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 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.

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 1 visit
≥140 mm 2 consecutive visits
Down-titration if:
SBP <130 mm 1 visit
<135 mm 2 consecutive visits

12. 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

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:

17. Major Cardiovascular Events
Relative risk of major CVD
Systolic blood pressure difference
between randomised groups (mmHg)
Lancet 2003; 362: 1527–35.

18. 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)
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 <130/80 mm Hg in patients with type 2 diabetes and <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: 1 2 3 4
BP Agents (number)
Am J Kidney Dis. 2000;36:

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.

20. Ischemic Heart Disease Mortality Rate
in Each Decade of Age
SBP
DBP
Age at risk:
256
256
80-89 y
128
128
70-79 y 64 64
60-69 y 32 32
IHD mortality
(absolute risk and 95% CI)
50-59 y 16 16
40-49 y 8 8 4 4 2 2 1 1
120
140
160
180 70 80 90
100
110
Usual SBP (mm Hg)
Usual DBP (mm Hg)
Lancet. 2002;360:

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 MI
0.90
Stroke
0.99
CHF
0.88
Major CV events
0.94
End-Stage renal disease
(ESRD)
1.01
n= 22,089
In 2009, a Cochrane systematic review of the evidence concluded that the evidence did not support a selecting a goal BP of < 140/90
Arguedas JA, et al. Cochrane Database Syst. Rev. 2009:CD

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?

25. ACCORD Results are Mixed
Outcome
Intensive
Events (%/yr)
Standard
HR (95% CI) P
CVD (Primary)
208 (1.87)
237 (2.09)
0.88 ( )
0.20
Cardiovascular Deaths
60 (0.52)
58 (0.49)
1.06 ( )
0.74
Total Stroke
36 (0.32)
62 (0.53)
0.59 ( )
0.01

26. ACCORD Adverse Events Adverse Events Intensive N (%) Standard P value
Serious AE
77 (3.3)
30 (1.3)
<0.0001
Hypotension
17 (0.7)
1 (0.04)
Syncope
12 (0.5)
5 (0.2)
0.10
Bradycardia or Arrhythmia
3 (0.1)
0.02
Hyperkalemia
9 (0.4)
0.01
Renal Failure
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:

27. Will the SPRINT Intervention produce an adequate difference in SBP?

28. ACCORD Systolic Pressures
Mean # Meds
Intensive:
Standard:
Average after 1st year: Standard vs Intensive, Delta = 14.2
N Engl J Med. 2010;362: 28

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.

31. For more information
Visit

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)

35. Questions