Hormonaalinen ehkäisy 2015 missä mennään & mitä uutta? Oskari Heikinheimo Naistenklinikka, HY ja Kätilöopiston sairaala, HYKS oskari.heikinheimo@helsinki.fi Gynecologi Practici 16.1.2015
OHeikinheimo conflicts of interest Employed by Hospital district of Helsinki and Uusimaa University of Helsinki Finnish medical society Duodecim Lectures, Ad-board memberships at Actavis Bayer AG Exelgyn Gedeon Richter MSD Board member at Suomen Lääketieteen säätiö Oheikinheimo consulting
Esityksen sisältö Millaista ehkäisyä Suomessa käytetään? Onko Suomessa pill scare? Hormonaalisen ehkäisyn viimeaikaisia trendejä Tuoreita tutkimustuloksia Hormonaalinen ehkäisy ja laskimotukos Hormonaalinen ehkäisy ja syöpä Yhteenveto
Use of various contraceptive methods in Finland 1998-2009 (Taloustutkimus)
Kovia uutisotsikoita syksyltä 2013
Ehkäisytablettien tukkumyynti www.fimea.fi
Millaisia systeemisesti vaikuttavia hormonaalisia ehkäisyvalmisteita Suomessa myydään? DDD/1000 as/vrk 20 18 16 14 12 10 8 6 4 2 0 II sukupolvi III sukupolvi DRSP Progest. ehkäisy E2 COC 2009 2010 2011 2012 2013 I-VI 2014 II sukupolvi = LNG ja norgestimaatti yhdistelmävalmisteet; III sukupolvi = desogestreeli ja gestodeeni; DRSP = drospirenoni; progestiiniehkäisy = kaikki systeemisesti vaikuttava progestin-only ehkäisy; E2 COC estradiolia sisältävät yhdistemätabletit.
HORMONAALINEN EHKÄISY JA LASKIMOTUKOS MISSÄ MENNÄÄN?
How common is DVT? Heinemann & Dinger, Contraception, 2007 Depends on how carefully one looks Screening after intercontinental flights 3-10% have signs of thrombosis Majority (> 90%?) asymptomatic Also 1% of the controls had signs of DVT The incidence among fertile aged women varies according to study strategy Registry based studies ~0.7-3.8 / 10.000 woman years Cohort studies ~3.8-12.2 /10.000 woman years Prospective studies ~13-14 / 10.000 woman years
Figures from DVT-studies... A clinician sees one case of DVT if he/she prescribes Combined (oral) contraception for ~ 750 women for one year In order to see reliably a difference of one patient between different preparations, the preparation should be prescribed to > 6000 women.
Dose of EE 2 vs the risk of thrombosis The association between EE and DVT first reported in the 1960 s (Jordan, Lancet 1961; Tyler, JAMA 1963) Gerstman et al., (Am J Epidemiol 1991;133:32) EE 2 > 50 µg - risk x 10 EE 2 < 50 µg - risk x 4 Leiden Trombofilia study (Lancet 1995;346:1593) EE 2 30 µg vs. 50 µg - risk x 3-4 with both doses Lidegaard et al., (BMJ 2009; 339: b2890) EE 2 20 vs. 30-40µg tablets - risk ~20%
Veritulpan esiintymiseen vaikuttavat myös Aika yhdistelmäehkäisyn aloituksesta Riski suurin käytön alussa TAI tauon jälkeen! Ikä 40v riski x 10 Ylipaino BMI 30 kg/m 2, riski x 3 Tupakointi Mahd trombofilia esim APC resistenssi
Incidence of DVT /10.000 woman years according to use vs. non-use of COC 16 14 12 10 8 6 No COC COC users 4 2 0 15-19 20-24 25-29 30-34 35-39 40-44
Continuing pill crises since 1995. DOES THE TYPE OF PROGESTIN IN COC MODIFY THE RISK OF DVT?
The composition of COC vs the risk of DVT - different results form diffent studies Lidegaard Ø et al., Acta Obstet Gynecol Scand 2012 III generation progestins vs LNG Drospirenone vs LNG Prospective studies (red bars) vs registry based studies (yellow bars)
Risk of venous thromboembolism Danish cohort study, 2001-9 Lidegaard et al., BMJ 2011 Registry based study of Danish women aged 15-49 Altogether 8 million woman years of observation >4000 cases of DVT, 2847 certain Women with underlying conditions (such as history of DVT, MI, cancer treatment ) excluded Type of COC Incidence of DVT RR 95%CI Non-use 3.7 / 10.000 II 2.9 2.2 3.8 III 6.6 5.6 7.5 DRSP 6.4 5.4 7.5
Risk of venous thromboembolism Danish cohort study, 2001-9, cont. In preparations containing LNG, DSG and GES risk of DVT lower if the EE 2 dose was 20 μg No increase in the risk of DVT with progestinonly preparations Conclusion 2000 women would need to shift from COC containing DES, GES or DRSP to a COC containing LNG to prevent one case of DVT
Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis Stegeman et al., BMJ 2013 Analysis of 26 studies published up to April 2013 Fatal or non-fatal first event of venous thrombosis Results classified according to estrogen dose, type of progestin, type of study (industry sponsored vs not) Risk of DVT in non-users 1.9-3.7/10.000 woman years Generation of progestin Risk of DVT 95% CI First (norethisterone) 3.2 2.0 5.1 Second (LNG) 2.8 2.0 4.1 Third (GSD, DSG, NRG) 3.8 2.7 5.4
Relative risk of DVT according to EE dose and type of progestin 20 or 30μg EE+LNG OR 20μg EE+GSD tablet associated with lowest risk of DVT
Cardiovascular and general safety of a 24-day regimens of DRSP-containing COCs Dinger et al., Contraception 2014 Prospective follow-up of >85100 women using COC Performed in USA and 6 European countries Follow-up for 2-6 years 206.296 WY of observation All women using COCs (including women >50y of age, with underlying disease etc.) included The incidence of DVT in different COCs LNG 9.8/10.000 non-drsp 9.6/10.000 DRSP21d 9.4/10.000 DRSP24d 7.2/10.000 Conclusion - the risk of DVT is similar in COCs containing different progestins
Yhdistelmäehkäisyvalmisteet ja tromboosi EMAn kannanotto X 2013 Euroopan lääkevirasto EMA selvitti eri yhdistelmävalmisteiden laskimotukosriskiä Ranskan lääkeviranomaisten pyynnöstä v 2013 Liittyykö III ja IV polven yhdistelmävalmisteisiin korkeampi laskimotukosriski kuin vanhempiin valmisteisiin? Onko laskimotukosriski riittävästi huomioitu eri valmisteiden tuoteinformaatiossa?
EMAn johtopäätökset Yhdistelmävalmisteiden hyödyt riskejä suuremmat Valmisteisiin liittyy kohonnut veritulppariski Riski jonkin verran suurempi III ja IV polven pillereillä verrattuna vanhempiin valmisteisiin Valmisten käyttöä ei tule lopettaa omatoimisesti jos ei oireita Riskeistä tulee tiedottaa paremmin sekä määrääjiä että käyttäjiä Valmisteyhteenvedot päivitetään Potilaskohtaisen riskin arviointia korostetaan; tarkistuslistat
Laskimotuksen esiintyvyys eri tilanteissa (www.fimea.fi)
The risk of DVT in women taking progestin-only contraception: a meta-analysis Mantha et al., BMJ, 2012 In a meta-analysis of 8 observational studies the use of progestinonly contraception (tablets, injectables, implants, LNG-IUS) was not associated with an increased risk of DVT. Injectable progestin (2 studies) was associated with a risk of DVT (RR 2.67 [95%CI 1.29-5.53]).
Combined oral contraceptives have multiple effects on the coagulation cascade Tchaikovski & Rosing, Thrombosis Research 2010 Coagulation factors: Fibrinogen, prothrombin, factors VII, VIII, IX and X and XI (<10-25%) Depending on the EE 2 dose Anticoagulants: Proteiini S and antithrombin III (<10-20%) Acquired resistance to activated protein-c (APC-resistance) Fibrinolysis: Activity of the fibrinolytic system
Impact of hormone-associated resistance to APC on the thrombotic potential of oral contraceptives Rühl et al., PlosOne 2014 21 healthy women starting EE containing COCs (various brands) Blood sampling at base-line and 3-mo intervals Analyzed for APC resistance Hemostatic parameters, thrombin generation All women developed APCresistance Thrombin levels not unchanged (i.e. no thrombin production)
Summary of the hemostatic changes Procoagulant factors Significant increases in several coagulation factors Natural anticoagulants APC resistance in all Decrease in protein S Despite increase capacity, there was no evidence of increased thrombin formation. when starting COC Rühl et al., PlosOne 2014
HORMONAALINEN EHKÄISY JA SYÖPÄRISKI MITÄ UUTTA?
Agency for Healthcare and Research Quality Evidence report Oral contraceptive use for the prevention of ovarian cancer Systematic review and meta-analysis of studies published since 1990 on the effects of OCP Approx 6500 citations reviewed Focus on Ovarian cancer Havrilesky et al., Obstetrics and Gynecology 2013 Breast, cervical, colorectal and endometrial cancer Gierisch et al., Cancer Epidemiol Biomarkers Prev 2013 Breast and ovarian canner in BRCA1/2 mutation carriers Moorman et al., J Clin Oncol 2013 Thromboembolism
Oral contraceptive pills as primary prevention for ovarian cancer Havrilesky et al., Obstetrics and Gynecology 2013 55 cohort and case control studies accepted
Oral contraceptive pills as primary prevention for ovarian cancer, cont. Ever-use of OCPs associated with decreased incidence of ovarian cancer (OR 0.73 [95% CI 0.66-0.81]) Significant duration-response relationship, reduction >50% in ovarian cancer incidence if OC use more than 10y. Mortality similarly reduced No correlation between the estrogen or progestin dose
OCP and breast cancer 44 studies identified Ever-use of OCP vs risk of breast cancer Overall OR 1.08; [1.0-1.17] No duration response effect More recent use associated with higher risk 0-5 years (OR 1.21 [1.0-1.4]) 5-10 y (OR 1.17 [1.0-1.4]) Moderate effect on breast cancer incidence
OCP and cervical cancer 12 studies Ever-use associated with nonsignificant risk of in situ (2.54 [0.95-6.78]) or invasive (1.29 [0.88-1.91]) cervical cancer No time-dependent risk Significant risk in HPV-positive women (3 studies) 5-9 y (2.82 [1.46-5.42]) 10y (4.03 [2.09-8.02])
OCP and endometrial cancer 9 studies Ever-use of OCP associated with reduced risk (OR 0.57 [0.43-0.77]) Protective effect greater in US base studies (OR 0.34 [0.25-0.47]) NNT 60
OCP and colorectal cancer 11 studies Ever-use of OCP associated with reduced risk (OR 0.86 [0.79-0.95]) No time dependent (1-60 vs. >60 mo.) effect NNT 132
OCP and the risk of ovarian and breast cancer among high-risk women Studies on women with BRCA1/2 mutations OR strong family history Effects of ever use of OCP among BRCA1/2 carriers is similar to that seen in other women Risk of ovarian cancer 0.58 [0.46-0.73] Risk of breast cancer 1.21 [0.93-1.58] Meta-analysis could not be performed for studies on strong family history
Conclusions from the Agency for Healthcare and Research Quality Evidence report Results largely similar to those published previously Some differences regarding the risk of cervical cancer Insufficient data on the effects of OCP among women with additional risk factors Smoking, heavy drinking, obesity etc Impact of changing OCP formulations difficult to assess
Recent oral contraceptive use by formulation and breast cancer risk Beaber et al. Cancer Res, 2014 Performed within GHC health plan enrollees in the Seattle area in 1990-2009 1105 cases of invasive breast cancer among 20-49 year old women vs. 22100 matched controls OCP purchases within the previous year from the health plan pharmacy records OC use during the previous year (vs. earlier or never use) was a risk factor for Breast cancer OR 1.5 [95%CI 1.3-1.9] ER+ breast cancer OR 1.7 [95%CI 1.3-2.1]
Type of OC vs. risk of breast cancer Beaber et al. Cancer Res, 2014 Estrogen dose OR 95%CI Low (20μg EE) 1.0 0.6-1.7 Moderate (30-35μg EE) * 1.6 1.3-2.0 High (50μg EE) * 2.7 1.1-6.2 Progestin type Estrane (norethisterone/neta) * 1.6 1.3-2.0 Gonane (LNG/norgest./DSG) 1.4 1.0-2.0 Type of COC Monophasic 1.5 1.2-1.9 Triphasic 1.8 1.2-2.5 * Duration response effect; longer the use, higher the risk
Oral contraceptive use and mortality after 36 years of follow-up in the Nurses Health Study Charlton ym., BMJ 2014 >120.000 naisen 36v jatkunut seurantatutkimus E-tabl käyttö (48% naisista) vs ei-käyttö (52%) vuosina 1976-82 E-tabl käytön vaikutusta kuolleisuuteen ja kuolinsyihin Seuranta-aikana n 31300 kuolemaa Ehkäisytabletin käyttö Ei vaikuttanut kokonaiskuolleisuuteen Lisäsi riskiä väkivaltaiselle kuolemalle HR 1.2, 95%CI 1.04-1.37 Pitkään jatkunut käyttö Alensi riskiä kuolla munasarjasyöpään HR 0.86, 95%CI 0.74-1.00 Lisäsi riskiä kuolla rintasyöpään HR 1.08, 95% CI 0.98-1.18, tredi p<0.001
How should we interpret the data? Young/first time user - which tablet should we prescribe? The safest one (regarding the risk of DVT)? The one offering potential patient specific health benefits (acne/depression/bloating)? The cheapest one? Long-time happy user (in her 40 ies) - which tablet should we continue with? The one she is happy with? E 2 containing? The one with lowest risk of DVT? Progestin-only / LARC method?
Types of progestogens in combined oral contraception: effectiveness and side-effects Lawrie et al., 2011 Main results 30 trials with almost 14.000 participants, 16 comparison of EE2 + different progestogen Only 4 double-blind comparisons At least 23 trials sponsored by pharmaceutical industry Conclusions Pregnancy rates comparable in all studies Less discontinuation with 2 nd vs. 1 st generation pills (RR 0.76, CI 0.67-0.86) 3 rd generation vs. 2 nd generation pills Less discontinuation (RR 0.77, CI 0.6-0.98) Less intermenstrual bleeding (RR 0.71, CL 0.55-0.91) Drospirenone vs. desogestrel containing pills More breast tenderness (RR 1.39, CI 1.04-1.86) More nausea (RR 1.46, CI 0.96-2.21)