Goals and Rationale

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Systolic Blood Pressure Intervention Trial
Goals and Rationale
American Society of Hypertension
May 20, 2012
Karen C. Johnson, MD, MPH
University of Tennessee Health Science Center
American Society of Hypertension, Inc. (ASH)
Disclosure of Relationships
Over the past 12 months Karen C. Johnson MD, MPH has received
grant funds from the National Heart Lung and Blood Institute (NHLBI)
and the National Institute of Diabetes, Digestive, and Kidney Disease
(NIDDK) of National Institutes of Health (NIH)
Systolic Blood Pressure
Intervention Trial
• SPRINT is a 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.
SPRINT Important Goals
SPRINT will test 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)
will reduce the occurrence of cardiovascular
disease (CVD).
N = 9250
SPRINT Primary Outcome
• Composite of
– MI
– Stroke
– Heart failure
– Acute coronary syndrome
– Cardiovascular death
The primary hypothesis is that CVD event rates will
be lower in the intensive intervention arm.
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 Other Outcomes
SPRINT MIND will test whether the lower SBP
goal influences the occurrence of dementia,
change in cognition, and change in brain
structure (on MRI).
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
Major Exclusion Criteria
•
•
•
•
•
•
Stroke
Diabetes
Congestive heart failure (symptoms or EF < 35%)
Proteinuria >1g/d
CKD with eGFR < 20 mL/min/1.73m2 (MDRD)
Adherence flags
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
Why is NIH Conducting 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 will provide critical evidence regarding feasibility
and benefits and potential risks of more intensive BP
control.
Why is NIH Conducting 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 will provide critical evidence regarding feasibility
and benefits and potential risks of more intensive BP
control.
Why is NIH Conducting 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 but treating to this goal is challenging
• Observational studies suggest benefits of SBP lowering may
extend to levels below 120 mm Hg.
• SPRINT will provide critical evidence regarding feasibility and
benefits and potential risks of more intensive BP control.
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.
Major Cardiovascular Events
1.50
1.25
1.00
0.75
0.50
0.25
-10
-8
-6
-4
-2
0
Systolic blood pressure difference
between randomised groups (mmHg)
Lancet 2003; 362: 1527–35.
2
4
Combination Therapy Is Often Needed
to
Achieve
Target
SBP
Goals
Trial (SBP Achieved)
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)
1
2
3
4
BP Agents (number)
Am J Kidney Dis. 2000;36:646-661.
18
Why is NIH Conducting 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 will provide critical evidence regarding feasibility
and benefits and potential risks of more intensive BP
control.
Ischemic Heart Disease Mortality Rate
in Each Decade of Age
SBP
DBP
Age at risk:
80-89 y
256
256
128
128
70-79 y
64
64
60-69 y
32
IHD
mortality 16
(absolute risk 8
and 95% CI)
4
32
16
50-59 y
2
2
1
1
40-49 y
8
4
120 140 160 180
Usual SBP (mm Hg)
Lancet. 2002;360:1903-1913.
70 80 90 100 110
Usual DBP (mm Hg)
Meta-Analysis: Treating to BP Goals Lower Than
140/90 mmHg Does Not Reduce Mortality or
Morbidity
OUTCOMES
Total mortality
MI
Stroke
CHF
Major CV events
End-Stage renal disease
(ESRD)
RELATIVE RISK
0.92
0.90
0.99
0.88
0.94
1.01
n= 22,089
Arguedas JA, et al. Cochrane
Database Syst. Rev.
2009:CD004349.
95 % CI
0.86-1.15
0.74-1.09
0.79-1.25
0.59-1.32
0.83-1.07
0.81-1.27
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
Why is NIH Conducting 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 will provide critical evidence regarding feasibility of
lowering blood pressure to lower goals and benefits and
potential risks of more intensive BP control.
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
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
Outcome
ACCORD Adverse Events
Intensive
N (%)
77 (3.3)
Standard
N (%)
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
Adverse Events
Serious AE
N Engl J Med. 2010;362:1575-85
P value
Will the SPRINT Intervention produce an
adequate difference in SBP?
Mean # Meds
Intensive:
Standard:
ACCORD Systolic Pressures
3.2
1.9
3.4
2.1
3.5
2.2
3.4
2.3
Average after 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2
N Engl J Med. 2010;362:1575-85
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
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.
• More intensive control of SBP might prevent strokes,
CVD, dementia, and progression of chronic kidney
disease.
• SPRINT will provide critical evidence on these important
questions.
For more information
• Visit www.SPRINTTrial.org
SPRINT Symposia Speakers
• SPRINT Design – Walter Ambrosius, PhD
• SPRINT and Chronic Kidney Disease – Alfred Cheung, MD
• SPRINT Mind – Jeff Williamson, MD
Take Home Message
Evidence from previous studies suggests
that the benefits to treating to a lower
systolic blood pressure goal outweigh the
risk but this has not been tested in a clinical
trial setting in persons at high risk for CVD.
SPRINT is designed to test this lower
systolic blood pressure goal of < 120 mm
Hg.
American Society of Hypertension, Inc. (ASH)
Disclosure of Relationships
Over the past 12 months Karen C. Johnson MD, MPH has received
grant funds from the National Heart Lung and Blood Institute (NHLBI)
and the National Institute of Diabetes, Digestive, and Kidney Disease
(NIDDK) of National Institutes of Health (NIH)
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