This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps health care decisionmakers patients and clinicians, health system leaders, and policymakersmake more informed decisions and improve the quality of health care services.
62
Embed
Systematic Evidence Review · Context: Although postmenopausal hormone replacement therapy is widely used, its risks and benefits are not well understood. Objective: To assess the
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps health care decisionmakers�patients and clinicians, health system leaders, and policymakers�make more informed decisions and improve the quality of health care services.
Systematic Evidence Review Number 11 Hormone Replacement Therapy and Risk of Venous Thromboembolism
Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 2101 East Jefferson Street Rockville, MD 20852 http://www.ahrq.gov Contract No. 290-97-0018 Task Order No. 2 Technical Support of the U.S. Preventive Services Task Force Prepared by: Oregon Health Sciences University Evidence-based Practice Center, Portland, Oregon Jill Miller, MD Benjamin K.S. Chan, MS Heidi Nelson, MD, MPH August 2002
iii
Preface
The Agency for Healthcare Research and Quality (AHRQ) sponsors the development of Systematic Evidence Reviews (SERs) through its Evidence-based Practice Program. With guidance from the third U.S. Preventive Services Task Force∗ (USPSTF) and input from Federal partners and primary care specialty societies, two Evidence-based Practice Centers�one at the Oregon Health Sciences University and the other at Research Triangle Institute-University of North Carolina�systematically review the evidence of the effectiveness of a wide range of clinical preventive services, including screening, counseling, immunizations, and chemoprevention, in the primary care setting. The SERs�comprehensive reviews of the scientific evidence on the effectiveness of particular clinical preventive services�serve as the foundation for the recommendations of the third USPSTF, which provide age- and risk-factor-specific recommendations for the delivery of these services in the primary care setting. Details of the process of identifying and evaluating relevant scientific evidence are described in the �Methods� section of each SER. The SERs document the evidence regarding the benefits, limitations, and cost-effectiveness of a broad range of clinical preventive services and will help to further awareness, delivery, and coverage of preventive care as an integral part of quality primary health care. AHRQ also disseminates the SERs on the AHRQ Web site (http://www.ahrq.gov/uspstfix.htm) and disseminates summaries of the evidence (summaries of the SERs) and recommendations of the third USPSTF in print and on the Web. These are available through the AHRQ Web site (http://www.ahrgq.gov/uspstfix.htm), through the National Guideline Clearinghouse (http://www.ncg.gov), and in print through the AHRQ Publications Clearinghouse (1-800-358-9295). We welcome written comments on this SER. Comments may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.
∗ The USPSTF is an independent panel of experts in primary care and prevention first convened by the U.S. Public Health Service in 1984. The USPSTF systematically reviews the evidence on the effectiveness of providing clinical preventive services--including screening, counseling, immunization, and chemoprevention--in the primary care setting. AHRQ convened the third USPSTF in November 1998 to update existing Task Force recommendations and to address new topics.
Carolyn M. Clancy, M.D. Acting Director Agency for Healthcare Research and Quality
Robert Graham, M.D. Director, Center for Practice and Technology Assessment Agency for Healthcare Research and Quality
iv
The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service.
v
Contents Structured Abstract ..............................................................................................................1 Systematic Evidence Review Chapter 1. Introduction .......................................................................................................3 Burden of Suffering ...................................................................................................3 Prior Recommendations.............................................................................................3 Analytic Frameworks and Key Questions .................................................................4 Chapter 2. Methods.............................................................................................................5 Literature Search Strategy..........................................................................................5 Inclusion/Exclusion Criteria ......................................................................................5 Size of Literature Reviewed.......................................................................................6 Data Extraction and Synthesis ...................................................................................6 Chapter 3. Results ...............................................................................................................9 Hormone Replacement Therapy Studies ...................................................................9 Randomized Controlled Trials.........................................................................9 Case-Control Studies .....................................................................................11 Cohort Study ..................................................................................................16 Meta-Analysis of HRT Studies................................................................................17 Studies of Selective Estrogen Receptor Modulators (SERMs)................................18 Chapter 4. Discussion ........................................................................................................21 Conclusions..............................................................................................................21 Limitations of the Literature ....................................................................................22 Future Research .......................................................................................................23 Acknowledgements............................................................................................................25 References..........................................................................................................................26 Appendix 1a. Search Strategy for Effects of Hormone Replacement Therapy on Coagulation...........................................................................................39 Appendix 1b. Search Strategy for Hormone Replacement Therapy Randomized Controlled Trials.................................................................................41 Appendix 1c. Search Strategy for Selective Estrogen Receptor Modulators (SERMs) ...............................................................................................42 Appendix 2. Hormone Replacement Therapy and Venous Thromboembolism Search Results..........................................................................................................43
vi
Appendix 3. Criteria for Grading the Internal Validity of Individual Studies..................44 Appendix 4. Evidence Tables (1-4) ..................................................................................46 Figures Figure 1. Benefits of Hormone Replacement Therapy: Analytic Framework 1...............32 Figure 2. Adverse Effects of Hormone Replacement Therapy: Analytic Framework 2 ............................................................................................................33 Figure 3. Risk for Venous Thromboembolism by Year of HRT Use...............................34 Figure 4. Meta-analysis of Estrogen Studies ....................................................................35 Tables Table 1. Studies of Hormone Replacement Therapy Included in Meta-analysis .............36 Table 2. Trials of Selective Estrogen Receptor Modulaters Reporting Thrombotic Events...................................................................................................37 Table 3. Summary of Evidence.........................................................................................38
v
Contents Structured Abstract ..............................................................................................................1 Systematic Evidence Review Chapter 1. Introduction .......................................................................................................3 Burden of Suffering ...................................................................................................3 Prior Recommendations.............................................................................................3 Analytic Frameworks and Key Questions .................................................................4 Chapter 2. Methods.............................................................................................................5 Literature Search Strategy..........................................................................................5 Inclusion/Exclusion Criteria ......................................................................................5 Size of Literature Reviewed.......................................................................................6 Data Extraction and Synthesis ...................................................................................6 Chapter 3. Results ...............................................................................................................9 Hormone Replacement Therapy Studies ...................................................................9 Randomized Controlled Trials.........................................................................9 Case-Control Studies .....................................................................................11 Cohort Study ..................................................................................................16 Meta-Analysis of HRT Studies................................................................................17 Studies of Selective Estrogen Receptor Modulators (SERMs)................................18 Chapter 4. Discussion ........................................................................................................21 Conclusions..............................................................................................................21 Limitations of the Literature ....................................................................................22 Future Research .......................................................................................................23 Acknowledgements............................................................................................................25 References..........................................................................................................................26 Appendix 1a. Search Strategy for Effects of Hormone Replacement Therapy on Coagulation...........................................................................................39 Appendix 1b. Search Strategy for Hormone Replacement Therapy Randomized Controlled Trials.................................................................................41 Appendix 1c. Search Strategy for Selective Estrogen Receptor Modulators (SERMs) ...............................................................................................42 Appendix 2. Hormone Replacement Therapy and Venous Thromboembolism Search Results..........................................................................................................43
vi
Appendix 3. Criteria for Grading the Internal Validity of Individual Studies..................44 Appendix 4. Evidence Tables (1-4) ..................................................................................46 Figures Figure 1. Benefits of Hormone Replacement Therapy: Analytic Framework 1...............32 Figure 2. Adverse Effects of Hormone Replacement Therapy: Analytic Framework 2 ............................................................................................................33 Figure 3. Risk for Venous Thromboembolism by Year of HRT Use...............................34 Figure 4. Meta-analysis of Estrogen Studies ....................................................................35 Tables Table 1. Studies of Hormone Replacement Therapy Included in Meta-analysis .............36 Table 2. Trials of Selective Estrogen Receptor Modulaters Reporting Thrombotic Events...................................................................................................37 Table 3. Summary of Evidence.........................................................................................38
1
Structured Abstract Context: Although postmenopausal hormone replacement therapy is widely used, its risks and
benefits are not well understood.
Objective: To assess the risk of venous thromboembolism with the use of postmenopausal
hormone replacement therapy (HRT) by literature review and meta-analysis.
Data Sources: All relevant English-language studies identified in MEDLINE (1966 to
December 2000), HealthSTAR (1975 to December 2000), Cochrane library databases, and
reference lists of key articles. Studies of selective estrogen receptor modulators (SERMs) were
identified in MEDLINE (1991 to December 2000).
Study Selection: All studies of postmenopausal HRT or SERMs reporting venous
thromboembolism as an outcome or adverse event.
Data Extraction: Twelve studies of HRT (3 randomized controlled trials, 8 case-control
studies, and one cohort study), and 5 randomized controlled trials of SERMs were identified.
We extracted data on number of participants, interventions, event rates, and confounders. Two
reviewers independently rated study quality based on established criteria.
Data Synthesis: We used Bayesian meta-analysis. Current HRT use was associated with an
increased risk of venous thromboembolism (relative risk [RR], 2.14; CI, 1.64-2.81). The absolute
rate increase was 1.5 venous thromboembolic events per 10,000 women in one year. Five case-
control studies reported highest risk within the first year of use (odds ratios [OR], 2.9-6.7). Data
from 5 randomized controlled trials of SERMs were not included in the meta-analysis. The 2
largest trials reported a similar increased risk of venous thromboembolism.
2
Conclusions: Postmenopausal HRT is associated with an increased risk of venous
thromboembolism, and this risk may be highest in the first year of use. SERMs are associated
with a similar increase in risk.
3
Chapter 1. Introduction
In this systematic evidence review (SER), we evaluate data on the relationship between
the use of postmenopausal hormone replacement therapy (HRT) and selective estrogen receptor
modulators (SERMs) and the risk for venous thromboembolism. We present results of a review
of the literature and a meta-analysis of studies reporting data on postmenopausal HRT and
venous trhomboembolism. This report is part of a larger project on the risks and benefits of HRT
prepared for the U.S. Preventive Services Task Force (USPSTF) to assist them in making
recommendations.
Burden of Suffering
The emerging emphasis on women�s health, coupled with an aging population, makes it
increasingly important for primary care physicians to be familiar with the risks and benefits of
postmenopausal HRT. Although postmenopausal HRT is widely used,1 it poses important
health risks. One suspected risk is an increase in venous thromboembolic events. Initially, this
relationship was based on studies of oral contraceptives2 and was not supported by studies of
HRT.3-5 Findings from more recent studies, however, indicate an increase in risk.6-13
Prior Recommendations
Because the literature addressing this issue was limited, previous USPSTF (1996)
reported that there was no conclusive evidence to support an association between
postmenopausal HRT and thrombosis.14
4
Analytic Frameworks and Key Questions
The analytic frameworks in Figures 1 and 2 show the target populations, interventions,
and health outcome measures we examined for the overall question of the benefits and risks of
postmenopausal HRT. Arrow 3 in Figure 2 corresponds to issues of HRT and venous
thromboembolism specifically covered in this report. One key question, �Does HRT increase the
risk for venous thromboembolism?� guided our literature review.
We were concerned with HRT as chemoprevention, and therefore focused on the use of
either estrogen alone or estrogen combined with progestins in healthy, postmenopausal women.
The SERM literature we reviewed was restricted to raloxifene and tamoxifen use in healthy
postmenopausal women.
5
Chapter 2. Methods Literature Search Strategy
We searched MEDLINE (1966 to December 2000) and HealthSTAR (1975 to December
2000) databases. Additional articles were obtained by reviewing reference lists of pertinent
studies and reviews. Multiple search terms were used because venous thromboembolism is
usually reported as a secondary or adverse outcome in studies with unrelated primary outcomes.
Search terms included hormone replacement therapy, estrogen replacement, thromboembolism,
risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement
Study. Ann Intern Med. 2000;132:689-696.
32. Coronary Drug Project Research Group. The Coronary Drug Project: findings leading to
discontinuation of the 2.5 mg/day estrogen group. JAMA. 1973;226:652-657.
30
33. Wenger N. Early risks of hormone therapy in patients with coronary heart disease [letter].
JAMA. 2000;284:41-43.
34. National Heart Lung and Blood Institute (NHLBI). Statement from Claudia Lenfant, MD,
NHLBI Director, on preliminary trends in the Women's Health Initiative (WHI). National
Heart, Lung and Blood Institute: Bethesda, Maryland; 2000.
35. Women's Health Initiative (WHI) Data and Safety Monitoring Board (DSMB). New
hormone program information. WHI HRT Update; 2001:1-2.
36. Kearon C, Julian JA, Newman TE, Ginsberg JS. Noninvasive diagnosis of deep venous
thrombosis. McMaster Diagnostic Imaging Practice Guidelines Initiative [published
erratum appears in Ann Intern Med. 1998;129(5):425]. Ann Intern Med. 1998;128:663-
677.
37. The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED)
Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism:
Results of the PIOPED. JAMA. 1990;263:2753-2759.
38. Rosenberg L, Palmer JR, Adams-Campbell LL. Postmenopausal female hormone use and
venous thromboembolic disease in black women [letter]. Am J Obstet Gynecol.
1997;177:1275.
39. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of
oral and transdermal estrogen/progesterone regimens on blood coagulation and
fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler
Thromb Vasc Biol. 1997;17:3071-3078.
40. Ruehlmann DO, Mann GE. Actions of oestrogen on vascular endothelial and smooth-
muscle cells. Biochem Soc Trans. 1997;25:40-45.
31
41. Koh K, Horne M, Cannon R. Effects of hormone replacement therapy on coagulation,
fibrinolysis, and thrombosis in postmenopausal women. Thromb Haemost. 1999;82:626-
633.
42. Whiteman MK, Cui Y, Flaws JA, Espeland M, Bush TL. Low fibrinogen level: A
predisposing factor for venous thromboembolic events with hormone replacement
therapy. Am J Hematol. 1999;61:271-273.
43. The Writing Group for the Estradiol Clotting Factors Study. Effects on haemostasis of
hormone replacement therapy with transdermal estradiol and oral sequential
medroxyprogesterone acetate: a 1-year, double-blind, placebo-controlled study. Thromb
Haemost. 1996;75:476-480.
44. Hoibraaten E, Qvigstad E, Arnesen H, Larsen S, Wickstrom E, Sandset P. Increased risk
of recurrent venous thromboembolism during hormone repacement therapy - results of
the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism
trial (EVTET). Thromb Haemost. 2000;84:961-967.
45. Glueck CJ, Wang P, Fontaine RN, Tracy T, Sieve-Smith L, Lang JE. Effect of exogenous
estrogen on atherothrombotic vascular disease risk related to the presence or absence of
the factor V Leiden mutation (resistance to activated protein C). Am J Cardiol.
1999;84:549-554.
46. Lowe G, Woodward M, Vessey M, Rumley A, Gough P, Daly E. Thrombotic variables
and risk of idiopathic venous thromboembolism in women aged 45-64 years.
Relationships to hormone replacement therapy. Thromb Haemost. 2000;83:530-535.
39
Appendix 1a. Search Strategy for Effects of Hormone Replacement Therapy on Coagulation 1 exp hormone replacement therapy estrogen replacement therapy 2 hormone replacement.tw. (Text word from title and abstract of article) 3 estrogen replacement.tw. 4 exp estrogens/ad,tu (ad = administration & dosage) (tu = therapeutic use) equilenin estrogens, catechol equilin estrogens, conjugated estradiol estrogens, non-steroidal estrone estriol estramustine chlorotrianisene coumestrol dienestrol diethylstilbestrol hexestrol zearalenone zeranol 5 exp estrogens, synthetic/ad,tu epimestrol ethinyl estradiol mestranol quinestrol 6 1 or 2 or 3 or 4 or 5 7 exp blood coagulation disorders antithrombin 111 deficiency disseminated intravascular coagulation Bernard-Soulier syndrome platelet storage pool deficiency protein C deficiency coagulation protein disorders protein S deficiency purpura, thrombocytopenic thrombasthenia thrombocythemia, hemorrhagic vitamin K deficiency 8 exp blood coagulation fibrinolysis 9 hypercoagulation.tw. 10 exp hemostasis blood coagulation platelet activation 11 exp thromboembolism cerebral embolism and thrombosis embolism, paradoxical 12 thrombophlebitis 13 pulmonary embolism 14 exp fibrinogen fibrinogens, abnormal fibrin fibrinogen degradation products fibrinopeptide A fibrinopeptide B 15 fibrinolysis 16 blood clot$.tw. 17 exp thrombosis coronary thrombosis purpura, thrombotic thrombocytopenic thromboembolism venous thrombosis 18 regional blood flow 19 blood flow velocity 20 exp anticoagulants 4-hydroxycoumarins acenocoumarol ancrod Appendix 1a. Search Strategy for effects of Hormone Replacement Therapy on Coagulation (continued)
40
citric acid coumarins dermatan sulfate dextran sulfate dextrans dicumarol edetic acid enoxaparin ethyl biscoumacetate gabexate heparin heparin, low-molecular weight heparinoids nadroparin pentosan sulfuric polyester phenindione phenprocoumon protein C protein S tedelparin tetrathionic acid warfarin 21 thrombo$.tw. 22 thrombolytic therapy 23 exp hemorrhage blood loss, surgical ecchymosis cerebral hemorrhage epitaxis eye hemorrhage gastrointestinal hemorrhage hemarthrosis hematocele hematoma hematuria hemobilia hemoperitoneum hemoptysis hemothorax postoperative hemorrhage retrobulbar hemorrhage purpura shock, hemorrhagic uterine hemorrhage 24 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 25 6 and 24 26 limit 25 to human 27 limit 26 to english language 28 (looked at english abstracts for foreign language articles)
41
Appendix 1b. Search Strategy for Hormone Replacement Therapy Randomized Controlled Trials 1 exp hormone replacement therapy estrogen replacement therapy 2 hormone replacement.tw. (text word taken from title and abstract of article) 3 estrogen replacement.tw. 4 exp estrogens/ad,tu (ad = administration & dosage; tu = therapeutic use) equilenin estrogens, catechol equilin estrogens, conjugated estradiol estrogens, non-steroidal estriol estrone 5 exp estrogens, synthetic/ad,tu estrogens, non-steroidal epimestrol chlorotrianisene ethinyl estradiol coumestrol mestranol dienestrol quinestrol diethylstilbestrol hexestrol zearalenone zeranol 6 1 or 2 or 3 or 4 or 5 7 limit 6 to randomized controlled trials (check for document type) 8 randomized controlled trials 9 randomized.tw. 10 8 or 9 11 6 and 10 12 7 or 11 13 limit 12 to human 14 limit 13 to english language 15 looked at english abstracts of foreign articles
42
Appendix 1c. Search Strategy for Selective Estrogen Receptor Modulators (SERMs) 1 (tamoxifen or raloxifene).mp. 2 Bone density/ or "bone density".mp. 2 exp osteoporosis/ or "osteoporosis".mp. 4 exp fractures/ or fracture$.mp. 5 exp hormone replacement therapy/ 6 estrogen replacement.mp. 7 2 or 3 or 4 or 5 or 6 8 1 and 7 9 limit 8 to (human and english language) 10 exp breast neoplasms/ 11 9 not 10 12 from 11 keep
43
Appendix 2. Hormone Replacement Therapy and Venous Thromboembolism Search Results
Appendix 3. Criteria for Grading the Internal Validity of Individual Studies Design-Specific Criteria and Quality Category Definitions25 Presented below are a set of minimal criteria for each study design and then a general definition of three categories- �good,� �fair,� and �poor� � based on those criteria. These specifications are not meant to be rigid rules but rather are intended to be general guidelines, and individual exceptions, when explicitly explained and justified, can be made. In general, a �good� study is one that meets all criteria well. A �fair� study is one that does not meet (or it is not clear that it meets) at least one criterion but has no known �fatal flaw.� �Poor� studies have at least one fatal flaw. Case Control Studies
Criteria: • Accurate ascertainment of cases • Nonbiased selection of cases/controls with exclusion criteria applied equally to both • Response rate • Diagnostic testing procedures applied equally to each group • Measurement of exposure accurate and applied equally to each group • Appropriate attention to potential confounding variable
Definition of ratings based on criteria above:
Good: Appropriate ascertainment of cases and nonbiased selection of case and control participants; exclusion criteria applied equally to cases and controls; response rate equal to or greater than 80 percent; diagnostic procedures and measurements accurate and applied equally to cases and controls; and appropriate attention to confounding variables.
Fair: Recent, relevant, without major apparent selection or diagnostic work-up bias but with response
rate less than 80 percent or attention to some but not all important confounding variables. Poor: Major selection or diagnostic work-up biases, response rates less than 50 percent, or inattention
to confounding variables. Randomized Controlled Trials and Cohort Studies
Criteria: • Initial assembly of comparable groups:
-for RCTs: adequate randomization, including first concealment and whether potential confounders were distributed equally among groups -for cohort studies: consideration of potential confounders with either restriction or measurement for adjustment in the analysis; consideration of inception cohorts
• Maintenance of comparable groups (includes attrition, cross-overs, adherence, contamination) • Important differential loss to follow-up or overall high loss to follow-up • Measurements: equal, reliable, and valid (includes masking of outcome assessment) • Clear definition of interventions • Important outcomes considered • Analysis: adjustment for potential confounders for cohort studies, or intention to treat analysis for
RCTs.
45
Appendix 3. Criteria for Grading the Internal Validity of Individual Studies (continued) Definition of ratings based on above criteria:
Good: Meets all criteria: Comparable groups are assembled initially and maintained throughout the study (follow-up at least 80 percent); reliable and valid measurement instruments are used and applied equally to the groups; interventions are spelled out clearly; important outcomes are considered; and appropriate attention to confounders in analysis. In addition, for RCTs, intention to treat analysis is used.
Fair: Studies will be graded �fair� if any or all of the following problems occur, without the fatal flaws
noted in the �poor� category below: Generally comparable groups are assembled initially but some question remains whether some (although not major) differences occurred in follow-up; measurement instruments are acceptable (although not the best) and generally applied equally; some but not all important outcomes are considered; and some but not all potential confounders are accounted for. Intention to treat analysis is done for RCTS.
Poor: Studies will be graded �poor� if any of the following fatal flaws exists: Groups assembled initially
are not close to being comparable or maintained throughout the study; unreliable or invalid measurement instruments are used or not applied at all equally among groups (including not masking outcome assessment); and key confounders are given little or no attention. For RCTs, intention to treat analysis is lacking.
Daly et al., 19967 18 /168 4 2.3 (0.6-8.1) Not Reported Not Reported Poor
Jick et al., 19968 42 /168 21 3.6 (1.6-7.8) 3.2 4,347 Good
Perez Gutthann et al., 19979 292 /10,000 37 2.1 (1.4-3.2) 2.7 7,142 Good
Varas-Lorenzo et al., 199810 171 /10,000 6 2.3 (1.0-5.3) 2.9 3,448 Good
Høibraaten et al., 199913 176 /352 50 1.22 (0.76-1.96) Not Reported Not Reported Fair
Boston Collaborative, 19743 152 /774 3 2.26 (0.61-8.41)� Not Reported Not Reported Poor
Cohort Studies Total Subjects
Grodstein et al., 199611 112,593 41 2.1 (1.2-3.8) 2.0§ 25,000§ Good
* calculated per 10,000 exposed women in one year� women needed to treat for one year to cause one additional event� calculated § current usersNote: ERA indicates Estrogen Replacement and Atherosclerosis; HERS, Heart and Estrogen/progestin Replacement Study; PEPI, Postmenopausal Estrogen/Progestin Interventions
36
Treatment Placebo Relative Risk Number Needed QualityStudy Subjects (N) Events (N) Events (N) (95% CI) to Harm� Rating
Does HRT increase the risk for venous thromboembolism?
I RCTs: Poor to good. Venous thromboembolism is a secondary outcome, groups randomized for cardiac outcomes, method of outcome assessment not reported.
II-2 Case-control: Poor to good. Analysis based on small numbers of cases, important confounders such as smoking not considered in some
II-2 Cohort: Good.
*Study design categories14
I: Randomized, controlled trialsII-1: Controlled trials without randomizationII-2: Cohort or case-control analytic studiesII-3: Multiple time seies, dramatic uncontrolled experimentsIII: Opinions of respected authorities, descriptive epidemiology
Outpatient and community; 20 U.S. sites; primary outcome nonfatal myocardial infarction or coronary artery disease death
Post menopausal,< 80 yrs, coronary artery disease, intact uterus.
68,561 Cardiac event within 6 mos of randomization; use of HRT within 3 mos of initial visit; history of VTE; history of breast or endometrial cancer.
2,763 1,380/1,383 67 Range 44-79 yrs.
CEE 0.625 mg/MPA 2.5 mg
PEPI, 199515
Outpatient; 7 U.S. academic centers; primary outcomes: high density lipoproteins, systolic blood pressure, insulin, fibrinogen.
Post menopausal, 45-64 yrs,with or without a uterus.
Not stated
Myocardial infarction within 6 mos; congestive heart failure, cerebrovascular accident, transient ischemic attach, prior breast or endometrial cancer; use of HRT within 3 mos.
Appendix 4 Evidence Table 2. HRT and Venous Thromboembolism--Case-Control Studies
Author, year
Devor, 199217
Daly, 19966
Daly, 19967
Jick, 19968
Perez-Gutthann, 19979
Varas-Lorenzo, 199810
Høibraaten, 199913
Boston Collaborative, (1974)3
Confounders not controlled
for
Adjusted OR (95% CI)
Exposed cases
Duration trends
Number Needed to
Harm
Quality of studies
Body mass index, varicose veins, smoking
VTE 0.79 (0.30-2.08)
6 Not analyzed Not able to calculate
Poor: not accurate ascertainment of cases, included VTE cases not present at admission; important confounders not included, significant difference between hospital length of stay between cases and controlsSmoking VTE 3.5 (1.8-7.0) 44 Highest risk with
first year of use 6,060 woman
yrs/1 VTEFair: did not control for smoking; 22 cases recruited retrospectively; analysis of dosages,route, and ERT/HRT based on small numbers.
Smoking, varicose veins
VTE 2.3 (0.6-8.1) 4 Not analyzed Not able to calculate
Poor: type and dose of HRT not included; not peer reviewed, published as letter to editor.
Not Stated VTE 3.6 (1.6-7.8) DVT 4.0 (1.6-9.7) PE 2.5 (0.5-12.2)
21 Highest risk with first year of use
4,347 woman yrs/1 VTE
Good: although analysis of dosages and ERT/HRT were based on small numbers and method of determining exposure was through formulary records.
Not Stated 2.1 (1.4-3.2) Current vs. Nonuser
37 Highest risk with first year of use
6,993 woman yrs/1 VTE
Good: although analysis of dosages and ERT/HRT were based on small numbers and method of determining exposure was through formulary records.
Smoking2.3 (1.0-5.3)Current vs. Nonuser
6 Highest risk with first year of use
5,000 woman yrs/1
VTE
Fair: did not include smoking, analysis based on 6 current users of ERT/HRT.
Varicose veins 1.22 (0.76 - 1.94) Current vs. Nonuser
50 Highest risk with first year of use
Not analyzed Fair: no clear method of outcome measurement. Dose of HRT not reported.
Body mass index, varicose veins, smoking
2.26 (0.61 - 8.41)** 3 Not analyzed 25,000 Poor: No clear method of outcome measurement. Dose and duration of HRT use not reported. Confounders not controlled for.