1. What should the Systolic BP treatment goal be in patients with CKD?

2. Age-Adjusted Rate of ESRD Due to Any Cause per 100,000 Person-Years, According to SBP and DBP in 332,544 Men Screened for MRFIT
N Engl J Med 1996;334:13-8

3. Combined CVD = CHD death, nonfatal MI, stroke, coronary revascularization procedures, hospitalized or treated angina, treated or hospitalized HF, and peripheral arterial disease (hospitalized, or outpatient revascularization)
Rahman, et al. Ann Intern Med. 2006;144:172-80

4. Outcomes: MDRD Study and Long-term Follow-up Period**
840 participants randomly assigned to:
Low BP
(n=432)
Usual BP
(n=408)
MDRD Trial
(1989–1993)
Kidney failure
(n=61)
Dead*
(n=12)
Kidney failure
(n=66)
Dead*
(n=7)
Alive†
(n=359)
Alive†
(n=335)
Long-term
Follow-up
(1993–2000)
Kidney failure
(n=207)
Dead*
(n=32)
Kidney failure
(n=220)
Dead*
(n=19)
Alive†
(n=120)
Alive†
(n=96)
Kidney failure
(n=268)
Alive†
(n=120)
Dead*
(n=44)
Kidney failure
(n=286)
Alive†
(n=96)
Dead*
(n=26)
Total
*The number of deaths include only those that occurred before kidney failure.
†“Alive” refers to participants who did not develop kidney failure or who died during the period of interest.
**Extended follow up period after completion of the MDRD Study
Sarnak MJ, et al. Ann Intern Med. 2005;142:

5. MDRD: Estimated Decline in GFR
Decline in GFR (mL/min)
Usual protein diet
Low-protein diet
[ns]
Usual blood pressure
Low blood pressure
[ns]
N Engl J Med.1994;330:

6. MDRD Follow-up Period: Risk for Kidney Failure
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0 –
Usual BP (MAP <107 mm Hg)
Low BP (MAP <92 mm Hg)
(80)
(141)
(99)
(188)
(166)
Cumulative Probability of Kidney Failure, %
(268)
(223)
RR reduction 22%, P=0.0056, unadjusted
*RR reduction 32%, P= , adjusted
(298)
(350)
(373)
Follow-up, mo
*Adjusted for baseline factors, UP excretion, age, polycystic kidney disease, black ethnicity, transferrin level, HDL-C, MAP, GFR, and dietary protein assignment.
Sarnak MJ, et al. Ann Intern Med. 2005;142:

7. MDRD Follow-up period: Risk for Kidney Failure or All-cause Mortality
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0 –
Usual BP (MAP <107 mm Hg)
Low BP (MAP <92 mm Hg)
(80)
(141)
(99)
(188)
(166)
Cumulative Probability |of Composite Endpoint, %
(223)
(268)
(298)
RR reduction 15%, P=0.0502, unadjusted
*RR reduction 23%, P=0.0024, adjusted
(350)
(373)
*Adjusted for baseline factors, UP excretion, age, polycystic kidney disease, black ethnicity, transferrin level, HDL-C, MAP, GFR, and dietary protein assignment.
Follow-up, mo
Sarnak MJ, et al. Ann Intern Med. 2005;142:

8. REIN-2 Trial Study Design
Multicenter, RCT of 338 patients with non-diabetic nephropathies (urine protein >1 g/d) taking ramipril 2.5–5 mg/day
Randomized to conventional (DBP <90 mm Hg) or intensified (SBP/DBP <130/80 mm Hg) blood-pressure control groups
Patients in intensified group received add-on therapy with felodipine (5–10 mg/day)
Primary endpoint: time to ESRD over 36-month follow-up period
REIN-2=Ramipril Efficacy In Nephropathy-2; RCT=randomized controlled trial.
Ruggenenti P, et al. Lancet. 2005;365:

9. REIN-2: Progression to ESRD*
Intensified control
P=0.99
Conventional control
*38 (23%) of 167 patients in the intensified-control arm and
34 (20%) of 168 patients in the conventional-control group
progressed to ESRD.
Ruggenenti P, et al. Lancet. 2005;365:

10. African American Study of Kidney Disease in Hypertensives (AASK)
Double-blind, 7-yr, 21-center, NIDDK sponsored trial involving 1094 African Americans with hypertensive renal disease
Patients randomly assigned to either:
Usual BP goal: MAP= (BP~140/90)
Low BP goal: MAP<92 (BP~125/75)
Patients randomly assigned to one of 3 antihypertensive drug regimens containing either a:
calcium channel blocker (amlodipine)
converting-enzyme inhibitor (ramipril); OR
beta blocker (metoprolol)
BP recommended to protect against CVD vs a lower BP goal thought need to protect against renal events

11. BP Goal Results: Main Clinical Composite Outcome During Trial Phase
HR=Hazard Ratio, adjusted for baseline covariates
BP Goal Results: Main Clinical Composite Outcome During Trial Phase
Cumulative Incidence (%) 5 10 15 20 25 30 35 40
Follow-Up Time (Months) 6 12 18 24 36 42 48 54 60
Lower BP (Achieved: 128/78)
Usual BP (Achieved: 141/85)
Low vs. Usual:
HR=0.98, p=0.85
During the treatment trial, no difference in outcome was seen between the two BP arms of the trial in the whole cohort
Wright , et al. JAMA 2002

12. BP Goal Results: Main Clinical Composite Outcome
Only Trial
Mixed Trial
and Cohort
Only Cohort
Lower BP
Usual BP
Cumulative Incidence (%) 10 20 30 40 50 60 70
Total Follow-Up Time (Months) 12 24 36 48 72 84 96
108
120
132
HR=0.90, p = 0.24
BP Goal Results: Main Clinical Composite Outcome
Across Both Trial + Cohort Phases
HR=Hazard Ratio, adjusted for baseline covariates
Low vs. Usual:
This lack of difference between the BP arms in the whole cohort persisted throughout the cohort phase also
Appel, et al. NEJM 2010

13. Interaction test of BP goal with baseline UP/Cr: p=0.007
Effects of Lower vs Usual BP Goal on Composite Outcome During Trial Period
HR=Hazard Ratio adjusted for baseline covariates
Baseline UP/Cr  0.22
Baseline UP/Cr > 0.22
Interaction test of BP goal with baseline UP/Cr: p=0.007
HR= 1.31, p=0.11
Lower BP
Usual BP
Follow-Up Time (Months)
HR=0.82, p=0.18
Cumulative Incidence (%) 10 20 30 40 50 60 70 12 24 36 48
Comparison by BP arms based on UP/Creat during treatment trial
Wright , et al. JAMA 2002

14. Interaction test of BP goal with baseline UP/Cr: p=0.015
Only
Trial
Mixed Trial and
Cohort
Only Cohort
Lower BP
Usual BP
Cumulative Incidence (%) 10 20 30 40 50 60 70 80 90
100
Follow-Up Months 24 84
108
132
HR=1.18
p = 0.16
Mixed
Trial and
HR= 0.72
p =
Baseline UP/Cr < 0.22
Baseline UP/Cr > 0.22
BP Goal Results (Stratified by UP/Cr): Composite Outcome During Trial and Cohort Phases
Interaction test of BP goal with baseline UP/Cr: p=0.015
Comparison of outcomes for BP arms by baseline UP/creat for trial and cohort
Appel, NEJM 2010

15. Chronic Kidney Disease (CKD) in SPRINT
Neither CV or renoprotective effects of lowering SBP to levels < 140 mm Hg has been clearly established.
CKD is a major risk factor for CVD; however, patients with CKD have been under represented in most CV trials that test interventional strategies, such as BP lowering.
Reducing SBP to levels <140 mm Hg may slow GFR decline in patients with significant proteinuria, but not in those with mild proteinuria. Even these data on renoprotection were derived only from subgroup analyses in small number of patients.
It is essential to test the efficacy and safety of SBP lowering in CKD patients.

16. SPRINT Design
Two-arm, multicenter, randomized controlled trial of 9,250 adults with SBP of at least 130 mm Hg.
Primary outcome: composite of cardiovascular events.
Sample enriched by including
4,300 persons with chronic kidney disease to permit assessment of treatment effects in this subgroup on CVD and an expanded composite outcome, including measures of progression of kidney disease.
3,250 seniors (at least 75 years old) to enhance assessment of treatment effects on CVD, dementia and change in cognition.
Other secondary outcomes include renal function, quality of life, and cost-effectiveness.
2 years of recruitment. 4-6 years of follow-up.

17. Who can participate? Men and women age 55 years or older
With systolic blood pressure of 130 mm Hg or higher
And at least one of the following
A history of CVD, or
Stage 3 CKD, or
At intermediate to high risk for CVD.
Patients with a history of stroke or diabetes are not eligible for SPRINT because of recently completed or ongoing other studies
Patients with a history of stroke or diabetes are not expected to be studied in SPRINT because other randomized clinical trials, such as the NINDS Stroke Prevention in Small Subcortical Stroke (known as SPS3) study and the NHLBI Action to Control Cardiovascular Risk in Diabetes (known as ACCORD) trial, are currently testing similar strategies in these patients. These studies will help inform how SPRINT is designed and conducted.

18. SPRINT’s Treatment Arms
Participants will be randomly assigned to one of two groups:
Intensive Treatment Group SBP < 120 mm Hg or
Standard Treatment Group SBP < 140 mm Hg (expected mm Hg)
Currently approved medications will be used in both groups.
Expected to take about 3 to 4 medications on average for the intensive treatment group versus about 2 medications on average for the standard group to achieve goals.

19. Thank you!
Questions?

20. Stroke Mortality in Each Decade of Age
SBP
DBP
Age at risk:
256
256
80-89 y
128
128
70-79 y 64 64
60-69 y 32 32
Stroke mortality
(floating absolute risk and 95% CI)
50-59 y 16 16 8 8 4 4 2 2 1 1
120
140
160
180 70 80 90
100
110
Usual SBP (mm Hg)
Usual DBP (mm Hg)
Prospective Studies Collaboration. Lancet. 2002;360: