1. Nephrology Journal Club The SPRINT Trial Parker Gregg
How High is Too High? The Definitive* Answer to What Your Patients’ Blood Pressures Should Be
Nephrology Journal Club
The SPRINT Trial
Parker Gregg
*Just kidding. We still have no idea what target blood pressures should be

2. Roadmap The SPRINT Trial Study design Results Primary endpoint
CKD patients
Renal endpoints
The ACCORD Trial
The AASK Trial

3. The SPRINT Trial

4. SPRINT Trial Study Design

5. Clinical Question
In 9631 non-diabetic patients does a target systolic blood pressure of 120 compared to 140 lead to differences in cardiovascular, renal, and mortality outcomes?

6. Study Design
Population:
Problem:
Intervention:
Comparator:

7. Study Design
Population: age >50, 1 CVD risk, non-diabetics, 28% with CKD (eGFR 20-60)
Problem:
Intervention:
Comparator:

8. Study Design
Population: age >50, 1 CVD risk, non-diabetics, 28% with CKD (eGFR 20-60)
Problem: BP target
Intervention:
Comparator:

9. Study Design
Population: age >50, 1 CVD risk, non-diabetics, 28% with CKD (eGFR 20-60)
Problem: BP target
Intervention: goal SBP 120
Comparator:

10. Study Design
Population: age >50, 1 CVD risk, non-diabetics, 28% with CKD (eGFR 20-60)
Problem: BP target
Intervention: goal SBP 120
Comparator: goal SBP 140

11. Study Design
Primary endpoint:
Question type:
Study design:

12. Study Design Primary endpoint: cardiovascular event or mortality
Question type:
Study design:

13. Study Design Primary endpoint: cardiovascular event or mortality
Question type: treatment
Study design:

14. Study Design Primary endpoint: cardiovascular event or mortality
Question type: treatment
Study design: RCT

15. Inclusion Criteria Age 50 or older SBP 130-180 mmHg
Increased risk of CV events:
Clinical or subclinical CV disease other than stroke
CKD (excluding PCKD) with eGFR by MDRD equation
Framingham 10 year risk score >15%
Age 75 years or older

16. Exclusion Criteria
Diabetes mellitus
Prior CVA

17. Baseline Characteristics

18. Baseline Characteristics

19. Baseline Characteristics
Statistically significant

20. Methods
After randomization adjusted anti-hypertensive med regimen according to algorithms similar to what was used in ACCORD
Thiazide diuretics encouraged as first line agent – preferred chlorthalidone
Loop diuretics encouraged for patients with advanced CKD
Beta blockers for CAD patients
Amlodipine was preferred CCB

21. Methods
Participants seen monthly for first 3 months, then q3 months thereafter
Meds for intensive group adjusted monthly for goal <120. For standard therapy arm meds were adjusted to target SBP and dose reduced if SBPs were <130 x1 or <135 x2 consecutive.

22. Outcomes Primary outcome:
Composite outcome of MI/ACS/CVA/acute decompensated heart failure/CV death
Secondary outcomes:
Individual components of primary outcome
All cause death
Composite of primary outcome and all cause death

23. Outcomes Adverse events: Hypotension Syncope Injurious falls
Electrolyte abnormalities
Bradycardia
AKI: if noted on admission or occurred during hospitalization and were in hospital d/c summary
Other monitored outcomes:
AKI

24. Renal Outcomes
CKD at baseline: composite of decrease in eGFR of 50% or more/development of ESRD requiring long term dialysis or transplant
No CKD at baseline: decrease in eGFR by 30% or more to a value of <60 mL/min/1.73m2
All participants: incident albuminuria (doubling of UACR from <10 to >10).

25. Follow Up

26. Follow Up
~10% in each arm
Intention to treat

27. Trial Validity Randomized? All patients accounted for?
Follow up complete?
Intention to treat analysis?
Double blind?
Groups similar?
Other than intervention, were the groups treated similarly?

28. SPRINT Trial Results
Will focus on primary outcome and renal-related outcomes for purposes of time

29. Achieved Blood Pressures
Did they achieve their target? Yes. “[R]apid and sustained between-group difference in systolic blood pressure” (121.4 in intensive treatment group and in standard treatment group).

30. Primary Outcome
Primary outcome in 562 participants (1.65% per year in intensive treatment group and 2.19% per year in standard treatment group) – hazard ratio 0.75 (95% CI 0.64 – 0.89). RR 25% lower in intensive treatment group.
Difference in primary outcome was apparent at 1 year
Relative risk of various outcomes:
- Heart failure 38% lower in the intensive arm
- CV death 43% lower in intensive arm
Total deaths 365 (155 in intensive treatment and 210 in standard treatment). Hazard ratio 0.73 (95% CI 0.60 – 0.90). All cause death 27% lower in intensive arm.

31. Let’s do some math!

32. Primary Outcome Present Primary Outcome Absent
Total
Goal SBP 120
Goal SBP 140

33. Primary Outcome Present Primary Outcome Absent
Total
Goal SBP 120
243
4435
4678
Goal SBP 140

34. Primary Outcome Present Primary Outcome Absent
Total
Goal SBP 120
243
4435
4678
Goal SBP 140
319
4364
4683

35. Primary Outcome Present Primary Outcome Absent
Total
Goal SBP 120
243
4435
4678
Goal SBP 140
319
4364
4683
562
8799
9631

36. Primary Outcome Present Primary Outcome Absent
Relative Risk
Primary Outcome Present
Primary Outcome Absent
Total
Goal SBP 120
243
4435
4678
Goal SBP 140
319
4364
4683
562
8799
9631
RR = + outcome / total intervention group + outcome / total control group

37. Primary Outcome Present Primary Outcome Absent
Relative Risk
Primary Outcome Present
Primary Outcome Absent
Total
Goal SBP 120
243
4435
4678
Goal SBP 140
319
4364
4683
562
8799
9631
RR = 243 / 4678 = = /

38. More Statistics
Relative risk reduction = (1 – relative risk) x 100 = (1 – 0.76) x 100 = 25%
Absolute risk reduction = 319/4364 – 243/4435
= (0.068 – 0.052) x 100
= 1.6%
Number needed to treat = 1/ARR
= 62.5

39. Primary Outcome

40. Secondary Outcomes
Primary outcome in 562 participants (1.65% per year in intensive treatment group and 2.19% per year in standard treatment group) – hazard ratio 0.75 (95% CI 0.64 – 0.89). RR 25% lower in intensive treatment group.
Difference in primary outcome was apparent at 1 year
Relative risk of various outcomes:
- Heart failure 38% lower in the intensive arm
- CV death 43% lower in intensive arm
Total deaths 365 (155 in intensive treatment and 210 in standard treatment). Hazard ratio 0.73 (95% CI 0.60 – 0.90). All cause death 27% lower in intensive arm.

41. Primary and Secondary Outcomes
Hazard Ratio (95% CI)
Relative Risk Reduction
Number Needed to Treat
Primary Outcome Event
0.75 ( )
25% lower in intensive treatment arm 61
Heart Failure
0.62 (0.45 – 0.84)
38% lower in intensive treatment arm
370
Death from CV Causes
0.57 (0.38 – 0.85)
43% lower in intensive treatment arm
172
Death from Any Cause
0.73 ( )
27% lower in intensive treatment arm 90

42. Death from Any Cause

43. Previous CKD Subgroup Interaction
In all comers primary outcome less likely in intensive treatment arm
In patients without previous CKD (72% of all comers) CI does not cross 1
In patients with previous CKD (28% of all comers) CI crosses 1

44. Renal Outcomes
CKD at baseline: composite of decrease in eGFR of 50% or more/development of ESRD requiring long term dialysis or transplant
No CKD at baseline: decrease in eGFR by 30% or more to a value of <60 mL/min/1.73m2
All participants: incident albuminuria (doubling of UACR from <10 to >10).

45. (95% CI) without CKD at Baseline
Renal Outcomes
Outcome
Hazard Ratio
(95% CI) with
CKD at Baseline
P value
(95% CI) without CKD at Baseline
Composite Renal Outcome
0.89 ( )
0.76 --
>50% Reduction in GFR
0.87 (0.36 – 2.07)
0.75
>30% Reduction in GFR to <60 ml/min/1.73m2
3.49 (2.44 – 5.10)
<0.001
Long-term Dialysis
0.57 (0.19 – 1.54)
0.27
Incident Albuminuria
0.72 (0.48 – 1.07)
0.11
0.81 (0.63 – 1.04)
0.10

46. Adverse Events Outcome Hazard Ratio P Value Serious Adverse Event 1.04
0.25
Hypotension
1.67
0.001
Syncope
1.33
0.05
Electrolyte Abnormality
1.35
0.02
AKI
1.66
<0.001
Orthostatic Hypotension
0.88
0.01
“A serious adverse event was defined as an event that was fatal or life­threatening, that resulted in clinically significant or persistent disability, that required or prolonged a hospitalization, or that was judged by the investigator to represent a clinically significant hazard or harm to the participant that might require medical or surgical intervention to prevent one of the other events listed above.”

47. SPRINT Trial Take Home Points
All comers have lower composite CV outcome in intensive treatment arm (driven by patients without CKD)
Patients with CKD (28% of participants) didn’t have significant decrease in composite outcome with intensive treatment
given lack of effect in CKD; this could mean 2 things: no effect in CKD or not enough power given CKD subgroup smaller; likely needs another trial to address
Patients without CKD at baseline had worse renal outcomes with intensive treatment

48. The ACCORD Trial

49. Clinical Question
In 4733 diabetic patients with creatinine <1.5 mg/dL does a target systolic blood pressure of 120 compared to 140 lead to differences in cardiovascular outcomes (composite of MI, CVA, and CV death)?

50. Primary and Secondary Outcomes
Hazard Ratio (95% CI)
P Value
Primary Outcome Event
0.88 (0.73 – 1.06)
0.20
Any CVA
0.59 (0.39 – 0.89)
0.01
Nonfatal CVA
0.63 (0.41 – 0.96)
0.03
Heart Failure
0.94 (0.70 – 1.26)
0.67
CV Death
1.06 (0.74 – 1.52)
0.74
Death from Any Cause
1.07 (0.85 – 1.35)
0.55

51. ACCORD Results

52. ACCORD Results

53. ACCORD Results

54. ACCORD Results

55. ACCORD Trial Take Home Points
Smaller study than SPRINT with same BP targets in a group of all diabetic patients
Excluded patients with creatinine >1.5 mg/dL
No significant difference in cardiovascular outcomes between groups other than CVA decreased in intensive treatment group

56. AASK Trial

57. Clinical Question
In 1094 black, non-diabetic patients with hypertensive CKD does a target mean blood pressure of 92 compared to lead to differences in progression of CKD?

58. Follow-up ranged from 8.8 to 12.2 years
Primary Outcome
Progression of chronic kidney disease (doubling of the serum creatinine level, a diagnosis of ESRD, or death)
Follow-up ranged from 8.8 to 12.2 years

59. Trial + Cohort Phase Outcomes
Hazard Ratio (95% CI)
P Value
Primary Outcome Event
All Patients
0.91 (0.77 – 1.08)
0.27
UPCR <0.22
1.18 (0.93 – 1.50)
0.16
UPCR >0.22
0.73 (0.58 – 0.93)
0.01
Doubling of Serum Creatinine or ESRD
0.95 (0.78 – 1.15)
0.59
1.39 (1.04 – 1.87)
0.12
0.76 (0.58 – 0.99)
0.04
ESRD or Death
0.85 (0.71 – 1.02)
0.08
1.12 (0.87 – 1.45)
0.39
0.67 (0.52 – 0.87)
0.002

60. AASK Results

61. AASK Trial Take Home Points
In all comers there was no benefit in progression of CKD with stricter blood pressure targets
Statistically significant decrease in progression of CKD with stricter blood pressure control among those with baseline proteinuria (33% of patients)
Primary outcome incidence in proteinuric patients was higher than in non-proteinuric patients

62. Over-Simplified Summary
Patients
Cardiovascular Outcomes
Renal Outcomes
All Comers
Favors intensive control
Mixed
No CKD
Favors standard control
Proteinuric CKD or Diabetes
No difference except CVA (but excluded creat >1.5)
Non-Proteinuric CKD and No Diabetes
No difference

63. Some Questions Raised

64. In our population of CKD patients without proteinuria, what should our target blood pressure be?
The SPRINT Trial didn’t separate out proteinuric and non-proteinuric CKD in their analysis, but the AASK trial suggests that proteinuric patients derived benefit from stricter BP control and non-proteinuric patients did not.

65. What should our blood pressure target be in diabetic CKD patients
What should our blood pressure target be in diabetic CKD patients? Would there be a difference in outcomes depending on degree of proteinuria?

66. Why were renal outcomes worse in patients without underlying CKD when given a more intensive blood pressure target?

67. ?