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THE SPRINT STUDY : NEW TARGETS FOR BP CONTROL

Vasilios Papademetriou, MD

Professor of Medicine

Georgetown University

Preliminary results announced August 20th 2015

Late breaking Trials at AHA ..75 min of presentations

Published along with five related papers in the NEJM

Selected as the best of “15 Notable Articles for 2015” in

NHLBI declared: “Landmark NIH study shows intensive BP

management saves lives”

It will change Medical Practice , it will change guidelines

WHY???

SYSTOLIC BLOOD PRESSURE

INTERVENTION TRIAL: SPRINT

Addressed an important question:

Is SBP<120 mmHg better <140 mmHg

Implications for patient’s health and outcomes

Pharmaceuticals, more medicine be used

Health care system, more visits to Drs

It was a well planned and well executed study

It was NOT a drug study

It was sponsored by NIH-NHLBI

Settle the debate about appropriate BP targets

SPRINT in historical perspective

WHYS IS SPRINT IMPORTANT

Prevalence of high blood pressure in adults ≥20 years of age by age and sex (National Health

and Nutrition Examination Survey: 2007–2012).

Dariush Mozaffarian et al. Circulation. 2016;133:e38-e360

Extent of awareness, treatment, and control of high blood pressure by age (National Health and

Nutrition Examination Survey: 2007–2012).

US age-standardized death rates* attributable to

cardiovascular diseases, 2000 to 2013.

Total CV mortality

CHD mortality

Stroke mortality

US age-standardized death rates* attributable to

cardiovascular disease by race/ethnicity, 2000 to 2013.

US age-standardized death rates* attributable to stroke by

race/ethnicity, 2000 to 2013.

Cardiovascular disease mortality trends for males and females

(United States: 1979–2013).

1980 1985 1990 1995 2000 2005 2010 2013

Series 1

RATES OF BP CONTROL AND

MORTALITY

EDWARD D. FREIS

In the animal Lab With his peers

EDWARD D. FREIS

At Georgetown At the VA Medical Center

Author of landmark VA studies

Severe HTN Mild to moderate HTN

VA CO-OP STUDIES: ED D. FREIS

ED FREIS

Ed Freis;stoke 1974;5:76-79

TOMHSVA MONORx

CONVINCE

ALLHAT

HAPPHY

INSIGHT

NORDILCAPPP

STOP-2

ACCOMPLISH

Clinical Trials in Hypertension

HR Black, 2003.

1960s 1970s 1980s 1990-1995 1996-1999 2000 2001-2003 2004-

Should we treat

diastolic HBP?

What is the

best way to

treat HBP?

Should we treat

DBP in older

persons?

What is the

goal of

treatment?

Should we

treat ISH in

persons?

Can we

prevent

hypertension?

Cooperative

Studies

ANHBP-1

STOP-1

SCOPEHDFP HOT

Syst-Eur

Syst-ChinaSHEP

TROPHY

CV events

CV Events

<90mmHg <85mmHg <80mmHg

PRINCIPAL RESULTS OF THE HYPERTENSION

OPTIMAL TREATMENT (HOT) RANDOMISED TRIAL

SBP: 143,141,139

Lancet 1998; 351: 1755–62

THE SHEP STUDY

JAMA, 1991;265:3255

4736 pts >60 yo, SBP=160-219, DBP<90 Meds: Chlorthalidone, atenolol, etc

Matching placebo

Placebo

treatment

BENEFIT OF BP CONTROL IN THE

ELDERLY

BENEFIT OF BP CONTROL IN

DIABETICS

BENEFIT OF BP CONTROL IN

PATIENTS WITH PRIOR CV DISEASE

GUIDELINES CHANGED

In grade 1 hypertensives (SBP 140–159mmHg or DPB

90–99mmHg) at low and moderate risk, drug therapy

should be started after a suitable period with lifestyle

changes

In grade 2 hypertension or high risk patients (

diabetics or patients with previous events) immediate

treatment is justified

In patients with high normal BP (SBP 130–139mmHg

or DPB 85–89mmHg) no trial evidence is available of

treatment benefits. Life style changes recommended

TREATMENT INITIATION

Lower is better

Earlier is better

Less than 140/90, <130/85, <120/85

<140/90 for ever

<150/90 age>60 yo

GUIDELINES

2014 JNC 8 GUIDELINES FOR THE

MANAGEMENT OF HYPERTENSION IN ADULTS

BLOOD PRESSURE TARGETS

The JAMA writing group was never endorsed by NHLBI, ACC or AHA, SPRINT disproved

Jacksom Wright: The minority view Wright JT Jr., Fine LJ, Lackland DT,Ogedegbe G, Dennison Himmelfarb CR.

Evidence supporting a systolic blood pressure goal of less than 150 mmHg in patients aged 60 or older:the minority view. Ann Intern Med 2014;160:499–503.

Alan Gradman : Editorial Optimal Blood Pressure Targets in Older Adults. How Low Is

Low Enough?*

Many other societies disagreed

REACTIONS

RESULTS FROM THE INVEST STUDY

BARGALORE ET AL,JACC:2014;64:784-95

Wright Jr. JT, Williamson DJ, Whelton PK et al. New Engl J Med. November 9, 2015.

SYSTOLIC BLOOD PRESSURE

INTERVENTION TRIAL: SPRINT

SPRINT Research QuestionExamine effect of more intensive high blood pressure treatment

than is currently recommended

Randomized Controlled Trial

Target Systolic BP

Intensive Treatment Goal SBP < 120 mm Hg

Standard TreatmentGoal SBP < 140 mm Hg

SPRINT design details available at:• ClinicalTrials.gov (NCT01206062)• Ambrosius WT et al. Clin. Trials. 2014;11:532-546.

SPRINT: Enrollment and Follow-up Experience

Randomized

(N=9,361)

Screened

(N=14,692)

Standard Treatment

(N=4,683)

Intensive Treatment

(N=4,678)

• Consent withdrawn 224 242• Discontinued intervention 111 134• Lost to follow-up 154 121

(Vital status assessment: entire cohort)

Analyzed 4,678 4,683(Intention to treat)

Demographic and Baseline CharacteristicsTotal

N=9361

IntensiveN=4678

StandardN=4683

Mean (SD) age, years 67.9 (9.4) 67.9 (9.4) 67.9 (9.5)

% ≥75 years 28.2% 28.2% 28.2%

Female, % 35.6% 36.0% 35.2%

White, % 57.7% 57.7% 57.7%

African-American, % 29.9% 29.5% 30.4%

Hispanic, % 10.5% 10.8% 10.3%

Prior CVD, % 20.1% 20.1% 20.0%

Mean 10-year Framingham CVD risk, % 20.1% 20.1% 20.1%

Taking antihypertensive meds, % 90.6% 90.8% 90.4%

Mean (SD) number of antihypertensive meds 1.8 (1.0) 1.8 (1.0) 1.8 (1.0)

Mean (SD) Baseline BP, mm Hg

Systolic 139.7 (15.6) 139.7 (15.8) 139.7 (15.4)

Diastolic 78.1 (11.9) 78.2 (11.9) 78.0 (12.0)

Selected Baseline Laboratory Characteristics

TotalN=9361

IntensiveN=4678

StandardN=4683

Mean (SD) eGFR, mL/min/1.73 m2 71.7 (20.6) 71.8 (20.7) 71.7 (20.5)

% with eGFR<60 mL/min/1.73m2 28.3 28.4 28.1

Mean (SD) Urine albumin/creatinine, mg/g 42.6 (166.3) 44.1 (178.7) 41.1 (152.9)

Mean (SD) Total cholesterol, mg/dL 190.1 (41.2) 190.2 (41.4) 190.0 (40.9)

Mean (SD) Fasting plasma glucose, mg/dL 98.8 (13.5) 98.8 (13.7) 98.8 (13.4)

Pre-specified Subgroups of Special Interest

• Age (<75 vs. ≥75 years)

• Gender (Men vs. Women)

• Race/ethnicity (African-American vs. Non African-American)

• CKD (eGFR <60 vs. ≥60 mL/min/1.73m2)

• CVD (CVD vs. no prior CVD)

• Level of BP (Baseline SBP tertiles: ≤132, 133 to 144, ≥145 mm Hg)-

Primary Outcome and Primary Hypothesis

• Primary outcome• CVD composite: first occurrence of

• Myocardial infarction (MI)

• Acute coronary syndrome (non-MI ACS)

• Stroke

• Acute decompensated heart failure (HF)

• Cardiovascular disease death

• Primary hypothesis*• CVD composite event rate lower in intensive

compared to standard treatment

*Estimated power of 88.7% to detect a 20% difference- based on recruitment of 9,250 participants, 4-6 years of follow-up and loss to follow-up of 2%/year.

Additional Pre specified Outcomes

• All-cause mortality

• Primary outcome + all-cause mortality

• Renal• Main secondary outcome:

• Participants with CKD at baseline: incidence of decline in eGFR ≥50% or ESRD

• Additional secondary outcomes:• Participants without CKD at baseline: incidence of decline in eGFR ≥30% (to <60

mL/min/1.73m2)

• Participants with or without CKD at baseline: Incidence of albuminuria Doubling of urinaryalbumin/creatinine(<10 to >10 mg/g)

Systolic BP During Follow-up

Mean SBP136.2 mm Hg

Mean SBP121.4 mm Hg

Average SBP(During Follow-up)

Standard: 134.6 mm Hg

Intensive: 121.5 mm Hg

Average number ofantihypertensivemedications

Number ofparticipants

Standard

Intensive

Year 1

Blood Pressure Change During Follow up

Medication Used

Number ofParticipants

Hazard Ratio = 0.75 (95% CI: 0.64 to 0.89)

Standard

Intensive(243 events)

During Trial (median follow-up = 3.26 years)Number Needed to Treat (NNT)

to prevent a primary outcome = 61

SPRINT Primary OutcomeCumulative Hazard

(319 events)

-25%P<0.001

Adapt from Figure 2B in the N Engl J Med manuscript

Include NNT

All-cause MortalityCumulative Hazard

Hazard Ratio = 0.73 (95% CI: 0.60 to 0.90)

During Trial (median follow-up = 3.26 years)

Number Needed to Treat (NNT)to Prevent a death = 90

Standard(210 deaths)

Intensive(155 deaths)

Number ofParticipants

Primary Outcome in the Six Pre-specified Subgroups of Interest

*Treatment by subgroup interaction

All-cause Mortality in the Six Pre-specified Subgroups of Interest

*p=0.34, after Hommeladjustment for multiplecomparisons

Primary and Secondary Outcomes and Renal Outcomes

Serious Adverse Events* (SAE) During Follow-up

All SAE reports

Number (%) of Participants

Intensive Standard HR (P Value)

1793 (38.3) 1736 (37.1) 1.04 (0.25)

SAEs associated with Specific Conditions of Interest

Hypotension 110 (2.4) 66 (1.4) 1.67 (0.001)

Syncope 107 (2.3) 80 (1.7) 1.33 (0.05)

Injurious fall 105 (2.2) 110 (2.3) 0.95 (0.71)Bradycardia 87 (1.9) 73 (1.6) 1.19 (0.28)

Electrolyte abnormality 144 (3.1) 107 (2.3) 1.35 (0.020)

Acute kidney injury or acute renal failure 193 (4.1) 117 (2.5) 1.66 (<0.001)

*Fatal or life threatening event, resulting in significant or persistent disability,requiring or prolonging hospitalization, or judged important medical event.

Number (%) of Patients with electrolyte abnormalities

or orthostatic hypotension

Number (%) of Participants

Intensive Standard HR (P Value)

Laboratory Measures1

Sodium <130 mmol/L 180 (3.9) 100 (2.2) 1.76 (<0.001)

Potassium <3.0 mmol/L 114 (2.5) 74 (1.6) 1.50 (0.006)

Potassium >5.5 mmol/l 176 (3.8) 171 (3.7) 1.00 (0.97)

Signs and Symptoms

Orthostatic hypotension2 777 (16.6) 857 (18.3) 0.88 (0.013)

Orthostatic hypotension with

dizziness 62 (1.3) 71 (1.5) 0.85 (0.35)

1. Detected on routine or PRN labs; routine labs drawn quarterly for first year, then q 6 months2. Drop in SBP ≥20 mmHg or DBP ≥10 mmHg 1 minute after standing (measured at 1, 6, and 12 months and yearly thereafter)

Should Diabetics be Included?

• Strokes were significantly reduced in ACCORD• All other end-points trended the right direction

• Longer follow-up showed significant reduction of primary end point and stroke

• ACCORDION extended follow- up for another 5 years• In 3957 pts of the standard Rx group intensive BP lowering resulted in

• 21% reduction of CV events (P=0.001) and • test of interaction became significant (P=0.037)

• Diabetics should be recommended for intensive BP reduction

Cushman, Bakris, AHA

SPRINT vs ACCORD

CKD group

Non-CKD group

INTENSIVE VS STANDARD TREATMENT OF BP

IN ACCORD CKD AND NON-CKD PATIENTS

Papademetriou…Doumas; In preparation

CKD group Non-CKD group

CHANGE IN ANY STROKE IN ACCORD

CKD AND NON-CKD PATIENTS

P<0.001

CKD group Non-CKD group

CHANGE IN NON-FATAL STROKE IN

ACCORD CKD AND NON-CKD PATIENTS

P<0.))!

HYPERTENSION: SPRINT

COMENTARIES

First, the results should not be considered a mandate for people to run out and get treated so their blood pressures are below 120. Age >50 yo

BP 130-180 on meds

Morbidities

Methods of measurement---tend to be lower

Should patients who did not qualify be included?

Second, the potential benefits of lowering blood pressure must be weighed against harms. Decrease CV events

Increase the risk of Kidney failure

Third, we need more information about the balance of risks and benefits for each person so that the choice can be personalized. The study will improve awarness

Better control

Re-focus on hypertension

THINGS TO KNOW ABOUT SPRINT

GENERALIZABILITY OF SPRINT RESULTS

TO THE U.S. ADULT POPULATION

Bress AP et al..; JACC 2016; 67:464-472

SPRINT: TO WHOM DO THE RESULTS

APPLY?

Gradman A: JACC 2016;67:473-6

SPRINT: TO WHOM DO THE RESULTS

APPLY?

Gradman A: JACC 2016;67:473-6May not be quite true

SPRINT-MIND

Mini-mental test at closing---underway

SPRINT ABPM

Correlation with events

Correlation with office BP

Details of gait, fragility, fractures, renal function

More that 104 proposals for manuscripts

MORE DATA FROM SPRINT

In every way, it will change everything

It will change practice

It will change targets; Treat 130 or more, target <120 systolic

It will change methods of measurement

It may decrease need for home BPs

It may decrease need for ABPM

It will need more office visits

It will need more lab tests

It will need more medicine, would it becost-effective?

It will

Save lives

Improve morbidity

Decrease hospitalizations and

May save money

HOW WILL SPRINT AFFECT YOUR

PRACTICE

Summary-Conclusions• In SPRINR, intensive therapy resulted in:

• 25% lower primary outcome (composite of CVD events) and

• 27% reduction of all cause mortality compared to Standard Group

• Treatment effect similar in all six pre-specified groups of interest

• The “number needed to treat” to prevent one event was:• 61 for primary outcome event and

• 90 for any death

• In participants with CKD at baseline, no differences in renal outcomes

• In participants without CKD at baseline, incidence of eGFR reduction ≥ 30% more common in Intensive Group

• No overall difference in serious adverse events (SAEs) between treatment groups

• Target BP<120 mmHg should be recommended for all high risk patients with hypertension ( who can tolerate it) and perhaps for most patients with DM

• Caution needed for the elderly and/or fragile patients

History of hypertension:

“Before SPRINT and After

SPRINT”

SPRINT: A LANDMARK STUDY

Do no Harm

Grants Wanted for good Research

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