Oral contraceptives and venous thromboembolism. Dose reduction - - PowerPoint PPT Presentation

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Oral contraceptives and venous thromboembolism. Dose reduction - - PowerPoint PPT Presentation

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Oral contraceptives and venous thromboembolism. Dose reduction matters. jvind Lidegaard Gynaecological Clinic Rigshospitalet Copenhagen University OC generations according to estrogen dose and progestagen type Progestagen generation 1 2

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SLIDE 1

Oral contraceptives and venous thromboembolism. Dose reduction matters.

Øjvind Lidegaard

Gynaecological Clinic Rigshospitalet Copenhagen University

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SLIDE 2

OC generations according to estrogen dose and progestagen type

Progestagen generation

1 2 ”2” 3 3 4 Estrans Levonor- Norges- Deso- Gesto- Dros- NETA gestrel timate gestrel dene pirenone

50high

  • 1st+

EVRA

  • 30-40mid -

+ 2nd + + + +4th 20low

  • Nuvaring3rd+

+ POP + +

  • +
  • Li/07
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SLIDE 3

OC types in DK according to estrogen dose during the period 1980-2007

0% 20% 40% 60% 80% 100%

80 82 84 86 88 90 92 94 96 98 00 02 04 06 07

Li/08

Sale statistics. Dansk Lægemiddelstatistik 30-40ug EE 50ug EE 20ug EE POP

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SLIDE 4

Use of oral contraceptives in DK

DDD/100 women/day at different ages

2 43 54 36 24 17 11 7 2

10 20 30 40 50 60

10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54

Li/08

www.laegemiddelstyrelsen.dk

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SLIDE 5

Hormonal contraception DK 2005

0% 20% 40% 60% 80% 100%

15-19 20-24 25-29 30-34 35-39 40-44 45-49

Li/08

3rd generation 2nd generation 4th generation

CPA

POP Sale statistics. www.laegemiddelstyrelsen.dk Hormone IUD 1st gen

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SLIDE 6

CTA, AMI & VTE in DK according to age

Pregnant and puerperal women excluded

10 20 30 40 50 60

15 20 25 30 35 40 15 20 25 30 35 40

Li/04 Incidence per 100,000 per year Lidegaard Ø. Am J Obstet Gynecol 1998; 179: S62-7.

DVT PE VTE AMI CTA CTA+ AMI Arterial thrombosis Venous thrombosis

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SLIDE 7

Thrombotic diseases in young women

Per 1 million per year CTA AMI VTE Incidence 170 62 230 Non pregnant 150 60 170 Mortality 3 15 2.7 Non pregnant 3 15 2.3 Case-fatality rate 2.3% 25% 1.3% Significant disability 30% 30% 5% Long-term survival ↓ ↓↓ →

  • Lidegaard. Am J Obstet Gynecol 1998; 179: s62-7

Li/04

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SLIDE 8

VTE: Genetic risk factors

Risk factor Prevalence RR Leiden fact V hetero 5% 8 Leiden fact V homoz 0.2% 64 Protein C insufficiency 0.2% 15 Protein S insufficiency <0.1% >10 Antithrombin III insuff. 0.02% 50 Prothrombin 20210A 2% 3 Hyperhomocysteinaemia 3% 3

Li/08

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SLIDE 9

VTE: Acquired risk factors

Prevalence RR Age ≥30 vs <30 50% 2.5 Pregnancy 4% 8 Adiposity (BMI>25) 36% 2 Varicose veins 8% 2 Immobilisation/trauma ? 2-10 Oral contraceptives 33% 3-4 Medical diseases 5%? 2-5

Li/08

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SLIDE 10

Incidence rate of VTE among pregnant and puerperal women, DK 1994-96. N=265

4 4 9 35 80 24 14 5 3

1

20 40 60 80 100

Non- preg Week 1-12 Week 13-24 Week 25-36 Week >36 Week 1-2 Week 3-4 Week 5-6 Week 7-8 Week 9-12

Incidence of VTE per 10,000 exposure years

Pregnancy (n=162) Puerperium (n=103)

Delivery

Li/04 www.lidegaard.dk/Slides

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SLIDE 11

Hormonal contraception and VTE Denmark 1995-2005

Danish Sex Hormone Register Study DaHoRS Øjvind Lidegaard, Rigshospitalet Ellen Løkkegaard, Glostrup Hospital Anne Louise Svendsen, Copenhagen University Carsten Agger,

Research Centre for Prevention and Health

Li/08

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SLIDE 12

OC and VTE: Objectives

OC axes Confounders

Dose of estrogen Age Year Other risk factors Type of progestagen Duration of use VTE risk

Li/08

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SLIDE 13

OC and VTE: Material

Inclusion

  • All women in Denmark 15-49 years old

during the period January 1995 through December 2005 (11 years) Exclusion

  • Pregnant women
  • Women with previous VTE or cancer
  • Women censored at their first VTE

Li/08

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SLIDE 14

OC and VTE: Methods

National Registry of Patients (NRP) VTE diagnoses, Previous CaVD/canc. Pregnancies National Registry of Medicinal products (NRM): OC use Medication against BP , DM, Hyperchol.

1995 2005

Statistics of Denmark Education, PIN-codes, address, vital status

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SLIDE 15

OC and VTE: Results

  • Observation years: 10.4 million
  • Current user years: 3.3 million
  • Former user years: 2.3 million
  • Never user years: 4.8 million
  • Number of included VTE:

4,213

  • VTE in current users of OC: 2,045
  • VTE in former users of OC:

667

  • VTE in never users of OC:

1,467

Li/08

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SLIDE 16

OC and VTE: Axes of significance

Correlation to VTE risk

  • Estrogen dose

Positive

  • Progestagen generation

Positive

  • Length of use

Negative

  • Age of the woman

Positive

  • Year (1995-2005)

Positive

  • Education

Negative

Li/08

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SLIDE 17

OC and VTE: Results

Crude IR/10,000wy Rate ratio*

  • Non use

3.1 1 ref.

  • OC all

6.3 2.8 (2.7-3.0)

  • Comb OC <1 yr

6.5 4.2 (3.7-4.7)

  • Comb OC 1-4yrs

5.4 3.0 (2.7-3.3)

  • Comb OC >4 yrs

7.7 2.8 (2.5-3.0)

  • 1st generation OC

7.8 2.7 (2.1-3.4)

  • 2nd generation OC 5.5

2.0 (1.8-2.3)

  • 3rd generation OC 6.8

3.6 (3.3-3.8)

  • 4th generation OC 7.8

4.0 (3.3-4.9)

*) Adjusted for age, year, education

Li/08

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SLIDE 18

OC and VTE: Results

Crude IR/10,000wy Rate ratio*

  • Non use

3.1 reference

  • POP, 30ug levo

1.8 0.6 (0.3-1.0)

  • POP, 75ug deso

3.3 1.1 (0.4-3.4)

  • Hormone-IUD

3.4 0.9 (0.6-1.3)

  • Year: Risk increases by 1.05 per year
  • Age: 15-19 years: 1.8 per 10.000 years

45-49 years: 6.6 per 10.000 years

*) Adjusted for age, year, education

Li/08

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SLIDE 19

OC and VTE: Progestagen type adjusted for duration of use

ug EE Neta Levo Norg Deso Gest Dros Cypr 50 1.4 1.2 na na na na na

1.0-2.1 0.9-1.7

30-40 1.0 Ref 1.2 1.8 1.9 1.6 1.9

0.7-1.4 1.0-1.5 1.5-2.2 1.6-2.2 1.3-2.1 1.5-2.4

20 na na na 1.5 1.5 na na

1.3-1.8 1.2-1.9

POP na 0.3 0.2-0.5 0.5 0.2-1.7 Mirena na 0.4 0.3-0.6

Li/08

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SLIDE 20

Risk of VTE according to estrogen dose

1,2 1,4 1,8 1,5 1,9 1,5

1 1,5 2 50 30-40 20

Li/08

Reference Norethisterone Gestodene Levonorgestrel Desogestrel ug EE Rate ratio Adjusted for age, year, education and length of use

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SLIDE 21

EURAS: Design

  • European Active Surveillance Study (EURAS),

part of phase IV commitment

  • Prospective multinational cohort study
  • Recruitment: 2000-2004
  • 142,475 womenyears of OC use, age 25 yrs.
  • Users stratified into DRSP, LNG, Other OCs
  • In total 118 VTE events
  • 92 (78%) DVT
  • 26 (22%) PE

Dinger et al. Contraception 2007; 75: 344-54

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SLIDE 22

EURAS vs Lidegaard

EURAS Lidegaard VTE 118 4.213 Non use 2.3 /104 wy 3.1 /104 wy 1st gen: na 7.8 /104 wy 2nd gen: 8.0 /104 wy 5.5 /104 wy 3rd gen: 9.9 /104 wy 6.8 /104 wy 4th gen: 9.1 /104 wy 7.8 /104 wy

Li/08

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SLIDE 23

EURAS vs Lidegaard

EURAS Lidegaard VTE 118 4.213 Non use 2.3 /104 wy 3.1 /104 wy 1st gen: na 7.8 /104 wy 2nd gen: 8.0 /104 wy 5.5 /104 wy 3rd gen: 9.9 /104 wy 6.8 /104 wy 4th gen: 9.1 /104 wy 7.8 /104 wy

Li/08

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SLIDE 24

Preferential prescribing

Are adipose women more likely to take 4th geneneration OCs? EURAS:

  • BMI Mean: Levo 22.0, 4th gen: 22.9
  • BMI >30: Levo: 4.4%, 4th gen: 7.0%
  • Mean age: Levo: 25.2 yrs. 4th gen 26.3 yrs

“The differences were small and the preferential prescribing pattern identified here could only slightly increase the incidence of VTE in the DRSP cohort”

Heinemann & Dinger. Drug safety 2004; 27: 1001-1018 Dinger et al. Contraception 2007; 75: 344-54

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SLIDE 25

OCs and SHBG changes

50 150 150 250 260 275 350

100 200 300 400

L N G N

  • r

g e s t E t

  • n
  • g

D e s

  • g

E V R A D R S P C P A % increase in SHBG Nuva Ring Patch

Odlin et al. Acta Obstet Gynecol Scand 2002; 81: 482-90

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SLIDE 26

OCs and activated protein C (APC) sensitivity test

Background

  • Protein C has an anticoagulant effect
  • Activated protein C (APC) enhances the

degradation of coagulation factors.

  • APC resistance can be inherited (Leiden V)
  • r acquired: pregnancy and OCs
  • APC resistance = reduced sensitivity for APC
  • Normalised APC sensitivity ratio (nAPCsr) is a

quantitave test for APC resistance.

Van Vliet et al. J Thromb Haemost 2004; 2: 2060-2

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SLIDE 27

OCs and activated protein C (APC) resistance test: Results

nAPCsr Shift to before after LNG 3.0 DRSP 3.1 3.6 DRSP 4.1 LNG 3.6 2.7 Desoges 4.1 DRSP 3.8 4.0 Gestod. 3.7 DRSP 2.8 2.8 Norgest 5.2 DRSP 4.6 4.9 NETA 3.6 DRSP 3.7 2.4 Conclusion: nAPCsr for DRSP is of same magnitude as for 3. generation progestagens

Van Vliet et al. J Thromb Haemost 2004; 2: 2060-2

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SLIDE 28

OC and VTE: Conclusion

Conclusion

  • Risk of VTE about 50% higher the first year
  • 30-40 → 20ug EE: 18% reduction in risk
  • Norgestimate same risk as 2nd generation.
  • 4th generation same risk as 3rd generation
  • 3rd/4th generation higher risk than 2nd gen
  • POP:

No risk (low/middle dose)

  • Hormone IUD:

No risk

Li/08

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SLIDE 29

OCs and thrombosis

Current status April 2008

CTA AMI VTE Non use 1 1 1 2nd gen: 2.5 1.5 2.5 3rd gen: 1.5 1.5 4.0 4th gen: na na 4.0

Li/08

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SLIDE 30

OC use in Denmark 1966-2007

5 10 15 20 25 30 35

66 70 75 80 85 90 95 00 05

Per cent

Calculated from total sale in DDD/fem pop 15-44 years. Li/08

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SLIDE 31

Thank you for your attention Presentation at: www.Lidegaard.dk