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

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

The SPRINT Trial

SPRINT Trial Study Design

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?

Study Design Population: Problem: Intervention: Comparator:

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

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

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

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

Study Design Primary endpoint: Question type: Study design:

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

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

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

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 20-60 by MDRD equation Framingham 10 year risk score >15% Age 75 years or older

Exclusion Criteria Diabetes mellitus Prior CVA

Baseline Characteristics

Baseline Characteristics

Baseline Characteristics Statistically significant

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

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 135-139 and dose reduced if SBPs were <130 x1 or <135 x2 consecutive.

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

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

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).

Follow Up

Follow Up ~10% in each arm Intention to treat

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?

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

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 136.2 in standard treatment group).

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.

Let’s do some math!

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

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

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

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

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

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 = 0.052 = 0.76 319 / 4683 0.068

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

Primary Outcome

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.

Primary and Secondary Outcomes Hazard Ratio (95% CI) Relative Risk Reduction Number Needed to Treat Primary Outcome Event 0.75 (0.64 - 0.89) 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 (0.60 - 0.90) 27% lower in intensive treatment arm 90

Death from Any Cause

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

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).

(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 (0.42 - 1.87) 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

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.”

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

The ACCORD Trial

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)?

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

ACCORD Results

ACCORD Results

ACCORD Results

ACCORD Results

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

AASK Trial

Clinical Question In 1094 black, non-diabetic patients with hypertensive CKD does a target mean blood pressure of 92 compared to 102-107 lead to differences in progression of CKD?

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

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

AASK Results

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

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

Some Questions Raised

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.

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?

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

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