have blood pressure goals below 140/90 mm Hg. They were not adequately powered to consider CVD outcomes. Nonetheless, they successfully demonstrated the feasibility of achieving significant separation in BP in large cohorts with advanced CKD. Given the rapid increase in the prevalence of CKD, the effects of aggressively lowering BP on the risks of CVD and CKD progression need to be clarified in a sample that appropriately mirrors the U.S. population with CKD (Sarnak and others, 2003). 1.2.2 SENIOR participants and SPRINT-MIND Including a large subgroup of participants aged 75+ will provide data on whether intensive BP treatment will reduce CVD and renal events in the elderly. Both the Treatment of Hypertension in Patients over 80 Years of Age (HYVET) (Beckett and others, 2008) and the SHEP (SHEP, 1991) trials found that a SBP delta of 15 and 11 mm Hg, respectively, between treated and placebo groups resulted in >30% reduction in stroke, HF, and overall CVD events in the treated groups. Unlike HYVET and SHEP, which had SBP levels of about 150 and 143 mm Hg at the end of the trials, SPRINT will have a substantially lower SBP target of < 120 mm Hg reduce the rate of CVD events compared to a strategy that targets a SBP of < 140 mm Hg? This hypothesis will be tested using a composite outcome including • cardiovascular death, • myocardial infarction, • stroke, • heart failure, and • non-MI acute coronary syndrome Version 4.0 13 November 1, 2012 ascertained over a follow-up period of up to 6 years. Interim monitoring for overall trial efficacy will be based on the accrued rate of this primary outcome. The anticipated event rate for this outcome is 2.2%/year. 2.2 Subgroup Hypotheses SPRINT will examine intervention effects in a number of subgroups; these are presented in greater detail in Chapter 10. Two subgroups are of particular interest due their connection to possible biological mechanisms affecting the primary outcome: 1. participants with and without CKD (eGFR < or ≥ 75 years at baseline. Consistency of the effects for the intervention on the primary outcome will also be examined in subgroups defined by gender, race/ethnicity (black vs. non-black), presence of clinical CVD at baseline (i.e., primary and secondary prevention participants) and tertiles of baseline systolic BP. Subgroup analyses for secondary outcomes are described in Chapter 10. 2.3 Secondary Hypotheses SPRINT prespecifies two types of secondary hypotheses. The first type will address secondary outcomes in analyses designed to support and confirm the primary analysis. These will include components of the primary composite outcome, total mortality, and a composite of the primary composite with total mortality (CVD-free survival). The other type addresses two areas of non-cardiovascular clinical effects: renal and cognitive outcomes. 2.3.1 Objectives for renal outcomes and the CKD subgroup 1. For the CKD subgroup, we will determine whether the intensive intervention arm experiences a lower rate of a composite of renal outcomes composed of: • ESRD or • A 50% decline from baseline eGFR 2. For the non-CKD subgroup, we will determine whether the intensive intervention arm experiences a lower rate of progression to CKD, defined as • ESRD or • 30% decrease from baseline eGFR and an end value of < 110 mm Hg. Not applicable if unable to stand due to wheelchair use. Version 4.0 17 November 1, 2012 4. Proteinuria in the following ranges (based on a measurement within the past 6 months) (a) 24 hour urinary protein excretion ≥1 g/day, or (b) If measurement (a) is not available, then 24 hour urinary albumin excretion ≥ 600 mg/day, or (c) If measurements (a) or (b) are not available, then spot urine protein/creatinine ratio ≥ 1 g/g creatinine, or (d) If measurements (a), (b), or (c) are not available, then spot urine albumin/creatinine ratio ≥ 600 mg/g creatinine, or (e) If measurements (a), (b), (c), or (d) are not available, then urine dipstick ≥ 2+ protein 5. Arm circumference too large or small to allow accurate blood pressure measurement with available devices 6. Diabetes mellitus. Participants taking medications for diabetes at any time in the last 12 months are excluded. Participants are also excluded if there is documentation of: FPG at or above 126 mg/dL, A1C ≥6.5 percent, a two-hour value in an OGTT (2-h PG) at or above 200 mg/dL or a random plasma glucose concentration ≥200 mg/dL. The diagnosis of diabetes must be confirmed on a subsequent day by repeat measurement, repeating the same test for confirmation. However, if two different tests (eg, FPG and A1C) are available and are concordant for the diagnosis of diabetes, additional testing is not needed. If two different tests are discordant, the test that is diagnostic of diabetes should be repeated to confirm the diagnosis. 7. History of stroke (not CE or stenting) 8. Diagnosis of polycystic kidney disease 9. Glomerulonephritis treated with or likely to be treated with immunosuppressive therapy 10. eGFR < 20 ml/min /1.73m2 or end-stage renal disease (ESRD) 11. Cardiovascular event or procedure (as defined above as clinical CVD for study entry) or hospitalization for unstable angina within last 3 months 12. Symptomatic heart failure within the past 6 months or left ventricular ejection fraction (by any method) < 35% 13. A medical condition likely to limit survival to less than 3 years, or a cancer diagnosed