)

Before the WHI, a number of studIes (randomIzedand observatIOnal) exammed the VTE nsk In conJunc­tIon with the US Preventive ServIces Task Force,MIller et af2 calculated a summary risk estimate forVTE on the basIs of a meta-analysis of 12 studIes thatused a variety of ERT/HRT products and doses2J-34

The meta-analysis revealed that the current use of post­menopausal ERT/HRT was assocIated wIth a 2-fold m­creased fISk of VTEs (RR, 2J4, 95% CI, L64-281)In the studIes that exammed the duratIon of use, thehighest RRs were observed withm the first 2 years;the summarv RR for year 1 m these studies was 3A9- -~95% cr, 2,33-5 59l

These studIes mcluded 3 randomIzed controlled tn­.lIs, the Heart and Estrogen/progestm Replacement

'1Study (HERS,-- and the Estrogen Replacement andAtherosclerOSIS tnal"4 (both secondary preventIOn tn­.lIs), and the pnmary prevention PostmenopausalEstrogen/Progestm InterventIons (PEP!) trIal,25 all ofwhich used contmuous combmed 0,625 mg CEE plus2,5 mg MPA. In the HERS (n = 2763 women) andthe Estrogen Replacement and AtheroscleroSIS tnal(n = 309 women), the average age of the women whosecases were studIed was >65 years,2i24 The relatIve haz­ard (RH) of VTEs with HRT use over a mean of 4,1years m the HERS was 2,89 (95% CI, L50-558)'3, inthe Estrogen Replacement and AtheroscleroSIS trial,the authors noted a small number of events over theaverage 3 2 years of follow-up. with no differences ob­<;erved between HRT users and placebo 24 In the Post­menopausal Estrogen/Progestm InterventIOns tnaL 875healthy postmenopausal wnmen (mean age, 56 years)were randomIzed to placebo, CEE 0 625 mg, or CEEcombmed WIth eIther contmuous MPA 25 mg, cyclIcMPA 10 mg (12 d/mo), or mIcronized progestm 200mg (12 d/mo)25 A total of 10 partiCIpants in the actIvetreatment groups and no patients m the placebo groupexperienced VTEs, no dIfferences were noted betweenERT/HRT groups, Oral CEE WIth or without MPAwas also the prImary type of ERTIHRT reportedlyused in the Nurses' Health Study, an observatIonalstudy of >112,593 women aged 30 to 55 years m197631 The authors noted that the current use of post­menopausal hormones. pnmanly ERT m thIS report,resulted m an mcreased nsk of primary pulmonaryemhohsm (RR, 2 1; 95% CI. L2-38),

StudIes that reported an mcreased risk of VTE withERT/HRT regImens other than CEE/MPA had slmJlarfindings 26-iO In a case-controlled <;tudy of women aged45 to 64 years that was cnnducted III the Umted Kmgdom,

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Daly et af" analyzed 103 cases (69 women with deep ve­nous thrombOSIS. 39 women with pulmonary embolism)and 178 control subjects; 44 women in each group werecurrently usmg estrogen products that mcluded oraleEE, 17a-estradlOl or estradlOl valerate, plperazme es­trone sulfate, and transdermal estradwl ApprOXImatelyone half of the hormone users m each group also useda progestm (type was not specified), and tIbolone was con­SIdered HRT The adjusted OR for VTE m current HRTusers, compared WIth nonusers, was 3,5 (95% CI, 1,8-7,0)The authors mdlcated that thcre were no significant dif­ferences in the fISk ofVTE between ERT and HRT, oraland transdermal therapy, or between lower-dose (eqUIva­lent to eEE 0,625 mg, 1713-estradlOll mg, or transdermaldelJvery of 17l3-estradlOl 50 Ilg per 24 hours) or hlgher­dose (eqUIvalent to CEE 1.25 mg. 1713-estradlOl 2 mg, ortransdermal dehvery of l713-estradlOll 00 Ilg per 24 hours)preparations,

In a large, populatIOn-based. case-controlled study mthe Umted Kmgdom (n = 347,253 women; 50 to 79years),n the adjusted OR for VTE m current HRT userswas 2 I (95% CI, 1 4-3 2) The Increased fISk was re­stncted to first-year users, the adjusted nRs for VTEwere 46 (05% CI, 25-114), 30 (95% CI, 14-65), and11 (95% CI, 06-21) m current users for I to 6 months,6 months to 1 year, and >1 year, respectively No dIffer­ence in risk was observed for estrogen alone or combmedWIth progestm, transdermal versus oral regImens, or forlower-dose (eqUIvalent to CEE 0,625 rug or transdermaldelivery of 1713-estrad10125 Jlg or 50 Jlg per 24 hours) ver­sus hIgher-dose (equivalent to CEE 1,25 mg or transder­mal dehvery of 1713-estradIOI 100 Jlg per 24 hours)therapy,

A slmJlar overall nsk of VTE (OR, 2,3, 95% CI, LO­5,3) was reported III an Italian populatIon cohort studyof 265,431 women aged 45 to 79 years. III whIch 79% ofthe women reported the use of transdermal estradIOL 2MAs noted in prevIous studIes, the increased nsk appearedto he re<;tncted to the first year of use (OR, 2.9; 95% CI,I 2-6 9) and, although data were lImIted, a hIgher VTEnsk was noted m women who used HRT (OR, 50;95% CI, 15-167) compared WIth ERT (OR, 14; 95%CI, 04-46)

In a populatIOn-based case-controlled study ofwomen aged 45 to 70 years III Norway, Hmbraatenet 011 30 analyzed the nsk of VTE m a total of 176 casesand 352 matched control subjects usmg hospital chartsfrom a penod of 6 years, The authors noted that onlyERT/HRT products that contallled estradiol wereused, but dIfferent progestms and both oral and trans­dermal routes of admmistratIOn were reported, Theadjusted OR for VTE m current users of HRT Wasnot increased significantly (OR, L22, 95% CI, 0,76­1,94); however. an mcreased nsk of VTE was notedduring the first year of use (OR. 3,54. 95% CI, 1,54­829).

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The overall eVidence supports an lllcreased nsk ofVTE that is associated with postmenopausal ERT/HRT RRs for VTEs range between 2,0 to 3,0, withthe greatest risk seen wlthlll the first 1 to 2 years ofuse, The data regardmg the nsk of VTE and postmeno­pausal ERT(HRT are consistent for all types of estro­gens and progestins,

StrokeAt least 4 randoml7ed placebo-controlled trIals, I ,23,2·U5

3b '~5b1 meta-analysIs, and many observatIonal studles-"-have reported the effects of postmenopausal ERT/HRT on stroke A recent meta-analysIs conducted forthe US PreventatIve Services Task Force3ti pooled re­sults from 9 observatIonal studles4l ,44,4Q,52,54,55,57-5Q that

\vere rated fair to good m qualIty With respect to internalvalIdity, The summary RR for overall stroke incidencewas increased among ever-users (RR, 1,12, 95% CI,1.01-1.23), the authors noted no differences betweencurrent, ever, and past users, In subanalyses, the RRwas elevated With HRT for thromboembolIc stroke(RR. 1.20; 95% CL 1.01-1.401. but not for subarachnOIdor mtracerebral stroke, 3~

In the HRT arm of the WHI trIal. the overall HR forstroke (fatal and nonfatal) was I 41 (nommal 95% CI,I 07-1 85) after an average of 5 2 years of follow-up I

When separated Into fatal or nonfatal events, CEE/MPA users had an mcreased rIsk for nonfatal stroke(HR, 150, n0ll1111aI95% CI, 108-208), but not for fatalstroke (HR, 1.18; nommal 95% CI, 0,58-2,50), The m­creased risk of stroke m HRT users appeared In year 2(HR, 1.72) and perSISted through year 5 (HR, 1.87), Ina recent subanalysls from thiS tnal, HRT was associatedwith an mcreased nsk for Ischemic stroke (HR. 144,95% CI, 1.09-1.90), but not for hemorrhagic stroke(HR, 0,82. 95% CL 0.43-1.56)60 In contrast to theWHL no increased rISk for any stroke was noted Inthe secondary preventIon trIals that randomly assignedwomen to CEE 0,625 mg/MPA 2,5 mg (the HERSand HERS II [an open-label. 2,7-year extension of theHERS]bl-b3 and the Estrogen Replacement and Athero-

'4scleroSIS tnal) -The Women's Estrogen for Stroke Tnal IS the only

randomized, placebo-controlled tnal that evaluated theeffects of 17~-estradlOlon stroke 15 A total of 664 post­menopausal women (mean age, 71 years) who recentlyhad an ischemiC or transient ischemiC stroke receIvedplacebo or 17~-estradlOl I mg, Women with a uterus re­ceived an annual IZ-day course of 5 mg of MPA , Anincreased RR of any stroke (RR, 2,30, 95% CI, 1,1­5,0) was observed in the ERT group within the first 6months of therapy, although no slgmficant differenceswere noted between treatment groups in either nonfatal(RR, 1,0; 95% CL 0,7-1.4) or fatal stroke (RK 29. 95%CI, 09-90) for the overall study (mean follow-up. 2,8years)

1157

In other studies that evaluated estrogens other thanCEE, 3 studies Included a vanety of different estro­gens, 1~ 54,5~ and I study appeared to mc1ude only formu­latIOns that contamed 17~-estradlOI55Thompson et al58

assessed the effects of 76 different ERT(HRT regimenson the nsk of stroke and myocardial lllfarction inwomen aged 45 to 69 years who were seen at 83 generalpractices In the Umted Kmgdom Sixty percent ofthe recorded prescrIptIOns In thiS case-CClntrolledstudy were WrItten for estroplpate, ethmyl estradlol(methyltestosterone, CEE, norethlsterone, dlethylstIl­bocstrol, and ethmyl estradIOl. On the basis of datafrom 109 cuses and 174 control subjects, the authorsreported no increase In the rIsk of stroke for eitherestrogens alone, progestIns alone, or combined HRTproducts~

In a DanIsh case-controlled study, Pedersen et .1154

evaluated the rISk of stroke subtypes m women aged45 to 64 years who had a nonfatal stroke from 1990through 1992 (1422 cases and 3171 control subJects)~

A varIety of different hormone regimens and prepara­tIons (tablets. patches. and preparatIons for mjectIons)were included m the analySIS, No assocliltIons were ob­served between the use of ERT or HRT and the risk ofsubarachnOid hemorrhage, mtracerebral hemorrhage. orthromboembolIc mfarctlOn For transIent IschemIC at­tacks, the current use of ERT (OR, 211; 95% CI,141-317), but not HRT (OR, 125, 95% CI, 086­1.82), was assOCiated With an Increased RR. Usmg theUS NatIOnal Registry of Myocardlill Infarction-3 data­base (n = 114,724 women [> 55 years old]), AngejU etal38 evaluated the impact of HRT use on the fisk ofIn-hospital hemorrhagiC and IschemiC stroke after anacute myocardial infarctlOn~ For the 7353 women (meanage, 71 years) who currently were receiving any estro­gen, progestm, or estrogen-progestm for reasons otherthan contraception, the adjusted RRs for ischemiCstroke were 0,89 (95'% CI, 0,66-1.81) and 0,88 (95%CI. 0,58-1.35) for hemorrhagic stroke.

A FinnIsh cohort study exammed the effects ofERT(HRT on morbidltv and mortahtv rates from stroke m. -7944 women who were born between 1923 and 1939(aged 57 to 64 at the ImtIatIon of follow-up evalua­tIons) 55 Current estrogen users (n = 988 women) re­ceived 1713-estradlol (mean dally dose, I 46 mg) atbaselIne; 139 women received a progestm The adjustedRR for stroke morbIdity (RR, 086; Q5% CI, 042-1.75)or death (RR, 0.16; 95% CI, 002-118) was not mflu­enced Significantly by current ERT/HRT use, althoughthe authors noted that the reductIon m stroke deathwas of borderline sigmficance (P = ,049), These datawere based on only 10 cases of stroke, I of which wasfatal,

There may be a dose-related effect of estrogens onthe rIsk of stroke, In the 20-year follow-up reportfrom the Nurses' Health Study (n = 70,533 women),

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the RR of stroke was Illcreased slgmficantly amongwomen who receIved CEE 0.625 mg (RR. 1.35;95% CI, 108-168) or those who received CEE > 125mg (RR, 163, 95% CL 1.18-1.26); however, therewas no associated Illcrease m stroke for CEE 0 3mg (RR, 0.54; 95°/0 CI, 028-106 [based on only 9

'i'cases}) --

Although the data for the fisk of stroke that was spe­Cific to postmenopausal HRT that contamed estrogensand progestms other than CEE and MPA are lImited,they are consistent with the total data that evaluatesthe nsk of stroke \vlth ERTjHRT

Coronary heart disease (CHO)Most publIshed observational studies that used a van­ety of postmenopausal honnone therapy products re­ported a 30% to 50% lower mCldence of CHD

. / RT 'i' Ii.! ii';among ERT H users.--'- -- In a recent meta-ana-lySIS that used studIes that were rated as faIr or goodm quality, Humphrey et albb reported a summary RRfor CHD of 080 (95% CI, 064-078) among currentusers of ERT!HRT However, when the authors evalu­ated only those studies that reported adJustmg for so­CIOeconomIc status, the reduction III RR for CHDwas no longer slgmficant (summary RR, 097; 95%CI, o82-1.16)

Data from recent randomized clInical tnals havefailed to show that ERTjHRT IS protective againstpnmary or secondary CHD. U3 35 h7 hX As noted previ­ously, the primary preventIOn WHI trial 1 and the sec­ondary prevention HERS:!3 mvestigated the effect ofcontmuous combined CEE 0.625 mg/MPA 2.5 mg onCHD in postmenopausal women who were 63 and 67years old, on average, respectively. In the WHI, the m­vestlgators reported an HR of 1.29 195% U. 1.02-1.631for CHD (nonfatal and fatal myocardial mfarctlon) IThe increase m the fisk of CHD m the HRT groupwas greate,t m year 1 (HR, I 78) ThIS potentIal trendof the nsk of an early event was also eVIdent m theHERS 23 The mcrease m fisk of recurrent CHD m yearI (RH, 152,05% CI, 101-220) decreased WIth contm­ued HRT use (P = .009, for trend III log RH), whichlead to an overall null findmg for the effect of HRTon the fisk of CHD events (RH, 0.99, 95% CI,0.80-122) over the average follow-up peflod of 4.1years.

Three additional randomized clImcal trIals of second­ary prevention of CHD, the Papworth HRT Atheroscle­rosis Study,h7 the Estrogen m the Prevention ofReinfan:tlon TnaLb8 and the Women's Estrogen forStroke Tnal35 used different fonns of ERT/HRT thatcontamed estradiOl. The Papworth HRT Atherosclero­SI' Study was a randomIzed, open-labeL blmd end-pomttnal of 255 postmenopau,al (average age, 67 years) Withangtographically proven IschemiC heart disease who re­ceived transdermal ERT (n = 5R women L transdennal

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HRT (n = 76 women), or no treatment (n = 121. .

women) for an average of 30 8 months b7 NeIther thetype of estrogens or proge,tm, that were used nor treat­ment do,es was reported HQspltalizatlOns for unstableangina, nonfatal myocardIal IllfarctlOn, and CHD deathwere the mam outcomes measured Over the 4-yeartflal, the event rate ratio with transdennal ERTjHRTwas 1.29 (95% CI, 0.84-1.95), WIth no differencesobserved between the ERT and HRT groups. The au­thors noted that the most frequently observed eventswere hospitalizations for unstable angma, whIch oc­curred mainly wIthm the first 2 years of recrUItment tothe trial,

In the Women's Estrogen for Stroke Tnal, CHD wasa secondary outcome III older (average age. 71 years)postmenopausal women (n = 664 women'l with a recentstroke who were aSSIgned randomly to receive 1713-estra­dlOl 1 mg (n = 337 women) or placebo (n = 327 women)for an average of 2 8 years 35 These authors reportedthat the RR for any cardIaC event (nonfatal or fatal)WIth ERT use was 1 I (95% CI, 06-1 0) and that theRR for nonfatal myocardIal mfarctIon was I 2 (95%CI, 05-25) Recent data from the Estrogen m the Pre­vention of Remfarctlon Tflal Illdlcated that estradIOlvalerate 2 mg also dId not prevent remfarctlon or car­diac death compared with placebo. b~ In this tnal, 1017postmenopausal women, aged 50 to 69 years, who hadsurvived a first myocardial infarction received ERT(n = 513 women) or placebo (n = 504 women) for 2years. The event rate ratio for eIther remfarctlon or car­diac death With ERT was 0.99 (95% CI, 0.70-1.41). Incontrast to previous studIes, the authors reported thatthe RR of cardiac death With ERT was lowest dunngthe first 3 months after entering the tnal 1RR. 0.33;95% CI, 0.1l-1.0n

This trend for nsk of early events with ERT/HRT III

women WIth established CHD was also noted III posthoc analyses of prospective observatIOnal cohorts thatused a vanety of formulatIons b'l-71 Heckbert et a1 6'l

evaluated recurrent CHD III 081 women (mean age,678 years) who had survived an mltlal myocardIalinfarction usmg data from the Group Health Coopera­tive, a health mamtenance orgamzatlon m WashIllgtonState. Unopposed estrogens (most common were ester­ified estrogens [70% of oral estrogen use] and CEE[28% of oral estrogen use]) were used 67% of the totaltime, combmed estrogen-progestm was used 33% ofthe time, with MPA virtually the only progestm used,The overall adjusted RH for recurrent myocardIal in­farction or CHD death was not influenced by ERT!HRT use (RH, 0.96, 95% CI, 0.62-150), however,there was a suggestIOn of an increased nsk Within thefirst 60 days of Imtiation or reIllltiation of therapy(RH, 216; 95% CL 094-495), followed by a reductionm nsk With use of ERTjHRT for >1 year (RH. 076;95% CI, 042-1 36)

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Similar findmgs were reported In an analysIs of 2489women with CHD from the Nurses' Health Study 70Women who InItIated postmenopausal ERT/HRT (pn­marily eEE with or without MPA) wIthm 1 year of anmyocardial mfarctIon had an RR for CHD events of1,25 (95% CI, 0,78-2,00); for the second and subsequentyears of use. the RRs were 0,55 195% CI. 0 13-2271 and•

0,38 (95% CI, 0.22-066). respectIvely In a retrospectIveanalysIs of women > 50 years from the CoumadInA"pmn Remfarchon Study (CARS) datahase, the HRfor recurrent first-year events of cardiac death, myocar­dIal InfarctIOn, or unstable angina was 144 (95% CI,105-1.99) for new users of ERT/HRT (median age, 58years) compared with never-users (median age, 67years),71 The types and dosages of hormones were notreported, In addition, the authors noted that new usersof ERT (n = 70) had a 48 ~ '0 occurrence of the compositeend POInt compared with 23% In new users of HRT(n = 26 women, P = ,014). However, there were fewmyocardial mfarctions and no deaths among the newusers ofERT/HRT. thus. the abIlity to detect real differ­ences was reduced.

In additIOn to the Incidence of CHD, Humphreyet al6fi evaluated ERT/HRT use and the nsk of CHDdeath In theIr meta-analysIs of 5 observatIOnal stud­le,,42.46.55,n7J that were rated as fair or good In qualIty

These studies Included the use of ERT/HRT that con­tamed pnmanly CEE and MPA40 and regimens that pn­marily wntamed 1713-estrau10155 Curn:nt use of ERT/HRT was associated With a reduced risk of CHD death(summary RR, 0,62; 95% CI, OAO-0,90), although anyuse of ERT/HRT (including current, past. or ever use)was not associated wIth a slgmficant reductIon III

CHD mortality fISk (summary RR. 0,74, 95% CI.0.36-1.45) .

Potential benefiCial effects of ERT/HRT use werealso found for In-hospital survival after myocardial In­farction. on the baSIS of the subset of 114.724 womenwho were > 55 years and who partIcipated In the Na­tional Registry of Myocardial InfarctIon-3 38.40 ShlIpaket al4u reported an adjusted OR of 065 (95% CI, 059­072), which Indicated an Improved rate of surVival mcurrent users of HRT (defined as the use of estrogen,progestm. or estrogen/progestm for reasons other thancontraceptIon) ThiS benefit was observed for all agegroups (55-64. 65-74, 75-84, and >84 years), wIth the re­ductIon m the adjusted OR for CHD mortalIty rategreatest for the youngest group of women (OR, 0,54;95% CI, OAI-O,71),

AdditIOnal data from patients who had undergonecoronary artery bypass suggest that estrogen may havebenefits in relation to vascular injury, Nussmeier etal74 conducted a retrospectIve analySIS of the recordsof 4259 patients who aged > 55 years and who under­went pnmary elective isolated coronary artery bypasssurgery at Texas Heart Institute in Houston, Women

1159

(n = 1161) who were receiVIng ERT/HRT at hospitaladmInistratIon (n = 256 women) had SignIficantly lessIn-hospital death compared With women who were not(P < ,005), Eighty-five percent of the HRT users weretakIng CEE or estradiol alone; the rest of the womenwere receiving CEE and MPA.

In summary. the early mcreased nsk ofCHD InCidenceWith CEE/MPA that was observed In the WHI 1 and theHERS23 has been documented more recently m both ran­domized clImcal tnalsh7 and retrospective analyses of ob­servatIOnal cohort studies that Investtgated ERT/HRTproducts that contaIned a vanety ofestrogens and proges­tins b9

-71 The potential reductIOn m risk of CHD deaths

that was seen III observational studies that used vanousERT/HRT products4042 ,40,55,72,7J has not been docu­mented III randomized clImcal studies With the use ofeither CEE/MPA I '3 or ERT/HRT that contained estra­dlOpredommantly.35 h7 08

Documented benefits of HRT

Osteoporosis

Fracture riskUntil the WHI tnal, there were no large, randomizedclInIcal tnals that were deSigned to evaluate the useof HRT on fracture nsk After a mean follow-up of5,2 years, the WHI IllvestIgators reported slgmficant re­ductions in hip (HR, 0,66; nominal 95% CI, 0,45-0,98),vertebral (HR, 0.66, nominal 95% CI, 0,44-0,98), andtotal fractures (HR, 0.76; nommal 95% CI, 0.69-0.85)with CEE/MPA 1 The WHI was also the first tnal toshow reductIOns in the risk of fracture III womenwho were not defined as "at risk" for osteoporosls75

Based on a prelImmary analysis. approximately 2.1 %women In the 50 to 64 year age group and about9.4% women III the 65 to 79 year age group were oste­oporotic accordmg to the baselIne bone mineral density(HMDI measurement76 Recentlv. Wells et Olin con-

•

ducted a meta-analySIS of 7 randomized clImcal tn-als,n,78-s3 not Includmg the WHI, that reported theRR of vertebral and nnnvertehral fractures WIth dIffer­ent fnrms of ERT/HRT (Includmg nral CEE With orWithout MPA, NETA. estradIOl valerate, micronIzed1713-estradlOl, and transdermal 1713-estradlOl) Thesummary or weighted RRs were 066 (95% CI, 0,41­1.07) for vertebral fractures and 0,87 (95% CI. 0,71­1,09) for nonvertebral fractures, When the WHI Waslater mcluded III the summary estimate for nonverte­bral fractures. the reduction in RR was 0,78 (95%CI, 0.64-0 96) X4

The decrease in fracture fISk with postmenopausalERT/HRT has been demonstrated In several large ob­servational studies. which Include the FrammghamHeart Studl5 and the Study of Osteoporotic Frac-

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tures8b In the Framingham study, 2873 women whowere aged 30 to 62 years at the time of the first examina­tion 0948-1951) were included in the analvsls; 60%

•

(n = 1720 women) were hvmg at the time the fracturedata were examined (1983-19l':5) R5 For those womenwho reported the use of estrogens (CEE was pnmanlyused) wIthm the past 2 years, the RR of hip fracture (ad­Justed for age and weight) was reduced (RR, 034;95% CI, 012-098) The Study of Osteoporotic Frac­tures, a prospective study of 9704 women ~65 years,evaluated the effects of different types of oral ERTand HRT on wnst and all nonvertebral fractures 8b

The current use of HRT resulted in reductions in the ad­justed RRs for both wnst (RR, 0,31, 95% CI, 0,11-0,84)and all nonvertebral fractures (RR, 0.51, 95% CI, 0.33­0,78), which were Similar to the reductions seen WithERT use,

HMOBecause low BMD IS the smgle hest predictor of fracturerISk m postmenopausal women,87 BMD has heen usedto evaluate the efficacy of antIresorptIve agents for post­menopausal osteoporosIs Three large, randomized clm­Ical tnals that used CEE/MPA, mcludmg lower doses,have documented benefiCial effects on lumbar spmeand hip BMDHs~(j In the 3-year Postmenopausal Estro­gen/Progestin Interventions tnal descnbed preVIOusly,both spme dnd hlP BMO increased approximately 5%and 2%, respectively, In the 2-year Women's Health,OsteoporosIs, Progestm, Estrogen (Women's HOPE)tnal of 749 postmenopausal women (average age, 52years). significant mcreases III spme and hlP BMD frombaselme were observed WIth CEE 0.625 mg/MPA 2,5 mgand With lower doses that contamed CEE 0.45 and 0,3mg With MPA I 5 mg 8'1 Increases ranged from I 7%to 3 5% for spme BMD and from I 9% to 2 6% forhip BMD for the lower and higher CEE/MPA do"e",respectively.

In their systematic review of 57 studies, Wells et .1177

evaluated randomized chnical tnals that used a vanetyof ERT/HRT products other than CEE/MPA Thesestudies mcluded oral regimens that contained ethmylestradIOl, NETA, estradiol valerate, 17~-estradiol, mes­tranol, gestranol, estrone sulfate, micronized progestm,or nylestriol and transdermal or cream regimens thatcontamed 1713-estradlOL The weighted mean differencem spine BMO With ERT/HRT compared with controlsubjects after 2 years for all studIes combmed was676% (95°/0 CI, 5,63%-7,89% L For hip (femoralneck site) BMO, the weighted mean dIfference be­tween ERT/HRT and control groups was 4 12% (95°/0CI, 3 45%-480%) after 2 years of treatment Theauthors did not find a difference m the effect onBMO among vanous fonnulatlOns of postmenopausalERT/HRT.

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HRT also has been shown to decrease biochemIcalmarkers of bone turnover that are correlated With an ill­

crease in BMO, In 2 large placebo-controlled trials oftransdennal 1713-estradlOl combmed cyclically With dy­drogesterone, Delmas et .1190 found that the Increase inBMD that was seen With HRT could be momtored hythe measurement of such markers as C-telopeptIde oftype I collagen In the Women's HOPE study, standardand lowt:r doses ofcontmuous combmed CEE/MPA SIg­mficantly reduced serum osteocalcm and unnary cross­linked N-telopeptldcs of type I collagen, '>vhlch are bIO­chemIcal markers of bone fonnatlon and boneresorptIOn, respectively, 89

The WHI findmgs confirm that HRT contmuesto be an Important therapy for the prevention of osteo­pOroSIS, Although large. randomized tnals of fracturensk With HRT products other than CEE/MPA arelackmg. BMD is mcreased with a vanety of ERT /HRT products, In addition. lower doses of ERT/HRT mcrease BMO, however, whether lower doses ofERT/HRT alsn reduce fracture nsk reqUires furtherresearch

Colorectal cancerBefore the WHI, the data on the RR of colon cancer andERT/HRT had been derived primanly from observa­tional studies, In the WHI, a reduction III the nsk of co­lorectal cancer was observed WIth CEE/MPA use (HR.0,63, nominal 95% CI, 0,43-0,9~) over an average of5,2 years,l These beneficial findmgs are consistent withthose reported in meta-analyses by Hebert-Croteau'lland Grodstein et .11'1' who summanzed data from studiesthat were conducted in several countnes and that useda vanety of ERT/HRT products. The overall RR forcolon cancer of 0,85 (95% CL 0.73-0,99) reported byHebert-Croteaul)[ was similar to that reported by Grod­stem et al'l2 (RR, 0 80; 95% CI. 0.74-0,861. these authorsnoted a summary RR for colorectal cancer of 066 (95%CI, 059-074)

AlthQugh the only large. randomIzed chmcal tnal toreport a reduction m colorectal cancer nsk With HRTused oral CEE °625/MPA 25 mg, I the fact that thesefindmgs are Similar to those noted m observational stud­ies that included a variety of ERT/HRT products wouldsuggest that postmenopausal women will benefit. re­gardless of the type of ERT/HRT regimen that wasused, The mechamsms behmd thiS benefit are yet to bedetermined, the role of estrogen receptors m the colomcepithelium is bemg imestlgated

9'

Menopausal symptomsOne of the pnmary concerns related to the overall risklhenefit analySIS of HRT m the WHI was the fact that theImportance of the relief of menopausal symptoms wasnnt consIdered and that women With severe menopausal

DWRITE 072615

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symptoms were excluded from the study, Because mostwomen ImtIate HRT for symptom rehef. mterpretatlOnof the findmgs from WHI may be affected by climcalpractice,

Incidence and effects of menopausal symptomsHot flushes, which are the most common symptom ofthe pen- and postmenopause penod, affect 68% Q4 to93% of women,lJ5 In addition to Increasing hot flushes,the menopausal transition is aSSOCiated With increasedcomplaints of vagmal dryness, paIn durmg mtercourse,IrritabIlIty, depressed mood, and sleep dIsorders,%-4g

Hot flushes and the phySiologiC events that accompanythem are part of a complex sequence of events that affectoverall qualIty of hfe for pen- and postmenopausalwomen,

Relief of menopausal symptomsRecent hterature on the efficacy and safety of ERT/HRT for the treatment of vasomotor symptoms mcludes>40 randomized controlled chmcal tnals These tnalsevaluated several estrogen compounds alone 10 vanousdelIvery systems and 10 combmatIon with a vanety ofprogestms,

Decreases 10 frequency and severity of hot flushescompared with placebo have been shown 10 a vanetyof studies that used the standard dose of CEE 0,6ZS91H

12

and those studies that involved lower doses 99 TheaddItIon of a progestm does not negate estrogen efficacyfor relief of hot flushes and even may enhance efficacyWith lower doses

qQ

SimIlar Improvement of vasomotor symptoms hasalso been shown in randomized controlled tnals Withother estrogens, mcludmg both oral 113-122 and transder­maI I12 ,123-125 reglmen~ In I comparatIve l2-week tnalof 204 postmenopausal women (average age, 52 years),oral CEE 0625 mg and transdermal estradIOl 50 j.lg/d prOVided Similar symptom relief 112

A dose-response has been reported with oral estro­gens (l7~-estradiol or CEE), whICh tends to disappearwhen a progestm (NETA or MPA) IS added99 117,118

In the Women's HOPE study, Utian et al9Q

noted thatlower doses of MPA (1,5 mg) combmed With lowerdoses of CEE (0.45 mg or 0,3 mg) were also effectIvefor the relIef of vasomotor symptoms,

A meta-analySIS of 10 placebo-controlled tnals dem­onstrated that a varIety of estrogens (estnoL 17~-estra­

dlOl, and CEEI that were admmIstered by oraLtransdermal, or vaginal routes were all effective in thetreatment of signs and symptoms of urogemtal atrophy,mcludmg dyspareuma 12b In the Women's HOPE study,the vagmal maturatIOn mdex, a measure of vagmal atro­phy, was SImIlarly Improved With standard and lower

99doses of oral CEE and MPA.

1161

Quality of lifeOnly a few studies that were deSIgned to evaluate the ef­fects of ERT/HRT on qualIty of lIfe have been placebo­controlled, and they generally enrolled small samplesWith a short duratIon of use A randomIzed, placebo­controlled study that mvolved 242 women (mean age,approXImately 53 years) found that health-related qual­ity of Me and well-bemg improved after 12 weeks of 50j.lg/d of transdermal estradiol, compared wIth pla­cebo, In SImIlar results have been found with standard­or lower-dose formulatIOns of estrogens (estenfiedestrogens, 17 ~-estradIOI, or CEE), whether combinedwith a progestm or not 12U 12~-liU

Recently, the WHI mvestIgators reported their find­ings for quality of life measures at basehne and I yearfor all women and after 3 vears m a subset of 1511

•

women, 131 Onlv about 17% of the women who were en-•

rolled in WHI were < 5 years smce menopause. a tImewhen menopausal symptoms are most severe and may

Ii'affect quality of hfe- After I year of treatment,HRT was aSSOCiated With ~lgO!ficant benefit~ III ~elf-re­

ported sleep disturbances, phySical functIOnIng, andbody pam, m contrast, no differences were noted 10

measures of SOCial functIonmg, mental health, and sex­ual satIsfactIon, The benefits that were noted 10 year Iwere not found after 3 years of treatment. In the 574symptomatic women, who were 50 to 54 years of age,only sleep dIsturbances were Improved after I year oftreatment It should be noted that the scales that wereused 10 the WHI were not those that are used conven­tIOnally to evaluate postmenopausal women, and therewas only I self-report question on sexualIty m womenwhose partner status was unknown.

Sleep and moodImprovements 10 sleep were associated WIth alleViationof vasomotor, somatic, and mood symptoms m a ran­dOffi!7ed crossover study of 63 postmenopausal women(mean age, 56 years) that adminIstered transdermal es­tradIOl either by gel or patch 133 SImilar posItive Impact

h b d h d 1114 I '·H ilJ hon sleep as een reporte 10 ot er stu les ,- - t atused a vanety of ERT/HRT products (oral CEE, 17~­

estradIOl, MPA, and NETA, or transdermal 17 ~-estra­

dIOljNETA),ERT/HRT has been associated with a posItive effect

on fatigue/energy and depressive mood m symptomaticwomen 10 randomIzed clInical tnals 137

,138 that used oralCEE WIth either MPA or norgestrel and III a prospectivestudy that used transdermal estradiol with either NETAor dydrogesterone. 13

1) With the exception of theHERS, 137 the average age of the women who were mves­tigated was < 55 years, The women in the HERS withflushmg symptoms were younger (63 vs 67 years old)and nearer to theIr last menstrual cvcle (13,7 vs 18 7

•

h . h 137 I h'years) than t ose Wit out symptoms. n t elr tnalof 33 postmenopausal women (mean age, 543 years),

DWRITE 072616

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PurdIe et all 38 reported that the improvement In anxIetyand depression wIth 12 weeks of oral CEE 0.625 mg pluscyclIc norgestrel 0.15 mg was not accompanied byimprovements m sleep qualIty In contrast, neIthermeasures of energy and fatIgue nor depres~lon wereImproved m the WHI tnal lJ1

A posItIve effect of ERT (eIther CEE or 17f3-estra­dlOl) has been reported m 2 small pIlot studIes that en­rolled depreSSIve postmenopausal women aged 41 to56 years. 140,141 In contrast, oral CEE does not havea beneficial impact on mood In older women (meanage range, 73 to 84 years) with dementIa.142-'44 Thesedata support the benefiCIal effects of dIfferent ERT/HRT products on menopausal symptoms. Althoughnot all studIes have demonstrated an improvement mqualIty of lIfe, sleep, or mood, those studIes that have re­ported Improvements have mcluded a variety of ERT/HRT regimens

In the recently publIshed WHI Memory Study 145(whIch mvolved a subset of 74RO women whf) dId nothave dementIa), 4532 partIcIpants were assIgned ran­domly to eIther combmatlQn HRT (0 625 mg CEE plus2 5 mg of MPA) or placebo dally Because the prImaryoutcome was the InCIdence of AlzheImer's dIsease anddementIa, recruItment was lImIted to women over theage of 65 years. Thus, the mean age of the populatIOnwas slIghtly >70 years when HRT was inItIated. TheprinCIpal finding of thIS report was an increased mCI­dence of dementIa in women on HRT (45 vs 22 eventsper 10,000 person-years), whIch resulted In an HR of2.05 (95% CI, 1.21-3.48). Although thIs outcomewould not have been ant[clpated 10 years ago, [t IS con­sIstent WIth the results obtaIned from the CacheCounty Study.146 whIch was publIshed In 2003. Thewomen In the Cache study had a mean age of 74 yearsPrevIous HRT use, or use for > 10 year~, was assoc[­ated WIth decreased fISk, wherea~ current use of < 10years was assocIated WIth mcreased nsk Th[s suggest~

that the InItIatIon of therapy late m lIfe IS not protec­tIve and may Increase nsk Numerous observatIonalstudIes have suggested a protective effect when hor­mones were InitIated at the time of menopause, whichsuggests that there may be a cntIcal tIme for the InItI­atIon of therapy to produce this effect.146-148 Most ofthese observatIonal studies do not gIve accurate infor­mation regardmg the type of hormone preparation thatwas used.

The second WHI Memory Study report showed non­slgmficant differences in cognitive dechne, althoughthere was a trend toward lower scores In the treatedgroup 14'/ Another recent report from the WHI showeda shght Increase In strokes (31%),6U which IS compa­tIble With the pnnclpal WHI report The latter findIngdoes raise the Issue of pOSSIble mIcrovascular eventsthat occur In susceptIble older women that leads todementIa

Warren

Comment

This review evaluates the lIterature that has amassed onthe nsks and benefits of postmenopausal hormones thathave been hIghlIghted by the recent findIngs from theWHI. I Although some InvestIgators have suggested thatthe data reported m the WHI cannot he generalIzed to,other HRT theraples,~ the eVIdence presented suggeststhat both the nsks and benefits that are assocIated WIthCEE 0625 mg/MPA 25 mg have been IdentIfied m stud­Ies that used other estrogens (eg, oral ethmyl estradIOl,17~-estradlOl, estradIOl valerate, plperazme estronesulfate, estnol, or transdermal 1713-estradlOl) and otherprogestins (eg, oral NETA, levonorgestrel, norgestreLor transdermal norethlsterone, and dydrogesterone). Al­though recent findmgs With lower doses of HRT havesuggested that the benefits of standard doses are mtact,whether lower doses wtll mmlmlze the nsks that are seenwIth standard doses remaInS to be determmed.

Acknowledgments

I thank Amy S Marren, MD, and Mary Sendl, RPh, fora~slstance In searchmg the hterature and developmg thetables, and Karen D Mittleman, PhD, and Stephen MParker, ELS, for theIr edltonal assistance

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54 Pedersen AT, Lldegaard 0, Kremer S, llttesen B Hormonereplacement therapy and nsk of non-fatal stroke. Lancet 19lJ7:350'1277-83

55 Sourander L, Rajala T, Ralhl I, Makmen J, Erkkola R,Helemus H CardIOvascular and cancer morb!dlty and morta!Ityam! suuden ~ardlac death In postmenopausal women on oestrogenreplacement therapy (ERT) Lancet IlJ'J8 ,3521 965-9.

56 GrodsteIn F, Stampfer MJ, Falkeborn M, Naessen T, Persson IPostmenopausal hormone therapv and ns" of cardIOvasculardisease and hip fracture In a cohort of Swedish womenEpldt'l11lology 1999,5476-80

57 Wtlson PWF, Garmon RJ, Castelli WP Postmenopausal estro­gen use, cIgarette smoking. and cardIOvascular morbIdIty III

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80 Komulamen M, Tuppuramen MT. Kroger H, Helkkmen AM,PunlJla E, Alha~a E, et al VItamIn D and HRT no benefitaddllJon~1 to that ofHRT alone m prevenlJon of bone loss In earlypostmenopausal women a 2 5-year randomized placebo-con­trolled study Osteoporos Int 1997,7120-32

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89 Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH Effect oflower doses of conjugated equme estrogens with and withoutmedro.xyprogesterone acetate on bone In early postmenopausalwomen JAMA 2002,2872668-76

90. Delmas PD, Hardy P, Garnero P, Dam M-P. MomtonngIndlv!dual response to hormone replacement therapy with bonemarkers Bone 2000,20 553-tJO

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92 GrodsteIn F, Newcomb PA, Stampfer MJ Postmenopausalhormone therapy and the nsk of colorectal cancer a review andmeta-analySIS Am J Med 19QQ,106 574-82

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99 Utliln WH, Shoupe D, Bachmann G. Pmkerton JV. Pickar JHReHef of vasomotor symptoms and vagmal atrophy With lowerdose, of conjugated equme estrogem and medroiiyprogesteroneacetate Fertll Stenl 2001 ;751065-7Q

100 Greendale GA. Reboussm BA. Hogan P. Barnabel VM,Shuma!-er S, Johnson S, et al Symplum reHef and Side effectsof postmenopausal hormones. results from the PostmenopausalEstrogen/Progestin Interventions Tnal Obstet Gynecol 1998,92982-8.

101 Scharf MB, McDannold MD. Stoler R, Zaretsky N, BerkOWItzDV Effects of estrogen replacement therapy on rates of cycHcaltern~tIng patterns and hot-flush events dunng sleep mpostmenopausal women a pIlot study Clm Ther 1997,11)304-11

102 LUCIano AA, de Souza MJ, Roy MP, Schoenfeld MJ. Nulsen JCHalvorson CV EvaluatIon of low-dose estrogen and progestIntherapy In po,tmenopausal women. A double-blInd, prmpectlvestudy of sequentlill versus contmUQUS therapy 1 Reprod Med19Q3.38207-14

103 Huber J, PalaCIOS S, Berglund L, Hanggl W, Sathanandan SM,Chnstau S, et al Effects of ttbolone and contInUOUS combmedhormone replacement therapy on bleedIng rates qualltv of lifeand tolerabIlitY In postmenopausal women BJOG 2002,101).886-93

104 Stnckler R, Stl'vall DW, Merritt D, Shen W, Wong M, Sllfen SLRalmufene and estrogen effects on quahty of hfe m healthypostmenopausal women a placebo-controlled randomIzed tnal.Obstet Gynecol 2000,% 350 -65

105 Kokcu A, Cetmkaya MB, Yamk F. Alper T, Malatyahoglu EThe comparISon of effects of ttbolone and conjugated estrogcn­medroxyproge,terone acetate therapy on sex ual performance mpQstmenopausa! women Matuntas 2000,36 75-80

100 Good WR. John VA, RamIrez M, HIggInS JE LompaflSon ofAlora~ estradIol matrIX transdermal delIvery system WIth oralconjugated eqUIne estmgen therapy In rehel'Ing menopausalsymptoms Chmactenc 1999,229-30

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/08. HIlditch JR. LeWIS J, Ross AH, Peter A, van Mans B, FranssenE, et al A companson of the effects of oral conjugated equIneestrogen and transdermal estradlOl-17~ combined With an oralprogestm on quahty of hfe In postmenopausal women Matuntas19%,24.177-84

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110 Slseles NO. HalperIn H. Benencla HJ. Berg G. PIlm!- S. Mesch V,et al A comparatIve study of two hormone replacement therapyregimens on safety and efficacy vanables Matuntas 1')')5,21201-10

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a randomlsed, muillcentre, double-bllOd, double-dummy study.Matunta. 1995,22 105-14

113 R"zt:nberg S. Caubel P, LIm PC Constant estrogen, mtennltlentprogestogen vs contlOuous combmed hormone replacementtherapy tolerablhty and effect on vasomotor symptoms Int]Gynaecol Ob.tet 2001,72.235-43

114 Saure A, Planellas J, P"u!sen HK. Jaszczak P A double-blmd.randomIzed, comparatIve study evaluatmg chnIl:al effects of twosequentIal estradIOl-progestogen combmatlOllS contammg eItherdesogestrel or medro\yprogesterone acetate m chmactencwomen Matuntas 2000,34 133-42

115. Sulak Pl, Caubel P. Urn PL, Creasy G Efficacy and safety ofa constant-estrogen, pulsed-progestors regImen m hormonereplacement therapy Int 1 Fertd Womens Med 1'l9'l;44286-06

110 Stadberg E. Mattsson L-A. Uvebrant M 17 ~-estradlol andnorethlsterone acetate m low doses as contmuous combmedhormone replacement therapy Matuntas 14%,2331-9

117 N"te!ov!Iz M, Lenlh'll JP Jr, Mcnennott M, Kerber IJ.NanavatI N. Arce l-C InItial 17B-estradlOl dose for treatmgvasomotor symptoms Obstet Gynecol 2000,95 726-31.

118 Speroff L, Symons 1, Kempfert N, Rowan 1 The effect of vary 109low-dose combmatlons of norethmdrone acetate and ethmylestradIOl (Femhrt~) on the frequency and IntensIty of vasomotorsymptoms. Menopause 2000,7383-90

119 Slm"n J, K!alber E, W!!ta R, R"wen A, Yang H-M nlfferenha!effects of estrogen-androgen and estrogen-only therapy on~asomotor symptoms, gonadotropm secretion, and endogenousandrogen bloavallabllIty m postmenopausal women Menopause1999,0 138-40

120. Rebar RW, Trabal J, Mortola 1 Low-dose estenfied estrogens(0.3 mg/day) long-term and short-term effects on menopausalsymptc>ms and quality c>f life m postmen"pausal wc>menChmactenc 2000.3176-82

121 Marslew U, Overgaard K, RllS BJ, Chnsllansen C. Two newcombmatlons of estrogen and progestogen for preventIOn ofpostmenopausal bone loss' long-term effects on bone, calcIUmand lIpid metabolism, chmactenc symptoms, and bleedmg ObstetGynecoI1992,79 202-10

122 Meuwlssen lH1M, BeIJl:rs-De Ble L, VihtamakJ 1 A I-yearcompanson of the efficacv and chlllcal tolerance m postmeno­pausal women of two hormone replacement therapIes contaInIngestradIOl m combmatlOn WIth eIther norge;trel or trimegestone"ynecol Endocrm,,1 2001,15 34'l-58

121 Pomel B, Genaualll AR, Costes D, Dam MP, Lelann L,Vandepol C Efficacy and tolerablltty of Menorest"" 50 comparedwah Estraderm"" ITS 50 m the treatment of postmenopausalsymptoms' a randomIzed. multIcenter. parallel group studyMatuTltas 1995,22207-18

124 ROLenbaum H, Blrkhauser M, De Nooyer C, Lambotte R, PomelR, Schneider H, et a! r"mpam"n of two estndw! transdermalsyslt:ms (O,:sl:lim1l' 50 and Estraderm TIS1\> 50) I, tolerability,adheSIOn and efficacy Matuntas 19%,25161-73

125 Utlan WH, Burry KA, Archer DF, Gallagher JC, BoyettRL, Guy MP, et al Efficacy and safety of low standard. andhigh dosages of an estradIOl transdermal system (Esclimlcompared With placebo on vasomotor Jymptoms In hIghlysymptomatlc men"pausal patIents Am J nh<tet Gyneco!199918171-9

120. Cardozo L, Bachmann G, McClish D, Fonda D, Blrgerson L.Meta-analysis of estrogen therapy m the management ofurogenital atrophy In postmenopausal women' second report ofthe Honnones and UrogenItal Therapy CommIttee ObstetGynECol 1998,92 722-7.

127 WIklund I, Karlberg J, Mattm!ll LA Quality of life "fpostmenopausal women on a regImen of transdermal estradIOltherapy. a double-blind placebo-controlled study. Am] ObstetGynecoI1993;168824-30

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128 Baerug U. Wmge T. Nordland G, Faber-Swensson E. Heldaas K.Norling B. et al. Do combmatlons of I mg estradIOl and [owdoses of NETA effectively control menopausal symptoms"C1!mactenc !9'l8, 1 2! 'l-28

129 Derman RJ, Dawood MY, Stone S. Quality of life dunngsequentIal honnone replacement therapy a placebo-controlledstudy Int J Fertii 1'1'15,40'73-8

130. Maheux R. Naud F" RIOUX M, Gremer R, Lemay A, Guy J. et alA randomized, double-blInd, placebo-controlled study on theeffect of conlugated estrogens on skIn thickness Am 1 ObstetGynec,,1 1994,170 642-'1

131 Hays 1, Ockene 11(, Brunner RL, Kotchen 1M, Manson JE,Pattelson RE, et al Effects of estrogen plus progestIn on health­related qualIty of life N Engl 1 Med 2003,3481839-54

132 Rodstrom K, Bengtsson C, L,ssner L. Milsom I, Sundh V,BJorkelund C A longitudInal study of the treatment of hotflushes the populatIOn study of women m Gothenburg dunnga quarter "f a century Men"pause 2002,'1156-61

133 Polo-Kantola P, Erkkola R, HelenJUs H. Inala K. Polo 0 Whendoes estrogen replacement therapy Impro~e sleep quality? Am JObstet Gynecol 19'1g, 178'1 002-9

134 Scharf M, Stover R, Wmthrow l, BerkowIlz D Comparativeeffects of Premann, EVlsta. and placebo on sleep architecture,sleep qualIty. and hot flush frequency In postmenopausal women[abstract] Int 1 Gyneco! nbstet 2000: 70(suppl)'55

135. WIklund I, Berg G, Hammar M, I(arlberg J, Lmdgren R, SandInK Long-term effect of transdennal honnonal therapy on aspe"tsof qualIty of life m postmenopausal women Matuntas IQQ2,\4225-3b

136 Keefe DL, Watson R, Naftolm F. Hormone replacement therapymay alleVIate sleep apnea In menopausal women a pilot studyMen"pause 1'lQQ ,6 1%-200

137 Hlatky MA. Boothroyd D. VJttmghoffE, Sharp P. Whooley MA.Quality-of-lIfe and depreSSIve symptoms m postmenopausalwomen after recelvmg honnone therapy' results from the heartand estrogen/progestm replacement study fHERS) tnal. lAMA2002,287591-7

138 PurdIe DW, Empson 1AC, Cnchton C, Macdonald L. Hormonereplacement therapy, sleep quahty and psych,,!oglca! we!l-bemgBJOG 1995,102735-9

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140 Carranza-Ura S, Valentmo-Flgueroa ML Estrogen therapy fordepreSSIOn m postmenopausal women Int 1 Gynecol Obstet 1999,6535-8

141. SchmIdt PJ, NIeman L, Danaceau MA, Tobm MB, Roca CA.Murphy lH, et al Estrogen replacement m penmenopause­related depreSSIOn' a preltmmary report Am 1 nbstet Gynecol2000,183414-20

142 Mulnard RA, Cotman CW, Kawas CW, van Dyck CH, Sano M,Doody R, et al. Estrogen replacement therapy for treatment ofmIld t" m"derate A!7helmer disease a randomIzed wntml!edtnat lAMA 2000,2831007-15

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144 Kyomen HH, Satlin A, WeI 1Y Estrogen therapy decreases thefrequency of phySically aggressIve behaVIOrs In severely de­mented , elderly, I"ng-term care faClhty patients results fmma short-term. double-blind, placebo-controlled chmca! tnal[abstract) 1 Am Genatr Soc 1997,45 S51

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146, Zandl PP, Carlson Mr, Plassmqn BL, Welsh-B"hmer KA,Mayer LS, Steffens DC, et al. Hormone replacement therapy andinCidence of Alzheimer disease In older women, the Cache CountyStudy J AMA 2002;2882123-9

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Strategic PubUcation Development BudgetStatus Report: April 25. 2003

PREMARIN FAMILY

I) Development ofNew Papers• Generalizability (M. Warrcn) $25.0oo• Current Opinion in Pharmacotherapy (invited review G. ,constantine) $25.000• Importance ofTreating Menopausal Symptoms (G. Bachmann) $25.000

2) Edits ofPapers• PVC study (Raymundo el1l1) $10.oo0• CV Events (Lobo) $10.000

3) PostcrslAbstracts• 3 Abstracts for HT monograph (COG!. HHS. FIGO) $4.000*• 3 Posters developed and produced (COGI. HHS. FIGO) $10.500*• ACOG (Lobo) (poster development and production) $8.5oo

Total Costs To Date $118.000

LOW-DOSEHr

I) Development ofNew Papers• Review for Pharmacists $25.000• Review for Nurses $25.000

2) Edits of2nd Year Papers• Endometrial " $10.000• Bone responder $10.000• BMI and body weight $10.000

3) Posters/Abstracts• 3 Abstracts for"COGI, HHS. FlGO $4.oo0*• 3 Posters developed and produced (COOl, HHS. FIGO) $10.500*• AbstractlPoster for Endocrine Society (Zinaman) $12.500• AbstractIPoster for ASBMR (Lindsay)..; , $12.5oo .• Poster for AANP (Freeman) (poster development,and production) $8.5oo

Total Costs To Date o $128.000

·Cost based on previously negotiated discount

EXHIBIT

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