Implications of SPRINT and Intensive Blood … of SPRINT and Intensive Blood Pressure Management ......

Implications of SPRINT and Intensive Blood Pressure Management

Matthew Sorrentino MD FACC FASH Professor of Medicine University of Chicago Section of Cardiology [email protected]

Ischemic Heart Disease Risk Increases

with SBP, DBP, and Age

CI, confidence interval; IHD, ischemic heart disease.

Lewington S, et al. Lancet. 2002;360(9349):1903-1913.

Systolic Blood Pressure

40-49 years

50-59 years

60-69 years

70-79 years

80-89 years

Age at risk:

IHD

mortality

(floating

absolute

risk and

95% CI)

256

128

64

32

16

8

4

2

1

120 140 160 180

Usual SBP (mm Hg)

Diastolic Blood Pressure

256

128

64

32

16

8

4

2

1

70 80 90 100 110

Usual DBP (mm Hg)

Age at risk:

40-49 years

50-59 years

60-69 years

70-79 years

80-89 years

LIFESTYLE MODIFICATIONS

Not at Goal BP (<140/90 mm Hg or <130/80 mm Hg for

diabetes/CKD)*

Without Compelling Indications With Compelling Indications

Stage 1 Hypertension Thiazide-type diuretics for

most; may consider ACEI, ARB, BB, CCB,

or combination.

Stage 2 Hypertension 2-drug combinations for

most (usually thiazide-type diuretics and ACEI,

or ARB, or BB, or CCB).

Drug(s) for Compelling Indications

Other antihypertensive drugs (diuretic, ACEI, ARB,

BB, CCB) as needed.

If not at goal BP, optimize dosages or add additional drugs until

goal BP is achieved. Consider consultation with hypertension specialist.

INITIAL DRUG CHOICES

Algorithm for Hypertension

Modified from Chobanian AV et al. JNC 7: Complete Report.

*150/90 aged 60 or older (Panel members JNC 8)

HOT Trial: BP Control Reduces Cardiovascular Events in Diabetics

Hansson L, et al. Lancet. 1998;351:1755–1762.

Majo

r C

V e

ven

ts*

1000 p

ati

en

t-yrs

30

25

20

15

10

5

0

P < .005

24.4

18.6

11.9

*includes all myocardial infarction, all strokes, and all other CV deaths

Diabetes Subgroup Target

Diastolic

BP

(mmHg)

Number of

Patients

Achieved†

Systolic

BP

(mmHg)

Achieved†

Diastolic

BP

(mmHg)

90 501 143.7 85.2

85 501 141.4 83.2

80 499 139.7 81.1

† Achieved = Mean of all BPs from 6 months

of follow-up to end of study

HOPE Study

The Heart Outcomes Prevention Evaluation (HOPE) Study was a multicenter, randomized trial enrolling 9,297 patients 55 years old with a history of cardiovascular disease, or diabetes plus at least one other cardiovascular risk factor

Patients were treated with ramipril 10 mg daily or placebo for an average of 4.5 years

Combined primary endpoint was the development of myocardial infarction, stroke, or cardiovascular death

Blood pressure in both groups at randomization was 139/79. Blood pressure at end of study was 136/76 in the ramipril group; 139/77 in the placebo group

Yusuf S, et al. N Engl J Med. 2000;342:145-153.

HOPE Study Outcomes: Events Per Patient Group

0

5

10

15

20

Placebo Ramipril

Combined Primary

Outcome*

Cardio- vascular

Death

Myocardial Infarction

Stroke Non-Cardiovascular

Death

Total Mortality

Yusuf S, et al. N Engl J Med. 2000;342:145-153.

RR=22% P<0.001

RR=26% P<0.001

RR=20% P<0.001

RR=32% P<0.001

RR=16% P=0.005

RR=0% P=NS

RR=Relative risk reduction

*The occurrence of myocardial infarction, stroke or cardiovascular death

24 Months

Prospective, Randomized, Double Blind, Multicenter

PTCA & Angiogram

2000 Patients

QCA

Endpoints: CHD Death, Resuscitated Arrest, Nonfatal MI, Stroke,

TIA, CABG, Revascularization, Unstable Angina, Hospitalized

CHF

Amlodipine 10 mg

Enalapril 20 mg

Placebo

100 sites

Comparison of Amlodipine versus Enalapril

to Limit Ischemic Occurrences of Thrombosis

CAMELOT Study Design

Nissen et al. JAMA. 2004;292(18); 2217-2226.

120

122

124

126

128

130

132

0 1 3 6 9 12 15 18 21 24

Systo

lic P

ressu

re (

mm

Hg

)

Placebo Enalapril Amlodipine

Months after randomization Nissen et al. JAMA. 2004;292(18); 2217-2226.

Systo

lic B

lood P

ressure

120

124

128

132

0 24 12

CAMELOT - Systolic Pressure All Three Treatment Groups

AHA Perspective/Hypertension Management and BP Goals Summary of Main Recommendations

adapted from Rosendorff C, et al. Circulation 2007;115:2761

Area of concern

BP Target

(mm Hg) Lifestyle †

modification Specific Drug Indications

General CAD prevention

<140/90 Yes Any effective antihypertensive drug or combination‡

High CAD risk* <130/80 Yes ACEI or ARB or CCB or thiazide or combination

Stable angina <130/80 Yes Β-blocker and ACEI or ARB

UA/NSTEMI <130/80 Yes Β-blocker and ACEI or ARB §

STEMI <130/80 Yes Β-blocker and ACEI or ARB §

LVD <120/80 Yes ACEI or ARB and Β-blocker and aldo antagonist and thiazide or loop diuretic and hydral/nitrate (blacks)

* diabetes, CKD, CAD or equivalent

† weight loss if appropriate, healthy diet, exercise, smoking cessation and alcohol moderation

‡ evidence supports ACEI or ARB, CCB, or thiazide as first-line

§ if anterior MI is present, if HTN persists, if LVD or HF is present, if diabetic

Hypertension Trials in DM: Active Tx v Placebo/Less Active Tx

Mancia Circ 2010;122:847

Many drugs/combinations provided to achieve goal BP according to randomized assignment.

Intensive Intervention:

2-drug therapy initiated: thiazide-type diuretic + ACEI, ARB, or b-blocker.

Drugs added and/or titrated at each visit to achieve SBP <120 mm Hg.

At periodic “milepost” visits: addition of another drug “required” if not at goal.

Standard Intervention:

Intensify therapy if SBP ≥160 mm Hg @ 1 visit or ≥140 mm Hg @ 2 consecutive visits

Down-titration if SBP <130 mm Hg @ 1 visit or <135 mm Hg @ 2 consecutive visits

ACCORD BP Protocol

110

120

130

140

0 1 2 3 4 5 6 7 8

Years Post-Randomization

SB

P (

mm

Hg

)

Intensive Standard

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

ACCORD - Systolic Blood Pressures

Pa

tie

nts

wit

h E

ve

nts

(%

)

0

5

10

15

20


0 1 2 3 4 5 6 7 8

Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death

HR = 0.88

95% CI (0.73-1.06)

Pa

tie

nts

wit

h E

ve

nts

(%

)

0

5

10

15

20


0 1 2 3 4 5 6 7 8

Pati

en

ts w

ith

Even

ts (

%)0

5

10

15

20


0 1 2 3 4 5 6 7 8

Nonfatal Stroke Total Stroke

HR = 0.63

95% CI (0.41-0.96) HR = 0.59

95% CI (0.39-0.89)

Five-year event rates Comparing the three more intensively treated

groups to the standard BP-lowering/standard glucose-lowering

treatment group in ACCORD BP trial.

Margolis KL et al. Diabetes Care 2014;37:1721-1728

Wright, JT Jr., et al. N.Engl.J.Med. 2015;373 : 2103-2116

SPRINT Trial

SPRINT Research Question

Examine 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 Treatment Goal SBP < 140 mm Hg

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

SPRINT Methods


SPRINT Methods Cont’d

EXCLUSION CRITERIA:

DM

Prior CVA

eGFR <20 or ESRD

ACS or revascularization within past 3 months

One-minute standing BP < 110 mmHg

LVEF <35% OR symptomatic HF within past 3 months

Other standard exclusions (poor prognosis from other disease, transplant patients, pregnancy, non-compliance, substance abuse, etc.)


SPRINT Methods Cont’d

Participants and study personnel were aware of group assignments, but outcome adjudicators were not

Treatment algorithms & formulary were similar to ACCORD

All medications provided for free

Investigators could also prescribe any other antihypertensive meds as needed

Investigators were encouraged to use the most evidence-based drug classes and drugs within each class (i.e. Chlorthalidone vs HCTZ, Amlodipine vs other CCB, Loops in advanced CKD patients, BB in CAD patients, etc.)


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

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


SPRINT: Demographic and 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-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)


SPRINT: Medications Used

Mean SBP 136.2 mm Hg

Mean SBP 121.4 mm Hg

Standard

Intensive

Year 1

SPRINT: Blood Pressure Change During Follow up


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 Outcome

(319 events)

-25% P<0.001

Primary Outcome – CVD composite - MI - ACS - CVA - CHF - CV death


Include NNT

SPRINT: All-Cause Mortality Cumulative Hazards

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

Intensive (155 deaths)

-27%


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.

Perkovic V, Rodgers A. N Engl J Med 2015. DOI: 10.1056/NEJMe1513301

Outcomes from SPRINT and ACCORD Trials and Combined Data from Both Trials.

Standardized Associations Between 10–mm Hg Lower Systolic BP and All-Cause Mortality, Macrovascular Outcomes, and Microvascular Outcomes in Patients with Diabetes

Emdin CA et.al. Blood Pressure Lowering in Type 2 Diabetes: A Systematic Review and Meta-analysis JAMA.

2015;313(6):603-615.

40 trials judged to be of low risk of bias (100 354 participants)

Should People with Diabetes be Included for a Lower BP Goal?

Yes:

ACCORD HTN was underpowered

ACCORD 4,733 vs 9,361 in SPRINT.

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)

Cushman, Bakris, AHA

Meta-analysis of large scale BP lowering trials

Percentage risk reduction in major CV events regressed Against the difference in achieved SBP between study treatment groups

10 mmHg reduction in SBP reduced risk: - CVD 20% - CHD 17% - Stroke 27% - CHF 28% - Mortality 13%

Similar efficacy for Patients with SBP Below 130 mmHg

Ettehad D et al. Lancet 2016;387:957

SPRINT Conclusions - In SPRINT, intensive therapy resulted in:

25% lower primary outcome (driven by heart failure events) and

27% reduction of all cause mortality compared to Standard Group

Treatment effect similar in all six pre-specified groups

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

were noted

No overall difference in serious adverse events (SAEs) between

treatment groups

Target BP around 120 mmHg recommended for all high risk patients

with htn (who can tolerate it) as well as for most people with DM

Caution needed for the older people with competing risks and/or

fragile patients

New Wording in UpToDate

This recommendation depends on the method used to determine BP. The ausculatory method using a manual cuff is the most common employed in clinical practice and, in addition, was the technique used in most clinical trials of antihypertensive therapy. In contrast, automated oscillometric BP (AOBP), using a device that can take multiple consecutive readings with the patient resting alone in a room, is infrequently employed in clinical practice but was the technique used in SPRINT. In general, systolic pressure readings are 5 to 10 mmHg lower with AOBP than with manual (ausculatory) measurement.

We recommend targeting a BP of 120 to 125/<90 mmHg rather than <140/<90 mmHg if AOBP measurements are used…We recommend targeting a BP of 125 to 130/<90 mmHg rather than <140/<90 mmHg if other methods of BP measurement are used.

The End

Implications of SPRINT and Intensive Blood … of SPRINT and Intensive Blood Pressure Management ......

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