Anticonceptive Drug Use and Increased Carotid and Femoral Plaque Prevalence: Population Data from ASKLEPIOS AHA Scientific Sessions 2007Orlando, Nov 6

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



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)



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.



• 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)



• 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)


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.



DISCUSSION• Current thrombotic risk Current thrombotic risk +

accumulation of subclinical atherosclerotic damage


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



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

Documents

Anticonceptive Drug Use and Increased Carotid and Femoral Plaque Prevalence: Population Data from ASKLEPIOS AHA Scientific Sessions 2007Orlando, Nov 6