P-piller, HT og apopleksi Øjvind Lidegaard Gynækologisk Klinik 4232 Rigshospitalet U-kursus i cerebrovaskulære sygdomme, 29. November 2006

P-piller, HT og CeVD Brug af p-piller og HT i Danmark Cerebral trombose - Epidemiologi hos yngre kvinder - Pp og cerebral trombose - HT og cerebral trombose Cerebral hæmorrhagi - Pp og cerebral hæmorrhagi - HT og cerebral hæmorrhagi U-kursus, 28. november 2006

P-piller, HT og CeVD Brug af p-piller og HT i Danmark Cerebral trombose - Epidemiologi hos yngre kvinder - Pp og cerebral trombose - HT og cerebral trombose Cerebral hæmorrhagi - Pp og cerebral hæmorrhagi - HT og cerebral hæmorrhagi U-kursus, 29. november 2006

OC use in Denmark 1966-2005 Per cent Calculated from total sale in DDD/fem pop 15-44 years. Li/05

OCs: Generations according to oestrogen dose and progestagen types Generation of progestagen 1. 2. "2". 3. 3. 4. EE dose Estrans Nor- gestrel Norges- timate Deso- Gestodene >50mcg EE – 50mcg EE + 30-40mcg EE 20mcg EE POP Dros- pirenon – 1st gen – 2nd gen 4th gen 3rd gen – – Li/04

OC types in DK according to estrogen dose during the period 1980-2000 50ug EE 30-40ug EE 20ug EE POP Sale statistics. Dansk Lægemiddelstatistik Li/04

Progestagen types in combined OC in Denmark 1985-2004 (%) Gest. 20ug Gestodene 30ug Desogestrel 20ug Levonorgestrel Desogestrel 30ug Norgestimate Norethisterone Sale statistics. www.laegemiddelstyrelsen.dk Li/05

Use of oral contraceptives in DK 2003 DDD/100 women/day at different ages www.laegemiddelstyrelsen.dk Li/05

Brug af p-piller i Danmark Ud af alle kvinder benytter i gennemsnit 33% i alderen 15-44 år p-piller mere end hver anden i alderen 20-25 år pp Blandt kvinder, som benytter p-piller bruger 70% p-piller med 30-40ug østrogen 2/3 p-piler med 3. el 4. generations gestagen 90% 2., 3. eller 4. generations p-piller 1% minipiller

HT sale DK 2002. DDD/1,000 per day www.dachre.dk Danish Sex Hormone Register Study (DaHORS).

HT sale DK 2004. DDD/1,000 per day www.dachre.dk Danish Sex Hormone Register Study (DaHORS).

P-piller, HT og CeVD Brug af p-piller og HT i Danmark Cerebral trombose - Epidemiologi hos yngre kvinder - Pp og cerebral trombose - HT og cerebral trombose Cerebral hæmorrhagi - Pp og cerebral hæmorrhagi - HT og cerebral hæmorrhagi U-kursus, 29. november 2006

P-piller, HT og CeVD Brug af p-piller og HT i Danmark Cerebral trombose - Epidemiologi hos yngre kvinder - Pp og cerebral trombose - HT og cerebral trombose Cerebral hæmorrhagi - Pp og cerebral hæmorrhagi - HT og cerebral hæmorrhagi U-kursus, 29. november 2006

CTA, AMI and VTE in DK 1980-93 Pregnant and puerperal women excluded Incidence per 100,000 per year CTA+ AMI Venous diseases Arterial diseases CTA VTE AMI DVT PE Li/04 Lidegaard Ø. Am J Obstet Gynecol 1998; 179: S62-7.

Thrombotic diseases in young women CTA AMI VTE Incidence/mio 170 62 230 Non pregnant 150 60 170 Mortality/mio 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

Risk factors for cardiovascular diseases in women of reproductive age CTA AMI VTE High age + + + Smoking + + - Hypertension + + - Diabetes + + - Family VTE - – + Family AMI + + - Family CTA + + - BMI >30 - + + Migraine + – - Varicose veins - – + Leiden fact V - – + Lidegaard, Nordisk Medicin 1998; 113: 187-90

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 Høibraaten E. HRT and risk of VTE. Diss. Oslo 2001 Li/04

Incidence rate of VTE among pregnant and puerperal women, DK 1994-96 Incidence rate of VTE among pregnant and puerperal women, DK 1994-96. N=265 Incidence of VTE per 10,000 exposure years Puerperium (n=103) Pregnancy (n=162) Delivery www.lidegaard.dk/Slides Li/04

Cerebral thromboembolic attacks (CTA) in DK, 1987-93, women 15-44 years old. Per mio years CTA=cerebral thrombosis (CT) + TIA CTA Incidence Deaths CT TCI Lidegaard. Am J Obstet Gynecol 1998; 179: S62-7 Li/02

P-piller, HT og CeVD Brug af p-piller og HT i Danmark Cerebral trombose - Epidemiologi hos yngre kvinder - Pp og cerebral trombose - HT og cerebral trombose Cerebral hæmorrhagi - Pp og cerebral hæmorrhagi - HT og cerebral hæmorrhagi U-kursus, 29. november 2006

Cerebral thromboembolism in DK Women and men 1980-86 Incidence per 100,000/year Lidegaard, Contraception 1996; 52: 85-92

OCs and cerebral thrombosis Cases/ OR Study PDS controls 2nd/3rd WHO 89-93 489/3967 2.7/1.7 Schwartz 91-95 175/1191 1.1 Heinemann 93-96 220/439 2.7/3.4 Lidegaard 94-98 626/4054 2.2/1.4 Lidegaard et al. Contraception 2002; 65: 197-205

CTA: Conclusion The risk of CTA decreases with decreasing estrogen dose. OCs with 3rd gen. progestagens confer a significantly lower risk of CTA than OCs with 2nd gen. progestagens.

OCs and thrombosis Current status November 2006* CTA AMI VTE 2nd gen: 2.5 1.5 3.0 3rd gen: 1.5 1.5 4.0

Clinical guidelines When OCs are prescribed Careful clinical history including risk factors and family disposition Previous thrombosis: No OCs Genetic predisposition Risk factor ≥5: No OCs VTE risk factor <5: Careful inform., 2nd gen No risk factors: Any low dose pill Arterial risk factors: 3rd gen. pill www.dsog.dk/guidelines Li/04

Migræne og p-piller Risiko for hjerneblodprop: Relativ risiko Migræne generelt 3 Migræne med aura 6 Migræne uden aura 2 2. Gen. p-pille 2,5 3. Gen. p-pille 1,5 Migræne + 2. Gen p-pille 7,5 Migræne + 3. Gen p-pille 4,5 Konklusion: Ikke p-piller til kvinder med migræne med aura. Ellers 3. generation

Rygning og p-piller Risiko for blodprop: Hjerne Hjerte Rygning under 10/dag 1,0 4 Rygning 10-20/dag 1,5 6 Rygning >20/dag 2,0 8 2. Gen. p-pille 2,5 1,5 3. Gen. p-pille 1,5 1,5 Konklusion: Ikke p-piller til kvinder der ryger over 20 cigaretter dagligt og som er over 35 år.

P-piller, HT og CeVD Brug af p-piller og HT i Danmark Cerebral trombose - Epidemiologi hos yngre kvinder - Pp og cerebral trombose - HT og cerebral trombose Cerebral hæmorrhagi - Pp og cerebral hæmorrhagi - HT og cerebral hæmorrhagi U-kursus, 29. november 2006

Womens health initiative (WHI) EPT vs placebo ET vs placebo Age: 50-79 50-79, -uterus Number: 16,608 10,739 Regimen: 0.6mg CEE/MPA 0.6mg CEE Follow up: 5.2 yrs, 6.8 yrs Average age: 63 years 64 years >60 years 66% 70% Hypertension 36% 48% BMI ≥25: 70%, 80% BMI ≥30: 34% 45% Rossouw et al. JAMA 2002; 288: 321-33 & JAMA 2004: 291: 1701

WHI results Coronary heart disease 1.3 0.9 0.6 Stroke 1.4 1.4 1.1 EPT ET 50-59 Coronary heart disease 1.3 0.9 0.6 Stroke 1.4 1.4 1.1 Venous thromboembolism 2.1 1.3 1.2 Breast cancer 1.3 0.8 0.7 Endometrial cancer 0.8 hysterect. Colorectal cancer 0.6 1.1 0.6 Hip fracture 0.7 0.6 NA Vertebral fracture 0.7 0.6 NA All cause mortality 1.0 1.0 0.7 Rossouw et al. JAMA 2002; 288: 321-33 & 2004: 291: 1701

HT og Cerebral trombose Hovedparten af observationsstudier har vist en let øget eller uændret risiko for cerebral trombose blandt kvinder, som aktuelt tager hormoner Nylige randomiserede studier har dog vist en 20-50% øget risiko for stroke blandt ældre hormonbehandlede risikokvinder Konklusion HT ikke indiceret som profylakse imod stroke/cerebral trombose. Relativt kontraindiceret til kvinder med tidligere cerebral trombose. Lemaitre et al. Arch Int Med 2002; 162: 1954-60 Li/02

P-piller, HT og CeVD Brug af p-piller og HT i Danmark Cerebral trombose - Epidemiologi hos yngre kvinder - Pp og cerebral trombose - HT og cerebral trombose Cerebral hæmorrhagi - Pp og cerebral hæmorrhagi - HT og cerebral hæmorrhagi U-kursus, 29. november 2006

Subarachnoid haemorrhage (SAH) and intracerebral haemorrhage (ICH) in women and men in Denmark 1994-98 Incidence per 100,000/year SAH women: n=2,027 SAH men: n=1,402 ICH women: n=3,709 ICH men: n=4,194 ICH-m ICH-w Only first ever events during the five-year period included SAH-w SAH-m www.lidegaard.dk/slides Li/02

Subarachnoid haemorrhage (SAH) and intracerebral haemorrhage (ICH) in women and men in Denmark 1994-98 Incidence per 100,000/year Only first ever events during the five-year period included Li/00

Cerebrovascular diseases in young women, DK 1987-93 Incidence per 100,000/year CT SAB TIA ICH Lidegaard, CNS Drugs 1997; 1: 1-5. Li/00

P-piller, HT og CeVD Brug af p-piller og HT i Danmark Cerebral trombose - Epidemiologi hos yngre kvinder - HT og cerebral trombose - Pp og cerebral trombose Cerebral hæmorrhagi - Pp og cerebral hæmorrhagi - HT og cerebral hæmorrhagi U-kursus, 29. november 2006 Li/04

OCs and cerebral hemorrhage Study Nat PDS Type cas/con RR 95% CI Inman UK 76 SAH 134/134 1.5 0.8-3.0 Thorog. UK 78 SAH 158/304 1.4 0.9-2.4 RCGP UK 68-90 SAH 73/219 1.5 0.6-3.7 ICH 22/66 1.1 0.2-7.1 WHO Eu 89-93 SAH 198/517 1.6 0.9-2.8 - - ICH 46/120 0.9 0.3-3.0 Schwartz US 91-95 CH 196/831 1.0 0.5-1.9 Lidegaard DK 97-98 CH 53/590 1.72nd0.9-3.2 1.53rd0.9-2.6 Li/02

OCs and cerebral haemorrhage Incidence per 100,000/year 1 2 3 4 5 6 7 8 1. Petitti Lancet 1978; i: 234-6. 2. Hannaford. Stroke 1994; 25: 935-42 3: WHO. Lancet 1996; 348: 505-10, 1989-93. 4: Petitti. N Engl J Med 1996; 335: 8-15. 1991-94. 5: Schwartz, Ann Int Med 1997; 127: 596-603. 6.Poulter Lancet 1999; 354: Li/04 7. Jick, Lancet 1999; 354, 8. Lidegaard, unpublished, 2000

Metaanalysis on HT and death OR, 95% CI Aim: HT, deaths, age Meta-analysis on 30 RCT 26,708 participants Salpeter et al. J Gen Intern Med 2004; 19: 791-804

OCs and CH: Conclusion Overall, no increased risk of intracerebral haemorrhage in current users of low-dose OCs. No difference in risk of SAB between OCs with 2nd and 3rd gen. progestagens. Li/00

OCs and apoplexy Current status November 2006 CTA SAB ICH 2nd gen: 2.5 1.5 1.0 3rd gen: 1.5 1.5 1.0

P-piller, HT og CeVD Brug af p-piller og HT i Danmark Cerebral trombose - Epidemiologi hos yngre kvinder - HT og cerebral trombose - Pp og cerebral trombose Cerebral hæmorrhagi - Pp og cerebral hæmorrhagi - HT og cerebral hæmorrhagi U-kursus, 29. november 2006 Li/04

HT and CH: Conclusion Overall, no increased risk of cerebral haemorrhage in women on HT. Previous cerebral haemorrhage not a contraindication against HT. Nelson et al. JAMA 2002; 288: 872-81 Li/04

Li/03

Useful links www.lidegaard.dk/slides www.dsog.dk/guidelines Li/04