A critical review of key Nephrology Clinical Trials, Lecture given 2017

1. A Critical Look
Recent Nephrology RCTs
Prof Meguid El Nahas, MD, PhD, FRCP
Professor of Nephrology & Chairman
Global Kidney Academy
Sheffield, UK

2. •RCTs in Nephrology Updates: 2015-2017
•Whats New?!
•Whats Valid?!

3. Selected highlights 2016
• CKD
• DKD
• AKI
• Transplantation

4. I am a
Nephrologist…
.

5. I can think
for
myself….

6. STOP & THINK

7. 5Whats
What is this intervention: FOR?
What is the Evidence: VALIDITY ?
What is the Relevance: UTILITY ?
What is the RISK:BENEFIT?
What is the COST:BENEFIT?

9. Selected highlights 2016
• CKD
• DKD
• AKI
• Transplantation

10. What is the name of this RCT?

11. What is SPRINT about?

12. SPRINT Study 2015

13. Will SPRINT Change your Practice?

14. STOP & THINK

15. SPRINT - overview
Intensive
sBP<120mmHg
RCT of intensive BP
control
Standard
sBP <140mmHg

16. SPRINT Major inclusion criteria
• ≥50 years old
• Systolic blood pressure : 130 – 180 mm Hg (treated or untreated)
• Additional cardiovascular disease (CVD) risk
Clinical or subclinical CVD (excluding stroke)
Chronic kidney disease (CKD), defined as eGFR 20 – <60 ml/min/1.73m2
Framingham Risk Score for 10-year CVD risk ≥ 15%
Age ≥ 75 years
At least one

17. Intensive sBP = 121.5
9361 participants
Standard sBP =134.6mmHg
Intensive sBP = 121mmHg
SPRINT – Good separation of BP

18. SPRINT - Primary Outcomes
27% risk reduction in death 25% risk reduction in CV endpoints
Deaths Cardiovascular events
1.65% event rate/yr in intensive group vs 2.19% in standard group

19. STOP & THINK

20. 5Whats
What is this intervention: FOR?
What is the Evidence: VALIDITY ?
What is the Relevance: UTILITY ?
What is the RISK:BENEFIT?
What is the COST:BENEFIT?

21. SPRINT Outcomes – Effect of intensive BP control
• Myocardial infarction - NONE
• Acute Coronary syndrome - NONE
• Stroke – NONE – !!!!???
• Acute heart failure - Reduced
• CVD death – Reduced
HIGHER use of diuretics in Intensive BP group

22. 5Whats
What is this intervention: FOR?
What is the Evidence: VALIDITY ?
What is the Relevance: UTILITY ?
What is the RISK:BENEFIT?
What is the COST:BENEFIT?

23. SPRINT - so what happened to CKD patients?
In patients with CKD at baseline NO difference in outcomes
In patients without CKD at baseline MORE CKD!

24. 5Whats
What is this intervention: FOR?
What is the Evidence: VALIDITY ?
What is the Relevance: UTILITY ?
What is the RISK:BENEFIT?
What is the COST:BENEFIT?

25. Clinical Usefulness compared to
Statistical Significance
NNT
• To prevent 1 Death = 90 patients for 3 years
• To prevent 1 CV event = 60 patients for 3 years

26. 5Whats
What is this intervention: FOR?
What is the Evidence: VALIDITY ?
What is the Relevance: UTILITY ?
What is the RISK:BENEFIT?
What is the COST:BENEFIT?

27. SPRINT – what about adverse events?
Higher risk of AKI (mild), hypotension, syncope, electrolyte disorders, visits
to emergency department

28. SPRINT
• Validity: Only affects CHF = Diuretic Effect
• Utility: None in CKD
• Risk v Benefit:
• High rate of AKI
• Increased incidence of CKD
• Cost v Benefit: High

31. Selected highlights 2016
• CKD
• DKD
• AKI
• Transplantation

32. • Empaglifozin – inhibits Sodium-Glucose Co-Transporter 2
• Osmotic diuretic
• RCT of 7020 type 2 diabetics at high risk of CV disease.
Empaglifozin vs standard of care

33. 38% risk reduction in CV death
Benefit driven by reduction in heart failure
Blood pressure lower with Empaglifozin
EMPA-REG Outcome study
Wanner C et al New England Journal of
Medicine. 375(4):323-334, July 28, 2016.

34. STOP & THINK

36. EMPA-REG Post Hoc Renal Outcomes
Wanner C et al New England Journal of
Medicine. 375(4):323-334, July 28, 2016.

37. EMPA-REG Post Hoc Renal Outcomes
RRT, double serum
creatinine death
Significant reduction in significant renal endpoints… but event rate low

38. STOP & THINK

39. 5Whats
What is this intervention: FOR?
What is the Evidence: VALIDITY ?
What is the Relevance: UTILITY ?
What is the RISK:BENEFIT?
What is the COST:BENEFIT?

40. Post-Hoc/Sub-Group Analysis
• Post Hoc Analysis = Not powered to test hypothesis
• Post Hoc Analysis = Hypothesis Generating

41. 5Whats
What is this intervention: FOR?
What is the Evidence: VALIDITY ?
What is the Relevance: UTILITY ?
What is the RISK:BENEFIT?
What is the COST:BENEFIT?

42. EMPA-REG

43. EMPA-REG
Validity: Osmotic Diuretic effect
Validity CKD:Post-hoc analysis (hypothesis generating)
Risk v Benefit: Serious Side effects incl. AKI
Cost v Benefit: High?

47. Selected highlights 2016
• CKD
• DKD
• AKI
• Transplantation

48. Is RCM Bad for your patient?

49. How big a risk is Radio Contrast nephropathy?
Analysis 8 million hospitalised patients
2017

50. RC Induced AKI

51. RC Induced AKI by Co-Morbidity

52. Selected highlights 2016
• CKD
• DKD
• AKI
• Transplantation

55. 5Whats
What is this intervention: FOR?
What is the Evidence: VALIDITY ?
What is the Relevance: UTILITY ?
What is the RISK:BENEFIT?
What is the COST:BENEFIT?

56. Post-Hoc Analysis

57. Belatacept in Renal Transplantation
BENEFIT-EXT
• Post Hoc Analysis = Not powered to test hypothesis
• Post Hoc Analysis = Hypothesis Generating

58. NS
NSGraft Survival
Patient Survival

59. Belatacept and Kidney Function

60. STOP & THINK

61. Belatacept in Renal Transplantation
• Post Hoc Analysis = Not powered to test hypothesis
• Post Hoc Analysis = Hypothesis Generating
• Comparator = Cyclosporin ?!
• Combined endpoints: +, Individual endpoints: -
• Statistical Trick…?!
• eGFR due to CyA Avoidance

63. Cochrane Database Systematic Review 2014

64. Selected highlights 2016
• CKD
• DKD
• AKI
• Transplantation

65. I am a
Nephrologist…
.

66. I can think
for
myself….

67. I can think
CRITICALLY

68. STOP & THINK