managing menstrual bleeding in women on anticoagulants · managing menstrual bleeding in women on...

Managing Menstrual Bleeding in Women on Anticoagulants

Dr. Shannon M. BatesEli Lilly Canada/May Cohen Chair in Women’s Health

Associate Professor, Department of MedicineMcMaster University

Disclosures for Shannon Bates, MD

Research Support/P.I. No relevant conflicts of interest to declare

Employee No relevant conflicts of interest to declare

Consultant No relevant conflicts of interest to declare

Major Stockholder No relevant conflicts of interest to declare

Speakers Bureau No relevant conflicts of interest to declare

Honoraria No relevant conflicts of interest to declare

Scientific Advisory Board No relevant conflicts of interest to declare

Salary Support Through an endowed chair funded, in part, by Eli Lilly Canada

• Review the potential impact of anticoagulant therapy on menstrual bleeding

• Discuss treatment options for management of abnormal uterine bleeding in anticoagulated women

Learning Objectives

• Normal menstrual bleeding§ Blood loss for 7 days of a cycle (between days 21 – 35)§ Average monthly blood loss is 35 - 40 mL

• Excessive menstrual bleeding (menorrhagia)§ Monthly blood loss >80 mL

t Prevalence in general population: 9 - 14%1

§ Interferes with physical, emotional, social & material quality of life● FIGO terminology (2011): abnormal uterine bleeding2

§ Heavy menstrual bleeding is the most common complaint

Excessive Menstrual Bleeding: Definition

1. Van Eijkeren MA et al. Obstet Gynecol Surv. 1989;44:421-4292. Fraser IS et al. Semin Reprod Med. 2011;29:383-390.

• Local causes§ Fibroids§ Endometrial hyperplasia§ Endometrial polyps

• Systemic causes§ Bleeding disorders§ Anticoagulant therapy§ Endocrine dysfunction (e.g. hypothyroidism, hyperprolactinemia)§ Ovulatory dysfunction (~ 20% of cases)

• Dysfunctional uterine bleeding (~ 40 - 60% of cases)

Abnormal Uterine Bleeding: Etiology

§ Adenomyosis§ Uterine leiomyoma§ Malignancy

• Measured menstrual blood loss and vitamin K antagonist therapy (VKA)

Anticoagulation & Abnormal Uterine Bleeding

Van Ekjkeren MA et al. Am J Obstet Gynecol. 1990;162:1261-1263

Measure Normal VKA Therapy Bleeding Disorder

Range (mL) <80 9 – 239 60 - 568

Mean (mL) NA 98 219Menorrhagia(n/N, %) 0/6 5/11 (46%) 5/6 (83%)

• 90 women (mean age: 36.6 y ± SD 7.6 y) treated with oral anticoagulants (VKA)


Sjalander A et al. J Thromb Thrombolysis. 2007;24:39-41

SymptomBefore VKA

AnticoagulationDuring VKA

Anticoagulation P value

Menorrhagia (%) 44.2 70.8 <0.001

Mean menses duration

5.6 days 6.1 days <0.01

Treatment for menorrhagia (%)

17.8 29.5 <0.01

• 53 women (age 20-50 y) initiating VKA anticoagulation


Huq FY et al. Contraception. 2011; 84:128-132

Symptom Before VKA Therapy

During VKA Therapy P value

Intermenstrual bleeding (%) 3 (5.6%) 14 (26.4%) 0.0098Flooding (N,%) 4 (7.5%) 27 (50.9%) 0.0010Clots (N,%) 18 (40.9%) 27 (50.9%) 0.0291

Anemia (N,%) 9 (17.0%) 18 (34.0%) 0.0704Mean menses duration 5.4 days 6.6 days 0.0008Pictorial Blood Assessment Chart (PBAC) Score > 100

NA 31 (66.0%) NA

• Direct-acting oral anticoagulants (DOACS)


1. Ferreira M et al. Br J Haematol. 2015 July 27.doi:10.1111/bjh.135832. Myers B et al. Br J Haematol. 2016 Mar 11.doi:10.111/bjh.140033. Marten S et al. Blood. 2015 (abstract 1131)

Measure Ferreira1 Myers2 Marten3

Study design Case series Local registry Registry + trial patientsN 128 139 154DOAC Rivaroxaban Rivaroxaban: 96

Apixaban: 43Rivaroxaban: 92%

Apixaban: 6%Menorrhagia 26 (20%) Rivaroxaban: 24 (25%)

Apixaban: 4 (9%)53 instances

0.32/exposure yearStrategies employed Temporary interruption

or â dose Resolution in 5/7 women

changing to apixabanTemporary interruption or â dose, tranexamic acid,

hormone therapy; surgery/intervention (9%)

DOAC discontinuation for menorrhagia

8 (6%) Rivaroxaban: 11 (11%)Apixaban: NA

NA

• Rivaroxaban vs. VKAAnticoagulation & Abnormal Uterine Bleeding

1. De Crem N et al. Thromb Res. 2015;136:749-753

Outcome Rivaroxaban VKA P-valueAbnormal uterine bleeding – N (%) 38/52 (73%) 35/52 (67%) NSObjective menstrual disturbances - N (%) 28/52 (54%) 26/52 (50%) NSProlonged bleeding (> 8 days) 13/48 (27%) 4/48 (8.3%) 0.017Intermenstrual bleeding 21/51 (41%) 13/50 (26%) NSBlood clots during menstruation 16/48 (33%) 17/49 (35%) NS

Subjective menstrual disturbances - N (%) 30/52 (58%) 29/51 (57%) NSProlongation of bleeding 22/52 (42%) 19/51 (45%) NSIncreased intensity 27/52 (52%) 24/51 (47%) NSInterference with daily life 6/52 (12%) 9/51 (18%) NS

Anemia/iron deficiency – N (%) 11/52 (21%) 12/52 (23%) NSMedical or surgical intervention – N (%) 13/52 (25%) 4/52 (7.7%) 0.032Change of contraceptive therapy 12/52 (23%) 4/52 (7.7%) 0.055Endometrial ablation or embolization 1/52 (1.9%) 1/52 (1.9%) NSHysterectomy 1/52 (1.9%) 0/52 (0.0%) NS

Anticoagulant therapy modification - N (%) 8/52 (15%) 1/52 (1.9%) 0.031Temporary interruption or â dose (> 3 days) 5/52 (9.6%) 1/52 (1.9%) NSChange of anticoagulant therapy 5/52 (9.6%) 1/52 (1.9%) NS


Abnormal Uterine Bleeding

No hormone use All hormonal therapies Estrogen-containing therapy Progestin-only therapy

Events/patient-yrs

%/year (95% CI)

Events/patient-yrs

%/year (95% CI)

Events/patient-yrs

%/year (95% CI)

Events/patient-yrs

%/year (95% CI)

All 148/693.0 21.4(18.1-25.1) 37/164.8 22.5

(15.8-31.0) 28/96.8 28.9(19.2-41.8) 9/67.9 13.3.

(6.1-25.1)

Rivaroxaban 98/319.1 30.7 (24.9-37.4) 24/80.6 29.8

(19.1-44.3) 19/46.9 40.5(24.4-63.3) 5/33.8 14.8

(4.8-34.5)

Enoxaparin/VKA 50/373.8 13.4

(9.9-17.6) 13/84.1 15.5 (8.2-26.4) 9/50.0 18.0

(8.2-34.2) 4/34.2 11.7 (3.2-30.0)

• Rivaroxaban vs. enoxaparin/VKA

Martinelli I et al. Blood. 2016:127:1417-1425Hazard Ratio: 0.56 (95% CI, 0.23-1.39)

• Involve Primary Care provider and/or Gynecologist• Role of the Thrombosis provider

§ Help determine extent of blood loss and effect on personal life§ Assess for and treat iron deficiency (ü CBC, ferritin)§ Ensure appropriate anticoagulation

t Assess for additional unnecessary Aspirin or NSAIDSt Review anticoagulant dosingt ü INR if warfarin, ü creatinine if DOAC, ü platelets

§ Help arrange for tests for bleeding disorder if clinical suspicion§ With other care providers ensure treatable causes not missed

t ßhCG (if onset recent)t Ensure pelvic exam ( ± ultrasound, hysteroscopy, endometrial biopsy)

Abnormal Uterine Bleeding: Assessment

Abnormal Uterine Bleeding: Management

Medical(1st line therapy once malignancy and significant pelvic pathology

excluded) • Non-hormonal

§ Temporary anticoagulant interruption or â in dose§ Change anticoagulants§ Tranexamic acid

• Hormonal§ Levonorgestrel (LNG) IUD§ Combined hormonal contraceptives§ Progestins

Interventional/Surgical• Endometrial ablation/Hysteroscopic endometrial ablation• Hysterectomy

Effectiveness not studied

Loss of futurefertility

• Choose self and effective therapy in conjunction with other health care providers

Options: Tranexamic Acid (TxA)

Tengborn L et al. Thromb Res. 2015;135:231-242 http://dx.doi.org/10.1016/j.thromres.2014.11.012

Lukes A et al. Obstet Gynecol. 2010;116:865-875doi: 10.1097/AOG.0b013e3181f20177

©2010byTheAmericanCollegeofObstetriciansandGynecologists.PublishedbyLippincottWilliams&Wilkins,Inc.

Recommended Dosing with Normal Renal Function

• Europe: 1 g orally three times daily for up to 4 days (dose may be increased to maximum of 4 g/day)

• US: 1.3 g orally three times daily for up to 5 days

Options: Tranexamic Acid (TxA) & VTE

Risk of VTE with Tranexamic Acid Use in Women Aged 15-49 yearsMeasure Berntorp1 Sundstrom2

VTE in association with TxA / Total VTE 15/662 (2.2%) 3/134 (2.4%)

Controls receiving TxA / total controls 61/1506 (4.1%) 4/552 (0.7%)Risk of VTE, odds ratio (95% CI) 0.55 (0.31 - 0.97) 3.20 (0.65 - 15.78)

TRANEXAMIC ACID (tranexamic acid tablets)Initial U.S. Approval: 1986

----------------------------------------------------------------------------------INDICATIONS AND USAGE---------------------------------------------------------------------------------------Tranexamic acid tablets is indicated for the treatment of cyclic heavy menstrual bleeding. (1) ------------------------------------------------------------------------------DOSAGE AND ADMINISTRATION----------------------------------------------------------------------------------• 1,300 mg (two 650 mg tablets) three times a day (3,900 mg/day) for a maximum of 5 days during monthly menstruation (2.1) • Renal impairment: Dosage adjustment is needed if serum creatinine concentration (Cr) is higher than 1.4 mg/dL (2.2)----------------------------------------------------------------------------DOSAGE FORMS AND STRENGTHS-------------------------------------------------------------------------------Tablets: 650 mg (3)-----------------------------------------------------------------------------------CONTRAINDICATIONS-------------------------------------------------------------------------------------------• Women with active thromboembolic disease or a history or intrinsic risk of thrombosis or thromboembolism, including retinal vein or artery occlusion (4.1) • Hypersensitivity to tranexamic acid (4.2)

1. Berntrop E et al. Thromb Haemost. 2001;86:714-715 2. Sundstrom A at al. BJOG. 2009;116:91-97

Options: Levonorgestrel (LNG) IUD• Systematic review: 21 randomized trials with

2082 women1

§ 7 studies compared LNG IUD vs oral therapiest LNG IUD more effective at â heavy menstrual

bleeding, improving quality of life, continuation at 2 years

t Minor adverse effects more common with LNG IUD• Drawbacks

§ Spotting initially, breast tenderness, pelvic pain, ovarian cysts§ Insertion procedure§ Cost

Lethaby A et al. Cochrane Database Syst Rev. 2015 Apr 30:4:CD002126

Options: LNG IUD in Anticoagulated Women

Before insertion3 months post

insertion6 months post

insertion P valuePBAC score LNG-IUD 239.50±33.24 207.35±26.32 155.60±24.05 .001

Control 253.95±29.32 251.40±31.17 255.10±28.22 .247Bleeding days LNG-IUD 6.80±1.15 4.90±0.91 2.00±0.70 .001

Control 6.90±0.96 6.60±1.23 6.90±0.97 .189Hgb LNG-IUD 10.33±0.84 10.11±0.73 12.07±0.67 .001

Control 10.10±0.86 9.64±0.71 10.01±0.81 .457Ferritin LNG-IUD 15.90±8.06 16.65±4.84 35.15±10.55 .001

Control 14.98±10.27 13.4±6.96 13.80±6.87 .707

PBAC

Sco

re

Kilic S et al. Contraception. 2009; 80:152-157http://dx.doi.org/10.1016/j.contraception.2009.02.007

Options: LNG IUD & VTE

Notes: OR: odds ratio; RR: relative risk; CI: confidence interval

1. Van Hylckama Vlieg et al. Arterioscler Thromb Vasc Biol. 2010;30:2297-23002. Lidegaard O et al. BMJ. 2012;344:32990 doi

Agent Van Hylckama Vlieg1 Lidegaard2

Study design Case control Registry

VTE Risk in Nonusers 1.0 2.1/10,000 pt yrsVTE Risk Estimate OR: 0.3

(95% CI, 0.1-1.1)RR: 0.6

(95% CI, 0.4-0.8)VTE Risk in Users NA 1.4/10,000 pt yrs

Contraceptive Type

Combined pill, patch, ring, injectable

POP DMPA or NET-EN Injection

LNG or ETG Implant

LNG-IUD Copper IUD

a) History of DVT/PE, not on anticoagulant therapyMEC Category 4 2 2 2 2 1

b) Acute DVT/PEMEC Category 4 3 3 3 3 1

c) DVT/PE and established on anticoagulant therapyMEC Category 4 2 2 2 2 1

Options: LNG IUD & VTE

World Health Organization. 2015

Medical Eligibility Criteria (MEC) Categories for Contraceptive Use1: Condition for which there is no restriction for the use of the contraceptive method2: Condition for which advantages of using the method generally outweigh theoretical or proven risks3: Condition for which theoretical or proven risks usually outweigh advantages of using the method4: Condition that represents an unacceptable health risk if the contraceptive method is used

POP: Progesterone only pill; DPMA: Depo medroxyprogesterone acetate; NET-EN: Norethisterone enanthanate; LNG: Levonorgestrel; ETG: etonogesterel

• World Health Organization

Options: Combined Contraceptives

• Combined hormonal contraceptives§ Oral contraceptive pill (cyclic or continuous)

t Randomized trials report â in menstrual blood loss ranging from 35 to 69%1

§ Contraceptive patcht Not specifically studied for treatment of abnormal uterine bleeding

§ Vaginal ringt Not specifically studied for treatment of abnormal uterine bleeding

1. Matteson KA et al. Obstet Gynecol. 2013;121:632

Options: Combined Contraceptives & VTE

*Adjusted for age, calendar year and educationLidegaard O et al. BMJ. 2012;344:32990 doi

Type Adjusted Relative Risk (95% CI)

Incidence/10,000 exposure years

Non-use 1.00 (reference) 2.05

COC (30-40 ug estrogen + levonogrestrel)

3.21 (2.70-3.81) 6.22

Patch 7.90 (3.54-17.65) 9.71

Vaginal Ring 6.48 (4.69-8.94) 7.75

Implant 1.40 (0.58-3.38) 1.70

Contraceptive Type



LNG or ETG Implant

LNG-IUD Copper IUD







POP: Progesterone only pill; DPMA: Depo medroxyprogesterone acetate; NET-EN: Norethisteroneenanthanate; LNG: Levonorgestrel; ETG: etonogesterel


• Theoretically, VTE risk should be dramatically reduced while on therapeutic doses of anticoagulation§ E.g. pregnancy

• ISTH SSC Guidelines1

§ Suggest hormonal therapy can be continued in selected patients receiving anticoagulant therapy if there is a strong indicationt Hormone therapy must be stopped before discontinuing

anticoagulants


1. Baglin T et al. J Thromb Haemost 2012;10:698-702

Options: Hormonal Therapy & VTE

No hormone use All hormonal therapies

Estrogen-containing therapy

Progestin-only therapy

Events/patient-yrs

%/year(95% CI)

Events/patient-yrs

%/year (95% CI)

Events/patient-yrs

%/year (95% CI)

Events/patient-yrs

%/year (95% CI)

All patients 38/811.0 4.7 (3.3-6.4) 7/187.5 3.7

(1.5-7.7) 4/109.5 3.7 (1.0-9.4) 3/78.0 3.8

(0.8-11.2)

Rivaroxaban 21/390.2 5.4 (3.3-8.2) 3/98.1 3.1

(0.6-8.9) 1/56.2 1.8 (0.1-9.9) 2/41.9 4.8

(0.6-17.2)

Enoxaparin + VKA 17/420.8 4.0

(2.4-6.5) 4/89.4 4.5 (1.2-11.5) 3/53.3 5.6

(1.2-16.5) 1/36.1 2.8 (0.1-15.4)

• Recurrent VTE: hormonal therapy & anticoagulants

Martinelli I et al. Blood. 2016:127:1417-1425

Hazard Ratio: 0.56 (95% CI, 0.23-1.39)

Options: Progestin Agents

1. SOGC Clinical Practice Guideline. J Obstet Gynaecol Can. 2013;35(5eSuppl):S1-S28 4. Irvine GA et al. BJOG. 1998;105:592-5982. Higham JM et al. AJOB. 1993;169:1134-1139 5. Kucuk T et al. Clin Exp Obstet Gyneol. 2008;35:57-603. Lethaby A et al. Cochrane Database Syst Rev. 2008;1:CD001016 6. Kaunitz AM. UpToDate (www.uptodate.com; April 1, 2016)

Agent Dose CommentOral progestins• Low dose, daily • norethindrone

0.35 mg daily• Not studied as treatment for abnormal uterine

bleeding1

• High dose, short cycle (luteal, 7-11 days)

• norethindrone5 mg 1-3 x daily

• Not an effective therapy for abnormal uterine bleeding2,3

• High dose, long-cycle (21 days, i.e. days 5-26)

• norethindrone5 mg 1-3 x daily

• Effective for abnormal uterine bleeding4 but not studied in anticoagulated women

• Potential for side effects1

Depot medroxyprogesterone acetate

• â abnormal uterine bleeding in one short term study5

Etonogestrel implant • Not known to be effective for abnormal uterine bleeding6

Options: Progestin Agents & VTE

• Meta-analysis: 8 observational studies (3,052 pts)

* Comparator: non-users

Mantha S et al. BMJ. 2012;345:e4944. doi: 10.1136/bmj.e4944

Agent Relative Risk (95% CI) Comment

All progestin only 1.03 (0.75-1.39)

Progestin-only pill 0.9 (0.57-1.47)Injectable progestin 2.67 (1.29-5.53) 2 studies only

Contraceptive Type



LNG or ETG Implant

LNG-IUD Copper IUD




Options: Progestins & VTE



POP: Progesterone only pill; DPMA: Depo medroxyprogesterone acetate; NET-EN: Norethisteroneenanthanate; LNG: Levonorgestrel; ETG: etonogesterel


Options: Hormonal Therapy & VTE

No hormone use All hormonal therapies Estrogen-containing therapy Progestin-only therapy

Events/patient-yrs

%/year (95% CI)

Events/patient-yrs

%/year (95% CI)

Events/patient-yrs

%/year (95% CI)

Events/patient-yrs

%/year (95% CI)

All patients 38/811.0 4.7 (3.3-6.4) 7/187.5 3.7

(1.5-7.7) 4/109.5 3.7 (1.0-9.4) 3/78.0 3.8

(0.8-11.2)

Rivaroxaban 21/390.2 5.4 (3.3-8.2) 3/98.1 3.1

(0.6-8.9) 1/56.2 1.8 (0.1-9.9) 2/41.9 4.8

(0.6-17.2)

Enoxaparin/VKA 17/420.8 4.0

(2.4-6.5) 4/89.4 4.5 (1.2-11.5) 3/53.3 5.6

(1.2-16.5) 1/36.1 2.8 (0.1-15.4)

• Recurrent VTE: progestin-only therapy & anticoagulants

Martinelli I et al. Blood. 2016:127:1417-1425Hazard Ratio: 0.56 (95% CI, 0.23-1.39)

• Abnormal uterine bleeding affects ≥20% of women taking anticoagulants§ Appears more frequent with rivaroxaban than with VKA§ Data for other DOACs limited

• Thrombosis MD needs to work with other health care providers to choose safe and effective therapy§ Medical treatment is first line therapy once malignancy and

significant pelvic pathology are excludedt Effectiveness of temporarily holding anticoagulants or â dose unknownt Tranexamic acid, LNG IUD, combined contraceptives, and depot

medroxyprogesterone all reduce menstrual bleeding and appear safe in women receiving anticoagulant therapy

Summary

managing menstrual bleeding in women on anticoagulants · managing menstrual bleeding in women on...

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