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

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

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

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;142:342-351.

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;330:877-884.

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=0.00003, adjusted (298) (350) (373) 0 24 48 72 96 120 144 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;142:342-351.

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) 0 24 48 72 96 120 144 *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;142:342-351.

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;365:939-946.

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;365:939-946.

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=102-107 (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

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

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

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

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 = 0.0076 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

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.

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.

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.

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 130-139 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.

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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;360:1903-1913.