Transcript SPRINT Design

Main Trial Design and Trial
Status
Walter T. Ambrosius, PhD
SPRINT Coordinating Center
Wake Forest School of Medicine
American Society of Hypertension, Inc. (ASH)
Disclosure of Relationships
Over 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
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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)
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CVD mortality
Myocardial infarction
Non-MI acute coronary syndrome
Stroke
Heart Failure
Key Secondary Objectives
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Total mortality
Progression of CKD
Probable dementia
Cognitive impairment
White matter lesions detected by MRI
Other Planned Analyses
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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 Relationships
Over 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).