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ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 1 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 2 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 3 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 4 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 5 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 6 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 7 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 8 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 9 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 10 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 11 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 12 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 13 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 14 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 15 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 16 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 17 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 18 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 19 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 20 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 21 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 22 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 23 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 24 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 25 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 26 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 27 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 28 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 29 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 30 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 31 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 32 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 33 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 34 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 35 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 36 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 37 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 38 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 39 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 40 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 41 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 42 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 43 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 44 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 45 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 46 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 47 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 48 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 49 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 50 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 51 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 52 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 53 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 54 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 55 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 56 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 57 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 58 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 59 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 60 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 61 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 62 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 63 ESAs Therapy: Friend or Foe? - Dr. Gawad Slide 64
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ESAs Therapy: Friend or Foe? - Dr. Gawad

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ESAs Therapy: Friend or Foe? - Dr. Gawad

  1. 1. ESAs Therapy: Friend or Foe? Mohammed Abdel Gawad Nephrology Specialist Kidney & Urology Center (KUC) Alexandria – EGY drgawad@gmail.com 7th International Conference of Mansoura University Nephrology Unit 29-30, March, 2017
  2. 2. ESAs Therapy use to correct Hb level: Friend or Foe? ESAs Therapy: Friend or Foe?
  3. 3. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  4. 4. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  5. 5. Nephrol Dial Transplant (2016) 00: 1–21
  6. 6. Expert Opin Drug Saf 2016; 15: 1021–1030 Nephrol Dial Transplant (2016) 00: 1–21 J Am Heart Assoc. 2013 Apr;2(2):e000128 ESA ↑ intra- cytosolic Ca Enhanced vascular alpha adrenergic sensitivity ↑ plasma endothelin levels ↓NO production Arterial remodeling Activation of RAAS Elevation of the thromboxane prostacyclin ratio Higher blood viscosity ESA therapy induced hypertension: Pathogenesis • ESA indirect effect: Related to Hb level • ESA direct effect: Related to action of ESA on vascular system and humoral factors
  7. 7. Expert Opin Drug Saf 2016; 15: 1021–1030 Nephrol Dial Transplant (2016) 00: 1–21 J Am Heart Assoc. 2013 Apr;2(2):e000128 ESA therapy induced hypertension: Pathogenesis • ESA indirect effect: Related to Hb level • ESA direct effect: Related to action of ESA on vascular system and humoral factors ESA therapy induced hypertension: Who at risk? ● Intravenous administration (versus subcutaneous) ● Hemodialysis (versus CAPD or no dialysis) ● Family history of hypertension
  8. 8. Expert Opin Drug Saf 2016; 15: 1021–1030 Nephrol Dial Transplant (2016) 00: 1–21 J Am Heart Assoc. 2013 Apr;2(2):e000128 ESA ↑ intra- cytosolic Ca Enhanced vascular alpha adrenergic sensitivity ↑ plasma endothelin levels ↓NO production Arterial remodeling Activation of RAAS Elevation of the thromboxane prostacyclin ratio Higher blood viscosity ESA therapy induced hypertension: Pathogenesis • ESA indirect effect: Related to Hb level • ESA direct effect: Related to action of ESA on vascular system and humoral factors Kidney Blood Press Res. 2012;35(2):71-6 ESA therapy induced hypertension: Who at risk? The CC genotype of the EPO gene at position 3434
  9. 9. Ann Intern Med. 2010 Jul 6;153(1):23-33. Targeting higher hemoglobin levels increases risks for hypertension
  10. 10. Targeting higher hemoglobin levels increases risks for hypertension
  11. 11. Am J Kidney Dis. 2013 Jan;61(1):44-56 31 trials (12,956 patients) High first-3-month mean ESA dose (per epoetin alfa–equivalent 10,000- U/wk increment) vs lower doses
  12. 12. Kidney International Supplements (2012) 2, 283–287 3.2: In initiating and maintaining ESA therapy, we recommend balancing the potential benefits of reducing blood transfusions and anemia-related symptoms against the risks of harm in individual patients (e.g., stroke, vascular access loss, hypertension).
  13. 13. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  14. 14. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  15. 15. Heart. 2013 Mar;99(6):365-72.
  16. 16. ESA therapy can contribute to vascular access stenosis or occlusion by promoting intimal hyperplasia and thrombosis Clin Drug Investig. 2016 Jun;36(6):421-31
  17. 17. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  18. 18. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  19. 19. N Engl J Med. 1998;339(9):584. 14 g/dL 10 g/dL Normal Hematocrit Trial (NHT) 1233 patients Both synthetic grafts and natural fistulae clotted more often in the normal hematocrit group
  20. 20. Nephron Clin Pract. 2012;121(3-4):c95-101
  21. 21. Nephron Clin Pract. 2012;121(3-4):c95-101 NHT
  22. 22. Kidney International Supplements (2012) 2, 283–287 3.2: In initiating and maintaining ESA therapy, we recommend balancing the potential benefits of reducing blood transfusions and anemia-related symptoms against the risks of harm in individual patients (e.g., stroke, vascular access loss, hypertension).
  23. 23. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  24. 24. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  25. 25. CHOIR: N Engl J Med. 2006; 355:2085-2098 CREAT: N Eng J Med. 2006;335:2071–84 TREAT: N Eng J Med. 2009;361:2019–32 But no statistical difference in stroke
  26. 26. Kidney International Supplements (2012) 2, 283–287 3.2: In initiating and maintaining ESA therapy, we recommend balancing the potential benefits of reducing blood transfusions and anemia-related symptoms against the risks of harm in individual patients (e.g., stroke, vascular access loss, hypertension).
  27. 27. Kidney International Supplements (2012) 2, 283–287 3.3: We recommend using ESA therapy with great caution, if at all, in CKD patients with active malignancy—in particular when cure is the anticipated outcome—(1B), a history of stroke (1B), or a history of malignancy (2C).
  28. 28. Circulation. 2011 Dec 20;124(25):2903-8
  29. 29. observational cohort of dialysis patients, n = 655 Thromb Res. 2014 Nov;134(5):1081-6
  30. 30. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  31. 31. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  32. 32. N Engl J Med 1998; 339:584-590 1233 patients Normal Hematocrit Trial (NHT) 14 g/dL 10 g/dL
  33. 33. CHOIR: N Engl J Med. 2006; 355:2085-2098 CREAT: N Eng J Med. 2006;335:2071–84 TREAT: N Eng J Med. 2009;361:2019–32
  34. 34. CHOIR: N Engl J Med. 2006; 355:2085-2098 CREAT: N Eng J Med. 2006;335:2071–84 TREAT: N Eng J Med. 2009;361:2019–32
  35. 35. Lancet. 2007 Feb 3;369(9559):381-8.
  36. 36. Kidney International Supplements (2012) 2, 283–287 No Specific recommendations regarding MI
  37. 37. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  38. 38. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  39. 39. Clin Drug Investig. 2016 Jun;36(6):421-31
  40. 40. This seems particularly true for solid tumors and, regarding tumor growth, especially for patients with head and neck cancer receiving radiotherapy only Clin Drug Investig. 2016 Jun;36(6):421-31
  41. 41. TREAT: N Eng J Med. 2009;361:2019–32 Higher risk of dying from cancer among the patients with a previous malignancy at least 5 years before randomization who were treated with darbepoetin alfa compared with placebo
  42. 42. Kidney International Supplements (2012) 2, 283–287 3.3: We recommend using ESA therapy with great caution, if at all, in CKD patients with active malignancy—in particular when cure is the anticipated outcome—(1B), a history of stroke (1B), or a history of malignancy (2C).
  43. 43. In malignancy: ESAs should be administered at the lowest possible dose and the treatment should increase the Hb level to the lowest level that avoids blood transfusions Clin Drug Investig. 2016 Jun;36(6):421-31
  44. 44. Leuk Res. 2010 Aug;34(8):981-5 n = 192 p < 0.0095) in responders as compared to non-responders
  45. 45. J Clin Oncol. 2008 Jul 20;26(21):3607-13.
  46. 46. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  47. 47. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  48. 48. Ann Intern Med. 2016 Apr 5;164(7):472-8 A meta-analysis including 17 RCT Hb levels of 9 to 12 g/dL compared with Hb levels >11 g/dL 7616 CKD and 2433 dialysis patients
  49. 49. A meta-analysis including 17 RCT Hb levels of 9 to 12 g/dL compared with Hb levels >11 g/dL 7616 CKD and 2433 dialysis patients Ann Intern Med. 2016 Apr 5;164(7):472-8
  50. 50. A meta-analysis including 17 RCT Hb levels of 9 to 12 g/dL compared with Hb levels >11 g/dL 7616 CKD and 2433 dialysis patients Ann Intern Med. 2016 Apr 5;164(7):472-8
  51. 51. Kidney International Supplements (2012) 2, 283–287 3.4.4 & 3.5.2: Individualization during initiation and maintenance of therapy is reasonable as some patients may have improvements in quality of life
  52. 52. Curr Opin Nephrol Hypertens. 2017 Mar 16.
  53. 53. Anemia may not be the dominant factor contributing to diminished HRQOL Other medical (adequacy, malnutrition, inflammation, and comorbidities) and patient (symptoms, mental health, and coping) factors should be concurrently addressed. Curr Opin Nephrol Hypertens. 2017 Mar 16.
  54. 54. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  55. 55. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?
  56. 56. Kidney International Supplements (2012) 2, 283–287 3.8.1: We recommend determining the initial ESA dose using the patient’s Hb concentration, body weight, and clinical circumstances. (1D)
  57. 57. Kidney International Supplements (2012) 2, 283–287 3.13.2: In patients with ESA hypo- responsiveness, we suggest avoiding repeated escalations in ESA dose beyond double the initial weight-based dose. (2D)
  58. 58. Kidney International Supplements (2012) 2, 283–287 Start appropriate dose and go slow: In general, the objective of initial ESA therapy is a rate of increase in Hb concentrations of 1.0 to 2.0 g/dl/month.
  59. 59. Kidney International Supplements (2012) 2, 283–287 ESAs Maintenance In general 11.5 Individualized >11.5 In all adults not >13 Higher risk of stroke, all cause, cardiovascular morbidity & mortality
  60. 60. Don’t forget Individualization
  61. 61. Home Messages • Hb normalization increases risk of HTN • Hb normalization increases risk of Vascular thrombo-embolism • Hb normalization increases risk of Stroke, although re-analysis of TREAT showed no risk, and there is a weak evidence that ESAs use in dialysis patients may be protective
  62. 62. Home Messages • Hb normalization increases risk of cardiac end points, but no statistical difference on MI • Use ESAs cautiously with malignancy, but there may be a benefit of ESAs with myelodysplastic syndrome • Individualize ESAs therapy according to QOL especially in young age patients
  63. 63. Home Messages ESAs Therapy: Friend or Foe? BW adjusted dose Go slow raise / month Monitor Hb Don’t normalize Hb Friend High doses (>2X adjusted BW) Rapid raise of Hb / month No Hb monitoring Normalized Hb Foe
  64. 64. Gawad Thank You
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