Contraccezione e tromboembolismo venoso Ida Martinelli Centro Emofilia e Trombosi Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico - Milano XXVII Congresso Nazionale FCSA Milano, 20-22.10.2016
First report, Lancet 1961 A general practitioner described a case of a 40-year-old nurse who developed bilateral pulmonary embolism 10 days after starting estrogen for endometriosis. Because enovid may produce uncontrollable vomiting and provoke pulmonary embolism and infarction, I would counsel caution in the use of this widely advertised drug
The risk of venous thrombosis is associated with both Estrogen Progestin dose type
OC estrogen content Change in estrogen dose over the years: 1960s 150 μg fi 100 μg fi 50 μg fi 30 μg fi 20 μg or less 2000 onward
Case-control studies DVT PE VTE objectively confirmed in all included cases OR (95%CI) Vandenbroucke (LETS) 1994 3.8 (2.4-6.0) Spitzer 1996 4.0 (3.1-5.3) Realini 1997 6.4 (1.2-34.2) Martinelli 1999 4.6 (2.6-8.0) Bloemenkamp 1999 3.9 (2.6-5.7) Sidney 2004 (incident VTE) 4.1 (2.8-6.0) 8.7 (EE=50 μg) 3.7 (EE=30 μg)
Effect of estrogen dose on VTE risk Lidegaard et al, Contraception 2002 dose EE OR (95%CI) 30-40 μg 1.0 (Ref.) 20 μg 0.6 (0.4-0.9) 50 μg 1.6 (0.9-2.8) ptrend=0.02
OC progestin content Divided into generations based on when progestins were first produced: 1 st generation (1960s): norethisterone, norethinodrel, lynestrenol, ethynodialacetate 2 nd generation (1970s): norgestrel, levonogestrel, norgestrone 3 rd generation (1980s): desogestrel, gestodene - widely used at the beginning of 1990s - 4 th generation (2000): drospirenone - widely used at the beginning of 2000 -
Effect of progestin type Helmerhorst et al, T&H 1997 100 RR 2.0 (1.7-2.8) 10 1 3 rd generation vs 2 nd generation
Progestin type and VTE MEGA Study, 1524 patients and 1760 controls van Hylckama Vlieg et al, BMJ 2009 OR (95%CI) Use 5.0 (4.2-5.8) Levonorgestrel (2nd) 3.6 (2.9-4.6) Gestodene (3rd) 5.6 (3.7-8.4) Desogestrel (3rd) 7.3 (5.3-10.0) Cyproterone acetate (1st) 6.8 (4.7-10.0) Drospirenone (4th) 6.3 (2.9-13.7)
Case-control study, incident VTE Sidney et al, Contraception 2004 cases controls n=196 n=746 OR (95%CI) OC use n (%) Never 31 (16) 141 (19) 1 (Ref.) Former 78 (40) 469 (63) 0.8 (0.5-1.2) Current 86 (44) 134 (18) 3.0 (1.9-4.8)
Risk of VTE during OC use Lidegaard et al, Contraception 2002 OR (95%CI) Non users 1.0 (Ref.) Short users (< 1 y) 7.0 (5.1-9.6) Long users (1-5 y) 3.6 (2.7-4.8) Very long users (> 5 y) 3.1 (2.5-3.8)
Risk of VTE and duration of OC use Martinelli et al, Thromb Res 2016
Risk of VTE and duration of OC use Martinelli et al, Thromb Res 2016
Risk of VTE and duration of OC use Martinelli et al, Thromb Res 2016
When should we be concerned? - known thrombophilia abnormalities - systemic risk factors for thrombosis - true family history of thrombosis
Risk of thrombosis associated with thrombophilia I N H E R I T E D antithrombin deficiency ++++ protein C deficiency +++ protein S deficiency ++ homoz. factor V Leiden +++ homoz. G20210A prothrombin +++ ACQUIRED antiphospholipid Ab ++++ heteroz. factor V Leiden + heteroz. G20210A prothrombin + MIXED hyperhomocysteinemia + high factor VIII + severe mild
Relative risk of DVT according to genotype and pill use Martinelli et al, ATVB 1999 OR (95% CI) V- II- / OC- 1 (Ref.) V- II- / OC+ 4.6 (2.6-8.0) V+ / OC- 2.4 (0.4-15.1) II+ / OC- 2.7 (0.6-12.7) V+ / OC+ 20.0 (4.2-94.3) II+ / OC+ 16.3 (3.4-79.1)
Annual incidence of venous thromboembolism Global 1 : 1,000 age < 45 1 : 10,000 pill use 5 : 10,000 F V Leiden 7 : 10,000 II - G20210A 4 : 10,000 pill and FVL or II 20-30:10,000 (2-3 : 1,000)
Is withholding/denying the pill worthwhile? Vandenbroucke et al, BMJ 1994 to prevent 1 VTE we have to withhold (or deny) the pill to 400 factor V Leiden women to find 400 carriers of factor V Leiden (assuming a 4% prevalence in the population) we need to test 10,000 women
HRT Oral estrogen-progestin estrogen only Transdermal estrogen-progestin estrogen only
Età e TVP Incidence Rate per 100.000 600 500 400 300 200 100 0 Males Females 0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 >79 (from Anderson et al, Arch Intern Med 1991)
HRT estrogen and progestin VTE objectively confirmed in all included cases OR (95%CI) Daly 1996 5.3 (1.9-14.6) Jick 1996 2.4 (0.8-7.3) UK-GPRD 1997 2.2 (1.4-3.5) Varas-Lorenzo 1998 5.0 (1.5-16.7) Grady 2000 (RCT) 2.7 (1.4-5.0) Russow 2002 (RCT) 2.1 (1.3-3.6)
Interaction model (estrogen-progestin HRT) DVT PE factor V Leiden absent present Lowe 2000 4.1 (1.3-13.3) 13.3 (4.3-41) Rosendaal 2002 3.9 (1.3-11.2) 15.5 (3.1-77) Herrington 2002 3.3 (1.1-9.8) 14.1 (2.7-72) Douketis 2003 3.2 (1.2-8.6) 17.1 (3.7-78) Cushman 2004 2.2 (1.4-3.5) 6.7 (3.1-14.5)
Annual incidence of venous thromboembolism global 1 : 1,000 age > 45 1-4 : 1,000 HRT use 2-4 : 1,000 F V Leiden 7 : 1,000 II - G20210A 4 : 1,000 HRT and FVL or II 15 : 1,000 (1.5 : 100)
Is withholding/denying HRT worthwhile? Vandenbroucke et al, BMJ 1994 to prevent 2 VTE we have to withhold (or deny) HRT to 100 factor V Leiden women to find 100 carriers of factor V Leiden (assuming a 4% prevalence in the population) we need to test 2,000 women
TAKE HOME MESSAGE (1) Thrombophilia screening before prescribing hormones is not cost-effective (= should not be done!) can be done in selected cases
TAKE HOME MESSAGE (2) Hormone prescription Healthy women, no concerns: ANY Healthy women + comorbidities, family history, mild thrombophilia: - prefer OC with low estrogen content and levonorgestrel (2 nd generation) - prefer transdermal HRT Symptomatic women: contraindication (consider OAT)
RECURRENT VTE - Martinelli et al, Blood 2016 Characteristic No hormonal therapy Any hormonal therapy Estrogen-containing therapy Progestin-only therapy Events/ patient-years %/year (95% CI) All patients 38/811 4.7 (3.3 6.4) Age <40 years 19/288 6.6 (4.0 10.3) 40 years 19/523 3.6 (2.2 5.7) Randomized treatment Rivaroxaban 21/390 5.4 (3.3 8.2) Enoxaparin/ VKA History of DVT/PE before index event 17/421 4.0 (2.4 6.5) Yes 4/162 2.5 (0.7 6.3) No 34/649 5.2 (3.6 7.3) Prior use of hormonal therapies Yes 13/200 6.5 (3.5 11.1) No 25/611 4.1 (2.7 6.0) Events/ patient-years %/year (95% CI) 7/188 3.7 (1.5 7.7) 2/107 1.9 (0.2 6.7) 5/80 6.3 (2.0 14.6) 3/98 3.1 (0.6 8.9) 4/89 4.5 (1.2 11.5) 0/19 0.0 (0.0 19.7) 7/169 4.2 (1.7 8.6) 7/162 4.3 (1.7 8.9) 0/26 0.0 (0.0 14.5) Events/ patient-years %/year (95% CI) 4/110 3.7 (1.0 9.4) 1/571 1.8 (0.0 9.8) 3/52 5.7 (1.2 16.8) 1/56 1.8 (0.1 9.9) 3/53 5.6 (1.2 16.5) 0/6 0.0 (0.0 63.1) 4/104 3.9 (1.1 9.9) Events/ patient-years %/year (95% CI) 3/78 3.8 (0.8 11.2) HR 0.56, 0.23-1.39 4/103 3.9 (1.1 9.9) 0/6 0.0 (0.0,58.2) 1/50 2.0 (0.1 11.1) 2/28 7.2 (0.9 26.1) 2/42 4.8 (0.6 17.2) 1/36 2.8 (0.1 15.4) 0/13 0.0 (0.0 28.6) 3/65 4.6 (1.0 13.5) 3/59 5.1 (1.1 14.9) 0/19 0.0 (0.0 19.3)
NEED OF ADEQUATE INDIVIDUAL COUNSELING!
Thank you for your attention!