Sarva sprint trial

Clinical Question
In patients at high risk for CVD but who do not
have a history of stroke or diabetes, does intensive
BP control (target SBP <120 mm Hg) yield superior
CV outcomes compared to standard treatment
(target SBP 135-139 mm Hg)?

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.

 There are two views of the relation between diastolic blood
pressure and risks of cardiovascular disease and death
 The most widely accepted is that risk is steadily rising with
diastolic blood pressure
 The other is that the relation follows a “J-curve”, in which
risks are also increased at low as well as high pressures

J-CURVE HYPOTHESIS
 Boutitie et al analyzed individual patient data from 40,233
subjects and concluded that the increased risk seen in
patients with low blood pressure was because of poor
existing health leading to low blood pressure
 Andersen’s et.al observation in the Framingham’s data
considered apparently showed that the risk of cardiovascular
disease decreases (rather than increases) with increasing
diastolic pressure to 89 mm hg, this controversy has
centered on the “J-curve effect”
Boutitie F, Gueyffier F, Pocock S, Fagard R, Boissel JP for the INDANA project steering
committee. J-shaped relationship between blood pressure and mortality in hypertensive
patients. Ann Intern Med. 2002;136:438–448.

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.

DESIGN
Multicenter, open-label, randomized controlled trial
N=9,361 patients without diabetes or stroke at
elevated CV risk
Intensive, target SBP <120 mm Hg (n=4,678)
Standard, target SBP 135-139 mm Hg (n=4,683)
Setting: 102 sites in the US and Puerto Rico

Enrollment: 2010-2013
This open-label trial was powered to detect a 20%
effect difference in the primary composite outcome
of MI, ACS without MI, stroke, acute HF, or CV
death, assuming an event rate of 2.2% per year in
the standard arm, and an average follow-up of 5
years

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)

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
• 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

Clinical CVD (non-stroke):
 Prior MI, PCI, CABG or carotid stenting
 ACS ± EKG changes, EKG changes on a stress test, or
ischemic findings on other cardiac imaging
 ≥50% stenosis of coronary, carotid, or LE artery, or
 AAA ≥5 cm
Subclinical CVD:
 Carotid artery calcium score ≥400 in prior 2 yearsor
 LVH on EKG, echocardiogram, or other imaging in prior 2
years

Major Exclusion Criteria
 DM
 Stroke
 Not on disease-appropriate antihypertensives (eg, beta blocker and
recent MI)
 Secondary cause of hypertension
 If able to stand, 1 min standing SBP <110

 Proteinuria in any of the following ranges:
 ≥1g/day urine protein
 ≥600 mg/day urine albumin
 Spot protein:creatinine ≥1g protein/g creatinine
 Spot albumin:creatinine ≥600 mg/g creatinine
 Urine dipstick ≥2+ protein if none of the above are available

 Polycystic kidney disease
 Glomerulonephritis
 eGFR < 20 mL/min/1.73 m2
 CV event, procedure, or UA hospitalization in prior 3 months
 Symptomatic HF in prior 6 months
 LVEF <35%

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

Patients randomized in an open label fashion to a group:
 Intensive group (target SBP <120 mm Hg)
 Standard (target SBP 135-139 mm Hg)
Antihypertensives were encouraged per standard practice:
 Thiazide diuretics (primarily chlorthalidone) were encouraged as
first-line agents
 Loop diuretics were encouraged for those with CKD
 Beta-blockers were encouraged for those with CAD
Lifestyle modifications were encouraged
Study medications were provided free of cost to participants

SPRINT Primary Outcome
Composite of
MI
Stroke
Heart failure
Acute coronary syndrome
Cardiovascular death

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

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

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

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

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 (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

1.BLOOD PRESSURE
 At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the
intensive-treatment group and 136.2 mm Hg in the standard-treatment
group, for an average difference of 14.8 mm Hg.
 The mean diastolic blood pressure at 1 year was 68.7 mm Hg in the
intensive-treatment group and 76.3 mm Hg in the standard-treatment
group

 Throughout the 3.26 years of follow-up, the mean systolic
blood pressure was 121.5 mm Hg in the intensive-treatment
group and 134.6 mm Hg in the standard-treatment group
 The relative distribution of antihypertensive medication
classes used was similar in the two groups, though the use
of each class was greater in the intensive-treatment group
 the mean number of bloodpressure medications was 2.8
( intensive ) and 1.8( standard)

3.PRIMARY OUTCOME
 243 – INTENSIVE
 319 – STANDARD
 DIFFERENCES
WERE EVIDENT
FROM 1 YEAR
ONWARDS

CKD
Among participants who had chronic kidney disease
at baseline, the number of participants with a
decrease in the eGFR of 50% or more or reaching
ESRD over the course of the trial did not differ
significantly between the two intervention groups

WITHOUT CKD
 Among participants who did not have chronic kidney disease at
baseline, a decrease in the eGFR of 30% or more to a value of less
than 60 ml per minute per 1.73 m2 occurred more frequently in the
intensive-treatment group than in the standard-treatment group
(1.21% per year vs. 0.35% per year)

DEATHS
 155 – INTENSIVE
 210 – STANDARD
 SEPERATION IS
APPARENT BY THE END
END OF 2 YEARS

SPRINT Power Summary: Primary
Outcomes
 88.7% power to detect a treatment effect of 20% of intensive
BP vs. standard BP
BP vs. standard BP among participants with eGFR of <60
ml/min/1.73m2
at baseline
BP vs. standard BP among participants at least 75 years old
at baseline

RESULTS
 SPRINT group with intensive treatment had lower incidence of
fatal and non-fatal cardio vascular events in comparable to
standard group
 Among participants who had chronic kidney disease at baseline,
the number of participants with a decrease in the eGFR of 50% or
more or reaching ESRD over the course of the trial did not differ
significantly between the two intervention groups

 Among participants who did not have chronic kidney disease
at baseline, a decrease in the eGFR of 30% or more to a
value of less than 60 ml per minute per 1.73 m2 occurred
more frequently in the intensive-treatment group than in the
standard-treatment group (1.21% per year vs. 0.35% per
year).
 Hypotension, Syncope , Hyponatremia were more in
intensive group than in standard group

POTENTIAL 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

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?

ACCORD Results are Mixed
Outcome
Intensive
Events (%/yr)
Standard
Events (%/yr)
CVD (Primary) 208 (1.87) 237 (2.09)
Cardiovascular Deaths 60 (0.52) 58 (0.49)
Total Stroke 36 (0.32) 62 (0.53)

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

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

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.

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.

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.

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.

REFERENCES
1. Hsia
J, et al. "Prehypertension and cardiovascular disease risk in the Women's
Circulation. 2007;115(7):855-860.
2.
Stamler J, et al. "Blood pressure, systolic and diastolic, and cardiovascula
Archives of Internal Medicine. 1993;153(5):598-615.
3. Law MR, et al. "Use of blood pressure lowering drugs in the
prevention of cardiovascular disease: meta-analysis of 147
randomised trials in the context of expectations from
prospective epidemiological studies." BMJ. 2009;338;b1665.
4. SPS3 Study Group. "Blood-pressure targets in patients with
recent lacunar stroke: the SPS3 randomised trial." The Lancet.
2013;382(9891):507-515
5. Roman GC. "Brain hypoperfusion: a critical factor in vascular
dementia." Neurological Research.. 2004;26(5):454-458.

REFERENCES
 Ympa YP, et al. "Has mortality from acute renal failure decreased? A
systematic review of the literature." American Journal of
Medicine. 2005;118(8):827-832.
 Hajjar ER, et al. "Polypharmacy in elderly patients." American Journal
of Geriatric pharmacotherapy. 2007;5(4):345-351.
 Bassler D, et al. "Stopping randomized trials early for benefit and
estimation of treatment effects: Systematic review and meta-regression
analysis." JAMA. 2010;303(12):1180-1187.
 Jump up↑ Perkovic V and Rodgers A. "Editorial: Redefining blood-
pressure targets -- SPRINT starts the marathon." The New England
Journal of Medicine. epub 2015-11-09.

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