THE SPRINT STUDY - Livemedia.grstatic.livemedia.gr/livemedia/documents/al18108_us75... · THE...
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THE SPRINT STUDY : NEW TARGETS FOR BP CONTROL
Vasilios Papademetriou, MD
Professor of Medicine
Georgetown University
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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 shows intensive BP
management saves lives”
It will change Medical Practice , it will change guidelines
WHY???
SYSTOLIC BLOOD PRESSURE
INTERVENTION TRIAL: SPRINT
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Addressed an important question:
Is SBP<120 mmHg better <140 mmHg
Implications for patient’s health and outcomes
Cost
Pharmaceuticals, more medicine be used
Health care system, more visits to Drs
It was a well planned and well executed study
It was NOT a drug study
It was sponsored by NIH-NHLBI
Settle the debate about appropriate BP targets
SPRINT in historical perspective
WHYS IS SPRINT IMPORTANT
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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.
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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.
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US age-standardized death rates* attributable to
cardiovascular diseases, 2000 to 2013.
Dariush Mozaffarian et al. Circulation. 2016;133:e38-e360
Copyright © American Heart Association, Inc. All rights reserved.
Total CV mortality
CHD mortality
Stroke mortality
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US age-standardized death rates* attributable to
cardiovascular disease by race/ethnicity, 2000 to 2013.
Dariush Mozaffarian et al. Circulation. 2016;133:e38-e360
Copyright © American Heart Association, Inc. All rights reserved.
Black
White
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US age-standardized death rates* attributable to stroke by
race/ethnicity, 2000 to 2013.
Dariush Mozaffarian et al. Circulation. 2016;133:e38-e360
Copyright © American Heart Association, Inc. All rights reserved.
Black
White
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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.
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0
10
20
30
40
50
60
1980 1985 1990 1995 2000 2005 2010 2013
Series 1
RATES OF BP CONTROL AND
MORTALITY
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EDWARD D. FREIS
In the animal Lab With his peers
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EDWARD D. FREIS
At Georgetown At the VA Medical Center
Author of landmark VA studies
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Severe HTN Mild to moderate HTN
VA CO-OP STUDIES: ED D. FREIS
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ED FREIS
Ed Freis;stoke 1974;5:76-79
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TOMHSVA MONORx
CONVINCE
ALLHAT
ANBP2
LIFE
HAPPHY
MAPHY
INSIGHT
NORDILCAPPP
STOP-2
VALUE
ASCOT
ACCOMPLISH
Clinical Trials in Hypertension
HR Black, 2003.
1960s 1970s 1980s 1990-1995 1996-1999 2000 2001-2003 2004-
2008
Should we treat
diastolic HBP?
What is the
best way to
treat HBP?
Should we treat
DBP in older
persons?
What is the
goal of
treatment?
Should we
treat ISH in
older
persons?
Can we
prevent
hypertension?
VA
Cooperative
Studies
MRC-1
ANHBP-1
EWPHE
MRC-2
STOP-1
SCOPEHDFP HOT
UKPDS
Syst-Eur
Syst-ChinaSHEP
TROPHY
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0
5
10
15
CV events
CV Events
<90mmHg <85mmHg <80mmHg
PRINCIPAL RESULTS OF THE HYPERTENSION
OPTIMAL TREATMENT (HOT) RANDOMISED TRIAL
SBP: 143,141,139
mmHg
Lancet 1998; 351: 1755–62
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THE SHEP STUDY
JAMA, 1991;265:3255
4736 pts >60 yo, SBP=160-219, DBP<90 Meds: Chlorthalidone, atenolol, etc
Matching placebo
Placebo
treatment
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BENEFIT OF BP CONTROL IN THE
ELDERLY
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BENEFIT OF BP CONTROL IN
DIABETICS
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BENEFIT OF BP CONTROL IN
PATIENTS WITH PRIOR CV DISEASE
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GUIDELINES CHANGED
2009
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In grade 1 hypertensives (SBP 140–159mmHg or DPB
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
TREATMENT INITIATION
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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
GUIDELINES
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2014 JNC 8 GUIDELINES FOR THE
MANAGEMENT OF HYPERTENSION IN ADULTS
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BLOOD PRESSURE TARGETS
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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
REACTIONS
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RESULTS FROM THE INVEST STUDY
BARGALORE ET AL,JACC:2014;64:784-95
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Wright Jr. JT, Williamson DJ, Whelton PK et al. New Engl J Med. November 9, 2015.
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SYSTOLIC BLOOD PRESSURE
INTERVENTION TRIAL: SPRINT
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SPRINT Research QuestionExamine effect of more intensive high blood pressure treatment
than is currently recommended
Randomized Controlled Trial
Target Systolic BP
Intensive Treatment Goal SBP < 120 mm Hg
Standard TreatmentGoal SBP < 140 mm Hg
SPRINT design details available at:• ClinicalTrials.gov (NCT01206062)• Ambrosius WT et al. Clin. Trials. 2014;11:532-546.
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SPRINT: Enrollment and Follow-up Experience
Randomized
(N=9,361)
Screened
(N=14,692)
Standard Treatment
(N=4,683)
Intensive Treatment
(N=4,678)
• Consent withdrawn 224 242• Discontinued intervention 111 134• Lost to follow-up 154 121
(Vital status assessment: entire cohort)
Analyzed 4,678 4,683(Intention to treat)
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Demographic and Baseline CharacteristicsTotal
N=9361
IntensiveN=4678
StandardN=4683
Mean (SD) age, years 67.9 (9.4) 67.9 (9.4) 67.9 (9.5)
% ≥75 years 28.2% 28.2% 28.2%
Female, % 35.6% 36.0% 35.2%
White, % 57.7% 57.7% 57.7%
African-American, % 29.9% 29.5% 30.4%
Hispanic, % 10.5% 10.8% 10.3%
Prior CVD, % 20.1% 20.1% 20.0%
Mean 10-year Framingham CVD risk, % 20.1% 20.1% 20.1%
Taking antihypertensive meds, % 90.6% 90.8% 90.4%
Mean (SD) number of antihypertensive meds 1.8 (1.0) 1.8 (1.0) 1.8 (1.0)
Mean (SD) Baseline BP, mm Hg
Systolic 139.7 (15.6) 139.7 (15.8) 139.7 (15.4)
Diastolic 78.1 (11.9) 78.2 (11.9) 78.0 (12.0)
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Selected Baseline Laboratory Characteristics
TotalN=9361
IntensiveN=4678
StandardN=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)
Mean (SD) Fasting plasma glucose, mg/dL 98.8 (13.5) 98.8 (13.7) 98.8 (13.4)
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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)-
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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.
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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 urinaryalbumin/creatinine(<10 to >10 mg/g)
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Systolic BP During Follow-up
Mean SBP136.2 mm Hg
Mean SBP121.4 mm Hg
Average SBP(During Follow-up)
Standard: 134.6 mm Hg
Intensive: 121.5 mm Hg
Average number ofantihypertensivemedications
Number ofparticipants
Standard
Intensive
Year 1
Blood Pressure Change During Follow up
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Medication Used
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Number ofParticipants
Hazard Ratio = 0.75 (95% CI: 0.64 to 0.89)
Standard
Intensive(243 events)
During Trial (median follow-up = 3.26 years)Number Needed to Treat (NNT)
to prevent a primary outcome = 61
SPRINT Primary OutcomeCumulative Hazard
(319 events)
-25%P<0.001
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Adapt from Figure 2B in the N Engl J Med manuscript
Include NNT
All-cause MortalityCumulative Hazard
Hazard Ratio = 0.73 (95% CI: 0.60 to 0.90)
During Trial (median follow-up = 3.26 years)
Number Needed to Treat (NNT)to Prevent a death = 90
Standard(210 deaths)
Intensive(155 deaths)
Number ofParticipants
-27%
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Primary Outcome in the Six Pre-specified Subgroups of Interest
*Treatment by subgroup interaction
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All-cause Mortality in the Six Pre-specified Subgroups of Interest
*
*p=0.34, after Hommeladjustment for multiplecomparisons
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Primary and Secondary Outcomes and Renal Outcomes
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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 110 (2.4) 66 (1.4) 1.67 (0.001)
Syncope 107 (2.3) 80 (1.7) 1.33 (0.05)
Injurious fall 105 (2.2) 110 (2.3) 0.95 (0.71)Bradycardia 87 (1.9) 73 (1.6) 1.19 (0.28)
Electrolyte abnormality 144 (3.1) 107 (2.3) 1.35 (0.020)
Acute kidney injury or acute renal failure 193 (4.1) 117 (2.5) 1.66 (<0.001)
*Fatal or life threatening event, resulting in significant or persistent disability,requiring or prolonging hospitalization, or judged important medical event.
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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 777 (16.6) 857 (18.3) 0.88 (0.013)
Orthostatic hypotension with
dizziness 62 (1.3) 71 (1.5) 0.85 (0.35)
1. Detected on routine or PRN labs; routine labs drawn quarterly for first year, then q 6 months2. Drop in SBP ≥20 mmHg or DBP ≥10 mmHg 1 minute after standing (measured at 1, 6, and 12 months and yearly thereafter)
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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
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SPRINT vs ACCORD
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CKD group
Non-CKD group
INTENSIVE VS STANDARD TREATMENT OF BP
IN ACCORD CKD AND NON-CKD PATIENTS
Papademetriou…Doumas; In preparation
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CKD group Non-CKD group
CHANGE IN ANY STROKE IN ACCORD
CKD AND NON-CKD PATIENTS
P<0.001
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CKD group Non-CKD group
CHANGE IN NON-FATAL STROKE IN
ACCORD CKD AND NON-CKD PATIENTS
P<0.))!
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HYPERTENSION: SPRINT
COMENTARIES
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First, the results should not be considered a mandate for people to run out and get treated so their blood pressures are below 120. 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 lowering blood pressure must be weighed against harms. Decrease CV events
Increase the risk of Kidney failure
Third, we need more information about the balance of risks and benefits for each person so that the choice can be personalized. The study will improve awarness
Better control
Re-focus on hypertension
THINGS TO KNOW ABOUT SPRINT
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GENERALIZABILITY OF SPRINT RESULTS
TO THE U.S. ADULT POPULATION
Bress AP et al..; JACC 2016; 67:464-472
.
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GENERALIZABILITY OF SPRINT RESULTS
TO THE U.S. ADULT POPULATION
Bress AP et al..; JACC 2016; 67:464-472
.
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GENERALIZABILITY OF SPRINT RESULTS
TO THE U.S. ADULT POPULATION
Bress AP et al..; JACC 2016; 67:464-472
.
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GENERALIZABILITY OF SPRINT RESULTS
TO THE U.S. ADULT POPULATION
Bress AP et al..; JACC 2016; 67:464-472
.
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SPRINT: TO WHOM DO THE RESULTS
APPLY?
Gradman A: JACC 2016;67:473-6
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SPRINT: TO WHOM DO THE RESULTS
APPLY?
Gradman A: JACC 2016;67:473-6May not be quite true
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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
MORE DATA FROM SPRINT
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In every way, it will change everything
It will change practice
It will change targets; Treat 130 or more, target <120 systolic
It will change methods of measurement
It may decrease need for home BPs
It may decrease need for ABPM
It will need more office visits
It will need more lab tests
It will need more medicine, would it becost-effective?
It will
Save lives
Improve morbidity
Decrease hospitalizations and
May save money
HOW WILL SPRINT AFFECT YOUR
PRACTICE
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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
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History of hypertension:
“Before SPRINT and After
SPRINT”
SPRINT: A LANDMARK STUDY
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Do no Harm
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Grants Wanted for good Research