UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research Oral Contraceptives and CVD Epidemiologic Effects TMM Farley Department of Reproductive Health and Research World Health Organization Geneva

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research Overview Rationale for WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone ContraceptionRationale for WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception Venous thromboembolism, stroke and myocardial infarctionVenous thromboembolism, stroke and myocardial infarction Supplement with data from other recent studiesSupplement with data from other recent studies Overall cardiovascular riskOverall cardiovascular risk

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research OC composition and patterns of use have changed since late 1970sOC composition and patterns of use have changed since late 1970s Most information refers to older productsMost information refers to older products No information available on risks in women from developing countriesNo information available on risks in women from developing countries “What are the cardiovascular risks associated with modern OCs used in modern ways?”“What are the cardiovascular risks associated with modern OCs used in modern ways?” WHO Study of Cardiovascular Disease and Steroid Hormone Contraception

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research WHO Study of Cardiovascular Disease and Hormonal Contraception

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research WHO CVD Study - Design Hospital-based case-control studyHospital-based case-control study 17 countries (12 developing, 5 in Europe)17 countries (12 developing, 5 in Europe) Conducted February January 1993Conducted February January 1993 First time cases of stroke, AMI or idiopathic VTE in women aged yearsFirst time cases of stroke, AMI or idiopathic VTE in women aged years 3 controls per case, matched on age, hospital and time period3 controls per case, matched on age, hospital and time period 2,242 stroke, 368 AMI, 1,143 VTE, 10,025 controls2,242 stroke, 368 AMI, 1,143 VTE, 10,025 controls

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research Venous Thromboembolism Adjusted odds ratio (95% CI) WHO, Lancet 1995; 346:1575

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research Risk Factors for Idiopathic VTE Increased relative risk withIncreased relative risk with –OC use –elevated body mass index –hypertension in pregnancy No effect on relative riskNo effect on relative risk –smoking, age, hypertension –duration of OC use –previous OC use WHO, Lancet 1995; 346:1575

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research VTE and Low Estrogen OCs Adjusted odds ratios (95% CI) WHO, Lancet 1995; 346:1575

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research VTE and Low Estrogen OCs Excess risk with desogestrel & gestodene compared with levonorgestrelExcess risk with desogestrel & gestodene compared with levonorgestrel –About 2.5  higher risk –Similar excess risk for the two products –Bias or confounding unlikely explanation Unexpected, Unexplained, Unwelcome, UncomfortableUnexpected, Unexplained, Unwelcome, Uncomfortable “Must be confirmed by independent research”“Must be confirmed by independent research”

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research 3 rd Gen vs. Levonorgestrel Adjusted risks relative to non-users (crude risk) Lancet 1995; 346:1582, 1589, 1593; BMJ 1996; 312: 83; Contraception 1998; 57: 291 Overall risk ratio (95% CI) 1.9 (1.5, 2.2)

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research Ischaemic Stroke Major risk factorsMajor risk factors –smoking –hypertension –rheumatic heart disease –diabetes Overall risk with OC use 2.9 ( )Overall risk with OC use 2.9 ( ) No effect of past OC use or duration of useNo effect of past OC use or duration of use

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research Ischaemic Stroke - smoking Pooled adjusted odds ratio (95% CI) [% controls] WHO, Lancet 1996; 348: 498

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research Ischaemic Stroke - Hypertension Pooled adjusted odds ratio (95% CI) [% controls] WHO, Lancet 1996; 348: 498

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research Ischaemic Stroke and Low Estrogen OCs Kaiser, CA1.2 (0.5, 2.6)Kaiser, CA1.2 (0.5, 2.6) Washington State1.4 (0.5, 3.8)Washington State1.4 (0.5, 3.8) Denmark1.6 (1.1, 2.4)Denmark1.6 (1.1, 2.4) WHO Europe1.4 (0.6, 3.1) Developing countries3.4 (2.2, 3.1)WHO Europe1.4 (0.6, 3.1) Developing countries3.4 (2.2, 3.1) TransNational2.8 (2.0, 3.8)TransNational2.8 (2.0, 3.8) RR (95% CI) compared with non-users

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research With Blood Pressure check WHO Europe1.3 (0.5, 3.5) WHO Developing 2.1 (1.1, 3.8) TransNational2.1 (1.4, 3.1)With Blood Pressure check WHO Europe1.3 (0.5, 3.5) WHO Developing 2.1 (1.1, 3.8) TransNational2.1 (1.4, 3.1) Without Blood Pressure check WHO Europe1.5 (0.5, 4.6) WHO Developing5.2 (2.9, 9.1) TransNational4.5 (2.6, 8.0)Without Blood Pressure check WHO Europe1.5 (0.5, 4.6) WHO Developing5.2 (2.9, 9.1) TransNational4.5 (2.6, 8.0) Ischaemic Stroke and Low Estrogen OCs RR (95% CI) compared with non-users

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research Ischaemic stroke - Conclusion Some excess risk associated with low estrogen dose OCsSome excess risk associated with low estrogen dose OCs Smoking and hypertension potentiate OC- associated riskSmoking and hypertension potentiate OC- associated risk Lower risk when screened for hypertensionLower risk when screened for hypertension No evidence of difference in risk according to OC type (2 nd vs. 3 rd generation)No evidence of difference in risk according to OC type (2 nd vs. 3 rd generation)

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research Haemorrhagic Stroke No difference according to BP checkingNo difference according to BP checking No impact on risk in women < 35 yearsNo impact on risk in women < 35 years About 2  risk in women over 35 yearsAbout 2  risk in women over 35 years Higher (relative) risk among older women, smokers, women with h x of hypertensionHigher (relative) risk among older women, smokers, women with h x of hypertension Smoking has greater impact on risk of haemorrhagic than ischaemic strokeSmoking has greater impact on risk of haemorrhagic than ischaemic stroke Consistent with data from Kaiser, CA (Petitti, 1996)Consistent with data from Kaiser, CA (Petitti, 1996)

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research Myocardial Infarction Major risk factorsMajor risk factors –smoking, hypertension, rheumatic heart disease, diabetes, hyperlipidaemia Overall risk with OC use 4.9 ( )Overall risk with OC use 4.9 ( ) No effect of past OC use or duration of useNo effect of past OC use or duration of use Lower risks with low compared with high dose OCsLower risks with low compared with high dose OCs

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research AMI - Hypertension & OC use Pooled adjusted odds ratio (95% CI) [% controls] WHO, Lancet 1997; 349: 1202

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research AMI - smoking & OC use Pooled adjusted odds ratio (95% CI) [% controls] WHO, Lancet 1997; 349: 1202

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research AMI - Conclusion Majority of cases (78%) occur in smokersMajority of cases (78%) occur in smokers Lower risk with low dose OCs, in women without CV risk factors and who reported BP check (similar observations in TransNational study)Lower risk with low dose OCs, in women without CV risk factors and who reported BP check (similar observations in TransNational study) Among women with no cardiovascular risk factors who do not smoke, RR = 1.1 in women with BP checkAmong women with no cardiovascular risk factors who do not smoke, RR = 1.1 in women with BP check

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research AMI and Type of OC Lancet 1997; 349: 1202; Contraception 1997; 56: 129; BMJ 1999; 318: 1579; NEJM 2001; 345: 1787

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research Overall Cardiovascular Risk Different risk factors for VTE and stroke or MIDifferent risk factors for VTE and stroke or MI Age distribution of VTE, stroke and MI cases very different over age rangeAge distribution of VTE, stroke and MI cases very different over age range Any reduction in MI risk for third generation OC users more important for older women and smokersAny reduction in MI risk for third generation OC users more important for older women and smokers

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research Age group (years) Incidence (per wyrs) Observed CVD Incidence Oxford VTE Haemorrhagic stroke Ischaemic stroke AMI J Epidemiol Comm Health 1998; 52: 775

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research CVD Incidence - Non-smoker 20-24y30-34y40-44y20-24y30-34y40-44y Events per 10 6 wyrs Non-OC userOC user

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research CVD Mortality - Non-smoker Non-OC userOC user 20-24y30-34y40-44y20-24y30-34y40-44y Deaths per 10 6 wyrs

UNDP/UNFPA/WHO/WORLD BANK HRPRHR Reproductive Health and Research OCs and CVD OCs most widely studied pharmacologic agentOCs most widely studied pharmacologic agent In young women without cardiovascular risk factors, OCs are safeIn young women without cardiovascular risk factors, OCs are safe Excess risk seen in older women, smokers and those with pre-existing risk factorsExcess risk seen in older women, smokers and those with pre-existing risk factors Risk-benefit of 2 nd vs. 3 rd generation OCsRisk-benefit of 2 nd vs. 3 rd generation OCs –VTE risk more important in younger women –MI risk more important in older women and smokers