1. Factors that may cause Bleeding with Enoxaparin Factors that may cause Bleeding with Enoxaparin Ohoud Alarfaj MS Candidate Supervised by: Dr. Hisham S. Abou-Auda Dr. Mohammad H. Daba Dr. Ahmad Al-Barraq

2. Introduction Objective Methodology Results Conclusion Introduction Objective Methodology Results Conclusion

3. 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.

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

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

6. 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.

7. 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.

8. 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. Dosage

9. 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.

10. 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.

11. LMWHs 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.

12. Factors 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.

13. 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.

14. A retrospective trial, conducted in King Khalid University Hospital (KKUH). Study design:

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

16. Data Collection Form

17. Variables were coded individually, and data were analyzed using (SPSS) ver. 13.0 for Windows. Frequencies, Condescriptives, Parametric tests, Nonparametric tests Logistic regression, Odds Ratio

18. Females Patients’ Age (years) 52.1 ± 19.9 (14 – 95) N = 178 Males 47.9 ± 16.6 (14 – 100) N = 222 Total 49.8 ± 18.2 (14 – 100) N = 400

19. Weight Females 80.2 ± 22.1 (27.8 – 151) N = 178 Males 75.2 ± 19.1 (38 – 186) N = 222 Total 77.4 ± 20.6 (27.8 – 186) N = 400 (kg) 165.7 ± 9.0 (138 – 189) Height (cm) 154.4 ± 6.4 (137 – 180) 159.4 ± 9.5 (137 – 189)

20. Dose 1 Frequency 1 Dose 2 n= 178 60.4 ± 25 (40-156) n= 178 60.4 ± 25 (40-156) (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 n= 20 38 ± 11.05 (20- 60) n= 20 38 ± 11.05 (20- 60) Males Females DOSES & FREQUENCY

21. Lab Data Female (n=222)Male (n=178) 11.6 ±1.9 (5.8 – 17.8)12.7 ± 2.2 (5.2 – 17.8) Hg (Male 14-18g/dl) (Female 11.5-15.5) 0.34 ± 0.06 (0.2 -053)0.63 ±3.4 (0.23 – 45.4) Hct (Male 0.39-0.49 l/l) (Female 0.33-0.43) 84 ±91.6 (24-922)97.4 ± 55.2 (38-413) Srcr (mg/dl) 16.4 ±6.6 (1- 54.7)15.8 ± 3.8 (11.8-35.5) Platelet time (sec) 42.2 ±23.4 (24.4-274)43.2 ± 14.7 (27.7-122.4) APTT (sec) 287.9 ±119.5 (1.1-896)290.9 ± 129 (14-795) Platelet count 1.4 ±0.80 (0.84-6.26)1.31 ± 0.52 (0.86-4.10) INR 117.6 ±58.8 (6-324.5)91.75 ± 50.2 (12.6-293.9) CLcr (ml/min)

22. Obese 49 % Overweight 27 % Underweight 2 % Normal 22 %

23. Underweight Normal Overweight Obesity (Class I) Obesity (Class II) Extreme Obesity 5 (2.8 %) 46 (25.8 %) 59 (33.1 %) 40 (22.5 %) 16 (9.0 %) 12 (6.7 %) 3 (1.4 %) 42 (18.9 %) 49 (22.1 %) 60 (27.0 %) 46 (20.7 %) 22 (9.9 %) Males Females

25. * Sickle Cell, Autoimmune hemolytic, Iron Deficiency

26. Warfarin Aspirin Clopidogril Digoxin Ibuprofen Diclofenac Indomethacin Dipyredamole 40 (22.5) 58 (26.1) 91 (51.1) 98 (44.1) 47 (26.4) 20 ( 9.0 ) 14 ( 7.9 ) 15 ( 6.8 ) 31 (17.4) 32 (14.4) 31 (17.4) 39 (17.6) 3 ( 1.7 ) 4 ( 1.8 ) 0 ( 0 ) 1 ( 0.5 ) Males Females N (%) Drugs that may affect bleeding risk Some patients were on more than one medication

27. 23.5 % BLEEDING Vaginal 94 Patients GI bleeding Hematuria Gum bleeding Epistaxis Hematoma Hemoptysis Melena 3 3 16 4 4 4 4 1 1 1 1 4 4 1 1 Unspecified 64

28. Age Weight BMI Gender No. of Drugs Disease Logistic regression and Odds Ratio 0.486 1.026 0.230 1.043 0.234 0.891 0.010 3.532 0.924 0.978 0.043 2.984 Variable p-Value Odds Ratio Variables May Contribute to Bleeding

29. Variable p-Value Odds Ratio Obesity CL cr Renal Function Total Dose Age Group Old Age 0.500 1.771 0.496 1.055 0.722 0.711 0.311 1.000 0.012 2.652 0.086 1.573 Variables May Contribute to Bleeding Logistic regression and Odds Ratio

30. MalesFemales Renal Function Normal Moderate Impairment Renal Failure 52.2 % 7.2 % 41 % 6.7 % 18.5 % 74.3 %

31. Statistically significant (X 2 test=7.329) p=0.0256 Bleeding & Renal Function NormalModerate Failure 258 114 28 20.5 %25.4 %42.9 %

32. Aspirin 44 (46.8 %) Warfarin 23 (24.5 %) Clopidogril 13 (13.8 %) Digoxin 5 (5.3 %) Ibuprofen 14 (14.9 %) Diclofenac 19 (20.2 %) Bleeding & Drugs

33. Number of Concomitant Drugs & Bleeding 0 0 25 (26.6 %) 1 1 34 (22.8 %) 4 4 3 (42.9 %) 5 - 6 0 (0 %) 3 3 8 (20.0 %) 2 2 24 (22.2 %) 94 149 108 40 7 7 2 2 Number Bleeding [N (%)] Patients Total 94 (100%) 400

34. Bleeding and Co-morbidities HTN DM Heart Failure Pregnancy Renal Failure Anemia IHD CAD SLE 39 (41.5 %) 40 (42.6 %) 5 ( 5.3 % ) 19 (20.2 %) 9 (20.2 %) 3 ( 3.3 % ) 19 (20.2 %) 2 ( 2.1 % ) 4 ( 4.3 % ) Disease Bleeding [ N (%) ] OR (95% CI) 0.98 (0.61 – 1.56) 1.42 (0.88 – 2.27) 0.80 (0.29 – 2.20) 2.62 (1.38 – 4.96) 1.69 (0.73 – 3.91) 1.11 (0.62 – 1.98) 0.81 (0.17 – 3.88) 1.90 (0.54 – 6.63) 1.09 (0.11 – 10.57)

35. NumberPatientsBleeding [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

36. Bleeding and Lab Parameters Hg (g/dL) 12.55 ± 2.05 10.84 ± 2.05 13.6 % No Bleeding Bleeding %▲ Sig *** p<0.0001 (S) Hct 0.37 ± 0.06 0.32 ± 0.05 13.5 % p<0.0001 (S) Platelet Time (sec) Platelet Time (sec) 16.1 ± 5.9 16.2 ± 4.3 0.6 % P=0.892 (NS) Platelet Count 294.7 ± 124.1 271.2 ± 121.6 8.0 % p=0.1076 (NS) APTT (sec) 42.5 ± 21.1 43.0 ± 15.9 1.18 % P=0.892 (NS) (N = 306) (N = 94)

37. INR 1.37 ± 0.74 1.35 ± 0.51 1.5 % p=0.822 (NS) S Cr 84.5 ± 52.1 108.1 ± 129. 5 27.9 % p=0.0104 (S) CL Cr ** (ml/min) 107.0 ± 54.7 103.2 ± 62.5 3.55 % p=0.5677 (NS) No Bleeding Bleeding %▲ 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

38. 1)Bazinet et al. Thrombosis Research 2005 Discussion Study AuthorsYear 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.

39. 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