Use of MHT in women with cardiovascular disease: a systematic review and meta-analysis

Figures & data

Table 1. Summary of included studies.

Study	Region	Type of study	Average follow-up (years)	Sample size (n)	Age (years), mean (SD)	Intervention/exposure	Outcomes
Randomized controlled trials
Blumel et al., 2003 [17]	Chile	DB, placebo	1 month	27	58.9 (4.5)	Estrogen: TE 50 μg/24 h patch	Flow-mediated vasodilation of the brachial artery
Byington et al., 2002 (HERS sub-study) [18]	USA	DB, placebo	3.75	362	67	Combined E + P: oral CEE 0.625 mg + oral MPA 2.5 mg daily	Progression of carotid atherosclerosis as measured by change in intimal-medial thickness on ultrasound
Cherry et al., 2002 (ESPRIT) [19]	England	DB, placebo	2	1017	62.3 (5.2)	Estrogen: oral EV 2 mg daily	First non-fatal reinfarction, cardiac death, death from another cause within 2 years of study entry
Clarke et al., 2002 (PHASE) [20]	England	Blinded, no placebo	2.5	255	67 (11.0)	Estrogen: TE patch alone (2.5 mg E2) Combined E + P: TE 3 mg + 4 mg NETA patch	Cardiac death, non-fatal myocardial infarction, hospitalization with angina, TIA
Collins et al., 2006 (WHISP) [21]	UK	DB, placebo	1	100	69.4 (8.6)	Combined E + P: E2 1 mg + oral NETA 0.5 mg daily	Lipids at 3 and 6 months after randomization
Grady et al., 2002 (HERS II) [22]	USA	DB, placebo	2.7	2321	67 (7)	Combined E + P: oral CEE 0.625 mg + oral MPA 2.5 mg daily	Non-fatal myocardial infarction, cardiac death, TIA
Hall et al., 1998 [23]	Sweden	DB, placebo	1	60	TE 58.6 (6.3) CEE 58.3 (6.5)	Combined E + P: (1) TE 50 μg/ 24 h alone for 18 days + 10 days of combined treatment with oral MPA 5 mg (2) Oral CEE 0.625 mg for 18 days followed by a combined treatment with MPA 5 mg for 10 days	Angina, myocardial infarction, coronary revascularization, CABG, CCF
Herrington et al., 2000 (ERA) [24]	USA	DB, placebo	3.2	309	Estrogen 66.3 (7.6) E + P 65.5 (6.5)	Estrogen: oral CEE 0.625 mg daily Combined E + P: oral CEE 0.625 mg + MPA 2.5 mg daily	Mean minimal coronary-artery diameter within each subject at follow-up
Herrington et al., 1999 [25]	USA	DB, placebo, crossover	0.4	24	66.8 (6.6)	Combined E + P: (1) oral CEE 0.625 mg + MPA 2.5 mg + lovastatin placebo (2) E + P placebo and lovastatin 20 mg daily (3) E + P and lovastatin 20mg daily	Lipids, flow-mediated vasodilation
Hodis et al., 2003 (WELL-HART) [26]	USA	DB, placebo	3.25	226	Estrogen 61.8 (6.7) E + P 64.4 (6.4)	Estrogen: oral E2 1 mg daily Combined E + P: oral E2 1 mg/day + MPA 5 mg for 12 days	Average (per participant) change from baseline in the percent stenosis in all lesions evaluated by quantitative coronary angiography
Howard et al., 2004 (WAVE sub-study) [27]	USA, Canada	DB, placebo	2.8	423	65.1	Estrogen: oral CEE 0.625 mg daily Combined E + P: oral CEE 0.625 mg + MPA 2.5 mg daily	Change in the mean minimum lesion diameter of all qualifying segments, incidence of myocardial infarction and death
Hulley et al., 1998 (HERS) [28]	USA	DB, placebo	4.1	2763	67 (7)	Combined E + P: oral CEE 0.625 mg + MPA 2.5 mg daily	Non-fatal myocardial infarction or cardiac death, TIA
Kanaya et al., 2003 (HERS sub-study) [29]	USA	DB, placebo	4.1	2763	67 (7)	Combined E + P: oral CEE 0.625 mg + MPA 2.5 mg daily	Incident diabetes: self-report of diabetes or disease complication, fasting glucose level of 6.9 mmol/l or greater or initiation of therapy with diabetes medication
Khan et al., 2003 (HERS sub-study) [30]	USA	DB, placebo	2.25	129	67 (7)	Combined E + P: oral 0.0625 mg CEE + 2.5 mg MPA daily	Incidence of repeat revascularization (PTCA and CABG) and of any CHD event (unstable angina, non-fatal myocardial infarction, CHD death, PTCA and CABG) after the index PTCA
Lamon-Fava et al., 2009 (ERA sub-study) [31]	USA	DB, placebo	3.1	309	Estrogen 66 (8) E + P 65 (7)	Estrogen: oral CEE 0.625 mg daily Combined E + P: oral CEE 0.625 mg/day + MPA 2.5 mg daily	Lipid subpopulations
Os et al., 2000 (EWA) [32]	Norway	DB, placebo	1	118	63 (range 59, 68)	Combined E + P: TE 50 μg/24 h + oral MPA 5 mg for 14 days every 3 months	Lipid concentrations at 3 and 12 months
Os et al., 2005 [33]	Norway	SB, no placebo	1	99	64 (range 49, 71)	Combined E + P: TE 50 μg/24 h μg + oral MPA 5 mg every 3 months	Insulin sensitivity index (HOMA-IR) and insulin secretion (HOMA-BCF)
Ouyang et al., 2006 (EAGAR) [34]	USA	DB, placebo	3.5	83	64 (8)	Combined E + P: oral E2 1 mg ± oral MPA 2.5 mg daily	Angiographic progression of saphenous vein graft following CABG, cardiac events
Pripp et al., 1999 [35]	Sweden	DB, placebo	1	60	CEE 58.3 (6.5) TE 58.6 (6.3)	Combined E + P: (1) oral CEE 0.625 mg daily + MPA 5 mg for 10 days (2) TE 50 μg + MPA 5 mg for 10 days	Ambulatory blood pressure, lipid concentrations at 6 and 12 months
Sbarouni, 1998 [36]	Greece	DB, placebo, crossover	0.25	18	66 (4)	Combined E + P: oral CEE 0.625 mg + MPA 2.5 mg with simvastatin 20 mg daily	Lipid concentrations after 8 weeks of treatment
Simon et al., 2001 (HERS sub-study) [37]	USA	DB, placebo	4.1	2763	67 (7)	Combined E + P: oral CEE 0.625 mg + MPA 2.5 mg daily	HERS looking at pre-specified secondary outcomes of stroke and TIA
Viscoli et al., 2001 (WEST) [38]	USA	DB, placebo	2.75	664	72 (10)	Estrogen: oral E2 1 mg daily	Death from any cause or non-fatal stroke, TIA and non-fatal myocardial infarction
Waters et al., 2002 (WAVE) [39]	USA, Canada	DB, placebo	2.8	423	65 (9)	Combined E + P: oral CEE 0.625 mg + MPA 2.5 mg daily	Mean change in minimum lumen diameter
Observational studies
Cherry et al., 2014 [40]	UK	Prospective cohort	14	1017	62.6	Estrogen: oral EV 2 mg daily	Death (all-cause, cardiac disease, stroke or cancer), cancer incidence
Heckbert et al., 2001 [41]	USA	Retrospective cohort	3.5	981	67.8	Estrogen (67%): esterified estrogen 70%, CEE 28%, other 2% Combined E + P (33%): oral estrogen + MPA	Recurrent coronary events
Khan et al., 2000 [42]	USA	Prospective cohort	1.25	129	52 (6)	Estrogen: 93% Combined E + P: 7%	Angiographic outcomes, cardiovascular events
O’Brien et al., 1996 [43]	USA	Retrospective cohort	1	243	62	Estrogen (81%): CEE 84%, estradiol 11%, estrone 5% Combined E + P (19%)	Mean difference in minimum luminal diameter between 6-month angiogram and post-procedure angiogram, all-cause mortality, myocardial infarction, CABG, repeat angiogram, angina classification
Parsons et al., 2004 [44]	37 countries	Retrospective cohort	1	4029	64	Estrogen (90%): CEE 45%, estradiol 3%, other/unspecified 52% Combined E + P 10%	90-day mortality, 1-year mortality, 90-day stroke/death/myocardial infarction
Sullivan et al., 1997 [45]	USA	Prospective cohort	10	1098	58.3	Estrogen 97% Combined E + P 3%	Survival

CABG, coronary artery bypass graft; CCF, congestive cardiac failure; CEE, conjugated equine estrogens; CHD, coronary heart disease; DB, double blinded; E2, estradiol; E + P, estrogen + progestogen; EV, estradiol valerate; HERS, Heart and Estrogen/progestin Replacement Study; HOMA-BCF, Homeostatic Model Assessment of Beta cell function; HOMA-IR,Homeostatic Model Assessment for Insulin Resistance; MPA, medroxyprogesterone acetate; NETA, norethisterone; PTCA, percutaneous transluminal coronary angioplasty; SB, single blinded; SD, standard deviation; TE, transdermal estradiol; TIA, transient ischemic attack.

Figure 1. Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) flow diagram for new systematic reviews which included searches of databases, registers and other sources. *Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools. From Page et al. [16]. For more information, see http://www.prisma-statement.org/

Figure 2. Forest plots of primary outcomes: menopausal hormone therapy (MHT) versus controls on (a) non-fatal myocardial infarction, (b) cardiovascular disease (CVD) death and (c) stroke. CI, confidence interval; M-H, Mantel–Haenszel.

Figure 3. Clinical approach to the management of menopausal symptoms in women with cardiovascular disease (CVD). ^†Diabetes mellitus may be associated with increased progression of atherosclerosis. *Oral menopausal hormone therapy (MHT) is associated with increased blood pressure and increased thrombotic risk.

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Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.