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Anticonceptive Drug Use and Increased Carotid and Femoral Plaque Prevalence: Population Data from ASKLEPIOS
AHA Scientific Sessions 2007 Orlando, Nov 6th, 2007
Ernst Rietzschel1,2
Marc De Buyzere1
Dirk De Bacquer2 Sofie Bekaert3
Patrick Segers4 P. Cassiman5
P. Verdonck4
Guy De Backer2
Thierry Gillebert1
on behalf of the Asklepios investigators.
Presenter Disclosure Information :No relationships to disclose. No unlabeled/unapproved uses of drugs or products.
1 Department of Cardiovascular Diseases, Ghent University, 2 Department of Public Health, Ghent University,3 Department of Molecular Biotechnology, Ghent University 4 Hydraulics Laboratory, IBITECH, Ghent University
5 Association of Primary Care Physicians ASKLEPIOS, Erpe-Mere
BACKGROUND: • Combination therapy with the female hormones estrogen and
progestin are among the most frequently used drugs in the world with approx. 100 million women taking oral contraceptives (OC).
• Recent large trials (WHI, HERS, Wisdom) have cast doubt on the cardiovascular safety of hormonal replacement therapy (HRT).
• In contrast to the active controversy surrounding HRT, very little attention has been focused on OC, a drug therapy using 10 to 100 fold higher levels of estrogen than HRT.
• Current evidence indicates an increased thrombotic risk (venous > arterial) for current OC users. This increased risk is believed to fall back to baseline upon cessation, without subclinical damage accumulation.
E. Rietzschel, on behalf of the ASKLEPIOS investigators AHA Scientific sessions 2007
Oral Contraceptive Use Linked to Higher Arterial Plaque Levels
UN Population Division (2006). World Contraceptive Use 2005
Anderson et al, JAMA 2004 ; Manson et al, NEJM 2003; Hsia et al Arch Intern Med 2006; Hulley et al, JAMA 1998
Baillargeon et al, JCEM 2005; Rosendaal et al ATVB 2002
E. Rietzschel, on behalf of the ASKLEPIOS investigators AHA Scientific sessions 2007
Oral Contraceptive Use Linked to Higher Arterial Plaque Levels
EXPERIMENTAL QUESTION• We describe the relation between carotid and femoral atherosclerosis
and long-term OC exposure. • Null hypothesis = no harm
STUDY SETTING : Random community sample • 2524 apparently healthy 35-55 year-old subjects from Erpe-Mere• Risk factors extensively profiled• Atherosclerosis imaging (GE/Vingmed VIVID 7 - 10-12 MHz probe).
• Bilateral carotid and femoral arteries• Plaque = a focal protrusion >50% compared to adjacent sites with an
absolute thickness >1.5 mm or with a protrusion into the lumen of >0.5 mm. • OC exposure was calculated from data provided by the subject,
and validated in conjunction with their primary care physician. Rationale, Design, Methods and Baseline Characteristics of the Asklepios Study.
Rietzschel et al. European Journal of Cardiovascular Prevention & Rehabilitation (2007)
E. Rietzschel, on behalf of the ASKLEPIOS investigators AHA Scientific sessions 2007
Oral Contraceptive Use Linked to Higher Arterial Plaque Levels
BASELINE CHARACTERISTICSAge (median; years) 45.7
BMI (kg/m2) 25.1 4.7
Metabolic syndrome (IDF) 12 %
Total cholesterol / HDL-cholesterol (mg/dl) 214 36 / 71 17
Systolic BP / diastolic BP (mmHg) 123 14 / 78 10
High - sensitive CRP (mg/l) 1.42 [ 0.62 – 3.42 ]
Active smoking (%) 17.7%
Fasting glycemia >=100 mg/dl or diabetes 9.7%
OC Exposure• 81% of our 1301 women have taken OC for ≥ 1 year.
(2002 US data: 82% of women 15-44y. CDC 2004)
• Median OC exposure was 13 years.
E. Rietzschel, on behalf of the ASKLEPIOS investigators AHA Scientific sessions 2007
Oral Contraceptive Use Linked to Higher Arterial Plaque Levels
• Prevalence of Unilateral disease (right or left artery)
• Odds ratio’s (OR) per 10 years of OC exposure were• carotid plaque 1.17 (1.00-1.33); p<0.05• femoral plaque 1.28 (1.10-1.47); p<0.01
0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0
Carotid plaque
Femoral plaque
OR for having unilateral plaqueEffect of OC exposure (per 10 years)
Adjusted for age, smoking, blood pressure, total & HDL-cholesterol, body mass index, diabetes, physical activity, fruit, vegetable and alcohol intake, educational achievement and drug therapy (lipid-lowering, antihypertensive, aspirin)
E. Rietzschel, on behalf of the ASKLEPIOS investigators AHA Scientific sessions 2007
Oral Contraceptive Use Linked to Higher Arterial Plaque Levels
• Prevalence of bilateral disease (right + left artery)
• More specific and stringent phenotype • OR per 10 years OC exposure were:
• carotid plaque 1.42 (1.03-1.84); p<0.05• femoral plaque 1.34 (1.05-1.63); p<0.05
0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0
Carotid plaque
Femoral plaque
OR for having bilateral plaqueEffect of OC exposure (per 10 years)
Adjusted for age, smoking, blood pressure, total & HDL-cholesterol, body mass index, diabetes, physical activity, fruit, vegetable and alcohol intake, educational achievement and drug therapy (lipid-lowering, antihypertensive, aspirin)
E. Rietzschel, on behalf of the ASKLEPIOS investigators AHA Scientific sessions 2007
CONCLUSIONS
• Use of OC is very common and associated with an unexpected increase in prevalence of carotid and femoral atherosclerosis in young, apparently healthy women.
• Our results suggest a 20-30% increased prevalence of plaque in the carotid and femoral arteries per 10 years of OC exposure.
• In the light of widespread (>80% of our population sample; 100
million women globally) and usually prolonged OC use (>10
years) these results suggest that OC use could be an important factor in the global atherosclerotic burden.
Oral Contraceptive Use Linked to Higher Arterial Plaque Levels
E. Rietzschel, on behalf of the ASKLEPIOS investigators AHA Scientific sessions 2007
DISCUSSION• Current thrombotic risk Current thrombotic risk +
accumulation of subclinical atherosclerotic damage
Oral Contraceptive Use Linked to Higher Arterial Plaque Levels
Born 1947 - 1967
1945 1950 19601955 1965 1970 19801975 19901985 1995 2000
Study start 200218 years: 1965 - 1985
1st gen 2nd gen 3rd genPil introduction (B)
• Mechanisms ?1. Hormonal: HRT benefit/harm not fully clarified2. Adverse impact of classic CRF : BP: + 4-9 mmHg, HDL, LDL
E. Rietzschel, on behalf of the ASKLEPIOS investigators AHA Scientific sessions 2007
Oral Contraceptive Use Linked to Higher Arterial Plaque Levels
Scientific
OC users
Short-term Long-term
Confirmation
Opportunity for better prevention
More research
No discontinuation !
Check & Control classic risk factors
Dept. Cardiovascular DiseasesFaculty of Medicine, Ghent University
Promotor Prof. Thierry Gillebert MD, PhDInvestigators: Ernst Rietzschel, MD &Marc De Buyzere, BSc, Michel Langlois, MD, PhD (clinical chemistry (AZ St-Jan, Bruges)
Cardiovascular Mechanics and Biofluid Dynamics Research UnitInstitute Biomedical Technology
(IBiTech), Ghent University
Promotor Prof. ir Pascal Verdonck, PhD Investigators : Prof. Ir. Patrick Segers, PhD, Ir. Tom Claessens, Ir. Sebastiaan Vermeersch
Dept. Epidemiology and Public Health Faculty of Medicine, Ghent University
Promotor Prof. Guy De Backer, MD, PhDInvestigator : Prof. Dirk De Bacquer, PhD
Department of Molecular Biotechnology, Faculty of Bioscience Engineering, Ghent University
Promotor Prof. Patrick Van Oostveldt, PhDInvestigators : Ir. Sofie Bekaert, PhD, Tim De Meyer
Primary Care Physicians : Asklepios VOF (89)Communities Erpe-Mere – Nieuwerkerken & MDC