Critical Evidence on Lower Systolic BP Goals from SPRINT Trial
1. 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
2. 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)
3. Systolic Blood Pressure
Intervention Trial
• SPRINT is a randomi zed 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.
4. 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
5. 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.
6. 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
7. 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).
8. 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
9. 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
10. 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
11. 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
13. 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.
14. 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.
15. 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.
16. 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.
17. Major Cardiovascular Events
Systolic blood pressure difference
between randomised groups (mmHg)
1.50
1.25
1.00
0.75
0.50
R e la tive r isk o f m a jo r C 0.25
-10 -8 -6 -4 -2 0 2 4
Lancet 2003; 362: 1527–35.
18. 18
Combination Therapy Is Often
Needed to Achieve Target SBP Goals
1 2 3 4
BP Agents (number)
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)
Am J Kidney Dis. 2000;36:646-661.
19. 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.
21. 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
1.01 0.81-1.27
(ESRD)
n= 22,089 Arguedas JA, et al. Cochrane
Database Syst. Rev.
2009:CD004349.
22. 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
23. 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.
24. 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?
26. 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
27. Will the SPRINT Intervention produce an
adequate difference in SBP?
28. ACCORD Systolic Pressures
Average after 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2
Mean # Meds
Intensive: 3.2 3.4 3.5 3.4
Standard: 1.9 2.1 2.2 2.3
N Engl J Med. 2010;362:1575-85
29. 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
30. 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.
32. SPRINT Symposia Speakers
• SPRINT Design – Walter Ambrosius, PhD
• SPRINT and Chronic Kidney Disease – Alfred Cheung, MD
• SPRINT Mind – Jeff Williamson, MD
33. 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.
34. 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)
Points of Emphasis / Key Messages
This figure shows the number of antihypertensive medications required by patients in different clinical trials to achieve target SBP goals. The clinical trials are those that randomly assigned patients to different levels of BP reduction.
On average, 3.2 different antihypertensive medications taken daily are required to achieve the recommended BP goal of &lt;130/80 mm Hg in patients with type 2 diabetes and &lt;130/85 mm Hg in patients with renal insufficiency. The achieved SBPs shown are for the low-pressure groups in these trials.
This figure used data from ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), MDRD (Modification of Dietary Protein in Renal Disease Trial), INVEST (International Verapamil SR-Trandolapril Study), AASK (African-American Study of Kidney Disease and Hypertension), UKPDS (United Kingdom Prospective Diabetes Study), RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan), ABCD (Appropriate Blood Pressure Control in Diabetes), HOT (Hypertension Optimal Treatment), and IDNT (Irbesartan in Diabetic Nephropathy Trial).
Reference
Updated from Bakris GL, Williams M, Dworkin L et al. Preserving renal function in
adults with hypertension and diabetes: a consensus approach. National Kidney Foundation
Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis.
2000;36:646-661.
In 2009, a Cochrane systematic review of the evidence concluded that the evidence did not support a selecting a goal BP of &lt; 140/90
