dynamed plus_ hormonal replacement therapy (hrt) and cardiovascular disease

20122015 DynaMed Plus Hormonal replacement therapy (HRT) and cardiovascular disease

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Hormonal replacement therapy (HRT) andcardiovascular diseaseRelated Summaries

see Hormonal replacement therapy (HRT) for overview of HRTCoronary artery disease (list of topics)

Overview

routine use of combined estrogen and progestin not recommended for prevention of chronicconditions in postmenopausal women (USPSTF Grade D)hormone replacement therapy (HRT) associated with increased risk for cardiovascular diseasevenous thromboembolism and stroke in systematic reviews and randomized trials

HRT does not reduce risk of cardiovascular disease but does increase risk of stroke andvenous thromboembolic events in postmenopausal women (level 1 [likely reliable] evidence)HRT increases risk of cardiovascular disease and venous thromboembolism in olderpostmenopausal women (level 1 [likely reliable] evidence)hormone therapy associated with increased risk of stroke in postmenopausal women (level 2[midshylevel] evidence)

observational studies have inconsistent evidence

Recommendations

United States Preventive Services Task Force (USPSTF) recommendationsroutine use of combined estrogen and progestin not recommended for prevention of chronicconditions in postmenopausal women (USPSTF Grade D)routine use of estrogen alone not recommended for prevention of chronic conditions inpostmenopausal women who have had a hysterectomy (USPSTF Grade D)Reference shy USPSTF recommendation statement on menopausal hormone therapy forprimary prevention of chronic conditions (Ann Intern Med 2013 Jan 1158(1)47 editorialcan be found in Ann Intern Med 2013 Jan 1158(1)69 or at USPSTF 2012 Oct 23 fullshytext)supporting systematic review for updated recommendations can be found in Ann Intern Med2012 Jul 17157(2)104 fullshytext

Canadian Task Force on Preventive Health Care (CTFPHC) recommendationsHRT for primary prevention of chronic diseases

use of combined estrogenshyprogestin therapy and estrogenshyonly therapy notrecommended for primary prevention of chronic diseases in menopausal women(CTFPHC Grade D)discuss risks and benefits of HRT for alleviating menopausal symptoms with


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individual patientsReference shy CMAJ 2004 May 11170(10)1535 fullshytext

postmenopausal HRT for primary prevention of cardiovascular and cerebrovascular diseaseuse of HRT not recommended for primary prevention of myocardial infarction andcardiovascular death in perimenopausal women without coronary artery disease(CTFPHC Grade D)insufficient evidence to make recommendation on use of HRT for primary preventionof stroke and death from cerebrovascular diseaseReference shy CMAJ 2004 Apr 27170(9)1388 fullshytext

American Heart Association scientific statement recommends not starting HRT for secondaryprevention of heart disease insufficient evidence to make recommendations regarding primaryprevention (Circulation 2001 Jul 24104(4)499 fullshytext)Heart and Stroke Foundation of CanadaCanadian Cardiovascular SocietySociety of Obstetriciansand Gynecologists of Canada (HSFCCSSOGC) position statement recommends against initiatingor continuing HRT in women for sole purpose of preventing future cardiovascular events (Can JCardiol 2002 Jul18(7)723 or at CCS 2002 Oct PDF)

HRT and Mortality

HRT does not affect mortality or rate of myocardial infarction but has small increased riskof stroke (level 1 [likely reliable] evidence)

based on systematic reviewsystematic review of 7 randomized placeboshycontrolled trials of hormone therapy (estrogenwith or without progestin) with 32523 womenno effect on allshycause mortality in metashyanalysis of 7 trials with 175676 personshyyears ofobservationno effect on coronary mortality in metashyanalysis of 7 trials with 181348 personshyyears ofobservationno effect on nonshyfatal acute myocardial infarction in metashyanalysis of 6 trials with 181823personshyyears of observationhormone therapy increased risk of stroke in metashyanalysis of 6 trials with 182185 personshyyears of observation (rate 51 vs 4 per 1000 personshyyears NNH 909 personshyyears)Reference shy BJOG 2006 Jan113(1)5

HRT not associated with significant effect on overall mortalitybased on systematic review and metashyanalysis of 30 randomized trials with 26708 womenReference shy J Gen Intern Med 2004 Jul19(7)791 fullshytext editorial can be found in J GenIntern Med 2004 Jul19(7)810 fullshytext commentary can be found in BMJ 2005 Jan1330(7481) ACP J Club 2005 JanshyFeb142(1)1 J Gen Intern Med 2005Feb20(2)212 fullshytextDynaMed commentary shyshy conclusion of lower mortality in women aged lt 60 years in thisreview not considered valid because

analysis was based on 4141 women in trials with mean age lt 60 yearsanalysis did not include 5522 women aged 50shy59 years in Womens Health Initiative(WHI) trial (which had overall mean age 63 years)analysis with WHI trial would find no difference in mortality

DynaMed commentary shyshy entire metashyanalysis fundamentally flawed by weighting studiesbased on number of deaths instead of sample size

for example consider the metashyanalysis of trials with mean age lt 60 years whichincluded 17 trials and 4141 women1 trial with high mortality in 130 ovarian cancer patients provided 3 of the overall


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sample size but was calculated as providing 41 of the weight in this metashyanalysissimilar conclusions for outcome of coronary heart disease events (reduced risk in women lt60 years old) reported in metashyanalysis of 23 trials with 39049 women conducted by sameauthors (J Gen Intern Med 2006 Apr21(4)363) but similar methodologic flaws limitvalidity of conclusion (DynaMed commentary)

HRT and Coronary Artery Disease

Efficacy in systematic reviews

HRT does not reduce cardiovascular mortality overall mortality or nonfatal myocardialinfarction but does increase risk of stroke (level 1 [likely reliable] evidence) and mayincrease venous thromboembolic events (level 2 [midshylevel] evidence) in postmenopausalwomen

based on Cochrane review limited by heterogeneitysystematic review of 19 randomized trials comparing oral hormone replacement therapy(HRT) (estrogen alone or in combination with progestogen) vs placebo or no treatment withge 6shymonth followshyup in 40410 postmenopausal womenno significant differences in

nonfatal myocardial infarction in analysis of 14 trials with 34841 womencardiovascular mortality in analysis of 9 trials with 33613 womenoverall mortality in analysis of 15 trials with 39868 womenangina in analysis of 5 trials with 30502 women

oral HRT associated withincreased stroke (risk ratio [RR] 124 95 CI 11shy141 NNH 165) in analysis of 10trials with 34672 womenincreased venous thromboembolic events (RR 192 95 CI 136shy269 NNH 118) inanalysis of 10 trials with 37313 women results limited by significant heterogeneityincreased pulmonary embolism (RR 181 95 CI 132shy248 NNH 242) in analysis of7 trials with 36316 women

Reference shy Cochrane Database Syst Rev 2015 Mar 10(3)CD002229similar results found in systematic review of 10 randomized trials (PLoS One20138(5)e62329 fullshytext)

Efficacy in randomized trials

Primary prevention

longshyterm use of HRT associated with more risks than benefits in healthy postmenopausalwomen (level 2 [midshylevel] evidence)

based on randomized trial with early terminationWomens Health Initiative (WHI) is largest randomized trial of HRT stopped early due torisks exceeding benefits16608 postmenopausal women aged 50shy79 years with intact uterus were randomized toHRT (equine estrogens 0625 mgmedroxyprogesterone acetate 25 mg [Prempro]) vsplacebo orally once daily for mean 52 years (range 35shy85 years)few women had cardiovascular disease at baseline (16shy19 had history of myocardialinfarction 28shy29 had history of angina 11shy15 had history of CABG or percutaneouscoronary intervention 07shy1 had history of stroke)


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discontinuation of study drug occurred in 42 HRT and 38 placebo patients whileaddition of HRT through personal clinician was started in 62 HRT and 107 placebopatients intentionshytoshytreat analysis was performed so results likely underestimate perprotocol resultsno differences in overall mortality or endometrial cancerresults reported as annualized percentages (event rates per year of therapy)

number needed to harm (NNH) or treat for benefit (NNT) reported as number treatedwith HRT for 1 yearcomparing HRT vs placebo (for adverse outcomes more common with HRT)

coronary heart disease events 037 vs 03 (P lt 005 NNH 1428)differences related to nonfatal myocardial infarctionsstroke 029 vs 021 (p lt 005 NNH 1250)invasive breast cancer 038 vs 03 (p lt 005 NNH 1250)venous thromboembolic event 034 vs 016 (p lt 005 NNH 555)pulmonary embolism 016 vs 008 (p lt 005 NNH 1250)absolute excess in risk 17 vs 151 (p lt 005 NNH 526) based on globalindex of death coronary heart disease event stroke pulmonary embolismbreast cancer endometrial cancer colorectal cancer or hip fracture

comparing HRT vs placebo (for adverse outcomes less common with HRT thanplacebo)

colorectal cancer 01 vs 016 (p lt 005 NNT 1667)hip fracture 01 vs 015 (p lt 005 NNT 2000)vertebral fracture 009 vs 015 (p lt 005 NNT 1429)any osteoporotic fracture 147 vs 191 (p lt 005 NNT 228)

Reference shy JAMA 2002 Jul 17288(3)321editorial can be found in JAMA 2002 Jul 17288(3)366 commentary can be found in BMJ2008 May 10336(7652)1033 (commentary can be found in BMJ 2008 May24336(7654)1148)considerable commentary can be found in JAMA 2002 Dec 11288(22)2819 CMAJ 2002Aug 20167(4)377 fullshytext ACP J Club 2002 SepshyOct137(2)41 J Fam Pract 2002Oct51(10)821 Evid Based Nurs 2003 Jan6(1)20 Can Fam Physician 2003 Feb49157Curr Rheumatol Rep 2003 Feb5(1)43 JAMA 2003 Dec 24290(24)3193 JAMA 2003 Jun25289(24)3241 JAMA 2004 Aug 11292(6)683 JAMA 2005 Mar 16293(11)1322JAMA 2006 Jul 19296(3)280 S Afr Med J 2003 Aug93(8)554 Evid Based Med 2008Oct13(5)142editorial commentary can be found in BMJ 2002 Jul 20325(7356)113 fullshytext (correctioncan be found in BMJ 2002 Aug 24325(7361)435) BMJ 2002 Nov 2325(7371)1036 fullshytext BMJ 2002 Nov 23325(7374)1243 fullshytext 3 years after halt of WHI trial HRT associated with higher rates of cancer but notcardiovascular disease (level 2 [midshylevel] evidence)

based on postintervention phase of randomized trial15730 women from WHI trial were followed for mean 24 years after halt of trial

8052 women from HRT group7678 women from placebo group

comparing HRT vs placebo during postintervention phaseallshycause mortality 29 vs 26 (not significant)malignancies (including invasive breast cancer endometrial or colorectalcancer) in 35 vs 28 (p lt 005 NNH 142)invasive breast cancer in 009 vs 008 (not significant)total cardiovascular disease events in 43 vs 42 (not significant)


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any fracture in 42 vs 45 (not significant)Reference shy JAMA 2008 Mar 5299(9)1036 commentary can be found in JAMA2008 Jun 18299(23)2744 ACP J Club 2008 Aug 19149(2)11

HRT does not provide cardiac protection and may slightly increase risk of coronaryevents

based on final results for coronary outcomes reported from WHI trialannualized percentage rates of coronary heart disease of 039 with HRT and 033with placebo were of borderline significanceReference shy N Engl J Med 2003 Aug 7349(6)523 commentary can be found in ACPJ Club 2004 MarshyApr140(2)46

nonshysignificant trend toward increased risk for coronary heart disease with HRT in olderwomen and decreased risk in younger women reported in secondary analysis of WHI trialbut absolute differences very small (JAMA 2007 Apr 4297(13)1465) correction can befound in JAMA 2008 Mar 26299(12)1426 commentary can be found in JAMA 2007 Aug8298(6)623 ACP J Club 2007 SepshyOct147(2)29 no significant differences in cardiovascular disease events between HRT and placebogroups 3 years after halt of WHI trial

15730 women from WHI trial were followed for mean 24 years after halt of trial8052 women from HRT group7678 women from placebo group

comparing HRT vs placebo during postintervention phaseallshycause mortality in 29 vs 26 (not significant)total cardiovascular disease events in 43 vs 42 (not significant)

101 vs 104 patients with coronary heart disease80 vs 79 patients with myocardial infarction121 vs 114 patients with coronary artery bypass graft or percutaneoustransluminal coronary angiography76 vs 64 patients with stroke44 vs 45 patients with deep vein thrombosis or pulmonary embolism

Reference shy JAMA 2008 Mar 5299(9)1036 commentary can be found in JAMA2008 Jun 18299(23)2744 ACP J Club 2008 Aug 19149(2)11

HRT does not appear to provide cardiac protection to women beginning therapy lt 10years after menopause

based on secondary analysis of WHI trialcompared to no HRT continuous use of estrogen plus progestin associated with

increased risk of coronary heart disease for first 2 years of use (hazard ratio236 95 CI 155shy362)nonsignificant increased risk of coronary heart disease for first 8 years of use(hazard ratio 169 95 CI 098shy289)

no significant difference in risk of coronary heart disease in subgroup of women whobegan HRT lt 10 years after menopause

for first 2 years (hazard ratio 129 95 CI 052shy318)for first 8 years (hazard ratio 064 95 CI 021shy199)

Reference shy Ann Intern Med 2010 Feb 16152(4)211 higher LDL cholesterol levels associated with higher risk of coronary heart disease inwomen taking HRT

based on nested caseshycontrol study with 359 women with coronary heart disease and820 controls from WHI trialsReference shy Arch Intern Med 2008 Nov 10168(20)2245

HRT increases risk of cardiovascular disease and venous thromboembolism in older


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postmenopausal women (level 1 [likely reliable] evidence)based on randomized trial5692 postmenopausal women aged 50shy69 years (mean age 63 years) who had ge 80compliance during 12 week runshyin period were randomized to hormone replacement therapyvs placebo

women with uterus were randomized to combination HRT (Prempro) vs placebo dailywomen without uterus and unwilling to take placebo were randomized to Prempro vsestrogen alone (Premarin) 0625 mg orally dailywomen without uterus and willing to take placebo were randomized to Prempro vsPremarin vs placebo daily

medroxyprogesterone acetate 5 mg (Premique) orally daily given to women with uterus andwithin 3 years of last period women aged 50shy53 years and older women with unacceptablebreakthrough bleedingmedian followshyup 119 months due to early closure of trialmajor cardiovascular disease defined as unstable angina requiring hospitalizationmyocardial infarction (fatal or nonshyfatal) or sudden coronary deathcomparing combination therapy vs placebo in analysis of 4385 women

major cardiovascular disease in 032 vs 0 (p lt 005 NNH 312)rate of major cardiovascular disease 269 vs 0 per 10000 personshyyears (p = 0016NNH 371 personshyyears)venous thromboembolism in 1 vs 014 (NNH 116)rate of venous thromboembolism 851 vs 115 per 10000 personshyyears (p lt 0001NNH 136 personshyyears)osteoporotic fractures 18 vs 26 (p lt 005 NNT 125)rate of osteoporotic fractures 1553 vs 2262 per 10000 personshyyears (p = 007)no significant differences in rates of cerebrovascular disease cancer or death

comparing combination HRT vs estrogen alone in 1641 womenno significant differences in major cardiovascular disease venous thromboembolismcancer osteoporotic fracture or deathsome combination HRT women counted in this analysis and in analysis compared toplacebo

of 11 women who had major cardiovascular events 9 were gt 64 years old and had othercardiovascular risk factorsReference shy WISDOM trial (BMJ 2007 Aug 4335(7613)239 fullshytext) editorial can befound in BMJ 2007 Aug 4335(7613)219 fullshytext commentary can be found in Evid BasedMed 2008 Apr13(2)52

synthetic estrogenprogestin may not reduce mortality heart failure or myocardialinfarction over 10 years in recently postmenopausal healthy women (level 2 [midshylevel]evidence)

based on cohort analysis of data from randomized trial without blinding1006 recently postmenopausal healthy women aged 45shy58 years (81 with intact uterus)randomized to HRT vs no HRT (no placebo given)

HRT for women with intact uterus (81) was triphasic estradiol plus norethisteroneacetateHRT for women with hysterectomy was triphasic estradiol 2 mgday only

all women had last menstrual bleeding 3shy24 months prior to randomization or hadperimenopausal symptoms (including irregular menstruations) and postmenopausal serumfollicle stimulating hormone valuesmean followshyup was 158 years

at 5 years 75 adhered to allocated group for ge 80 of time


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after mean 101 years of treatment women were encouraged to stop HRT due toadverse events reported in Womenrsquos Health Initiative trial

comparing HRT vs no HRT at 10 year followshyupmortality 3 vs 52 (p = 0084)heart failure in 02 vs 14 (p = 007)myocardial infarction in 02 vs 08 (p = 021)

no significant difference inany cancer breast cancer deep vein thrombosis or stroke at 10 or 16 year followshyupmortality heart failure or myocardial infarction at 16 year followshyup

Reference shy BMJ 2012 Oct 9345e6409 fullshytext early HRT not associated with atherosclerosis progression at 4 years (level 3 [lacking direct]evidence)

based on randomized trial without clinical outcomes727 healthy menopausal women aged 42shy58 years without prior cardiovascular diseaseevents and 6shy36 months since last menses randomized to 1 of 3 interventions and followedfor 4 years

oral conjugated equine estrogens 045 mgday with progesterone 200 mg for 12 daysper monthtransdermal 17 betashyestradiol 50 mcgday with progesterone 200 mg for 12 days permonthplacebo

mean carotid artery intimashymedia thickness increase of 0007 mmyear with no significantbetweenshygroup differencesReference shy Ann Intern Med 2014 Aug 19161(4)249

estrogen alone does not have benefits that outweigh risks overall in postmenopausal womenwith prior hysterectomy (level 2 [midshylevel] evidence)

based on randomized trial with early termination10739 postmenopausal women aged 50shy79 years with prior hysterectomy in WomensHealth Initiative (WHI) trial randomized to conjugated equine estrogen 0625 mg (Premarin)vs placebo orally daily for mean of almost 7 yearstrial stopped early by NIH since there was no benefit in primary outcome of reducingcardiovascular diseasecomparing estrogen vs placebo groups

coronary heart disease death or myocardial infarction in 333 vs 367 (notsignificant)stroke in 298 vs 217 (p lt 005 NNH 123)venous thromboembolism in 19 vs 144 (not significant)invasive breast cancer in 177 vs 228 (hazard ratio 126 95 CI 1shy159)colorectal cancer 115 vs 107 (not significant)hip fracture 072 vs 118 (p lt 005 NNT 217)any fracture 7 vs752 (p lt 005 NNT 192)overall mortality 548 vs 532 (not significant)

Reference shy JAMA 2004 Apr 14291(14)1701 editorial can be found in JAMA 2004 Apr14291(14)1769 Nephrol News Issues 2004 Aug18(9)54 61 commentary can be found inJAMA 2004 Aug 11292(6)683 summary can be found in Am Fam Physician 2005 Jan1571(2)371no prevention of coronary disease in final outcomes comparing estrogen vs placebo resultswere not statistically significant for myocardial infarction coronary death revascularizationhospitalized angina confirmed angina hospitalized heart failure acute coronary syndromeor any of 4 combinations of these outcomes (Arch Intern Med 2006 Feb 13166(3)357)


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no significant differences in most outcomes after 10 yearsbased on 107 year followshyup of 7645 women from Womens Health InitiativeEstrogenshyAlone Trialpostintervention annualized risk for outcome comparing estrogen vs placebo

coronary heart disease 064 vs 067 (not significant)stroke 036 vs 041 (not significant)deep vein thrombosis 017 vs 027 (hazard ratio 063 95 CI 041shy098)invasive breast cancer 026 vs 034 (not significant)hip fracture 036 vs 028 (not significant)

no significant differences in mortality coronary heart disease mortality myocardialinfarction pulmonary embolism or colorectal cancerReference shy JAMA 2011 Apr 6305(13)1305 fullshytext editorial can be found inJAMA 2011 Apr 6305(13)1354 (correction can be found in JAMA 2011 Jun15305(22)2418)

Secondary prevention

HRT does not reduce overall rate of coronary events in postmenopausal women withestablished coronary disease (level 1 [likely reliable] evidence)

based on randomized trial (Heart and Estrogenprogestin Replacement Study [HERS])2763 postmenopausal women lt 80 (mean age 667) with coronary disease (stable for at least6 months) and intact uterus randomized to conjugated equine estrogens 0625 mg plusmedroxyprogesterone acetate 25 mg in 1 tablet (Prempro) vs placebo orally once dailymultiple exclusion criteria including poor compliance in placebo runshyin periodmean followshyup 41 years82 those assigned to hormone treatment were taking it at 1 year 75 at 3 yearsno significant differences comparing Prempro vs placebo in

primary outcome of nonfatal myocardial infarction or coronary heart disease mortality(125 vs 127) coronary mortality (51 vs 42)nonfatal myocardial infarction (84 vs 93)coronary revascularizationunstable anginaheart failureresuscitated cardiac arreststroke or transient ischemic attackperipheral arterial diseaseallshycause mortality

no overall effect despite 11 lower LDL cholesterol and 10 higher HDL cholesterol levelsin hormone groupstatistically significant time trend with more coronary events in hormone group in year 1and fewer in years 4 and 5increased risks comparing Prempro vs placebo

venous thromboembolic events (25 vs 09 NNH [number needed to harm] 60)gallbladder disease (61 vs 45 NNH 625 borderline statistical significance)

no increased risk of fracture cancer or total mortality interpretation

based on pattern of early increase in risk of coronary events starting HRT notrecommend for secondary preventiongiven favorable pattern of coronary events after several years of therapy it could beappropriate for women already receiving HRT to continue


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Reference shy JAMA 1998 Aug 19280(7)605 editorial can be found in JAMA 1998 Aug19280(7)650 commentary can be found in ACP J Club 1999 JanshyFeb130(1)8 JAMA1999 Mar 3281(9)794 J Am Geriatr Soc 2000 Dec48(12)1717 JAMA 2001 Nov28286(20)2544 JAMA 2003 Jun 25289(24)3241

no significant effect after longer followshyup of HERS trialafter 41 years of randomized treatment openshylabel HRT was prescribed at physiciansdiscretion and 2321 (93 of surviving cohort) continued followshyup for 27 yearsproportions with 80 adherence to hormones decreased from 81 to 45 in HRT groupand increased from 0 to 8 in placebo groupno significant differences in rates of coronary death myocardial infarction coronaryrevascularization hospitalization for unstable angina or heart failure stroke or transientischemic attack or peripheral arterial diseaseReference shy JAMA 2002 Jul 3288(1)49 correction can be found in JAMA 2002 Sep4288(9)1064 editorial can be found in JAMA 2002 Jul 3288(1)99 summary can be foundin Am Fam Physician 2002 Dec 166(11)2155 commentary can be found in ACP J Club2003 JanshyFeb138(1)6

estrogen does not prevent cardiac events at end of 2shyyear treatment or 14shyyear followshyup inpostmenopausal women with myocardial infarction (level 1 [likely reliable] evidence)

based on randomized trial1017 postmenopausal women aged 50shy69 years who survived first myocardial infarctionwere randomized to estradiol valerate 2 mg orally once daily vs placebo for 2 yearsno significant differences in reinfarction cardiac death or overall mortalityReference shy ESPRIT trial (Lancet 2002 Dec 21360(9350)2001) editorial can be found inLancet 2002 Dec 21shy28360(9350)1996 commentary can be found in Lancet 2003 Feb15361(9357)612 summary can be found in Am Fam Physician 2003 Jun 1567(12)2612 similar findings at 14 years

based on followshyup of ESPRIT trial411 women died during followshyupmean followshyup 14 years for mortality and 126 years for cancer incidenceno significant differences in allshycause cardiacshyrelated or cancershyrelated mortality orin cancer incidenceReference shy BJOG 2014 May121(6)700

transdermal HRT may not prevent coronary events in women with ischemic heart disease(level 2 [midshylevel] evidence)

based on randomized trial without blinding255 postmenopausal women with angiographically proven ischemic heart disease wererandomized to transdermal HRT vs no treatment for mean 308 months40 HRT patients vs 7 placebo patients withdrewevent rate (hospital admission with unstable angina proven myocardial infarction or cardiacdeath) was 154 with HRT vs 119 with no treatment per 100 patientshyyears (not significant)trend toward worse outcome with HRT increased with pershyprotocol analysisReference shy BJOG 2002 Sep109(9)1056

nonclinical outcomesneither HRT nor antioxidant vitamins reduced progression of coronary stenosis (level 3[lacking direct] evidence)

based on nonclinical outcome in randomized trial423 postmenopausal women with 15shy75 coronary stenosis randomized in a 2 x 2factorial design to 0625 mgd of conjugated equine estrogen (plus 25 mgd ofmedroxyprogesterone acetate for women who had not had a hysterectomy) vsmatching placebo and 400 IU of vitamin E twice daily plus 500 mg of vitamin C


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twice daily vs placebono significant difference between groups in mean change in minimum lumen diameterfrom baseline to concluding angiogramReference shy JAMA 2002 Nov 20288(19)2432) commentary can be found in J FamPract 2003 Feb52(2)112 BMJ 2003 Feb 15326(7385) JAMA 2003 Feb26289(8)982 summary can be found in Am Fam Physician 2003 Mar 1567(6)1371

HRT does not affect progression of coronary atherosclerosis (level 3 [lacking direct]evidence)

based on 2 randomized trials309 women with angiographically confirmed coronary atherosclerosis randomized toconjugated estrogen 0625 mg vs conjugated estrogen 0625 mg plusmedroxyprogesterone acetate 25 mg vs placebo orally once daily for mean 32 years

both treatment groups reduced LDL and increased HDL cholesterol but nodifferences in minimal coronary artery diameters or rates of clinicalcardiovascular eventsReference shy N Engl J Med 2000 Aug 24343(8)522 editorial with multiplecriticisms can be found in N Engl J Med 2000 Aug 24343(8)572 commentarycan be found in N Engl J Med 2000 Dec 21343(25)1891

226 postmenopausal women with coronary artery lesions randomized to doubleplacebo vs micronized 17shybetashyestradiol (Estrace) 1 mg orally once daily plus placebo12 daysmonth vs 17shybetashyestradiol (Estrace) 1 mg orally once daily plusmedroxyprogesterone acetate (Provera) 5 mg orally once daily 12 daysmonth formedian 33 years

no significant differences in changes in percent stenosesReference shy N Engl J Med 2003 Aug 7349(6)535

Effect on biochemical markers of cardiovascular risk

hormone replacement therapy may decrease total cholesterol highshydensity lipoproteincholesterol and body mass index in postmenopausal women with diabetes (level 3 [lackingdirect] evidence)

based on nonclinical outcomes in randomized trial with low completion rate150 postmenopausal women with type 1 diabetes or nonshyinsulinshytreated type 2 diabetesrandomized to hormone replacement therapy (Kliofem) vs placebo for 12 monthscompletion rate lt 60results by diabetes type not reported separatelycomparing hormone replacement therapy vs placebo

hormone replacement therapy significantly decreased total cholesterol highshydensitylipoprotein cholesterol (HDLshyC) and body mass indexno significant differences in glycemic control blood pressure menopausal symptomscores lowshydensity lipoprotein cholesterol (LDLshyC) triglycerides and apoprotein A1or B

Reference shy Diabetes Obes Metab 2004 Jan6(1)16no additional trials found in Cochrane review evaluating hormone replacement therapy inwomen with type 1 diabetes (Cochrane Database Syst Rev 2013 Jun 6(6)CD008613)

combination 17shybeta estradiol and norethindrone acetate shown to reduce LDL cholesterol totalcholesterol and apolipoprotein B levels in randomized controlled trial (Arch Intern Med 2000 Nov27160(21)3315)

HRT and Stroke


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in systematic reviewsHRT increases risk of stroke in postmenopausal women

HRT increases risk of stroke (level 1 [likely reliable] evidence)based on 2 systematic reviewssystematic review and metashyanalysis of 28 randomized trials with 39769women

compared to control HRT increased risk of any stroke (271 vs 203NNH 147) ischemic stroke (205 vs 159 NNH 217) and fatal stroke(037 vs 029 NNH 1250)no significant differences in rates of hemorrhagic stroke or transientischemic attackReference shy BMJ 2005 Feb 12330(7487)342 fullshytext editorial can befound in BMJ 2005 Feb 12330(7487)345

systematic review of 31 trials with 44113 patients taking progesterone andorestrogen

compared to control HRT associated with increased risk ofstroke odds ratio (OR) 132 in 18 trials with 36523 patients (p lt00001)nonshyfatal stroke OR 128 in 10 trials with 32680 patients (p =0004)fatal stroke OR 135 in 11 trials with 32935 patients (notsignificant)transient ischemic OR 105 in 7 trials with 6035 patients (notsignificant)

Reference shy Eur Heart J 2008 Aug29(16)2031 fullshytext commentary canbe found in Evid Based Med 2009 Feb14(1)18

hormone therapy associated with increased risk of stroke in healthypostmenopausal women (level 2 [midshylevel] evidence)

based on systematic review of trials with methodologic limitationssystematic review of 3 randomized trials comparing hormone therapy vsplacebo or control in 30005 healthy postmenopausal women

mean age ranged from 50shy64 yearsduration of hormone therapy ranged from 3shy10 yearsduration of followshyup ranged from 3shy158 years

methodologic limitations included at least 1 oflack of blindinglack of intentionshytoshytreat analysiswide confidence intervals

metashyanalyses were dominated by single followshyup study of WHI trialsincluding 75 of randomized patientshormone therapy associated with increased risk of stroke

overall (hazard ratio (HR) 115 95 CI 103shy128) in analysis of 2 trialsduring intervention (HR 132 95 CI 112shy156) in analysis of 3 trials

no significant differences in postinterventional risk of stroke in 1 trialReference shy Menopause 2014 Nov21(11)1204

in randomized trialsHRT does not reduce risk of stroke and may increase risk of stroke

HRT associated with increased risk of stroke (level 2 [midshylevel] evidence)based on randomized trial with early terminationWomens Health Initiative (WHI) is largest randomized trial of HRT stopped


1215

early due to risks exceeding benefits16608 postmenopausal women aged 50shy79 years with intact uterus wererandomized to HRT (equine estrogens 0625 mgmedroxyprogesterone acetate25 mg [Prempro]) vs placebo orally once daily for mean 52 years (range 35shy85 years)151 HRT patients (178) vs 107 placebo patients (132) had strokes (p lt005 NNH 220)Reference shy JAMA 2003 May 28289(20)2673) commentary can be found inACP J Club 2003 NovshyDec139(3)62 summary can be found in Am FamPhysician 2004 Jan 169(1)204

hormonal replacement therapy does not reduce risk for stroke in postmenopausalwomen with coronary artery disease (level 1 [likely reliable] evidence)

based on randomized trial2763 postmenopausal women with preshyexisting coronary heart disease in HERStrial were randomized to HRT (conjugated estrogens plus medroxyprogesteroneacetate) vs placebo for about 4 yearsge 1 stroke occurred in comparing HRT vs placebo 5 with HRT vs 43 withplacebo (not significant)Reference shy Circulation 2001 Feb 6103(5)638 fullshytext

estrogen did not reduce risk for recurrent stroke or mortality in randomized trial(level 2 [midshylevel] evidence)

based on randomized rial with high discontinuation rate664 postmenopausal women with ischemic stroke or transient ischemic attackrandomized to estradiolshy17shybeta 1 mg vs placebo daily for mean 28 years116 women in estradiol group (34) and 79 women in placebo group (24)discontinued study drugno differences in rates of mortality or nonfatal strokeestrogen associated with higher risk of fatal stroke and worse neurologic andfunctional deficits with nonfatal strokesReference shy N Engl J Med 2001 Oct 25345(17)1243 fullshytext commentary canbe found in N Engl J Med 2002 Mar 21346(12)942 ACP J Club 2002 MayshyJun136(3)96 EvidenceshyBased Medicine 2002 MayshyJun7(3)90

inconsistent results in observational studiesHRT associated with decreased risk for coronary heart disease but increased risk forstrokes in (level 2 [midshylevel] evidence)

based on 2 cohort studies from Nurses Health Studybased on prospective study of 70533 postmenopausal women followed for 20 years(Ann Intern Med 2000 Dec 19133(12)933 in BMJ 2001 Jan 6322(7277)60)summary can be found in Am Fam Physician 2001 Aug 164(3)504stroke risk with current HRT use increased for women starting HRT at any age andany time relative to menopause

shortshyterm (lt 5 years) HRT not associated with increased risk of stroke in youngwomen but analysis based on small number of womenReference shy Arch Intern Med 2008 Apr 28168(8)861

current highshydose transdermal HRT and any dose oral HRT may increase risk ofstroke

based on nested caseshycontrol studyoriginal cohort of all women aged 50shy79 years between January 1987 and October2006 from 400 general practices in United Kingdom15710 women aged 50shy79 years with first recorded stroke and 59958 matched


1315

controls evaluated for current HRT usecurrent HRT use in 51 cases and 46 controlsincreased risk of stroke with (vs no HRT use)

any current transdermal HRT use (adjusted rate ratio 095 95 CI 075shy12)current lowshydose transdermal HRT use (rate ratio 081 95 CI 062shy105)current highshydose transdermal HRT use (rate ratio 189 95 CI 115shy311)any current oral HRT use (rate ratio 128 95 CI 115shy142 similar findingswith low and high doses)

Reference shy BMJ 2010 Jun 3340c2519 fullshytextHRT associated with increased risk of stroke among hypertensive but not normotensivewomen in prospective cohort of 13122 Danish nurses gt 44 years old (Arch Neurol 2003Oct60(10)1379)

HRT and Peripheral Arterial Disease

HRT did not prevent peripheral arterial disease in randomized trialbased on WHI trial described above with 16608 womenrates of hospitalization for peripheral arterial disease were low with annualized rates of008 for carotid disease 006 for lower extremity arterial disease and 002 forabdominal aortic aneurysmHRT did not affect overall incidence of peripheral arterial events trend toward increasedincidence in first 2 years and decreased incidence in last 2 yearsReference shy Circulation 2004 Feb 10109(5)620

HRT use gt 1 year associated with reduced risk for peripheral arterial disease in crossshysectional study of 2196 women 55shy80 (Arch Intern Med 2000 Sep 11160(16)2498 in JAMA2000 Dec 6284(21)2702)

Guidelines and Resources

Guidelines

United States guidelines

United States Preventive Services Task Force (USPSTF) recommendation on menopausal hormonetherapy for primary prevention of chronic conditions can be found at USPSTF 2012 Oct 23 fullshytext or in Ann Intern Med 2013 Jan 1158(1)47 fullshytext editorial can be found in Ann Intern Med2013 Jan 1158(1)69 or at National Guideline Clearinghouse 2013 Jan 2138537

American College of Obstetricians and Gynecologists (ACOG) Committee Opinion 565 onhormone therapy and heart disease can be found in Obstet Gynecol 2013 Jun121(6)1407 fullshytextAmerican Heart Association (AHA) scientific statement on hormone replacement therapy andcardiovascular disease can be found in Circulation 2001 Jul 24104(4)499 fullshytext

Canadian guidelines

Canadian Task Force on Preventive Health Care (CTFPHC) recommendation statements onhormone replacement therapy for primary prevention of chronic diseases can be found inCMAJ 2004 May 11170(10)1535 fullshytext


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postmenopausal hormone replacement therapy for primary prevention of cardiovascular andcerebrovascular disease can be found in CMAJ 2004 Apr 27170(9)1388 fullshytext

Heart and Stroke Foundation of CanadaCanadian Cardiovascular SocietySociety of Obstetriciansand Gynecologists of Canada (HSFCCSSOGC) position statement on hormone replacementtherapy and cardiovascular disease can be found in Can J Cardiol 2002 Jul18(7)723 or at CCS2002 Oct PDF

European guidelines

Polish Gynecological SocietyPolish Cardiological SocietyPolish Menopause and AndropauseSociety (Polskiego Towarzystwa GinekologicznegoPolskiego TowarzystwaKardiologicznegoPolskiego Towarzystwa Menopauzy i Andropauzy) joint position statement oneffects of HRT on the cardiovascular system can be found in Kardiol Pol 2009 Jan67(1)72[Polish]

Review articles

AHRQ comparative effectiveness review on menopausal symptoms comparative effectiveness oftherapies can be found at AHRQ Comparative Effectiveness Review 2015 Mar147 PDF

review can be found in Adv Stud Med 2006 Jun6(6)267 PDF commentary can be found in AdvStud Med 2006 JulshyAug6(7)329 PDFeditorial discussion on disagreement between randomized and observational trials on HRT andcardiovascular risk can be found in Lancet 2009 Apr 11373(9671)1233 commentary can befound in Lancet 2009 Jun 13373(9680)2026

References

Recommendation grading systems used

United States Preventive Services Task Force (USPSTF) grades of recommendation (June 2007shyJune 2012)

Grade A shy USPSTF recommends the service with high certainty of substantial net benefitGrade B shy USPSTF recommends the service with high certainty of moderate net benefit ormoderate certainty of moderateshytoshysubstantial net benefitGrade C shy clinicians may provide the service to select patients depending on individualcircumstances however only small benefit is likely for most individuals without signs orsymptomsGrade D shy USPSTF recommends against providing the service with moderateshytoshyhighcertainty of no net benefit or harms outweighing benefitsGrade I shy insufficient evidence to assess balance of benefits and harmsReference shy USPSTF Grade Definitions

Canadian Task Force on Preventive Health Care (CTFPHC) grades of recommendationGrade A shy good evidence to recommend clinical preventive actionGrade B shy fair evidence to recommend clinical preventive actionGrade C

conflicting evidence does not allow recommendation for or against use of clinical


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preventive actionother factors may influence decision making

Grade D shy fair evidence to recommend against clinical preventive actionGrade F shy good evidence to recommend against clinical preventive actionGrade I

insufficient evidence (in quantity or quality) to make recommendationother factors may influence decision making

ReferencesCTFPHC new grades for recommendations (CMAJ 2003 Aug 5169(3)207 fullshytext)CTFPHC recommendation statement on hormone replacement therapy for primaryprevention of chronic diseases (CMAJ 2004 May 11170(10)1535 fullshytext)CTFPHC recommendation statement on postmenopausal hormone replacementtherapy for primary prevention of cardiovascular and cerebrovascular disease (CMAJ2004 Apr 27170(9)1388 fullshytext)

DynaMed editorial process

DynaMed topics are created and maintained by the DynaMed Editorial TeamOver 500 journals and evidenceshybased sources (DynaMed Content Sources) are monitored directlyor indirectly using a 7shyStep evidenceshybased method for systematic literature surveillanceDynaMed topics are updated daily as newly discovered best available evidence is identifiedThe participating members of the DynaMed Editorial Team have declared that they have nofinancial or other competing interests related to this topicThe participating reviewers have declared that they have no financial or other competing interestsrelated to this topic unless otherwise indicatedMcMaster University is a partner that provides support in identifying PracticeshyChanging DynaMedUpdates Over 1000 practicing physicians from 61 disciplines in 77 countries rate these articles tohelp you find the most useful new evidence affecting your practiceF1000 is a partner that provides support in identifying PracticeshyChanging DynaMed Updates Over2000 practicing clinicians from 20 disciplines in 60 countries rate these articles to help you findthe most useful new evidence affecting your practice

Special acknowledgements

Derek Hubbard MD (Clinical Assistant Professor of Family Medicine University of WisconsinWisconsin United States) provides peer review

How to cite

National Library of Medicine or Vancouver style (International Committee of Medical JournalEditors)

DynaMed Plus [Internet] Ipswich (MA) EBSCO Information Services 1995 shy Record No116363 Hormonal replacement therapy (HRT) and cardiovascular disease [updated 2014Sep 24 cited place cited date here] [about 11 screens] Available fromhttpwwwdynamedcomloginaspxdirect=trueampsite=DynaMedampid=116363 Registrationand login required


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individual patientsReference shy CMAJ 2004 May 11170(10)1535 fullshytext

postmenopausal HRT for primary prevention of cardiovascular and cerebrovascular diseaseuse of HRT not recommended for primary prevention of myocardial infarction andcardiovascular death in perimenopausal women without coronary artery disease(CTFPHC Grade D)insufficient evidence to make recommendation on use of HRT for primary preventionof stroke and death from cerebrovascular diseaseReference shy CMAJ 2004 Apr 27170(9)1388 fullshytext

American Heart Association scientific statement recommends not starting HRT for secondaryprevention of heart disease insufficient evidence to make recommendations regarding primaryprevention (Circulation 2001 Jul 24104(4)499 fullshytext)Heart and Stroke Foundation of CanadaCanadian Cardiovascular SocietySociety of Obstetriciansand Gynecologists of Canada (HSFCCSSOGC) position statement recommends against initiatingor continuing HRT in women for sole purpose of preventing future cardiovascular events (Can JCardiol 2002 Jul18(7)723 or at CCS 2002 Oct PDF)

HRT and Mortality

HRT does not affect mortality or rate of myocardial infarction but has small increased riskof stroke (level 1 [likely reliable] evidence)

based on systematic reviewsystematic review of 7 randomized placeboshycontrolled trials of hormone therapy (estrogenwith or without progestin) with 32523 womenno effect on allshycause mortality in metashyanalysis of 7 trials with 175676 personshyyears ofobservationno effect on coronary mortality in metashyanalysis of 7 trials with 181348 personshyyears ofobservationno effect on nonshyfatal acute myocardial infarction in metashyanalysis of 6 trials with 181823personshyyears of observationhormone therapy increased risk of stroke in metashyanalysis of 6 trials with 182185 personshyyears of observation (rate 51 vs 4 per 1000 personshyyears NNH 909 personshyyears)Reference shy BJOG 2006 Jan113(1)5

HRT not associated with significant effect on overall mortalitybased on systematic review and metashyanalysis of 30 randomized trials with 26708 womenReference shy J Gen Intern Med 2004 Jul19(7)791 fullshytext editorial can be found in J GenIntern Med 2004 Jul19(7)810 fullshytext commentary can be found in BMJ 2005 Jan1330(7481) ACP J Club 2005 JanshyFeb142(1)1 J Gen Intern Med 2005Feb20(2)212 fullshytextDynaMed commentary shyshy conclusion of lower mortality in women aged lt 60 years in thisreview not considered valid because

analysis was based on 4141 women in trials with mean age lt 60 yearsanalysis did not include 5522 women aged 50shy59 years in Womens Health Initiative(WHI) trial (which had overall mean age 63 years)analysis with WHI trial would find no difference in mortality

DynaMed commentary shyshy entire metashyanalysis fundamentally flawed by weighting studiesbased on number of deaths instead of sample size

for example consider the metashyanalysis of trials with mean age lt 60 years whichincluded 17 trials and 4141 women1 trial with high mortality in 130 ovarian cancer patients provided 3 of the overall


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dynamed plus_ hormonal replacement therapy (hrt) and cardiovascular disease

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