Chairperson: Dr. AKM Abul Hossain Chairperson: Dr. AKM Abul Hossain

Assistant Professor Assistant Professor

Department of Obstetric & Department of Obstetric & Gynaecology Gynaecology

Mymensingh Medical College Mymensingh Medical College

Speaker: Dr. Kanchan Sarker Speaker: Dr. Kanchan Sarker

Resident Surgeon Resident Surgeon

Department of Obstetric & Department of Obstetric & Gynaecology Gynaecology

Mymensingh Medical College Hospital Mymensingh Medical College Hospital

Mymensingh Mymensingh

Source:Source: Critical Care 2011, Vol. 15, Issue. Critical Care 2011, Vol. 15, Issue. 2, p. 1172, p. 117

Published: 15 April 2011Published: 15 April 2011

Author:Author: Anne-Sophie Ducloy-BouthorsAnne-Sophie Ducloy-Bouthors, , Brigitte Brigitte JudeJude, , Alain DuhamelAlain Duhamel, , Françoise BroisinFrançoise Broisin, , Cyril Cyril HuissoudHuissoud, , Hawa Keita-MeyerHawa Keita-Meyer, , Laurent Laurent MandelbrotMandelbrot1, 1, Nadia TilloucheNadia Tillouche, , Sylvie FontaineSylvie Fontaine, , Françoise Le GoueffFrançoise Le Goueff, , Sandrine Depret-MosserSandrine Depret-Mosser, , Benoit ValletBenoit Vallet, , The EXADELI Study GroupThe EXADELI Study Group and and Sophie SusenSophie Susen

High-dose tranexamic acid High-dose tranexamic acid reduces blood loss in reduces blood loss in

postpartum haemorrhagepostpartum haemorrhage

IntroductionIntroduction Postpartum haemorrhage (PPH) Postpartum haemorrhage (PPH)

remains a leading cause of early remains a leading cause of early

maternal death, accounting for about maternal death, accounting for about

300,000 deaths worldwide every year, 300,000 deaths worldwide every year,

and of morbidity related to anaemia, and of morbidity related to anaemia,

blood transfusion and haemorrhage-blood transfusion and haemorrhage-

related ischaemic complications. related ischaemic complications. PPH is poorly predictable, but its direct PPH is poorly predictable, but its direct

causes are mainly uterine atony, trauma causes are mainly uterine atony, trauma

to the genital tract and retained to the genital tract and retained

placentaplacenta

Accordingly, detailed guidelines have Accordingly, detailed guidelines have

been issued for optimal use of obstetric been issued for optimal use of obstetric

interventions and uterotonic drugs. interventions and uterotonic drugs.

In contrast, haemostatic abnormalities in In contrast, haemostatic abnormalities in

this setting have long been considered this setting have long been considered

consequences of uncontrolled bleeding, consequences of uncontrolled bleeding,

not deserving of early specific treatment. not deserving of early specific treatment.

Thus, haemostatic drugs are not Thus, haemostatic drugs are not

routinely used as a first-line intervention routinely used as a first-line intervention

in PPHin PPH

Antifibrinolytic agents, mainly Antifibrinolytic agents, mainly

tranexamic acid (TA), have been tranexamic acid (TA), have been

considered to reduce blood loss and considered to reduce blood loss and

transfusion requirements in various transfusion requirements in various

elective surgeries elective surgeries

A more efficient approach could be to A more efficient approach could be to

administer TA after the onset of PPH, administer TA after the onset of PPH,

as recently suggested. However, no as recently suggested. However, no

study has yet assessed the efficacy and study has yet assessed the efficacy and

risk of such a strategy. risk of such a strategy.

Objectives: Objectives: Primary objective: Primary objective: To assess the efficacy To assess the efficacy

of TA in the reduction of blood loss in PPHof TA in the reduction of blood loss in PPH Secondary objectives:Secondary objectives: To assess the To assess the

effect of TA on effect of TA on Duration of bleeding Duration of bleeding Anaemia Anaemia Need for invasive procedures such as Need for invasive procedures such as

hysterectomy, surgical artery ligatures and hysterectomy, surgical artery ligatures and

embolisationembolisation Need for transfusion. Need for transfusion.

MethodsMethods This academic multicentred, randomised, This academic multicentred, randomised,

controlled, open-label study evaluated the controlled, open-label study evaluated the efficacy and safety of TA in women with PPH.efficacy and safety of TA in women with PPH.

The trial was conducted between 2005 and The trial was conducted between 2005 and 2008 in eight French obstetric centres 2008 in eight French obstetric centres

Inclusion criteria:Inclusion criteria: Patients with PPH >800 Patients with PPH >800 mL were included in the study. mL were included in the study.

Exclusion criteria:Exclusion criteria: were age <18 years, were age <18 years, absence of informed consent, caesarean absence of informed consent, caesarean section, presence of known haemostatic section, presence of known haemostatic abnormalities before pregnancy and history of abnormalities before pregnancy and history of thrombosis or epilepsy. thrombosis or epilepsy.

Sample size:Sample size: 144 women fully completed the protocol (72 in 144 women fully completed the protocol (72 in

the control group and 72 in the TA group).the control group and 72 in the TA group).

Procedure:Procedure: Immediately after inclusion, patients were Immediately after inclusion, patients were

randomised to receive either TA (TA group) or randomised to receive either TA (TA group) or

no antifibrinolytic treatment (control group). no antifibrinolytic treatment (control group). In the TA group, a dose of 4 g of TA was mixed In the TA group, a dose of 4 g of TA was mixed

with 50 mL of normal saline and administered with 50 mL of normal saline and administered

intravenously over a 1-hour period. After the intravenously over a 1-hour period. After the

loading dose infusion, a maintenance infusion loading dose infusion, a maintenance infusion

of 1g/hour was initiated and maintained for 6 of 1g/hour was initiated and maintained for 6

hours.hours.

In both study groups, packed red blood cells In both study groups, packed red blood cells

(PRBCs) and colloids could be used (PRBCs) and colloids could be used

according to French guidelines. Vascular according to French guidelines. Vascular

loading was as follows: crystalloid Ringer's loading was as follows: crystalloid Ringer's

lactate solution was administered to lactate solution was administered to

compensate for blood loss. compensate for blood loss.

However, at any time in both groups, However, at any time in both groups,

additional procoagulant treatments or additional procoagulant treatments or

invasive procedures could be used in cases invasive procedures could be used in cases

of intractable bleeding (PPH >2,500 mL or of intractable bleeding (PPH >2,500 mL or

blood flow >500 mL/30 minutes). blood flow >500 mL/30 minutes).

Results Results Table 1Table 1

Maternal and obstetric characteristicsMaternal and obstetric characteristicsaa

GroupGroup TATA ControlControl P P valuevalue

Number of patientsNumber of patients 7272 7272

Mean age, yr (± SD)Mean age, yr (± SD) 29 (4)29 (4) 28 (5)28 (5) 0.550.55

Mean weight, kg (± SD)Mean weight, kg (± SD) 67 (16)67 (16) 65 (12)65 (12) 0.540.54

Mean height, cm (± SD)Mean height, cm (± SD) 164 (5)164 (5) 165 (6)165 (6) 0.180.18

Parity: primiparae, Parity: primiparae, n n (%)(%) 46 (64)46 (64) 50 (69)50 (69) 0.060.06

Mean gestational age, weeks (± SD)Mean gestational age, weeks (± SD) 39.5 (2)39.5 (2) 39.5 (1.8)39.5 (1.8) 0.970.97

Twin pregnancies, Twin pregnancies, n n (%)(%) 4 (6)4 (6) 3 (4)3 (4) 0.60.6

Abnormal placental insertion, Abnormal placental insertion, n n (%)(%) 2 (3)2 (3) 3 (4)3 (4) 0.80.8

Oxytocin for labour induction, Oxytocin for labour induction, n n (%)(%) 9 (12)9 (12) 12 (17)12 (17) 0.880.88

Mean labour duration, hours (± SD)Mean labour duration, hours (± SD) 6 (3)6 (3) 6 (3)6 (3) 0.820.82

Epidural analgesia, Epidural analgesia, n n (%)(%) 59 (82)59 (82) 61 (84)61 (84) 0.450.45

Instrumental delivery, Instrumental delivery, n n (%)(%) 7 (9)7 (9) 10 (14)10 (14) 0.850.85

Oxytocin at delivery, Oxytocin at delivery, n n (%)(%) 30 (42)30 (42) 31 (42)31 (42) 0.890.89

Mean newborn weight, g (± SD)Mean newborn weight, g (± SD) 3,475 (610)3,475 (610) 3,489 (526)3,489 (526) 0.890.89

Atony-related PPH, Atony-related PPH, n n (%)(%) 54 (75)54 (75) 50 (69)50 (69) 0.410.41

Table 2Table 2

PPH managementPPH managementaa

GroupGroup TATA ControlControl P P valuevalue

Number of patientsNumber of patients 7272 7272

Mean crystalloid loading at T3, mL (± Mean crystalloid loading at T3, mL (±

SD)SD)934 (575)934 (575) 949 (712)949 (712) 0.540.54

Mean colloid loading at T3, mL (± SD)Mean colloid loading at T3, mL (± SD) 611 (500)611 (500) 736 (459)736 (459) 0.130.13

Mean total loading volume, mL, (± SD)Mean total loading volume, mL, (± SD) 1,547 (722)1,547 (722) 1,672 (787)1,672 (787) 0.360.36

Prostaglandins for PPH, Prostaglandins for PPH, n n (%)(%) 36 (48)36 (48) 34 (43)34 (43) 0.740.74

Postpartum thromboprophylaxis, Postpartum thromboprophylaxis, n n (%)(%) 16 (22)16 (22) 14 (20)14 (20) 0.80.8

Bar graph illustrating blood loss for each woman in the Bar graph illustrating blood loss for each woman in the two groupstwo groups. . Black bars = TA group, white bars = control group. Black bars = TA group, white bars = control group. The The yy-axis represents the volume of blood loss (in millilitres). -axis represents the volume of blood loss (in millilitres). The The xx-axis values are the rank of each woman according to the -axis values are the rank of each woman according to the amount of blood loss.amount of blood loss.

Graph showing time from enrolment until PPH cessation in the two groupsGraph showing time from enrolment until PPH cessation in the two groups . . Solid line = TA group, dashed line = control group. Solid line = TA group, dashed line = control group. P P = 0.003. Time points of the study (T2 = 0.003. Time points of the study (T2

= T1 + 30 minutes, T3 = T1 + 2 hours, T4 = T1 + 6 hours) are indicated on the = T1 + 30 minutes, T3 = T1 + 2 hours, T4 = T1 + 6 hours) are indicated on the xx-axis. The -axis. The time of each invasive procedure is indicated by an arrow. time of each invasive procedure is indicated by an arrow.

Table 3Table 3

Assessment of PPH-related outcomeaAssessment of PPH-related outcomea

GroupGroup TATA ControlControl P P valuevalue

Number of patientsNumber of patients 7272 7272

Evolution to severe PPH, Evolution to severe PPH, n n (%)(%) 27 (35)27 (35) 37 (50)37 (50) 0.070.07

Haemoglobin drop >4 g/dL, Haemoglobin drop >4 g/dL, n n (%)(%) 19 (25)19 (25) 32 (43)32 (43) 0.020.02

PRBC transfusion before T4, PRBC transfusion before T4, n n (%)(%) 10 (13)10 (13) 13 (18)13 (18) 0.170.17

Arterial embolisation, Arterial embolisation, n n (%)(%) 5 (6.8)5 (6.8) 5.1 (6.1)5.1 (6.1) 11

Surgical arterial ligature or hysterectomy, Surgical arterial ligature or hysterectomy, n n (%)(%) 00 2 (2.7)2 (2.7) 0.240.24

Intensive care unit stay, Intensive care unit stay, n n (%)(%) 3 (3.9)3 (3.9) 5 (6.7)5 (6.7) 11

Mild dyspnea, Mild dyspnea, n n (%)(%) 0 (0)0 (0) 1 (1.3)1 (1.3) 11

Table 4Table 4

Side effects of treatmentSide effects of treatmentaa

GroupGroup TATA ControlControl P P valuevalue

Number of patientsNumber of patients 7272 7272

Severe side effectsSevere side effects

Deep vein thrombosis, Deep vein thrombosis, n n (%)(%) 2 (3)2 (3) 1 (1)1 (1) 0.40.4

  Renal failure, Renal failure, n n (%)(%) 0 (0)0 (0) 0 (0)0 (0) --

Seizures, Seizures, n n (%)(%) 0 (0)0 (0) 0 (0)0 (0) --

Maternal death,Maternal death,n n (%)(%) 0 (0)0 (0) 0 (0)0 (0) --

Nonsevere side effectsNonsevere side effects

Nausea/vomiting, Nausea/vomiting, n n (%)(%) 12 (15)12 (15) 1 (2)1 (2) 0.0020.002

Dizziness, Dizziness, n n (%)(%) 4 (5)4 (5) 3 (4)3 (4) 0.280.28

DiscussionDiscussion In the present study, they include women In the present study, they include women

who had blood loss >800 mL to select women who had blood loss >800 mL to select women with a high risk of severe PPH, thereby with a high risk of severe PPH, thereby strengthening their results. strengthening their results.

TA was chosen because it has been TA was chosen because it has been demonstrated to be a potent antifibrinolytic demonstrated to be a potent antifibrinolytic agent in elective surgical patients and agent in elective surgical patients and because it is the most often used because it is the most often used antifibrinolytic agent worldwide. TA has the antifibrinolytic agent worldwide. TA has the additional advantage of being inexpensive additional advantage of being inexpensive and easy to stock and handle. It remains the and easy to stock and handle. It remains the only antifibrinolytic agent available in France only antifibrinolytic agent available in France at present. at present.

The volume of each patient blood loss in The volume of each patient blood loss in

the two groups was significantly lower in the two groups was significantly lower in

the TA group than in the control group. the TA group than in the control group.

The duration of bleeding was lower in the The duration of bleeding was lower in the

TA group. TA group.

Bleeding was stopped by 30 minutes in Bleeding was stopped by 30 minutes in

63% women in the TA group & 46% in 63% women in the TA group & 46% in

control group. control group.

Total blood loss was 49% lower in the TA Total blood loss was 49% lower in the TA

group than in the control group. group than in the control group.

Haemostatic embolization was performed Haemostatic embolization was performed

in 5 women in both group in 5 women in both group

Hysterectomy or surgical uterine artery Hysterectomy or surgical uterine artery

ligation was performed in two women in ligation was performed in two women in

control group & none in TA group.control group & none in TA group.

Only side effects they recorded were Only side effects they recorded were

gastro-intestinal & neurological gastro-intestinal & neurological

manifestation which were mild & manifestation which were mild &

reversible but were more frequent in the reversible but were more frequent in the

TA group than in the control group. TA group than in the control group.

Potential limitationsPotential limitations The study is open-label, unblinded character. The study is open-label, unblinded character.

Therefore, the results are at risk of bias. Therefore, the results are at risk of bias. The design of this study was not powered to show The design of this study was not powered to show

decreases in maternal death or number of decreases in maternal death or number of invasive procedures, which are the ultimate goals invasive procedures, which are the ultimate goals of maternity treatment. of maternity treatment.

The power of the study does not allow for a The power of the study does not allow for a definite conclusion regarding the risk of definite conclusion regarding the risk of thrombosis related to TA in this setting. thrombosis related to TA in this setting.

The study was performed in tertiary care and The study was performed in tertiary care and secondary care women's hospitals in a high-secondary care women's hospitals in a high-income country, which allowed for optimal income country, which allowed for optimal obstetrical management. Whether these results obstetrical management. Whether these results can be reproduced in a suboptimal environment. can be reproduced in a suboptimal environment. This factor is important to consider, since TA has This factor is important to consider, since TA has the clear advantage of being an inexpensive, the clear advantage of being an inexpensive, stable, easy-to-use drug, even in low-income stable, easy-to-use drug, even in low-income countries. countries.

Conclusions Conclusions This study is the first to demonstrate that TA This study is the first to demonstrate that TA

can reduce blood loss and maternal can reduce blood loss and maternal

morbidity in ongoing PPH. morbidity in ongoing PPH. Adverse effects were only mild and Adverse effects were only mild and

transient, even at the relatively high doses transient, even at the relatively high doses

used, but the study was not powered to used, but the study was not powered to

address safety issues.address safety issues. These encouraging data strongly support the These encouraging data strongly support the

need for a large, international, double-blind need for a large, international, double-blind

study to investigate the potential of TA to study to investigate the potential of TA to

reduce maternal morbidity worldwide. reduce maternal morbidity worldwide.

Key messagesKey messages

This study represents the first This study represents the first

demonstration that antifibrinolytic demonstration that antifibrinolytic

treatment can decrease blood loss treatment can decrease blood loss

and maternal morbidity in women and maternal morbidity in women

with PPH, which is a leading cause with PPH, which is a leading cause

of maternal death. of maternal death.