Anne H. Calhoun, MD, FAHS Professor of Anesthesiology Professor of Psychiatry

Transcription

1 Combined Hormonal Contraceptives & Migraine with Aura Anne H. Calhoun, MD, FAHS Professor of Anesthesiology Professor of Psychiatry University of North Carolina Partner/Co-Founder Carolina Headache Institute Durham, NC HEADACHE INSTITUTE

2 Consultant: Depomed, Lilly, Teva Research Support: Autonomic Technologies, ElectroCore, Scion Neurostim Speakers Bureau: Depomed, Merck, Teva Disclosures

3 Off-label use will be discussed: d No combined hormonal contraceptive (CHC) or estrogen is approved for prevention of migraine For clarity, I may use brand names when discussing CHCs Various formulations may share ingredients, yet have vastly different impact on migraine due to the architecture & dose of the pill I have no conflict of interest related to any contraceptive Disclosures

4 1. Review estrogen concentrations o in women s life cycles and compare these to various hormonal preparations 2. Understand some of the neurologic consequences to declines in estrogen concentration ti 3. Review the risks and benefits of CHCs 4. Examine the controversy regarding stroke risk and MwA, and how these risks are altered with different CHCs Objectives

5 Practical ca Gynecology ogy for the Headache Specialist

6 Hormones in the Menstrual Cycle E 2 Prog (pg/ml) (ng/ml) Cycle Day Menses

7 Estrogen in the Menstrual Cycle E 2 (pg/ml) Cycle Day Menses

8 Estrogen: Cyclic vs. Pregnancy 18,000 16,000 14, ,

9 Postmenopausal ( HT ) Estrogen E 2 (pg/ml) Cycle Day

10 Low Dose Oral Contraceptive E 2 (pg/ml) Cycle Day

11 Ultra-Low Dose Oral Contraceptive E 2 (pg/ml) Cycle Day

12 Progestogens Two kinds of progestogens Natural: Progesterone (not in any HC) Synthetic: Progestin (contained in all HCs) Contraception is achieved via 1 or more of 3 progestin-dependent p mechanisms: Prevents ovulation Thickens cervical mucus to prevent sperm penetration Renders endometrium inhospitable to implantation

13 Combined Hormonal Contraceptives Estrogen is added to the progestin Improves bleeding profile Estrogen inhibits follicle development (which helps prevent ovulation) First CHC was Enovid-10 Approved in 1957; each active pill contained: 9850 μg of norethynodrel (progestin) Equal in potency to more than an entire pack of modern OCs (which average μg of the progestin) 150 μg of mestranol (estrogen) Today s lowest dose pills have 10μg EE

14 Components of CHCs *Estrogen concentrations are multiplied by a factor of 10 to make them visible in the table.

15 Side-Effects of Placebo Pills 70% of OC users experience headache during the placebo week 1 Peak incidence is on 3 rd day of placebo week Elimination of placebo pills is associated with: Improvement in mood scores Improvement in headache scores 2 Less pelvic pain Flow-mediated vasodilation parallels E 2 levels 3 Minimal just before menses Greatest in the follicular phase 1 Sulak PJ, Scow RD, Preece C, et al. Obstetrics and gynecology Sulak P, Willis S, Kuehl T, et al. Headache Kawano H, Motoyama T, Ohgushi M, et al. Annals of internal medicine

16 Side-Effects of Placebo Pills Menstrual angina may reflect coronary vasospasm triggered by declines in circulating estrogen 1 Myocardial ischemia is more easily induced when estrogen concentrations decline perimenstrually 2 Question: Do cardiovascular AEs on triptans cluster in the menstrual window? 1 Choo WK. J Med Case Reports Lloyd GW, Patel NR, McGing E, et al. Does angina vary with the menstrual cycle in women with premenopausal coronary artery disease? Heart. 2000;84:

17 The Architecture of OCs (Estrogen Component Only) No longer available in the US High Dose OC Natural cycle 100 µg 50 µg 35 µg Stepped EE decline 20 μg EE equivalent 100 μg EE decline 50 μg EE decline 35 μg EE decline 35 μg EE decline EE triphasic 30 µg 20µg 20µg/ 0 /10µg 10 µg 30 μg EE decline 30 μg EE decline 20 μg EE decline 20 μg EE decline 10 μg EE decline Extended cycle, 30 µg / placebo in week 13 Extended cycle, 30 µg / 10 µg in week μg EE decline 20 μg EE decline Extended cycle, 20 µg / 10 µg in week 13 Continuous, 20 µg 10 μg EE decline No decline

18 262 Women On Oral Contraceptives: Cyclic Prevalence of Headaches 60 Any HA HA graded 6 on scale 40 TAGE PERCEN 20 0 ACTIVE PILLS ACTIVE PILLS Sulak PJ, Scow RD, Preece C, et al. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:

19 When Estrogen Concentrations Fall: 5HT concentration ti in the CNS declines Serotonin synthesis declines MAO increases Serotonergic receptors decrease Serotonergic postsynaptic p responsiveness & neurotransmitter uptake declines ß-endorphins decrease CGRP concentrations increase

20 CHCs: Risks... & Benefits VTE, MI, Stroke Especially in smokers who take high dose OCs Hypertension & adverse lipid profiles Uncommon with low-dose 2 nd & 3 rd generation OCs Increased risk of cervical dysplasia & CIN Contraceptive efficacy 40-80% reduction in ovarian Ca 50-80% reduction in endometrial Ca 50% reduction in benign breast disease & benign ovarian tumors Improved menstrual regularity Decreased menstrual flow & anemia Reduced menstrual cramping Reduction in PID Improvement in acne, hirsutism, and insulin sensitivity Huber JC, Bentz EK, Ott J, Tempfer CB. Expert opinion on pharmacotherapy. 2008;9:

21 Oral Contraceptives in Migraine with Aura: Revisiting the Controversy

22 1975 US Case-Control Control Study: OCs & Stroke in Young Women Variable Stroke Cases Hospital Controls (n=140) (n=340) Current OC use 72.8% 28.8% 4.4 OC + migraine 12.9% 4.4% 4.6 A correlation OC + smoking of estrogen doses 20.0% to stroke could not 6.8% be made since 23 (NR) of the 25 OC women + mild with HTN thrombotic stroke 10% who were taking 4.1% a mestranol-containing 5.2 OC formulation + moderate took the HTN % mcg dose, and all 201.8% taking the estradiol 8.9 OC + severe HTN formulation 8.6% took the 50 mcg dose. 0.9% 13.6 RR Collaborative Group for the Study of Stroke in Young Women. JAMA :7,

23 Recall that the RR of stroke with use of OCs was 4.4 in 1975 when only high dose pills were available Today, the highest dose pill available in the US contains 50μg EE; these pills account for less than 1% of OC sales in the US Does Dose Matter?

24 Risk of Stroke with OCs Nested case-control control analysis by Hannaford et al. examined data collected from RGCP Oral Contraceptive study to determine the relationship between OC use and first-ever stroke High-dose OCs ( 50mcg) had ~6-fold increased risk 30-35mcg formulations conferred no increased risk Similar data were reported in a WHO study: Risk of ischemic stroke with 50mcg pills was 5.3 Risk with pills <50mcg was 1.5 (NS) Comprehensive Gynecology, Lentz GM, et al.

25 Stroke in Users of Low-dose OCs Population based, US case controlled study 408 strokes occurred in 1.1 million women (3.6 million women years) Conclusions: Stroke is rare in women of reproductive age Low dose OCs did not increase risk of stroke Odds ratio by variable Ischemic Hemorrhagic Current regular smoker 2.66 ( ) 2.70 ( ) Treated for hypertension 779( ( ) ( ) 06) Treated for diabetes Current use of OC 7.15 ( ) 2.50 (NS) 0.96 (NS) 1.18 (NS) Petitti DB, et al. NEJM

26 ACOG Consensus Statement In 2006 ACOG recommended against use of OCs in migraine with aura, citing 3 reasons: 1. A concern that all women with migraine are at increased risk of stroke if they take OCs 2. A pooled analysis of 2 large U.S. case-control studies found a 2-fold increased risk of ischemic stroke among migraineurs using OCs 3. A Danish population-based case-control study found a 3-fold increased risk of ischemic stroke among migraineurs using OCs

27 ACOG Consensus Statement In 2006 ACOG recommended against use of OCs in migraine with aura, citing 3 reasons: 1. A concern that all women with migraine are at increased risk of stroke if they take OCs 2. A pooled analysis of 2 large U.S. case-control studies found a 2-fold increased risk of ischemic stroke among migraineurs using OCs 3. A Danish population-based case-control study found a 3-fold increased risk of ischemic stroke among migraineurs using OCs

28 OCs, Ischemic CVA & Migraine in Women World Health Organization Ischemic Stroke Study* Cases (n=141) Controls (n=373) Mean (SD) age (y) 35.8 (5.8) 35.5 (5.9) Mean (SD) BMI 25.0 (4.6) 24.4 (4.3) Current OC use (%) Post-secondary Educ. (%) Current smokers (%) Self reported history (%) Hypertension HTN during pregnancy Diabetes mellitus Rheumatic heart dis Family history (%) Stroke Migraine - - *WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet 1996;348:

29 OCs, Ischemic CVA & Migraine in Women World Health Organization Ischemic Stroke Study Migraine Study** Cases (n=141) Controls (n=373) Cases (n=86) Controls (n=214) Mean (SD) age (y) 35.8 (5.8) 35.5 (5.9) 36.1 (6.3) 35.9 (6.3) Mean (SD) BMI 25.0 (4.6) 24.4 (4.3) 25.0 (4.8) 24.6 (5.0) Current OC use (%) Post-secondary Educ. (%) Current smokers (%) Self reported history (%) Hypertension HTN during pregnancy Diabetes mellitus Rheumatic heart dis Family history (%) Stroke Migraine *WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet 1996;348:

30 OCs, Ischemic CVA & Migraine in Women World Health Organization Ischemic Stroke Study Migraine Study** Cases (n=141) Controls (n=373) Cases (n=86) Controls (n=214) Mean (SD) age (y) 35.8 (5.8) 35.5 (5.9) 36.1 (6.3) 35.9 (6.3) Mean (SD) BMI 25.0 (4.6) 24.4 (4.3) 25.0 (4.8) 24.6 (5.0) Current OC use (%) Post-secondary Educ. (%) Current smokers (%) Self reported history (%) *Among OC users who experienced ischemic stroke, the majority were using high dose pills ( 50 mcg EE) Hypertension HTN during pregnancy Diabetes mellitus Rheumatic heart dis Family history (%) Stroke Migraine *WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet 1996;348:

31 Conclusions by the Authors of WHO Collaborative Study 86 Cases of Ischemic CVA, 214 Controls Adjusted risk of ischemic stroke was significantly associated with: migraine >12 yrs duration OR 4.61 ( ) migraine with aura (MA) OR 8.37 ( ) frequent MA (>12x/yr) OR ( ) In no case did correction for oral contraception usage significantly alter these odds ratios **Donaghy M, Chang C L, Poulter N, Duration, frequency, and type of migraine and the risk of ischaemic stroke in women of childbearing age. J Neurol Neurosurg Psychiatry. 2002;73:

32 ACOG Consensus Statement In 2006 ACOG recommended against use of OCs in migraine with aura, citing 3 reasons: 1. A concern that all women with migraine are at increased risk of stroke if they take OCs 2. A pooled analysis of 2 large U.S. case-control studies found a 2-fold increased risk of ischemic stroke among migraineurs using OCs 3. A Danish population-based case-control study found a 3-fold increased risk of ischemic stroke among migraineurs using OCs

33 ACOG Consensus Statement In 2006 ACOG recommended against use of OCs in migraine with aura, citing 3 reasons: 1. A concern that all women with migraine are at increased risk of stroke if they take OCs 2. A pooled analysis of 2 large U.S. case-control studies found a 2-fold increased risk of ischemic stroke among migraineurs using OCs 3. A Danish population-based case-control study found a 3-fold increased risk of ischemic stroke among migraineurs using OCs

34 OCs & Stroke in Young Women: Danish Case-Control C Study Variable Stroke Cases (n=626) Controls (n=4017) Adjusted OR Migraine 17.1% 6.4% 3.2 HBP 10.5% 1.4% 5.0 Hyperlipidemia 9.1% 0.6% 11.0 Smoking 58.8% 38.6% (Reported by cigs/day) Diabetes 4.3% 0.4% 5.6 Current OC use 33.9% 29.8% Progestin only 0.6% 0.7% NS 20 mcg EE 29% 2.9% 40% 4.0% NS mcg EE 24.0% 23.7% mcg EE 4.2% 1.1% 4.7 Lidegaard O et al. Contraceptives and cerebral thrombosis: a five-year national case-control study. Contraception :3,

35 ACOG Consensus Statement In 2006 ACOG recommended against use of OCs in migraine with aura, citing 3 reasons: 1. A concern that all women with migraine are at increased risk of stroke if they take OCs 2. A pooled analysis of 2 large U.S. case-control studies found a 2-fold increased risk of ischemic stroke among migraineurs using OCs 3. A Danish population-based case-control study found a 3-fold increased risk of ischemic stroke among migraineurs using OCs

36 ACOG Consensus Statement In 2006 ACOG recommended against use of OCs in migraine with aura, citing 3 reasons: 1. A concern that all women with migraine are at increased risk of stroke if they take OCs 2. A pooled analysis of 2 large U.S. case-control studies found a 2-fold increased risk of ischemic stroke among migraineurs using OCs 3. A Danish population-based case-control study found a 3-fold increased risk of ischemic stroke among migraineurs using OCs

37 Ischemic Stroke in Young Women: Pooled Analysis of 2 US Studies 171 Cases of Ischemic CVA, 846 Controls OC use Kaiser Perm. Univ. of Wash. Pooled Cases/Controls (119/341) OR Cases/Controls (52/505) OR Cases/Controls (171/846) OR Never 27/ / / Current 10/27 Past 82/257 Not Current Current 10/27 5/ / (NS) (NS) (NS) ( ) 38/ (NS) 120/ (NS) 109/ / / (NS) 5/ (NS) 15/ (NS) Schwartz, SM et al. Stroke and use of low-dose oral contraceptives in young women. Stroke. 1998;29(11):

38 Ischemic Stroke in Young Women: Pooled Analysis of 2 US Studies 171 Cases of Ischemic CVA, 846 Controls Risk of stroke was 11/100,000 woman-years Only 11 of 1017 cases & controls were current users of high dose OCs 2 ischemic, 2 hemorrhagic, 7 controls 17% of cases & controls were smokers on OCs Risk of stroke was not increased among current low-dose OC users No evidence of trends in risk with recency or duration of use among past or current users Schwartz, SM et al. Stroke and use of low-dose oral contraceptives in young women. Stroke. 1998;29(11):

39 Ischemic Stroke in Young Women: Pooled Analysis of 2 US Studies 171 Cases of Ischemic CVA, 846 Controls Conclusions are based on only 4 cases Prevalence of migraine was identical: 7.8% of cases 7.7% of controls (adjusted por=2)

40 Ischemic Stroke in Young Women: Pooled Analysis of 2 US Studies 171 Cases of Ischemic CVA, 846 Controls Risk of stroke was 11/100,000 woman-years Only 11 of 1017 cases & controls were current users of high dose OCs 2 ischemic, 2 hemorrhagic, 7 controls 17% of cases & controls were smokers on OCs Risk of stroke was not increased among current low-dose OC users No evidence of trends in risk with recency or duration of use among past or current users Schwartz, SM et al. Stroke and use of low-dose oral contraceptives in young women. Stroke. 1998;29(11):

41 Migraine with aura is more common in high estrogen environments, accounting for its infrequent occurrence with menses MRM is associated with the late luteal phase decline in estrogen Calhoun AH et al. The impact of extended-cycle vaginal ring contraception on migraine aura: a retrospective case series. Headache 2012;52:

42 Use of a typical 35μg EE OC will increase the magnitude of estrogen withdrawal Increases likelihood/intensity of MRM It matches or increases the peak exposure to estrogen of the natural cycle, and extends it over 3 weeks Increases aura frequency (& thereby, potentially increases stroke risk) Calhoun AH et al. The impact of extended-cycle vaginal ring contraception on migraine aura: a retrospective case series. Headache 2012;52:

43 Extended use of a ring contraceptive that contains 15μg EE lowers peak exposure to estrogen Decreases aura frequency Addition of 0.075mg 0 of 17ββ estradiol in week 13 limits decline in estrogen to the equivalent of 10 μg EE Decreases likelihood of MRM Calhoun AH et al. The impact of extended-cycle vaginal ring contraception on migraine aura: a retrospective case series. Headache 2012;52:

44 A Pilot Study: Hormonal Prevention of Aura At baseline, subjects averaged 3.2 migraine auras/mon Treatment was associated with decrease in aura frequency to 0.2/month Mean observation time of 8 months No subject recorded an increase in aura frequency MRM was eliminated in 91.3% of the evaluable subjects Calhoun A, Ford S, Pruitt A. The impact of extended-cycle vaginal ring contraception on migraine aura: a retrospective case series. Headache 2012;52:

45 Recent Newsbreaks Combined Hormonal Contraceptives and Stroke Risk

46 CHCs and Risk of Stroke/MI 15-year prospective p population-based p study examined risk of MI and stroke in healthy CHC users 1,626,158 women aged (14,251,063 person-years of observation) 3,311 thrombotic strokes and 1,725 MIs occurred Overall risk for stroke and MI is small 21.4/100,000 person-years for stroke 10.1/100,000 person-years for MI Absolute risk of thrombotic stroke and MI was not significantly increased with 20μg EE pills (very low dose) Risk was increased ( ) with 30-40μg EE pills The progestin dose had no influence on these endpoints Lidegaard O, Lokkegaard E, Jensen A, Skovlund C, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med 2012;366:

47 CHCs and Risk of Stroke/MI Data from a cohort of >800,000 CHC users were analyzed, and 3 formulations were compared to 20μg EE OCs: Oral drospirenone 3.0/30μg EE Transdermal patch (6.0 mg norelgestromin/0.75 mg EE; delivers 20 μg EE/24 hrs) Vaginal ring (11.7 mg etonogestrol/2.7 mg EE; delivers 15 μg EE/24 hrs) Compared to 20μg EE pills, there was increased risk for stroke and MI only with the 30μg EE/drospirenonecontaining pills (RR 2.01 [ ]) Highest risk was in the older cohort, ages years No significant risks were seen with the other preparations Sidney S, Cheetham T, Connell hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users. Contraception 2012;87:

48 Summary: Argument against using OCs in MwA is based on concerns that All women are at increased risk of stroke with OCs FALSE High dose OCs increase risk MwA confers an independent increased risk of stroke TRUE and risk increases with frequency Combining these factors might produce additive risk Evidence suggests otherwise

49 Thank You! Anne H. Calhoun, MD, FAHS Professor of Anesthesiology Professor of Psychiatry University of North Carolina Partner/Co-Founder Carolina Headache Institute Durham, NC HEADACHE INSTITUTE