Systolic Blood Pressure Intervention Trial

Systolic Blood Pressure Intervention Trial

• SPRINT is an unmasked open-label 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.

• It was sponsored by NIH

SPRINT Networks and Sites

SPRINT Important Goals

SPRINT tested 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)

is able reduce the occurrence of cardiovascular disease (CVD)

Rationale behind 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 was conducted to gain 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

Systolic blood pressure difference between randomised groups (mmHg)

Rel

ativ

e ris

k of

maj

or

CVD

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.

8

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

1281286464

32321616

88

4422

11

SBPSBP

40-49 y40-49 y

Age at risk:Age at risk:

70-79 y70-79 y

60-69 y60-69 y50-59 y50-59 y

80-89 y80-89 y

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

256256

1281286464

32321616

88

4422

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 0.86-1.15MI 0.90 0.74-1.09Stroke 0.99 0.79-1.25CHF 0.88 0.59-1.32Major CV events 0.94 0.83-1.07End-Stage renal

disease (ESRD)

1.01 0.81-1.27

n= 22,089Arguedas 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

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

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

SPRINT Primary Outcome

• Composite of• MI• Stroke• Heart failure• Acute coronary syndrome• Cardiovascular death

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 to 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)• Risk of non-adherence

Subgroups

• Motivated by biologically plausible hypotheses:• CKD vs. non-CKD• <75 vs. 75+ years of age• Black vs. non-black

• Others:• CVD vs. no prior CVD• Gender• SBP tertiles at baseline

Primary Outcomes in Subgroups• Formal tests within subgroups were not

planned• Interactions between subgroup indicators

and intervention arm was tested• Regardless of interaction test, overall

conclusion applies to all subgroups

Event Rate Calculations for Primary Outcome• Based on ALLHAT data provided by ALLHAT,

all three arms not stopped early, without diabetes at baseline

• 4.39 %/yr (using hospitalized angina rather than non-MI ACS)

• Need to modify the rate for the SPRINT population

Modifications from ALLHAT• Factors increasing event rate:

• SPRINT having older participants• Use of Framingham risk score of ≥15%• Oversampling of stage 3 and 4 CKD

• Factors decreasing event rate:• Temporal trend towards reduced rate in other studies• More rigorous definition of non-MI ACS

• Exact impact of these is unclear• To be conservative, ALLHAT’s rate was halved and assumed 2.2

%/yr

Comparison to ACCORD• ACCORD event rate was 2.09 %/yr in standard BP and 1.87

%/yr in intensive BP• ACCORD:

• Excluded people with CKD due to concerns about metformin for glycemia question

• Did not recruit age >80 years in the main trial• Lipid trial enrolled almost all people with low HDL, excluding

these high risk people from the BP trial• Did not include non-fatal heart failure or non-MI acute coronary

syndrome• Thus, SPRINT was believed to have a higher event rate than

ACCORD

SPRINT Assumptions

• The event rate for the SPRINT composite outcome is• 2.2 %/yr in the standard BP arm• 4 %/yr for standard BP participants with eGFR

<60 ml/min/1.73m2

• 3.5 %/yr for standard BP participants ≥75 years old

SPRINT Assumptions, Cont.• Sample sizes (planned):

• 9250 participants in SPRINT (primary outcome and incident dementia)

• 4300 participants with eGFR < 60 ml/min/1.73m2

• 3250 participants ≥75 years old• Uniform recruitment over 2 years• Minimum follow-up is 3 years, 10 months (assumes that

closeout visits occur uniformly over a 4 month period)• Two-sided tests at the 0.05 level are used• Annual loss to follow-up is 2 %/yr

• 3 %/yr for incident dementia

SPRINT Power Summary: Primary Outcomes• 88.7% power to detect a treatment effect of 20% of intensive

BP vs. standard BP• 81.9% power to detect a treatment effect of 20% of intensive

BP vs. standard BP among participants with eGFR of <60 ml/min/1.73m2 at baseline

• 84.5% power to detect a treatment effect of 25% of intensive BP vs. standard BP among participants at least 75 years old at baseline

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

Preliminary Results• Intensive management of SBP to a target of <120 mm Hg

reduced rates of complications of high blood pressure (including heart attacks, heart failure, and stroke)

by 30% and lowered the risk of death by almost

25% as compared to a systolic blood pressure target of <140 mm Hg.

• The interim analyses indicate these results are consistent for the overall study population.

• The subgroup analysis is going on & when completed, the final results will be published in a peer – reviewed journal.

Action taken : Study was stopped due to benefit• The study was monitored by a Data Safety Monitoring Board

(DSMB), which performed interim analyses of study results to look for any indication that one treatment arm was superior to the other.

• Because of the superior benefits of the more intensive blood pressure treatment intervention on the primary outcome and on total mortality, the DSMB recommended unblinding the study and communicating these important results to participants, investigators, and the public.

• NHLBI concurred with this assessment and accordingly ended the blood pressure intervention of SPRINT, notified trial participants and investigators, and has reported publicly these initial findings.

Unanswered Questions• What are the effects of intensive blood pressure lowering on1) dementia and cognitive functioning (SPRINTMIND)2) decline in kidney function ?

• SPRINTMIND study is examining whether the lower blood pressure target will reduce the incidence of dementia, slow the decline in cognitive function, and result in less cerebral small vessel disease (as shown on MRI) compared to those in the standard group.

• Data collection and analysis continue on the SPRINTMIND study as well as to assess kidney outcomes.

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.

• The interim results of the SPRINT study reaffirm the critical importance of blood pressure control as the best approach to reduce the complications of hypertension e.g.heart attacks and strokes.

• Within few months, the final result will be published and it will definitely lead to change of existing guidelines & clinical practice.