Tranexamic Acid in Gynaecology

1
Tranexamic Acid in Gynaecology Obstetrics

• Prof. Surendra Nath Panda, M.S.
• Dept. of Obstetrics and Gynecology
• M.K.C.G.Medical College, Berhampur.

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Blood The essence of Life
STOP BLOOD LOSS
STOP BLOOD LOSS
LIFE GOES ON
3
Women are always at Risk of Loosing Blood
FROM MENARCHEE TO MENOPAUSE
DUB
PPH
IN NORMALCY OR PREGNANCY
CX
DUB
DUB
APH
IN HEALTH OR DISEASE
HOW TO STOP IT?
4
Events in Hemostasis
1) Vasoconstriction
3) Blood clotting
2) Platelet plug formation
4) Fibrinolysis
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Events in Haemostasis
COAGULATION
Prothrombin
Thrombin
Fibrinogen
Fibrin
forms
Clot
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Events in Haemostasis
FIBRINOLYSIS
Plasminogen
Plasmin
dissolves
Clot
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Events in Hemostasis
COAGULATION AND FIBRINOLYSIS
8
Events in Hemostasis
Presenting Tranexamic Acid
COAGULATION AND FIBRINOLYSIS
TRANEXAMIC ACID
Tranexamic Acid
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Tranexamic Acid

• Synthetic amino acid, first introduced in Sweden
  in1969.
• Chemically it is Tranexamic-stereo isomer of 1,
  4, -aminomethylcyclohexane carboxylic acid.
• Formula C8H15NO2.
• Molecular Wt.-157.
• Prevents fibrinolysis and breakdown of clot.
• It is a competitive inhibitor of plasminogen
  activation.
• At very high concentration, it is also a non
  competitive inhibitor of Plasmin.
• It is also a very weak inhibitor of thrombin.

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Tranexamic Acid
Mechanism of Action

• Tranexamic acid inhibits conversion of
  plasminogen to plasmin, hence prevents breakdown
  of clot.
• Increases collagen synthesis which preserves the
  fibrin matrix and increases the tensile strength
  of the clot
• These actions of Tranexamic acid help in
  stabilizing the clot

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Tranexamic Acid
Pharmacokinetics

• Absorption after oral administration is 30-50
• Food has no influence on absorption
• Presystemic metabolism nil
• Plasma half-life 1.4h
• Is able to cross the blood-aqueous barrier in the
  eyes.
• Can also cross the damaged blood-brain barrier
• Rapidly diffuses into joint fluid and the
  synovial membrane.

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Tranexamic Acid
Pharmacokinetics

• Plasma protein binding is negligible
• Undergoes negligible metabolism in the body.
• Mainly eliminated unchanged in the urine.
• Excretion occurs by glomerular filtration via the
  kidneys.
• Passes through the placenta and its
  concentration in the cord blood may reach that of
  maternal blood.

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Tranexamic Acid
Clinical Pharmacology

• The antifibrinolytic effect of Tranexamic acid is
  related mainly to a reversible complex formation
  with plasminogen, which prevents its activation
  to plasmin.
• Tranexamic acid is 7 to 10 times more potent than
  Epsoilon-aminocaproic acid EACA.
• Tranexamic acid produces a considerably higher
  and more sustained antifbrinolytic activity in
  tissues than does EACA.

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Tranexamic Acid
Clinical Pharmacology

• Adverse effects- are rare and mainly limited to
• Nausea, Vomiting Diarrhea, Allergy and
  occasionally an Orthostatic reaction.
• There is a theoretical risk of an increased
  thrombotic tendency, like deep vein thrombosis,
  during prolonged treatment as with any
  fibrinolysis inhibitors.
• Contraindications -
• Severe renal insufficiency
• Hematuria

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Tranexamic Acid
Pregnancy And Lactation

• PregnancyTranexamic acid crosses over to the
  foetus. It is not known whether a reduction of
  the normally high fibrinolytic activity in the
  foetus and neonate is harmful. 
• LactationTranexamic acid is secreted in the
  mother's milk. This concentration is only a
  hundredth of the corresponding serum levels and
  the drug may be given during lactation without
  risk to the child.  

Ref Collin Dollery. Tranexamic Acid. In
'Therapeutic Drugs. 2nd edition. 1999.pgT150-T153
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Tranexamic Acid
Uses in OBGYN

• To Prevent / reduce blood loss in -
• Dysfunctional Uterine Bleeding
• IUD Menorrhagia.
• Conization / Amputation of Cervix.
• Post Partum Hemorrhage.
• Ante Partum Hemorrhage.
• During/After Abdominal/Vaginal Surgery
• Available in both Oral and Inj. (IV) forms

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Dysfunctional Uterine Bleeding

• Most common menstrual disorder.
• Can affect any women from menarche to menopause.
• Often the first clinical diagnosis for any
  excessive menstrual bleedings.
• Diagnosis has to be confirmed by a process of
  exclusion of pathological causes.

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Types of DUB
OVULATION
PHASE CHANGE
END. HIST
MENSTRUAL PATERN
NORMAL
NORMAL
SHORTENED F P
POLYMENORRHAGIA MENORRHAGIA
NORMAL
NORMAL
LONG F P
OLIGOMENORRHOEA MENORRHAGIA
ABNORMAL COR.LUT
SHORT L P
DEFICIENT SEC. END.
PRE MENS. SPOTTING MENORHAGIA
PERSISTENT COR. LUT
LONG L P
WELL DEV. SEC. END
PROLONGED CYCLES
DEFICIENT PRO. END.
SHORT CYCLES
POLYMENORRHAGIA MENORRHAGIA
ANOVULATION (Insufficient follicles)
OLIGOMENORRHOEA METROPATHIA HAEMORRHAGICA
PROL. CYCLES
PRO. / HYPERPLASTIC
ANOVULATION (Polycystic Ovaries)
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Dysfunctional Uterine Bleeding-WHY?

• Exact pathophysiology still not known.
• Basis of excessive bleeding?
• Endocrine abnormality -estrogen - progesterone
  imbalance (usually estrogen dominance).
• Deficiency in clotting mechanism.
• Altered prostaglandin synthesis in favor of E2
  than F2?.

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D U B - Management Options
D C (ESH)
MEDICAL
CONSERVATIVE
?
SPONTANEOUS CURE
RECURENCE / FAILURE
CURE
H-Hysteroscopy ES-Endometrial Sampling
D C / HES
-SURGERY- -HYSTERCTOMY -ENDOMETRIAL ABLATION
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Medical Treatment for DUB

• HORMONES
• EsPr (COCP)
• Progestogens
• Norethisterone?
• MPA
• LNG IUS
• Danazol
• GnRHa
• Estrogen
• Androgens Estrogen
• Ethamsylate

• ANTIFIBRINOLYTICS
• TRANEXAMIC ACID (TA)
• Epsilon Amino Caproic Acid
• NSAIDs
• Mefenamic acid (MA)
• Naproxen,Ibuprofen, Aspirin
• SERMS
• Radiotherapy ??

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Evidence Based Medicine
(E B M)

• Evidence-Based Medical Treatment for DUB may be
• Grade A - based on randomized controlled trials.
• Grade B - based on other robust. experimental or
  observational studies.
• Grade C - based on more limited evidence but the
  advice relies on expert opinion and has the
  endorsement of respected authorities.

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COC Pills
E B M

• Combined oral contraceptives (COCs) can be used
  to reduce menstrual blood loss (A) RCOG, 1998.
• They are thought to reduce blood loss by inducing
  regular shedding of a thinner endometrium.
• In one small randomized trial, the COC reduced
  menstrual blood loss by 43 and was as effective
  as mefenamic acid, naproxen, and low dose danazol
  Iyer et al. 2001.
• The effectiveness of the COC at reducing
  menstrual blood loss is supported by other
  non-randomized and non-controlled studies RCOG,
  1998.
• The COC is a reasonable first choice for women
  who also require contraception.
• In addition, it may reduce associated
  dysmenorrhoea Wilson et al. 2001.

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LNG IUS
E B M

• A progestogen releasing intrauterine device is an
  effective treatment for menorrhagia (A)
• It reduces menstrual blood loss by up to 90
• Its main advantages are relief of dysmenorrhoea,
  effective contraception, and long-term control of
  menorrhagia following insertion Sturridge and
  Guillebaud, 1996.
• Satisfaction and quality of life ratings are
  high, although there is a lack of data comparing
  it to other established treatments.
• It is much cheaper over 5 years compared to other
  treatments, although it becomes expensive if
  removed before that time limit.
• The main disadvantages are intermenstrual
  bleeding and breast tenderness in the first few
  months following insertion.
• Expulsion rates range from 3.3-5.9 within 12
  months Lethaby et al. 2001e.

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NASIDs
E B M

• Mefenamic acid is an effective treatment for
  reducing heavy menstrual blood loss (A) RCOG,
  1998.
• Although mefenamic acid has been studied the
  most, it is likely that other nonsteroidal
  anti-inflammatory drugs (NSAIDs) are as effective
  Lethaby et al. 2001a.
• NSAIDs are thought to act by reducing uterine
  prostaglandin levels, which are elevated in women
  with excessive menstrual bleeding.
• NSAIDs reduce menstrual blood loss by 20-50
  RCOG, 1998.
• Comparative studies show that they are less
  effective than tranexamic acid or danazol, but
  are as effective as other medical treatments
  Duckitt, 2000 Lethaby et al. 2001a.
• They reduce associated dysmenorrhoea Zhang and
  Li Wan Po, 1998 Wilson and Farquhar, 2000.

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Tranexamic Acid
E B M

• Tranexamic acid is an effective treatment for
  reducing heavy menstrual blood loss (A) RCOG,
  1998.
• It reduces menstrual blood loss by 40-50
  Lethaby et al. 2001b.
• Being a plasminogen activator inhibitor, its use
  is rational as an increase in the level of
  plasminogen activators is found in the
  endometrium of women with heavy menstrual
  bleeding compared to those with normal menstrual
  loss.

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Tranexamic Acid
E B M

• Comparative studies show it to be more effective
  in reducing menstrual blood loss RCOG, 1998
  Duckitt, 2000 Lethaby et al. 2001b. than
• nonsteroidal anti-inflammatory drugs,
• luteal phase oral progestogens, and
• ethamsylate
• It has not been compared to the combined oral
  contraceptive pill or the levonorgestrel
  intrauterine system.
• It is well tolerated, with no significant
  increase in reported adverse events compared to
  placebo or other treatments Lethaby et al.
  2001b.
• There is no evidence of an increased incidence of
  thrombogenic disease (e.g. deep vein thrombosis)
  RCOG, 1998 Lethaby et al. 2001b.

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Danazol
E B M

• Danazol inhibits secretion of pituitary
  gonadotrophins and also has androgenic,
  anti-oestrogenic, and anti-progestogenic
  activity.
• It reduces excessive menstrual bleeding by up to
  80 NZ, 1998 RCOG, 1999.
• It is poorly tolerated, due to androgenic side
  effects of weight gain, hirsutism, acne, mood
  changes, and occasionally deepening of the voice,
  which may be irreversible.
• It should generally only be used selectively,
  following specialist advice NZ, 1998 RCOG,
  1998.

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Ethamsylate
E B M

• Ethamsylate is thought to reduce capillary
  bleeding by correcting abnormal platelet
  function.
• There is some evidence that it may achieve small
  reductions in menstrual blood loss, but this is
  unlikely to be clinically significant RCOG,
  1998 Duckitt, 2000.
• Ethamsylate, at currently recommended doses, is
  not an effective treatment for menorrhagia (A)
  RCOG, 1998.

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GnRHa
E B M

• Gondadotrophin releasing hormone analogues
  initially stimulate pituitary secretion of
  gonadotrophins and then rapidly inhibit secretion
  due to pituitary down-regulation.
• This results in anovulation, markedly reduced
  oestrogen levels, and amenorrhoea.
• They are poorly tolerated and cannot be used
  long-term.
• They should only be used selectively following
  specialist advice RCOG, 1998.
• Some are licensed for endometrial thinning prior
  to intrauterine surgery or for reduction of size
  of uterine fibroids and associated bleeding
  before surgery.

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Progestogens (oral)
E B M

• Several reviews have highlighted the lack of good
  trial data and the likely poor efficacy of
  commonly used regimes EHCB, 1995 NZ, 1998
  RCOG, 1998 Duckitt, 2000 Lethaby et al. 2001c.
  
• Low dose, luteal phase administration of
  norethisterone is not an effective treatment for
  menorrhagia (A) RCOG, 1998.
• Luteal phase progestogens (taken from Day 15 or
  19 to Day 26 of the cycle) have not been studied
  in placebo-controlled trials, but comparative
  studies indicate that they are inferior to other
  medical treatments Lethaby et al. 2001c.
• Progestogen treatment for 21 days of each cycle
  reduces menstrual blood loss by about 90, but is
  poorly tolerated. In one study, only 22 of women
  were willing to continue treatment RCOG, 1998
  Duckitt, 2000 Lethaby et al. 2001c.
• Norethisterone 15 mg daily for 10 days is
  licensed to arrest menstrual bleeding, and may be
  useful for some women who present with heavy,
  prolonged bleeding BNF 41, 2001

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Progestogens (long-acting)
E B M

• Continued use of long-acting progestogens renders
  most women amenorrhoeic and therefore could be
  considered for use in menorrhagia (C) RCOG,
  1998.
• However, there is no trial data available on
  their use in the treatment of menorrhagia and
  they are not licensed for this indication.
• Medroxyprogesterone acetate (MPA) is available as
  a depot injection for contraception. It may cause
  unpredictable, irregular spotting and bleeding in
  the first few months of use, and may cause heavy
  bleeding in 1-2 of women. However, after using
  it for a year, 45-50 of women are amenorrhoeic
  RCOG, 1998.
• MPA may be an option for women who require
  contraception but who are unable or unwilling to
  use the combined oral contraceptive pill or the
  levonorgestrel intrauterine system.

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E B M
Treatment of Menorrhagia during menstruation
randomized controlled trial of Ethamsylate,
Mefenamic acid, and Tranexamic acid
John Bonnar, Professor and Head of Department,
Brian L Sheppard, Associate Professor of Human
Reproduction Trinity College Department of
Obstetrics and Gynaecology, Trinity Centre for
Health Sciences, St James' Hospital and The
Coombe Women's Hospital, Dublin
BMJ. 1996313579-582
Objective To compare the efficacy and
acceptability of Ethamsylate, Mefenamic acid, and
Tranexamic acid for treating Menorrhagia.
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E B M
Treatment of Menorrhagia during menstruation
randomized controlled trial of Ethamsylate,
Mefenamic acid, and Tranexamic acid
Design Randomized controlled trial. Setting A
university department of obstetrics and
gynaecology. Subjects 76 women with
dysfunctional uterine bleeding. Interventions
Treatment for five days from day 1 of menses
during three consecutive menstrual periods. 27
patients were randomised to take ethamsylate 500
mg six hourly, 23 patients to take mefenamic acid
500 mg eight hourly, and 26 patients to take
tranexamic acid 1 g six hourly
Main outcome measures Menstrual loss measured by
the alkaline haematin method in three control
menstrual periods and three menstrual periods
during treatment duration of bleeding patient's
estimation of blood loss sanitary towel usage
the occurrence of dysmenorrhoea and unwanted
events.
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E B M
Treatment of Menorrhagia during menstruation
randomized controlled trial of Ethamsylate,
Mefenamic acid, and Tranexamic acid
Results
Fig 1--Mean menstrual blood loss of 27 patients
during three pretreatment (control) cycles and
three cycles during treatment with ethamsylate,
23 patients during three pretreatment cycles and
three cycles during treatment with mefenamic
acid, and 26 patients during three pretreatment
cycles and three cycles during treatment with
tranexamic acid. Bars are SD
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E B M
Treatment of Menorrhagia during menstruation
randomized controlled trial of Ethamsylate,
Mefenamic acid, and Tranexamic acid
Results
Fig 2--Mean menstrual blood loss during three
control and three treatment cycles in patients
treated with ethamsylate (no reduction in blood
loss), mefenamic acid (20 reduction in blood
loss), and tranexamic acid (54 reduction in
blood loss). Bars are SD
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E B M
Treatment of Menorrhagia during menstruation
randomized controlled trial of Ethamsylate,
Mefenamic acid, and Tranexamic acid
Conclusions Tranexamic acid given during
menstruation is a safe and highly effective
treatment for excessive bleeding. Patients with
dysfunctional uterine bleeding should be offered
medical treatment with Tranexamic acid before a
decision is made about surgery.
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Antifibrinolytics for heavy menstrual bleeding
(Cochrane Review conclusions)
E B M

• Antifibrinolytic therapy causes a greater
  reduction in objective measurements of heavy
  menstrual bleeding when compared to placebo or
  other medical therapies (NSAIDS, oral luteal
  phase progestagens and ethamsylate).
• This treatment is not associated with an increase
  in side effects compared to placebo, NSAIDS, oral
  luteal phase progestagens or ethamsylate.
• Flooding and leakage and sex life is
  significantly improved after tranexamic acid
  therapy when compared with oral luteal
  progestogens but no other measures of quality of
  life were assessed.
• No study has used resource cost as an outcome.
• There are no data available within randomised
  controlled trials which record the frequency of
  thromboembolic events.

From- The Cochrane Library, Issue 3, 2002.
Oxford Lethaby A, Farquhar C, Cooke
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Evidence-Based Treatment for DUB
E B M
Effective treatments for Menorrhagia -

• Tranexamic acid
• Non-steroidal anti-inflammatory drugs
• Combined oral contraceptives
• Cyclical (21 days) progestogens
• The Levo Norgestrel releasing intrauterine system
  (LNG IUS / Mirena)

Inappropriate management is being applied even
though effective medical treatments exist (above)
and have a rational basis for their use.
Increased use of effective treatments will
improve patient choice and provide an alternative
to surgery.
40
E B M
T A
M A
41
Hormonal Treatment for DUB
E B M
Problems -

• Treatment has to be individualized.
• Not suitable for all ages and all types.
• Response is erratic and unpredictable.
• SIDE EFFECTS So discontinuation and
  noncompliance.
• Failures are common.
• Cost effectiveness?
• Surgery is often resorted to.

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Final Verdict on Tranexamic Acid
E B M

• It is the most effective and acceptable of the
  drug therapies currently available for DUB.
• It induces a reduction in menstrual blood loss of
  around 50 in the majority of patients.
• However, Tranexamic acid is ineffective in around
  15 of patients, and
• Its acceptability is compromised in
  approximately 20-30 of patients, due to the side
  effects.

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Guidelines and Statements From Governmental
Agencies and Professional Associations were also
reviewed
E B M

• United Kingdom
• Cochrane Menstrual Disorders and Subfertility
  Group (Cochrane Collaboration)
• Disorders of the Menstrual Cycle (Royal College
  of Obstetricians and Gynaecologists, UK)
• Menorrhagia (Prodigy, UK)
• North Essex Guidelines For The Management Of
  Menorrhagia In Primary Care (Equip, UK)
• The Initial Management of Menorrhagia (Royal
  College of Obstetricians and Gynaecologists, UK)
• The Management of Menorrhagia in Secondary Care
  (Royal College of Obstetricians and
  Gynaecologists, UK)

44
Guidelines and Statements From Governmental
Agencies and Professional Associations were also
reviewed
E B M

• United States
• Abnormal Vaginal Bleeding (American College of
  Radiology)
• Menstrual disorders (American Board of Family
  Practice)
• Surgical Alternatives to Hysterectomy for
  Abnormal Uterine Bleeding (Minnesota Health
  Technology Advisory Committee, US)
• Canada
• Guidelines for the Management of Abnormal Uterine
  Bleeding (The Society of Obstetricians and
  Gynaecologists of Canada)

45
Guidelines and Statements From Governmental
Agencies and Professional Associations were also
reviewed
E B M

• Australia
• IMB - Guidelines For Referral (Medicine
  Australia)
• New Zealand
• Guidelines for the Management of Heavy Menstrual
  Bleeding (New Zealand Guidelines Group)
• Recommended Medical Investigations and Treatment
  for Heavy Menstrual Bleeding (New Zealand
  Guidelines Group)

46
Treatment for Menorrhagia (DUB) Current
Recommendation
E B M
TA 1G TDS / M A 500mg TDS / Both, from 1st day of
period for days of heavy flow (Not more than 4
days)
Does not need contraception / prefers non
hormonal treatment
If blood flow is reduced to an acceptable level ,
continue treatment indefinitely.
Use for 3 months
If blood flow is not reduced to an acceptable
level or unacceptable side effects, review and
try other modalities.
47
Treatment for Menorrhagia (DUB) Current
Recommendation
E B M
Needs contraception / prefers hormonal treatment
21 days Cyclical MPA / Long Acting Progestogens
COC Pills
LNG IUS
TA
TA
TA
Review after 3 months. Add MA if necessary.
Review after 6 months. If flow still unacceptable
reassess.
Review after 3 months.
48
Treatment for Menorrhagia (IUD)Current
Recommendation
E B M
T A 1G TDS alone / with / or M A 500mg TDS, from
1st day of period for days of heavy flow (Not
more than 4 days)
Has an non hormonal IUCD
If flow is not reduced to an acceptable level or
unacceptable side effects, remove IUCD suggest
alternative contraception.
If blood flow is reduced to an acceptable level ,
continue treatment indefinitely.
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Tranexamic Acid for DUBSummary
E B M

• Tranexamic Acid in doses of 1G TDS/QDS is a very
  safe and effective alternative.
• Adding Mefenamic Acid 500mg TDS will further
  improve the results specially in patients having
  dysmenorhea as well.
• It should be used as primary / first line of
  treatment particularly where the cycle is regular
  or contraception is not desired.
• It can also be used along with OCP / MPA where
  cycle control /contraception is required.

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Tranexamic Acid in Conization

• Post operative heavy bleeding after knife
  conization occurs in about 15 of cases,
  requiring extra measures.
• High concentration of Plasminogen has been
  observed in Cx.
• Tranexamic Acid, is a logical solution in such
  patients.
• In doses of 1.5G/day for 12 days post
  operatively, double blind studies have shown a
  70 reduction in blood loss.

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Tranexamic Acid in APH PPH

• Bleeding from placental sites usually result from
  the structural weakness defects in the
  placental blood vessels.
• Tranexamic acid in doses of 1G (IV/Oral) TDS, by
  prtomoting stable coagulation at the site of
  bleeding, can be of help in-
• Placenta Previa (2nd half of pregnancy).
• Abruptio Placentae.
• Persistent Post Partum Hemorrhage

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Blood The essence of Life
STOP BLOOD LOSS WITH TRANEXAMIC ACID
53
Thank you