Main Trial Design and Trial Status

Walter T. Ambrosius, PhDSPRINT Coordinating Center

Wake Forest School of Medicine

American Society of Hypertension, Inc. (ASH)

Disclosure of RelationshipsOver the past 12 months

Over the last 12 months, Walter T. Ambrosius, PhD, has received research support from the National Heart, Lung, and Blood Institute (NHLBI), the National Eye Institute (NEI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Institute on Aging (NIA) of the National Institutes of Health (NIH).

Outline

• SPRINT Locations• SPRINT Outcomes• Primary and secondary analyses• Subgroups• Event rate justification• Sample size calculations• Power summary• Ancillary studies• Current recruitment status

SPRINT Networks and Sites

Primary Outcome Composite (CVD)

• CVD mortality

• Myocardial infarction

• Non-MI acute coronary syndrome

• Stroke

• Heart Failure

Key Secondary Objectives

• Total mortality

• Progression of CKD

• Probable dementia

• Cognitive impairment

• White matter lesions detected by MRI

Other Planned Analyses

• Achieved blood pressure

• Adverse events

• Health related quality of life

• Cost

• Various laboratory assays– Chemistry profile, fasting glucose, lipid profile

Primary Analysis

• Primary analysis will use a Cox proportional hazards model (time to event)

• Stratified by clinical site

• Intention to treat principle will be used

Subgroups

• Motivated by biologically plausible hypotheses:– CKD vs. non-CKD– <75 vs. 75+ years of age– Black vs. non-black

• Others:– CVD vs. no prior CVD– Gender– SBP tertiles at baseline

Primary Outcomes in Subgroups

• Formal tests within subgroups are not planned

• Interactions between subgroup indicators and intervention arm will be tested

• Regardless of interaction test, overall conclusion applies to all subgroups

Event Rate Calculations for Primary Outcome

• Based on ALLHAT data provided by ALLHAT, all three arms not stopped early, without diabetes at baseline

• 4.39 %/yr (using hospitalized angina rather than non-MI ACS)

• Need to modify the rate for the SPRINT population

Modifications from ALLHAT

• Factors increasing event rate:– SPRINT will have older participants– Use of Framingham risk score of ≥15%– Oversampling of stage 3 and 4 CKD

• Factors decreasing event rate:– Temporal trend towards reduced rate in other studies– More rigorous definition of non-MI ACS

• Exact impact of these is unclear• To be conservative, we halved ALLHAT’s rate and

assumed 2.2 %/yr

Comparison to ACCORD

• ACCORD event rate was 2.09 %/yr in standard BP and 1.87 %/yr in intensive BP

• ACCORD:– Excluded people with CKD due to concerns about metformin for

glycemia question– Did not recruit age >80 years in the main trial– Lipid trial enrolled almost all people with low HDL, excluding

these high risk people from the BP trial– Did not include non-fatal heart failure or non-MI acute coronary

syndrome

• Thus, we believe SPRINT will have a higher event rate than ACCORD

SPRINT Assumptions

• The event rate for the SPRINT composite outcome is– 2.2 %/yr in the standard BP arm– 4 %/yr for standard BP participants with eGFR

<60 ml/min/1.73m2

– 3.5 %/yr for standard BP participants ≥75 years old

SPRINT Assumptions, Cont.

• Sample sizes:– 9250 participants in SPRINT (primary outcome and incident

dementia)– 4300 participants with eGFR < 60 ml/min/1.73m2

– 3250 participants ≥75 years old

• Uniform recruitment over 2 years• Minimum follow-up is 3 years, 10 months (assumes that

closeout visits occur uniformly over a 4 month period)• Two-sided tests at the 0.05 level are used• Annual loss to follow-up is 2 %/yr

– 3 %/yr for incident dementia

SPRINT Power Summary: Primary Outcomes

• 88.7% power to detect a treatment effect of 20% of intensive BP vs. standard BP

• 81.9% power to detect a treatment effect of 20% of intensive BP vs. standard BP among participants with eGFR of <60 ml/min/1.73m2 at baseline

• 84.5% power to detect a treatment effect of 25% of intensive BP vs. standard BP among participants at least 75 years old at baseline

Funded Ancillary Studies

• SPRINT FAST (Factors affecting Atherosclerosis Study), Srini Beddhu, MD, University of Utah (NIDDK)

• MYH9 and other validated CKD genes in SPRINT, Barry Freedman, MD, Wake Forest (NIDDK)

• SPRINT HEART, Dalane Kitzman, MD, Wake Forest (NHLBI)

• Reduction in Pulse wave velocity as a predictor of CV outcomes in SPRINT, Mark Supiano, MD, U of Utah (NHLBI)

• SPRINT MIND The Kidneys, Manju Tamura, MD, Stanford (NIDDK)

Current Trial Status

• DSMB has evaluated enrollment and adherence and recommended continuation

• Currently recruiting at or above our weekly target

• Anticipate meeting our target of 9250, over 58% complete

Take Home Message

• SPRINT is a randomized clinical trial of systolic blood pressure lowering from usual goal to lower-than-usual goal in 9250 participants with 88.7% power to detect a 20% reduction in the primary composite CVD outcome

American Society of Hypertension, Inc. (ASH)

Disclosure of RelationshipsOver the past 12 months

Over the last 12 months, Walter T. Ambrosius, PhD, has received research support from the National Heart, Lung, and Blood Institute (NHLBI), the National Eye Institute (NEI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Institute on Aging (NIA) of the National Institutes of Health (NIH).