the sprint study

THE SPRINT STUDY :
NEW TARGETS FOR BP CONTROL
Vasilios Papademetriou, MD
Professor of Medicine
Georgetown University
SYSTOLIC BLOOD PRESSURE
INTERVENTION TRIAL: SPRINT
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Preliminary results announced August 20th 2015
Late breaking Trials at AHA ..75 min of presentations
Published along with five related papers in the NEJM
Selected as the best of “15 Notable Articles for 2015” in
NEJM
 NHLBI declared: “Landmark NIH study show s intensive BP
management saves lives”
 It w ill change Medical Practice , it will change guidelines
 WHY???
W HYS IS SPRINT IMPORTANT
 Addressed an important question:
 Is SBP<120 mmHg better <140 mmHg
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Implications for patient’s health and outcomes
Cost
Pharmaceuticals, more medicine be used
Health care system, more visits to Drs
It was
It was
It was
Settle
a well planned and well executed study
NOT a drug study
sponsored by NIH-NHLBI
the debate about appropriate BP targets
SPRINT in historical perspective
Prevalence of high blood pressure in adults ≥20 years of age by age and sex (National Health
and Nutrition Examination Survey: 2007–2012).
Dariush Mozaffarian et al. Circulation. 2016;133:e38-e360
Copyright © American Heart Association, Inc. All rights reserved.
Extent of awareness, treatment, and control of high blood pressure by age (National Health and
Nutrition Examination Survey: 2007–2012).
Dariush Mozaffarian et al. Circulation. 2016;133:e38-e360
Copyright © American Heart Association, Inc. All rights reserved.
US age-standardized death rates* attributable to
cardiovascular diseases, 2000 to 2013.
Total CV mortality
CHD mortality
Stroke mortality
Dariush Mozaffarian et al. Circulation. 2016;133:e38-e360
Copyright © American Heart Association, Inc. All rights reserved.
US age-standardized death rates* attributable to
cardiovascular disease by race/ethnicity, 2000 to 2013.
Black
White
Dariush Mozaffarian et al. Circulation. 2016;133:e38-e360
Copyright © American Heart Association, Inc. All rights reserved.
US age-standardized death rates* attributable to stroke by
race/ethnicity, 2000 to 2013.
Black
White
Dariush Mozaffarian et al. Circulation. 2016;133:e38-e360
Copyright © American Heart Association, Inc. All rights reserved.
Cardiovascular disease mortality trends for males and females
(United States: 1979–2013).
Dariush Mozaffarian et al. Circulation. 2016;133:e38-e360
Copyright © American Heart Association, Inc. All rights reserved.
RATES OF BP CONTROL AND
MORTALITY
60
50
40
30
20
10
0
1980 1985 1990 1995 2000 2005 2010 2013
Series 1
EDWARD D. FREIS
In the animal Lab
With his peers
EDWARD D. FREIS
At Georgetown
At the VA Medical Center
Author of landmark VA studies
VA CO-OP STUDIES: ED D. FREIS
Severe HTN
Mild to moderate HTN
ED FREIS
Ed Freis;stoke 1974;5:76-79
Clinical Trials in Hypertension
Should we treat
diastolic HBP?
1960s
2008
1980s
1990-1995
EWPHE
MRC-1
ANHBP-1 SHEP
MRC-2
HAPPHY
MAPHY TOMHS
VA MONORx
CAPPP
STOP-2
2001-2003
2004-
SCOPE
CONVINCE
VALUE
ALLHAT
ASCOT
ANBP2 ACCOMPLISH
LIFE
Syst-Eur
Syst-China
STOP-1
HR Black, 2003.
2000
HOT
UKPDS
HDFP
VA
Cooperative
Studies
1996-1999
Should we treat
DBP in older
persons?
What is the
goal of
treatment?
1970s
What is the
best way to
treat HBP?
Should we
treat ISH in
Can we
older
prevent
persons? hypertension?
INSIGHT
NORDIL
TROPHY
PRINCIPAL RESULTS OF THE HYPERTENSION
OPTIMAL TREATM ENT (HOT) RANDOM ISED TRIAL
SBP: 143,141,139
mmHg
CV Events
15
10
5
0
CV events
<90mmHg
<85mmHg
Lancet 1998; 351: 1755–62
<80mmHg
THE SHEP STUDY
4736 pts >60 yo, SBP=160-219, DBP<90
Meds: Chlorthalidone, atenolol, etc
Matching placebo
Placebo
treatment
JAMA, 1991;265:3255
BENEFIT OF BP CONTROL IN THE
ELDERLY
BENEFIT OF BP CONTROL IN
DIABETICS
BENEFIT OF BP CONTROL IN
PATIENTS WITH PRIOR CV DISEASE
GUIDELINES CHANGED
2009
TREATMENT INITIATION
 In grade 1 hypertensives (SBP 140–159mmHg or DPB
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90–99mmHg) at low and moderate risk, drug therapy
should be started after a suitable period with lifestyle
changes
In grade 2 hypertension or high risk patients (
diabetics or patients with previous events) immediate
treatment is justified
In patients with high normal BP (SBP 130–139mmHg
or DPB 85–89mmHg) no trial evidence is available of
treatment benefits. Life style changes recommended
GUIDELINES
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Lower is better
Earlier is better
Less than 140/90, <130/85, <120/85
<140/90 for ever
<150/90 age>60 yo
2014 JNC 8 GUIDELINES FOR THE
M ANAGEM ENT OF HYPERTENSION IN ADULTS
BLOOD PRESSURE TARGETS
REACTIONS
The JAMA writing group was never
endorsed by NHLBI, ACC or AHA, SPRINT
disproved
Jacksom Wright: The minority view
 Wright JT Jr., Fine LJ, Lackland DT,Ogedegbe G, Dennison Himmelfarb CR.
Evidence supporting a systolic blood pressure goal of less than 150
mmHg in patients aged 60 or older:the minority view. Ann Intern Med
2014;160:499–503.
Alan Gradman : Editorial
 Optimal Blood Pressure Targets in Older Adults. How Low Is
Low Enough?*
Many other societies disagreed
RESULTS FROM THE INVEST STUDY
BARG AL O RE E T AL , J AC C :2 0 1 4 ;64 :78 4-9 5
Wright Jr. JT, Williamson DJ, Whelton PK et al. New Engl J Med. November 9, 2015.
SYSTOLIC BLOOD PRESSURE
INTERVENTION TRIAL: SPRINT
SPRINT Research Question
Examine effect of more intensive high blood pressure treatment
than is currently recommended
Randomized Controlled Trial
Target Systolic BP
Standard Treatment
Goal SBP < 140 mm Hg
Intensive Treatment
Goal SBP < 120 mm Hg
SPRINT design details available at:
• ClinicalTrials.gov (NCT01206062)
• Ambrosius WT et al. Clin. Trials. 2014;11:532-546.
SPRINT: Enrollment and Follow-up Experience
Screened
(N=14,692)
Randomized
(N=9,361)
Intensive Treatment
Standard Treatment
(N=4,678)
(N=4,683)
• Consent withdrawn
• Discontinued intervention
• Lost to follow-up
Analyzed
(Intention to treat)
224
111
154
242
134
121
4,678
4,683
(Vital status assessment: entire cohort)
Demographic and Baseline Characteristics
Mean (SD) age, years
% ≥75 years
Female, %
White, %
African-American, %
Hispanic, %
Prior CVD, %
Mean 10-year Framingham CVD risk, %
Taking antihypertensive meds, %
Mean (SD) number of antihypertensive meds
Mean (SD) Baseline BP, mm Hg
Systolic
Diastolic
Total
N=9361
Intensive
N=4678
Standard
N=4683
67.9 (9.4)
28.2%
35.6%
57.7%
29.9%
10.5%
20.1%
20.1%
90.6%
1.8 (1.0)
67.9 (9.4)
67.9 (9.5)
28.2%
28.2%
36.0%
35.2%
57.7%
57.7%
29.5%
30.4%
10.8%
10.3%
20.1%
20.0%
20.1%
20.1%
90.8%
90.4%
1.8 (1.0)
1.8 (1.0)
139.7 (15.6)
78.1 (11.9)
139.7 (15.8)
139.7 (15.4)
78.2 (11.9)
78.0 (12.0)
Selected Baseline Laboratory Characteristics
Total
N=9361
Intensive
N=4678
Standard
N=4683
Mean (SD) eGFR, mL/min/1.73 m2
71.7 (20.6)
71.8 (20.7)
71.7 (20.5)
% with eGFR<60 mL/min/1.73m2
28.3
28.4
28.1
Mean (SD) Urine albumin/creatinine, mg/g
42.6 (166.3)
44.1 (178.7)
41.1 (152.9)
Mean (SD) Total cholesterol, mg/dL
190.1 (41.2)
190.2 (41.4)
190.0 (40.9)
98.8 (13.5)
98.8 (13.7)
98.8 (13.4)
Mean (SD) Fasting plasma glucose, mg/dL
Pre-specified Subgroups of Special Interest
• Age (<75 vs. ≥75 years)
• Gender (Men vs. Women)
• Race/ethnicity (African-American vs. Non African-American)
• CKD (eGFR <60 vs. ≥60 mL/min/1.73m2)
• CVD (CVD vs. no prior CVD)
• Level of BP (Baseline SBP tertiles: ≤132, 133 to 144, ≥145 mm Hg)-
Primary Outcome and Primary Hypothesis
• Primary outcome
• CVD composite: first occurrence of
• Myocardial infarction (MI)
• Acute coronary syndrome (non-MI ACS)
• Stroke
• Acute decompensated heart failure (HF)
• Cardiovascular disease death
• Primary hypothesis*
• CVD composite event rate lower in intensive
compared to standard treatment
*Estimated power of 88.7% to detect a 20% difference
- based on recruitment of 9,250 participants, 4-6 years of follow-up and loss to follow-up of 2%/year.
Additional Pre specified Outcomes
• All-cause mortality
• Primary outcome + all-cause mortality
• Renal
• Main secondary outcome:
• Participants with CKD at baseline: incidence of decline in eGFR ≥50% or ESRD
• Additional secondary outcomes:
• Participants without CKD at baseline: incidence of decline in eGFR ≥30% (to <60
mL/min/1.73m2)
• Participants with or without CKD at baseline: Incidence of albuminuria
Doubling of urinary
albumin/creatinine
(<10 to >10 mg/g)
Blood Pressure Change During Follow up
Systolic BP During Follow-up
Year 1
Average SBP
Mean SBP
136.2 mm Hg
(During Follow-up)
Mean SBP
121.4 mm Hg
Standard
Intensive
Standard: 134.6 mm Hg
Intensive: 121.5 mm Hg
Average number of
antihypertensive
medications
Number of
participants
Medication Used
SPRINT Primary Outcome
Cumulative Hazard
Hazard Ratio = 0.75 (95% CI: 0.64 to 0.89)
-25%
P<0.001
Standard
(319 events)
Intensive
(243 events)
During Trial (median follow-up = 3.26 years)
Number Needed to Treat (NNT)
to prevent a primary outcome = 61
Number of
Participants
All-cause Mortality
Cumulative Hazard
Hazard Ratio = 0.73 (95% CI: 0.60 to 0.90)
Standard
deaths)
Adapt from Figure 2B in the(210
N Engl
J Med manuscript
During Trial (median follow-up = 3.26 years)
Number Needed to Treat (NNT)
to Prevent a death = 90
-27%
Intensive
(155 deaths)
Include NNT
Number of
Participants
Primary Outcome in the Six
Pre-specified Subgroups of Interest
*Treatment by subgroup interaction
All-cause Mortality in the Six
Pre-specified Subgroups of Interest
*
*p=0.34, after Hommel
adjustment for multiple
comparisons
Primary and Secondary Outcomes and Renal Outcomes
Serious Adverse Events* (SAE) During Follow-up
All SAE reports
Number (%) of Participants
Intensive
Standard
HR (P Value)
1793 (38.3) 1736 (37.1)
1.04 (0.25)
SAEs associated with Specific Conditions of Interest
Hypotension
Electrolyte abnormality
110 (2.4)
107 (2.3)
105 (2.2)
87 (1.9)
144 (3.1)
66 (1.4)
80 (1.7)
110 (2.3)
73 (1.6)
107 (2.3)
1.67 (0.001)
1.33 (0.05)
0.95 (0.71)
1.19 (0.28)
1.35 (0.020)
Acute kidney injury or acute renal failure
193 (4.1)
117 (2.5)
1.66 (<0.001)
Syncope
Injurious fall
Bradycardia
*Fatal or life threatening event, resulting in significant or persistent disability,
requiring or prolonging hospitalization, or judged important medical event.
Number (%) of Patients with electrolyte abnormalities
or orthostatic hypotension
Number (%) of Participants
Intensive
Standard
HR (P Value)
Laboratory Measures1
Sodium <130 mmol/L
180 (3.9)
100 (2.2)
1.76 (<0.001)
Potassium <3.0 mmol/L
114 (2.5)
74 (1.6)
1.50 (0.006)
Potassium >5.5 mmol/l
176 (3.8)
171 (3.7)
1.00 (0.97)
Signs and Symptoms
Orthostatic hypotension2
Orthostatic hypotension with
dizziness
777 (16.6) 857 (18.3)
62 (1.3)
71 (1.5)
0.88 (0.013)
0.85 (0.35)
1. Detected on routine or PRN labs; routine labs drawn quarterly for first year, then q 6 months
2. Drop in SBP ≥20 mmHg or DBP ≥10 mmHg 1 minute after standing (measured at 1, 6, and 12 months and yearly thereafter)
Should Diabetics be Included?
• Strokes were significantly reduced in ACCORD
• All other end-points trended the right direction
• Longer follow-up showed significant reduction of primary
end point and stroke
• ACCORDION extended follow- up for another 5 years
• In 3957 pts of the standard Rx group intensive BP lowering resulted in
• 21% reduction of CV events (P=0.001) and
• test of interaction became significant (P=0.037)
• Diabetics should be recommended for intensive BP reduction
Cushman, Bakris, AHA
SPRINT vs ACCORD
INTENSIVE VS STANDARD TREATMENT OF BP
IN ACCORD CKD AND NON-CKD PATIENTS
CKD group
Non-CKD group
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Papademetriou…Doumas; In preparation
CHANGE IN ANY STROKE IN ACCORD
CKD AND NON-CKD PATIENTS
CKD group
Non-CKD group
P<0.001
CHANGE IN NON-FATAL STROKE IN
ACCORD CKD AND NON-CKD PATIENTS
CKD group
Non-CKD group
P<0.))!
HYPERTENSION: SPRINT
COMENTARIES
THINGS TO KNOW ABOUT SPRINT
 First, the results should not be considered a mandate for people
to run out and get treated so their blood pressures are below
120.
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Age >50 yo
BP 130-180 on meds
Morbidities
Methods of measurement ---tend to be lower
Should patients who did not qualify be included?
 Second, the potential benefits of low ering blood pressure must
be w eighed against harms.
 Decrease CV events
 Increase the risk of Kidney failure
 T hird, w e need more information about the balance of risks and
benefits for each person so that the choice can be personalized.
 T he study will improve awarness
 Better control
 Re-focus on hypertension
GENERALIZABILITY OF SPRINT RESULTS
TO THE U.S. ADULT POPULATION
.
Bress AP et al..; JACC 2016; 67:464-472
GENERALIZABILITY OF SPRINT RESULTS
TO THE U.S. ADULT POPULATION
.
Bress AP et al..; JACC 2016; 67:464-472
GENERALIZABILITY OF SPRINT RESULTS
TO THE U.S. ADULT POPULATION
.
Bress AP et al..; JACC 2016; 67:464-472
GENERALIZABILITY OF SPRINT RESULTS
TO THE U.S. ADULT POPULATION
.
Bress AP et al..; JACC 2016; 67:464-472
SPRINT: TO WHOM DO THE RESULTS
APPLY?
Gradman A: JACC 2016;67:473-6
SPRINT: TO WHOM DO THE RESULTS
APPLY?
May not be quite true
Gradman A: JACC 2016;67:473-6
MORE DATA FROM SPRINT
 SPRINT-MIND
 Mini-mental test at closing---underway
 SPRINT ABPM
 Correlation with events
 Correlation with office BP
 Details of gait, fragility, fractures, renal function
 More that 104 proposals for manuscripts
HOW W ILL SPRINT AFFECT YOUR
PRACTICE
 In every w ay, it w ill change everything
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It
It
It
It
It
It
It
It
will change practice
will change targets; Treat 130 or more, target <120 systolic
will change methods of measurement
may decrease need for home BPs
may decrease need for ABPM
will need more office visits
will need more lab tests
will need more medicine, would it becost-effective?
 It will
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Save lives
Improve morbidity
Decrease hospitalizations and
May save money
Summary-Conclusions
• In SPRINR, intensive therapy resulted in:
• 25% lower primary outcome (composite of CVD events) and
• 27% reduction of all cause mortality compared to Standard Group
• Treatment effect similar in all six pre-specified groups of interest
• The “number needed to treat” to prevent one event was:
• 61 for primary outcome event and
• 90 for any death
• In participants with CKD at baseline, no differences in renal outcomes
• In participants without CKD at baseline, incidence of eGFR reduction ≥ 30%
more common in Intensive Group
• No overall difference in serious adverse events (SAEs) between treatment
groups
• Target BP<120 mmHg should be recommended for all high risk patients
with hypertension ( who can tolerate it) and perhaps for most patients
with DM
• Caution needed for the elderly and/or fragile patients
SPRINT: A LANDMARK STUDY
History of hypertension:
“Before SPRINT and After
SPRINT”
Do no Harm
Grants Wanted for good Research