Factors that may causeBleeding with EnoxaparinFactors that may cause

Bleeding with Enoxaparin

Ohoud AlarfajOhoud AlarfajMS CandidateMS Candidate

Supervised by:Supervised by:

Dr. Hisham S. Abou-AudaDr. Hisham S. Abou-Auda

Dr. Mohammad H. DabaDr. Mohammad H. Daba

Dr. Ahmad Al-BarraqDr. Ahmad Al-Barraq

IntroductionObjectiveMethodologyResultsConclusion

IntroductionObjectiveMethodologyResultsConclusion

Enoxaparin is in a class of medications called low molecular weight heparins (LMWH).

Enoxaparin is in a class of medications called low molecular weight heparins (LMWH).

LMWH is a class of medication used as an anticoagulant in diseases that cause thrombosis, as well as prophylaxis in situations that lead to a high risk of thrombosis.

LMWH is a class of medication used as an anticoagulant in diseases that cause thrombosis, as well as prophylaxis in situations that lead to a high risk of thrombosis.

LMWH is the product of enzymatic or chemical degradation of unfractionated heparin (UFH).

LMWH is the product of enzymatic or chemical degradation of unfractionated heparin (UFH).

LMWH results from studies in late 1970s to developing other safer form from heparin.

LMWH results from studies in late 1970s to developing other safer form from heparin.

In 1982 Kakkar et al was the first one who evaluates LMWH in humansIn 1982 Kakkar et al was the first one who evaluates LMWH in humans

Enoxaparin used to prevent blood clots.Enoxaparin used to prevent blood clots.

Used for several days after hip or knee replacement surgery , and in some cases following abdominal surgery, while you are unable to walk.

Used for several days after hip or knee replacement surgery , and in some cases following abdominal surgery, while you are unable to walk.

Also used if you are unable to get out of bed because of a serious illness.

Also used if you are unable to get out of bed because of a serious illness.

In addition, enoxaparin is used to prevent blood clots from forming in the arteries of the heart during certain types of chest pain and heart attacks.

In addition, enoxaparin is used to prevent blood clots from forming in the arteries of the heart during certain types of chest pain and heart attacks.

May be used for other conditions as determined by physician.May be used for other conditions as determined by physician.

Most of the available data comes from pharmacokinetic or population pharmacodynamic studies or clinical reports. Results in patients with renal impairment suggest that a reduction in calculated creatinine clearance levels is associated with an increased risk of accumulation of anti-Xa activity.

Most of the available data comes from pharmacokinetic or population pharmacodynamic studies or clinical reports. Results in patients with renal impairment suggest that a reduction in calculated creatinine clearance levels is associated with an increased risk of accumulation of anti-Xa activity.

The initial dose of enoxaparin: 1.5 mg/kg once daily or 1 mg/kg twice daily.

The initial dose of enoxaparin: 1.5 mg/kg once daily or 1 mg/kg twice daily.

Participants on dialysis were given 75% of the other subjects’ recommended initial dosage, i.e., 1.125 mg/kg once daily or 0.75 mg/kg twice daily.

Participants on dialysis were given 75% of the other subjects’ recommended initial dosage, i.e., 1.125 mg/kg once daily or 0.75 mg/kg twice daily.

DosageDosage

Due to the hydrophilic disposition of enoxaparin, accumulation is likely in patients with renal dysfunction, thereby increasing the risk of hemorrhagic complications if standard weight adjusted treatment doses are used.

Due to the hydrophilic disposition of enoxaparin, accumulation is likely in patients with renal dysfunction, thereby increasing the risk of hemorrhagic complications if standard weight adjusted treatment doses are used.

Enoxaparin treatment doses are calculated in terms of actual patient weight, but, because the drug is not distributed in fat, there is a possibility of excessive drug exposure in obese patients.

Enoxaparin treatment doses are calculated in terms of actual patient weight, but, because the drug is not distributed in fat, there is a possibility of excessive drug exposure in obese patients.

LMWHs have many adverse effects and the main one is bleedingLMWHs have many adverse effects and the main one is bleeding

Significant bleeding requires medical evaluation or is associated with at least a 3% reduction in hematocrit, or more than 12 g/L (1.2 g/dL) reduction in the hemoglobin level.

Significant bleeding requires medical evaluation or is associated with at least a 3% reduction in hematocrit, or more than 12 g/L (1.2 g/dL) reduction in the hemoglobin level.

Factors may affect bleeding riskFactors may affect bleeding risk

Concomitant drugs:warfarin, nonsteroidal anti-inflammatory, aspirin, ibuprofen, diclofenac, indomethacin, dipyredamole, digoxin, or clopidogrel.

Concomitant drugs:warfarin, nonsteroidal anti-inflammatory, aspirin, ibuprofen, diclofenac, indomethacin, dipyredamole, digoxin, or clopidogrel.

Concomitant disease:a history of gastrointestinal bleeding, Hypertension, diabetes mellitus, heart failure, pregnancy, anemia, SLE and kidney disease.

Concomitant disease:a history of gastrointestinal bleeding, Hypertension, diabetes mellitus, heart failure, pregnancy, anemia, SLE and kidney disease.

Other factors:Age.Obesity.

Other factors:Age.Obesity.

To determine the factors that may affect LMWH such as (age, weight, renal function, disease, drugs, etc.).

To determine the factors that may affect LMWH such as (age, weight, renal function, disease, drugs, etc.).

To check if there is any correlation between occurrence of bleeding and these factors among patients receiving LMWH.

To check if there is any correlation between occurrence of bleeding and these factors among patients receiving LMWH.

A retrospective trial, conducted in King Khalid University Hospital (KKUH).

A retrospective trial, conducted in King Khalid University Hospital (KKUH).

Study design:Study design:

The demographic data of patients: (age, sex, weight, height, BMI, Srcr). The demographic data of patients: (age, sex, weight, height, BMI, Srcr).

A special data collection form was used.A special data collection form was used.

Other concomitant drugs prescribed to the patient and concomitant diseases were also recorded.

Other concomitant drugs prescribed to the patient and concomitant diseases were also recorded.

Data Collection FormData Collection Form

Variables were coded individually, and data were analyzed using (SPSS) ver. 13.0 for Windows.

Variables were coded individually, and data were analyzed using (SPSS) ver. 13.0 for Windows.

Frequencies, Condescriptives, Parametric tests, Nonparametric testsFrequencies, Condescriptives, Parametric tests, Nonparametric tests

Logistic regression, Odds RatioLogistic regression, Odds Ratio

FemalesFemales

Patients’ Age (years)Patients’ Age (years)

52.1 ± 19.952.1 ± 19.9 (14 – 95)(14 – 95) N = 178N = 178

MalesMales

47.9 ± 16.647.9 ± 16.6 (14 – 100)(14 – 100) N = 222N = 222

TotalTotal

49.8 ± 18.249.8 ± 18.2 (14 – 100)(14 – 100) N = 400N = 400

WeightWeight

FemalesFemales

80.2 ± 22.180.2 ± 22.1 (27.8 – 151)(27.8 – 151) N = 178N = 178

MalesMales

75.2 ± 19.175.2 ± 19.1 (38 – 186)(38 – 186)N = 222N = 222

TotalTotal77.4 ± 20.677.4 ± 20.6 (27.8 – 186)(27.8 – 186)

N = 400N = 400

(kg)

165.7 ± 9.0165.7 ± 9.0 (138 – 189)(138 – 189)HeightHeight(cm)

154.4 ± 6.4154.4 ± 6.4 (137 – 180)(137 – 180)

159.4 ± 9.5159.4 ± 9.5 (137 – 189)(137 – 189)

Dose 1Dose 1

Frequency 1Frequency 1

Dose 2Dose 2

n= 178

60.4 ± 25

(40-156)

n= 178

60.4 ± 25

(40-156)

(12-24) hr(12-24) hr

n= 3

60 ± 20

(40- 80)

n= 3

60 ± 20

(40- 80)

n= 222

56.5 ± 20.5

(30-120)

n= 222

56.5 ± 20.5

(30-120)

(12-24) hr(12-24) hr

n= 20

38 ± 11.05

(20- 60)

n= 20

38 ± 11.05

(20- 60)

MalesMales FemalesFemales

DOSES & FREQUENCY

Lab DataLab Data

Male (n=178)Female (n=222)

Hg (Male 14-18g/dl)

) Female 11.5-15.5( 12.7 ± 2.2) 5.2 – 17.8(11.6 ±1.9) 5.8 – 17.8(

Hct (Male 0.39-0.49 l/l)

) Female 0.33-0.43( 0.63 ±3.4) 0.23 – 45.4(0.34 ± 0.06) 0.2- 053(

Srcr (mg/dl)97.4 ± 55.2) 38-413(84 ±91.6) 24-922(

Platelet time (sec) 15.8 ± 3.8) 11.8-35.5(16.4 ±6.6) 1 -54.7(

APTT (sec) 43.2 ± 14.7) 27.7-122.4(42.2 ±23.4) 24.4-274(

Platelet count290.9 ± 129) 14-795(287.9 ±119.5) 1.1-896(

INR1.31 ± 0.52) 0.86-4.10(1.4 ±0.80) 0.84-6.26(

CLcr (ml/min)91.75 ± 50.2) 12.6-293.9(117.6 ±58.8) 6-324.5(

ObeseObese

49 %49 %

OverweightOverweight 27 %27 %

UnderweightUnderweight

2 %2 %NormalNormal

22 %22 %

UnderweightUnderweight

NormalNormal

OverweightOverweight

Obesity (Class I)Obesity (Class I)

Obesity (Class II)Obesity (Class II)

Extreme ObesityExtreme Obesity

5 (2.8 %)5 (2.8 %)

46 (25.8 %)46 (25.8 %)

59 (33.1 %)59 (33.1 %)

40 (22.5 %)40 (22.5 %)

16 (9.0 %)16 (9.0 %)

12 (6.7 %)12 (6.7 %)

3 (1.4 %)3 (1.4 %)

42 (18.9 %)42 (18.9 %)

49 (22.1 %)49 (22.1 %)

60 (27.0 %)60 (27.0 %)

46 (20.7 %)46 (20.7 %)

22 (9.9 %)22 (9.9 %)

MalesMales FemalesFemales

* Sickle Cell, Autoimmune hemolytic, Iron Deficiency

WarfarinWarfarin

AspirinAspirin

ClopidogrilClopidogril

DigoxinDigoxin

IbuprofenIbuprofen

DiclofenacDiclofenac

IndomethacinIndomethacin

DipyredamoleDipyredamole

40 (22.5)40 (22.5) 58 (26.1)58 (26.1)

91 (51.1)91 (51.1) 98 (44.1)98 (44.1)

47 (26.4)47 (26.4) 20 ( 9.0 )20 ( 9.0 )

14 ( 7.9 )14 ( 7.9 ) 15 ( 6.8 )15 ( 6.8 )

31 (17.4)31 (17.4) 32 (14.4)32 (14.4)

31 (17.4)31 (17.4) 39 (17.6)39 (17.6)

3 ( 1.7 )3 ( 1.7 ) 4 ( 1.8 )4 ( 1.8 )

0 ( 0 )0 ( 0 ) 1 ( 0.5 )1 ( 0.5 )

MalesMales FemalesFemalesN (%)N (%) N (%)N (%)

Drugs that may affect bleeding riskSome patients were on more than one medication

23.5 %23.5 %

BLEEDINGBLEEDINGVaginalVaginal

94 Patients94 Patients

GI bleedingGI bleeding

HematuriaHematuria

Gum bleedingGum bleeding

EpistaxisEpistaxis

HematomaHematoma

HemoptysisHemoptysis

MelenaMelena

33

1616

44

44

11

11

44

11

UnspecifiedUnspecified 6464

AgeAge

WeightWeight

BMIBMI

GenderGender

No. of DrugsNo. of Drugs

DiseaseDisease

Logistic regression and Odds RatioLogistic regression and Odds Ratio

0.4860.486 1.0261.026

0.2300.230 1.0431.043

0.2340.234 0.8910.891

0.0100.010 3.5323.532

0.9240.924 0.9780.978

0.0430.043 2.9842.984

VariableVariable p-Valuep-Value Odds RatioOdds Ratio

Variables May Contribute to BleedingVariables May Contribute to Bleeding

VariableVariable p-Valuep-Value Odds RatioOdds Ratio

ObesityObesity

CLcrCLcr

Renal FunctionRenal Function

Total DoseTotal Dose

Age GroupAge Group

Old AgeOld Age

0.5000.500 1.7711.771

0.4960.496 1.0551.055

0.7220.722 0.7110.711

0.3110.311 1.0001.000

0.0120.012 2.6522.652

0.0860.086 1.5731.573

Variables May Contribute to BleedingVariables May Contribute to Bleeding

Logistic regression and Odds RatioLogistic regression and Odds Ratio

Males Females

Renal FunctionRenal Function

Normal Moderate Impairment Renal Failure

52.2%

7.2%

41%

6.7%

18.5%

74.3%

Statistically significant (X2 test=7.329) p=0.0256Statistically significant (X2 test=7.329) p=0.0256

Bleeding & Renal FunctionBleeding & Renal Function

Normal Moderate Failure258 114 28

20.5 % 25.4 % 42.9 %

AspirinAspirin 44 (46.8 %)44 (46.8 %)

WarfarinWarfarin 23 (24.5 %)23 (24.5 %)

ClopidogrilClopidogril 13 (13.8 %)13 (13.8 %)

DigoxinDigoxin 5 (5.3 %)5 (5.3 %)

IbuprofenIbuprofen 14 (14.9 %)14 (14.9 %)

DiclofenacDiclofenac 19 (20.2 %)19 (20.2 %)

Bleeding & DrugsBleeding & Drugs

Number of Concomitant Drugs & BleedingNumber of Concomitant Drugs & Bleeding

00 25 (26.6 %)25 (26.6 %)

11 34 (22.8 %)34 (22.8 %)

44 3 (42.9 %)3 (42.9 %)

5 - 65 - 6 0 (0 %)0 (0 %)

33 8 (20.0 %)8 (20.0 %)

22 24 (22.2 %)24 (22.2 %)

9494

149149

108108

4040

77

22

NumberNumber Bleeding [N (%)]Bleeding [N (%)]PatientsPatients

TotalTotal 94 (100%)94 (100%)400400

Bleeding and Co-morbiditiesBleeding and Co-morbidities

HTNHTN

DMDM

Heart FailureHeart Failure

PregnancyPregnancy

Renal FailureRenal Failure

AnemiaAnemia

IHDIHD

CADCAD

SLESLE

39 (41.5 %)39 (41.5 %)

40 (42.6 %)40 (42.6 %)

5 ( 5.3 % )5 ( 5.3 % )

19 (20.2 %)19 (20.2 %)

9 (20.2 %)9 (20.2 %)

3 ( 3.3 % )3 ( 3.3 % )

19 (20.2 %)19 (20.2 %)

2 ( 2.1 % )2 ( 2.1 % )

4 ( 4.3 % )4 ( 4.3 % )

DiseaseDisease Bleeding [ N (%) ]Bleeding [ N (%) ] OR (95% CI)OR (95% CI)

0.98 (0.61 – 1.56)0.98 (0.61 – 1.56)

1.42 (0.88 – 2.27)1.42 (0.88 – 2.27)

0.80 (0.29 – 2.20)0.80 (0.29 – 2.20)

2.62 (1.38 – 4.96)2.62 (1.38 – 4.96)

1.69 (0.73 – 3.91)1.69 (0.73 – 3.91)

1.11 (0.62 – 1.98)1.11 (0.62 – 1.98)

0.81 (0.17 – 3.88)0.81 (0.17 – 3.88)

1.90 (0.54 – 6.63)1.90 (0.54 – 6.63)

1.09 (0.11 – 10.57)1.09 (0.11 – 10.57)

Number Patients Bleeding [N (%)]

Number of Concomitant Disease & Bleeding

0 132 23) 17.4%(

1 102 29) 28.4%(

2 89 21) 23.6%(

3 61 15) 24.6%(

4 15 6 )40.0%(

Total 399 94

Bleeding and Lab Parameters

Hg (g/dL)Hg (g/dL) 12.55 ± 2.0512.55 ± 2.05 10.84 ± 2.0510.84 ± 2.05 13.6 %13.6 %

No BleedingNo Bleeding BleedingBleeding %▲%▲ Sig***Sig***

p<0.0001 (S)p<0.0001 (S)

HctHct 0.37 ± 0.060.37 ± 0.06 0.32 ± 0.050.32 ± 0.05 13.5 %13.5 % p<0.0001 (S)p<0.0001 (S)

Platelet Time(sec)Platelet Time(sec)

16.1 ± 5.916.1 ± 5.9 16.2 ± 4.316.2 ± 4.3 0.6 %0.6 % P=0.892 (NS)P=0.892 (NS)

Platelet CountPlatelet Count 294.7 ± 124.1294.7 ± 124.1 271.2 ± 121.6 271.2 ± 121.6 8.0 %8.0 % p=0.1076 (NS)p=0.1076 (NS)

APTT (sec)APTT (sec) 42.5 ± 21.142.5 ± 21.1 43.0 ± 15.943.0 ± 15.9 1.18 %1.18 % P=0.892 (NS)P=0.892 (NS)

)N = 306( )N = 94(

INRINR 1.37 ± 0.741.37 ± 0.74 1.35 ± 0.511.35 ± 0.51 1.5 %1.5 % p=0.822 (NS)p=0.822 (NS)

SCrSCr 84.5 ± 52.184.5 ± 52.1 108.1 ± 129. 5108.1 ± 129. 5 27.9 %27.9 % p=0.0104 (S)p=0.0104 (S)

CLCr**

(ml/min)CLCr**

(ml/min) 107.0 ± 54.7107.0 ± 54.7 103.2 ± 62.5103.2 ± 62.5 3.55 %3.55 % p=0.5677 (NS)p=0.5677 (NS)

No BleedingNo Bleeding BleedingBleeding %▲%▲ Sig***Sig***

Bleeding and Lab Parameters

*** T-Test or Wilcoxon Rank Sum Test

** Calculated by Cockroft & Gault equation

*** Normality or NonNormality was ascertained by Shapiro Wilks Test

1) Bazinet et al.

Thrombosis Research

2005

Discussion

Study Authors Year Conclusion

No dose adjustments are required in obese patients .

but in renally impaired patients adjustments may be necessary.

2 (Green et al. J Clin Pharmacol

2003 Dose adjustments of enoxaparin are required in obese patients to

reduce risk of bleeding .

3 (Ellis et al. Thrombosis/Hemostasis

2006 They suggest that in patients with high risk of bleeding such as old age, obese, renal failure, special care should be taken when LMWH is used. And monitoring should be considered.

Is laboratory monitoring of LMWH necessary?

Bounameaux et al.(2004) NO

Harenberg et al.(2004) YES

But i think from my results that the monitoring is important in high risk patients such as (old age- obese- renal failure).

• Because if patients have risks for bleeding this may lead to

increase bleeding when use LMWH.

Discussion