The SPRINT trial tested whether treating systolic blood pressure to a lower goal of <120 mm Hg compared to <140 mm Hg would reduce cardiovascular events. Interim results found the intensive treatment reduced cardiovascular complications by 30% and mortality by 25%, leading the trial to stop early. Final results are forthcoming to determine effects on other outcomes like dementia and kidney function.

1. Systolic Blood Pressure Intervention
Trial

2. Systolic Blood Pressure
Intervention Trial
• SPRINT is an unmasked open-label
randomized controlled clinical trial
examining the effect of a high blood
pressure treatment strategy aimed at
reducing systolic blood pressure (SBP) to
a lower goal than is currently
recommended.
• It was sponsored by NIH

3. SPRINT Networks and Sites

4. SPRINT Important Goals
SPRINT tested whether a treatment strategy
aimed at reducing systolic blood pressure to:
• lower goal (SBP < 120 mm Hg)
compared with
• currently recommended (SBP < 140 mm Hg)
is able reduce the occurrence of
cardiovascular disease (CVD)

5. Rationale behind SPRINT
• High blood pressure is one of the most common
conditions among middle-aged and older adults, and is a
leading risk factor for stroke, heart disease, chronic
kidney disease, and other conditions.
• Previous trials demonstrate effectiveness of treating SBP
to about 140 mm Hg.
• Observational studies suggest benefits of SBP lowering
may extend to levels below 120 mm Hg.
• SPRINT was conducted to gain critical evidence regarding
feasibility and benefits and potential risks of more
intensive BP control.

6. BP Lowering Treatment is Effective
but Challenging
Average Percent Reduction in previous trials targeting higher SBP
goals
• Stroke incidence: ~35-40%
• Myocardial Infarction: ~20-25%
• Heart Failure: ~50%
Benefits relate to extent of SBP lowering
Multiple medications often needed for control but significant side-
effects may occur
Lancet. 2000;356:1955-64.

7. Major Cardiovascular Events
Systolic blood pressure difference
between randomised groups (mmHg)
Relativeriskofmajor
0.25
0.50
0.75
1.00
1.25
1.50
-10 -8 -6 -4 -2 0 2 4
Lancet 2003; 362: 1527–35.

8. 8
Combination Therapy Is Often
Needed to Achieve Target SBP Goals
Am J Kidney Dis. 2000;36:646-661.
BP Agents (number)
Trial (SBP Achieved)
1 2 3 4
UKPDS (144 mm Hg)
RENAAL (141 mm Hg)
ALLHAT (138 mm Hg)
IDNT (138 mm Hg)
HOT (138 mm Hg)
INVEST (133 mm Hg)
ABCD (132 mm Hg)
MDRD (132 mm Hg)
AASK (128 mm Hg)

9. IHDIHD
mortalitymortality
(absolute risk(absolute risk
and 95% CI)and 95% CI)
Usual SBP (mm Hg)Usual SBP (mm Hg)
Lancet. 2002;360:1903-1913.Lancet. 2002;360:1903-1913.
schemic Heart Disease Mortality Rateschemic Heart Disease Mortality Rate
in Each Decade of Agein Each Decade of Age
120120 140140 160160 180180
256256
128128
6464
3232
1616
88
44
22
11
SBPSBP
40-49 y40-49 y
Age at risk:Age at risk:
70-79 y70-79 y
60-69 y60-69 y
50-59 y50-59 y
80-89 y80-89 y
Usual DBP (mm Hg)Usual DBP (mm Hg)
7070 8080 9090 110110100100
256256
128128
6464
3232
1616
88
44
22
11
DBPDBP

10. Meta-Analysis: Treating to BP Goals Lower
Than 140/90 mmHg Does Not Reduce
Mortality or Morbidity
OUTCOMES RELATIVE
RISK
95 % CI
Total mortality 0.92 0.86-1.15
MI 0.90 0.74-1.09
Stroke 0.99 0.79-1.25
CHF 0.88 0.59-1.32
Major CV events 0.94 0.83-1.07
End-Stage renal disease
(ESRD)
1.01 0.81-1.27
n= 22,089
Arguedas JA, et al. Cochrane Database Syst. Rev.
2009:CD004349.

11. POTENTIAL COSTS / RISKS OF
LOWER THAN INDICATED BP
TARGETS
• Increased cost of potentially unnecessary medications
• Increased risk of medication side effects
• Increased clinic visits if BP not at lower goal
• Increased monitoring required
• More complicated regimen that may jeopardize adherence
to evidence-based treatment of other risk factors
• Potential increased risk of lower BP goals

12. Clinical Trial Evidence of
Lower SBP Goals is Unclear
• ACCORD
• BP question: Does a strategy targeting
systolic blood pressure (SBP) <120 mm Hg
reduce CVD events compared to a strategy
targeting SBP <140 mm Hg in 4,700
participants with type 2 diabetes at high risk
for CVD events?

13. ACCORD Results are Mixed
Outcome
Intensive
Events (%/yr)
Standard
Events (%/yr) HR (95% CI) P
CVD (Primary) 208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20
Cardiovascular
Deaths
60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74
Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01

14. ACCORD Adverse Events
Adverse Events
Intensive
N (%)
Standard
N (%)
P value
Serious AE 77 (3.3) 30 (1.3) <0.0001
Hypotension 17 (0.7) 1 (0.04) <0.0001
Syncope 12 (0.5) 5 (0.2) 0.10
Bradycardia or Arrhythmia 12 (0.5) 3 (0.1) 0.02
Hyperkalemia 9 (0.4) 1 (0.04) 0.01
Renal Failure 5 (0.2) 1 (0.04) 0.12
eGFR ever <30 mL/min/1.73m2
99 (4.2) 52 (2.2) <0.001
Any Dialysis or ESRD 59 (2.5) 58 (2.4) 0.93
Dizziness on Standing†
217 (44) 188 (40) 0.36
N Engl J Med. 2010;362:1575-85

15. Equipoise
• The SPRINT hypothesis has never been tested in a
randomized clinical trial setting in participants
without diabetes or stroke
• Epidemiologic data is suggestive of benefit
• The ACCORD results, though negative overall, did not
rule out substantial benefit, however there may be
increased risk of certain adverse events with lower
blood pressures

16. SPRINT Primary Outcome
• Composite of
• MI
• Stroke
• Heart failure
• Acute coronary syndrome
• Cardiovascular death

17. SPRINT Other Outcomes
• Renal outcomes
• For Chronic Kidney Disease (CKD),
composite of:
• ESRD or 50% decline in eGFR
• For non-CKD, progression to CKD:
• ESRD or 30% decrease in eGFR to
a value of < 60 mL/min/1.73m2

18. SPRINT Other Outcomes
SPRINT MIND to test whether the lower SBP
goal influences the occurrence of dementia,
change in cognition, and change in brain
structure (on MRI)

19. Major Inclusion Criteria
• At least 50 years old
• Systolic blood pressure
– SBP: 130 – 180 mm Hg on 0 or 1 medication
– SBP: 130 – 170 mm Hg on up to 2 medications
– SBP: 130 – 160 mm Hg on up to 3 medications
– SBP: 130 – 150 mm Hg on up to 4 medications
• Risk (one or more of the following)
– Presence of clinical or subclinical CVD (not stroke)
– Chronic Kidney Disease (CKD), defined as eGFR 20 – 59
ml/min/1.73m2
– Framingham Risk Score for 10-year CVD risk ≥ 15%
– Not needed if eligible based on preexisting CVD or CKD
– Age ≥ 75 years

20. Major Exclusion Criteria
• Stroke
• Diabetes
• Congestive heart failure (symptoms or EF < 35%)
• Proteinuria >1g/d
• CKD with eGFR < 20 mL/min/1.73m2
(MDRD)
• Risk of non-adherence

21. 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

22. Primary Outcomes in
Subgroups
• Formal tests within subgroups were not
planned
• Interactions between subgroup indicators
and intervention arm was tested
• Regardless of interaction test, overall
conclusion applies to all subgroups

23. 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

24. Modifications from ALLHAT
• Factors increasing event rate:
• SPRINT having 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, ALLHAT’s rate was halved and assumed
2.2 %/yr

25. 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, SPRINT was believed to have a higher event rate than
ACCORD

26. 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

27. SPRINT Assumptions, Cont.
• Sample sizes (planned):
• 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

28. 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

29. SPRINT Intensive
Intervention
• Blood pressure medications are added
and/or titrated at each study visit to
achieve SBP <120 mm Hg
• Intervention goal is to create a minimum
mean difference between randomized
groups of at least 10 mm Hg

30. SPRINT Standard
Intervention
• Intensify therapy if:
• SBP ≥160 mm Hg @ 1 visit
• ≥140 mm Hg @ 2 consecutive visits
• Down-titration if:
• SBP <130 mm Hg @ 1 visit
• <135 mm Hg @ 2 consecutive visits

31. Medication Classes Provided by
SPRINT
• Angiotensin converting enzyme (ACE)-inhibitors
• Angiotensin receptor blockers (ARBs)
• Direct vasodilators
• Thiazide-type diuretics
• Loop diuretics
• Potassium-sparing diuretics
• Beta-blockers
• Sustained-release calcium channel blockers (CCBs)
• Alpha1-receptor blockers
• Sympatholytics

32. Preliminary Results
• Intensive management of SBP to a target of <120 mm Hg
reduced rates of complications of high blood
pressure (including heart attacks, heart failure, and stroke)
by 30%and lowered the risk of death by almost
25% as compared to a systolic blood pressure target of
<140 mm Hg.
• The interim analyses indicate these results are consistent for
the overall study population.
• The subgroup analysis is going on & when completed, the final
results will be published in a peer – reviewed journal.

33. Action taken : Study was
stopped due to benefit
• The study was monitored by a Data Safety Monitoring Board
(DSMB), which performed interim analyses of study results to
look for any indication that one treatment arm was superior
to the other.
• Because of the superior benefits of the more intensive blood
pressure treatment intervention on the primary outcome and
on total mortality, the DSMB recommended unblinding the
study and communicating these important results to
participants, investigators, and the public.
• NHLBI concurred with this assessment and accordingly ended
the blood pressure intervention of SPRINT, notified trial
participants and investigators, and has reported publicly these
initial findings.

34. Unanswered Questions
• What are the effects of intensive blood pressure lowering on
1) dementia and cognitive functioning (SPRINTMIND)
2) decline in kidney function ?
• SPRINTMIND study is examining whether the lower blood
pressure target will reduce the incidence of dementia, slow
the decline in cognitive function, and result in less cerebral
small vessel disease (as shown on MRI) compared to those in
the standard group.
• Data collection and analysis continue on the SPRINTMIND
study as well as to assess kidney outcomes.

35. Summary
• High blood pressure is a leading cause of death and disability
in the US and world-wide.
• Current treatment approaches are effective, but challenging,
and may leave residual risk due to hypertension at levels of
140 mm Hg.
• The interim results of the SPRINT study reaffirm the critical
importance of blood pressure control as the best approach to
reduce the complications of hypertension e.g.heart attacks and
strokes.
• Within few months, the final result will be published and it will
definitely lead to change of existing guidelines & clinical practice.