IHD mortality (floating absolute risk and 95% CI)

Usual SBP (mm Hg)

IHD, ischemic heart disease. Prospective Studies Collaboration. Lancet. 2002;360:1903-1913.

Ischemic Heart Disease Mortality Rate in Each Decade of Age

120 140 160 180

256

128

64

32

16

8

4

2

1

SBP

40-49 y

Age at risk:

70-79 y

60-69 y

50-59 y

80-89 y

Usual DBP (mm Hg)

70 80 90 110 100

256

128

64

32

16

8

4

2

1

DBP

Incidence of the Primary Outcome (first occurrence of death, nonfatal MI,

or nonfatal stroke) by SBP and DBP Strata in INVEST Trial

Messerli, FH, et. al. Ann Intern Med 2006;144:884-893.

Blo

od

pressu

re (

mm

Hg

)

0 12 36 60 Months of follow-

up

SHEP Average Blood Pressure During Follow-up

24 48

50

65

80

95

110

125

140

155

170

185

200

0

SHEP=Systolic Hypertension in the Elderly Program SHEP Research Group. JAMA. 1991;265:3255-3264. Copyright ©1991, American Medical Association.

0

1

2

3

4

5

6

7

8

9

10

Cu

mu

lati

ve s

tro

ke r

ate

p

er 1

00

perso

ns

0 12 36 60

Months of follow-up

SHEP Cumulative Stroke Rate

24 48 72

P=0.0003

Placebo (n=2,371)

Active Rx (n=2,365)

SHEP=Systolic Hypertension in the Elderly Program SHEP Research Group. JAMA. 1991;265:3255-3264. Copyright ©1991, American Medical Association.

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

Rela

tive r

isk (

95

% C

I)

Stroke CHD

Active Therapy vs. Placebo

CHF Death

0.63

0.46

0.68

0.87

CVD

0.75

SHEP Cardiovascular Disease Endpoints

SHEP Research Group. JAMA. 1991;265:3255-3264.

SHEP=Systolic Hypertension in the Elderly Program

CHD=coronary heart disease; CHF=congestive heart failure; CVD=cardiovascular disease

SYMPTOM Active treatment group Placebo group

Cardiopulmonary - faintness on standing 12.8 10.6

- feelings of unsteadiness or imbalance 33.7 32.9

- loss of consciousness/passing out 2.2 1.3

Psychosocial

- unusual worry or anxiety 25.5 24.1

- problems in sexual function 4.8 3.2

Other - Falls 12.8 10.4

- Fractures 2.4 2.0

SHEP – Prevalance of Troublesome Symptoms

SHEP Syst-Eur Syst-China HYVET

Entry SBP 160-219 160-219 160-219 160-199

Mean Age 72 71 75 84

Goal SBP <145* <150 <150 <150

Baseline 170 174 171 173

Achieved: 142 151 151 144

Treatment

Achieved: control 155 161 160 159

Systolic BP in Large HTN Trials Testing SBP Goals: SHEP, Syst-Eur, Syst-China, HYVET

* Integrated SBP goal, personal communication, Barry Davis SBP = systolic blood pressure

All stroke (30% reduction)

Placebo

IndapamideSR ±perindopril

Indapamide

SR

±perindopril

Placebo

P=0.055

GUIDELINE POPULATION Goal BP, mm

Hg Initial Drug Treatment

Options

2014 JNC8

General ≥ 60 y

General < 60 y

<150/90

<140/90

NONBLACK: thiazide-type diuretic, ACE1, ARB, or CCB BLACK: thiazide‐type diuretic or CCB

ESH/ESC 2013

General nonelderly

General elderly <80 y

General ≥80 y

<140/90

<150/90

<150/90

Diuretic, β‐blocker, CCB, ACEI, or ARB

Guideline Comparisons of Goal BP and Initial Drug

Therapy – JNC8 Report

ACCORD Double 2 x 2 Factorial Design

Intensive

Glycemic

Control 5128

Standard

Glycemic

Control 5123

Lipid BP

Placebo Fibrate Intensive

<120 mm

Standard

<140 mm

2371 2362 2753 2765

1383 1374

1391 1370

1193

1178 1184

1178

10,251

4733* 5518 * 94% power for 20% reduction in event rate, assuming

standard group rate of 4% / yr and 5.6 yrs follow-up

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

The ACCORD TRIAL: Achieved Systolic Blood Pressures Intensive vs. Control Arms

Pa

tie

nts

wit

h E

ve

nts

(%

)

0

5

10

15

20

Years Post-Randomization

0 1 2 3 4 5 6 7 8

Pati

en

ts w

ith

Even

ts (

%)

0

5

10

15

20

Years Post-Randomization

0 1 2 3 4 5 6 7 8

Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death Total Stroke

HR = 0.88 95% CI (0.73-1.06)

HR = 0.59 95% CI (0.39-0.89) NNT for 5 years = 89

Background – SPRINT Senior

• Prevalence of hypertension is > 75% among those 75 years of age or older

• Optimal SBP target especially controversial in older, frail patients

• Observational evidence of inverse relationship between SBP and mortality

• Concerns regarding falls and fall-related injury due to antihypertensive therapy

• Cognitive and quality of life outcomes not certain

17

SPRINT Research Question Randomized controlled clinical trial to examine effect of more

intensive high blood pressure treatment strategy than is

currently recommended (standard treatment)

Target Systolic BP

Intensive Treatment

Goal SBP < 120 mm Hg

Standard Treatment

Goal SBP < 140 mm Hg

SPRINT design details available at: • ClinicalTrials.gov (NCT01206062)

• Ambrosius WT et al. Clin Trials 2014;11:532-546. 18

Major Inclusion Criteria

• ≥50 years old

• Systolic blood pressure: 130 – 180 mm Hg, allowed to be on up to 4 antihypertensive medications depending on SBP

• Additional cardiovascular disease (CVD) risk

• Clinical or subclinical CVD (excluding stroke)

• Chronic kidney disease (CKD), defined as eGFR

20 – <60 ml/min/1.73m2 based on MDRD equation

• Framingham Risk Score for 10-year CVD risk ≥ 15%

• Age ≥ 75 years

At least one of these risk factors

19

BP Interventions • BP monitored monthly for 3 months and every 3

months thereafter (additional visits could be scheduled)

• Antihypertensive medication titration decisions based on mean BP (3 readings at each visit), using a structured stepped-care approach

• Agents from major antihypertensive drug classes available free of charge

• Periodic assessment for orthostatic hypotension and related symptoms

• Intensive participants started on 2 drugs, with option of starting with 1 drug in those 75+ years. 2nd drug then added at second visit if not at goal

• Standard group participants were down-titrated if BP too low.

20

Major Exclusion Criteria

• Stroke

• Diabetes mellitus

• Polycystic kidney disease

• Congestive heart failure (symptoms or EF < 35%)

• Proteinuria >1g/d

• CKD with eGFR < 20 mL/min/1.73m2 (MDRD)

• Adherence concerns

21

Baseline Characteristics

Total N=9361

Intensive N=4678

Standard N=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-yr Framingham CVD risk, % 20.1% 20.1% 20.1%

Not taking antihypertensive meds, % 9.4% 9.2% 9.6%

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) 22

The SPRINT Research Group. N Engl J Med 2015. DOI: 10.1056/NEJMoa1511939

Systolic Blood Pressure in the Two Treatment Groups over the Course of the Trial

Decision to Stop BP Intervention

• On August 20, 2015, NHLBI Director (Dr. Gary Gibbons) accepted the DSMB recommendation to inform SPRINT investigators and participants of CVD results

• Concurrently, decision made to stop BP intervention

• Blinded data for secondary non-CVD outcomes (e.g., dementia and cognitive impairment) being collected at final close-out visit and this process will be completed in 2016

24

The SPRINT Research Group. N Engl J Med 2015. DOI: 10.1056/NEJMoa1511939

Primary Outcome and Death from Any Cause

During Trial: Number Needed to Treat (NNT) to prevent a primary outcome in one participant = 61

During Trial: Number Needed to Treat (NNT) to prevent death in one participant = 90

The SPRINT Research Group. N Engl J Med 2015. DOI: 10.1056/NEJMoa1511939

Forest Plot of Primary Outcome According to Subgroups

Hypertension in the Very Elderly Trial (HYVET)

“We found no evidence of an interaction between baseline FI and treatment with antihypertensives on risk of stroke, death from all causes, or cardiovascular events in very elderly people. Furthermore, the burden of frailty was similar to that seen in population studies.”

Warwick et al. BMC Medicine 2015;13(1):1-8.

Cumulative Hazards for SPRINT Primary Outcome and All-Cause Mortality in Participants 75 and older

HR: 0.67 95% CI (0.51 to 0.86)

NNT = 28 at 3.26 years

HR: 0.68 95% CI (0.50 to 0.92)

NNT = 41 at 3.26 years

Cumulative Hazards for SPRINT Primary Outcome by Frailty Status

HR: 0.23 95% CI: 0.23 to 0.95 HR: 0.63 95% CI: 0.43 to 0.92 HR: 0.68 95% CI: 0.45 to 1.02

Interaction p-value = 0.838

Cumulative Hazards for SPRINT Primary Outcome by Gait Speed

HR: 0.65 95% CI: 0.41 to 1.02 HR: 0.68 95% CI: 0.48 to 0.95

Interaction p-value = 0.732

Serious Adverse Events (SAE) and Conditions of Interest During Follow-up for Participants

75 Years and Older at Randomization

Intensive Standard

N %/yr N %/yr HR p-value

Serious Adverse Events 640 21.6 638 21.7 1.00 0.931

Conditions of Interest

Hypotension 36 0.9 24 0.6 1.55 0.098

Syncope 46 1.2 37 1.0 1.25 0.328

Bradycardia 41 1.1 43 1.1 0.90 0.650

Electrolyte abnormality 58 1.5 41 1.1 1.47 0.061

Injurious Fall 70 1.8 79 2.1 0.91 0.575

Acute Kidney Injury or Acute

Renal Failure 75 2.0 54 1.4 1.40 0.061

N denotes participants with events

Summary and Conclusions

• SPRINT was designed to examine effects of more intensive

antihypertensive therapy than currently recommended

• Rapid and sustained difference in SBP achieved between the 2

treatment arms regardless of age or frailty status

• Trial stopped early, due to CVD & mortality benefit, after a

median follow-up of 3.3 years

• For persons age 75+, incidence of primary outcome (composite

of CVD events) 33% lower in Intensive compared to Standard

Group and all-cause mortality reduced by 32%

• The “number needed to treat” for age 75+ to prevent a primary

outcome event or death during a median follow-up of 3.26 years

was 28 and 41, respectively

Relevance of Frailty to SPRINT

• Translation of clinical trial results into clinical practice

• Concerns about selection biases and generalizability of trial cohorts, especially for geriatric populations

• For example, recruitment for the Hypertension in the Very Elderly Trial (HYVET) mainly from Eastern Europe and China, may not generalize well to Western, developed countries1

• Concern is that trial cohorts are healthier, have less co-morbidity, are less frail, which perhaps limits external validity to clinical practice

1Morley JE. J Am Geriatr Soc 2013;61:1197-8.