ESAs Therapy: Friend or Foe? - Dr. Gawad

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. ESAs Therapy use to correct Hb level: Friend or Foe? ESAs Therapy: Friend or Foe?

3. Talk Outline • Hypertension • Vascular diseases: • Vascular Thrombo-embolism • Stroke • Myocardial infarction (& cardiovascular outcomes) • Malignancy • Quality of life • How to use ESAs?

5. Nephrol Dial Transplant (2016) 00: 1–21

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. 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. 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. Ann Intern Med. 2010 Jul 6;153(1):23-33. Targeting higher hemoglobin levels increases risks for hypertension

10. Targeting higher hemoglobin levels increases risks for hypertension

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. 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).

15. Heart. 2013 Mar;99(6):365-72.

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

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. Nephron Clin Pract. 2012;121(3-4):c95-101

21. Nephron Clin Pract. 2012;121(3-4):c95-101 NHT

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

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. Circulation. 2011 Dec 20;124(25):2903-8

29. observational cohort of dialysis patients, n = 655 Thromb Res. 2014 Nov;134(5):1081-6

32. N Engl J Med 1998; 339:584-590 1233 patients Normal Hematocrit Trial (NHT) 14 g/dL 10 g/dL

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. 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. Lancet. 2007 Feb 3;369(9559):381-8.

36. Kidney International Supplements (2012) 2, 283–287 No Specific recommendations regarding MI

39. Clin Drug Investig. 2016 Jun;36(6):421-31

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. 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. 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. 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. Leuk Res. 2010 Aug;34(8):981-5 n = 192 p < 0.0095) in responders as compared to non-responders

45. J Clin Oncol. 2008 Jul 20;26(21):3607-13.

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. 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. 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. 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. Curr Opin Nephrol Hypertens. 2017 Mar 16.

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.

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. 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. 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. 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. Don’t forget Individualization

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. 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. 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. Gawad Thank You

ESAs Therapy: Friend or Foe? - Dr. Gawad

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