Systolic Blood Pressure Intervention Trial Goals and Rationale

Systolic Blood Pressure Intervention Trial Goals and Rationale

American Society of HypertensionMay 20, 2012

Karen C. Johnson, MD, MPHUniversity of Tennessee Health Science Center

American Society of Hypertension, Inc. (ASH)

Disclosure of RelationshipsOver 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 GoalsSPRINT 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 MIND will test whether the lower SBP goal influences the occurrence of dementia, change in cognition, and change in brain structure (on MRI).

SPRINT Other Outcomes

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

• 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

SPRINT Standard Intervention

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.



• Previous trials demonstrate effectiveness of treating SBP to about 140 mm Hg but treating to this goal is challenging



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

Systolic blood pressure difference between randomised groups (mmHg)

Rel

ativ

e ri

sk o

f m

ajo

r C

VD

0.25

0.50

0.75

1.00

1.25

1.50

-10 -8 -6 -4 -2 0 2 4

Lancet 2003; 362: 1527–35.

18

Combination Therapy Is Often Needed to Achieve Target SBP

Goals

Am J Kidney Dis. 2000;36:646-661.

BP Agents (number)

Trial (SBP Achieved)

1 2 3 4

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)

IHDIHDmortalitymortality

(absolute risk (absolute risk and 95% CI)and 95% CI)

Usual SBP (mm Hg)Usual SBP (mm Hg)

Lancet. 2002;360:1903-1913.Lancet. 2002;360:1903-1913.

Ischemic Heart Disease Mortality Ischemic Heart Disease Mortality Rate Rate

in Each Decade of Agein Each Decade of Age

120120 140140 160160 180180

256256

128128

6464

3232

1616

88

44

22

11

SBPSBP

40-49 y40-49 y

Age at risk:Age at risk:

70-79 y70-79 y

60-69 y60-69 y

50-59 y50-59 y

80-89 y80-89 y

Usual DBP (mm Hg)Usual DBP (mm Hg)7070 8080 9090 110110100100

256256

128128

6464

3232

1616

88

44

22

11

DBPDBP

Meta-Analysis: Treating to BP Goals Lower Than 140/90 mmHg Does Not Reduce Mortality or Morbidity OUTCOMES RELATIVE

RISK95 % 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

(ESRD)

1.01 0.81-1.27

n= 22,089

Arguedas JA, et al. Cochrane Database Syst. Rev. 2009:CD004349.

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





• 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

OutcomeIntensive

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

ACCORD Adverse EventsAdverse 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

Will the SPRINT Intervention produce an adequate difference in SBP?

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

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 Design – Walter Ambrosius, PhD

• SPRINT and Chronic Kidney Disease – Alfred Cheung, MD

• SPRINT Mind – Jeff Williamson, MD

SPRINT Symposia Speakers

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.

Take Home Message

American Society of Hypertension, Inc. (ASH)

Disclosure of RelationshipsOver 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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Systolic Blood Pressure Intervention Trial Goals and Rationale

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