sprinting to treat hypertension: have the goals for ...€¦ · • participants in sprint and...

SPRINTING TO TREATHYPERTENSION:

HAVE THE GOALS FOR TREATINGHIGH BLOOD CHANGED

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Joachim H. Ix, MD, MAS, FASN

Professor of Medicine

Chief; Division of Nephrology-Hypertension

University of California San Diego

• Summarize current JNC8 guidelines.

Agenda

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• Present recent results from the SPRINT trial.

Agenda

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• Evaluate SPRINT in the subset of elderly patients.

Agenda

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Agenda

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• Give my opinions about current guidelines in light of SPRINT trialresults.

Current Blood Pressure Guidelines in the US“JNC-8” Guidelines

Subgroup BP Target

Age ≥ 60 years < 150 / 90 mmHg

Age < 60 years < 140 / 90 mmHg

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Diabetes mellitus < 140 / 90 mmHg

CKD < 140 / 90 mmHg

James PA, et al. JAMA 2014; 311: 507-520.

Observational Data – Hazard Ratio* for Mortality by SBPLevel in 398,419 Kaiser Southern California Patients

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* Adjusted for age, sex, race, BMI, CKD, DM, CVD, CVA.

Sim JJ, J Am Coll. Cardiol., 2014; 65: 588-97.

• Randomized 9,361 persons age 50 or older with:

• SBP > 130mmHg• Increased CVD Risk (any of the 3 factors below):

• Prevalent CVD or subclinical CVD.

• 10 year Framingham risk score > 15%.

• CKD (eGFR 20-60 ml/min per 1.73m2)

• Excluded

Systolic PRessure INtervention Trial

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• Excluded

• Diabetes

• Prior stroke

• Overt proteinuria (urine protein/Cr > 1g/g).

• Intentionally oversampled:

• Participants aged > 75 years; 2,639 (28%)• Participants with CKD; 2,646 (28%)

• Included ~90 clinical sites across the US and Puerto Rico

SPRINT Investigators, NEJM 2015; 373: 2103-2116

• Randomized to SBP target < 120mmHg vs. < 140mmHg.

• Primary outcome: Composite CVD (MI, ACS, Stroke, HF, CVD death)

• Secondary endpoints included:

• All-cause mortality

• CKD progression


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• If eGFR ≥ 60 at baseline, sustained 30% decline and eGFR < 60 at follow-up.

• If eGFR < 60 at baseline, halving of eGFR, dialysis, or transplant.

• Change in cognitive function

• Trial stopped early in August 2015, with mean follow-up 3.2 years.



134.6 mmHg, 1.8 meds

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121.5 mmHg, 2.8 meds


SPRINT CVD Outcome Results(Primary Outcome)

Number Needed to Treat for 3.26 Years

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11 SPRINT Investigators, NEJM 2015; 373: 2103-2116

61

Death from Any Cause(Secondary Outcome)




90

Safety in SPRINT

Event Intensive(N=4678)

Standard(N=4683)

P-value

All Serious Adverse Events 1793 1736 0.25

Injurious Falls 105 110 0.71

Hypotension 110 64 0.001

Syncope 107 80 0.05


Syncope 107 80 0.05

Electrolyte Abnormalities 144 107 0.02

AKI 193 117 < 0.001

Clinic

Measured OrthostaticHypotension Alone

777 857 0.01

With Dizziness 62 71 0.35

CKD Progression in SPRINT

Participants withoutCKD at Baseline

Intensive(N=3332)

Standard(N=3345)

HR (95% CI) P-value

> 30% ↓ in eGFR &eGFR < 60

127 37 3.49 (2.44, 5.10) <0.001


Participants withCKD at Baseline

Intensive(N=1330)

Standard(N=1316)

HR (95% CI) P-value

Composite Renal Outcome 14 15 0.89 (0.42, 1.87) 0.76

> 50% ↓ in eGFR 10 11 0.87 (0.36, 2.07) 0.75

Dialysis 6 10 0.57 (0.19, 1.54) 0.27

Key Outcomes in the CKD Subset

Event Intensive Standard HR (95% CI) P-valueInteraction

CVD (Primary) Endpoint

No CKD (N=6715) 135 193 0.70 (0.56, 0.87)0.36CKD (N=2646) 108 126 0.82 (0.63, 1.07)


0.36CKD (N=2646) 108 126 0.82 (0.63, 1.07)

Death (Secondary)

No CKD (N=6715) 85 115 0.75 (0.57, 1.00)0.76CKD (N=2646) 70 95 0.73 (0.53, 1.00)

SPRINT ACCORD

Sample Size 9,361 4,733

SRPINT vs. ACCORD

16 Perkovic, NEJM 2015; 373: 2175-2178

Current Blood Pressure Guidelines in the US“JNC-8” Guidelines

Subgroup BP Target

Age ≥ 60 years < 150 / 90 mmHg

Age < 60 years < 140 / 90 mmHg

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Diabetes mellitus < 140 / 90 mmHg

CKD < 140 / 90 mmHg

James PA, et al. JAMA 2014; 311: 507-520.

Study(Year)

Mean Age(Samplesize)

Population StartingSBP

Target BP MeanAchievedSBP

PrimaryOutcome

Result

SHEP(1991)

72 years(4,736)

US 170 < 160 ifstart BP >180;otherwise20mmHgreduction

155 vs.143

Stroke Interventionbetter(HR 0.64,p=0.0003)

Trials of “More Intense” BP Treatment in the ElderlyLeading to JNC-8 Recommendations

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HYVET(2008)

83 years(3,845)

Europe,China,Australia, &Tunisia

173 < 150 / 80vs.placebo

139 vs.154

Stroke 30%reduction instroke(p=0.06)

JATOS(2008)

74 years(4,418)

Japan 172 < 140 vs.< 160

136 vs.146

CVD andrenalcomposite

No benefit(3.89 vs.3.90%,p=0.99)

CARDIO-Sis(2009)

67 years(1,111)

Europe 163 < 130 vs.< 140

136 vs 139 Change inLVH(2◦ CVD*)

(50%reduction inCVD)*

VALISH(2010)

76 years(3,260)

Japan 170 < 140 vs.< 150

137 vs.142

CompositeCVD (renal)

No benefit(HR 0.89,p=0.38)

“Absence of Evidence is Not Evidence of Absence”

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Carl Sagan - Astronomer

Donald Rumsfeld – Military Strategist

Age Matters Dramatically for BP and CVDEvents

BP Prevalence by Age

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Whelton P, Ann. Rev. Public Health 2015. 36:109–30.

Age Coronary Stroke

Age Matters Dramatically for theAbsolute Benefit of BP lowering and

CVD EventsAnnual Death Rate per 100,000 Persons in the US in

1999-2010, Stratified by Age

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Age CoronaryHeartDisease

Stroke

< 65 years 30 7

≥ 65 years 1,038 356

Adapted from Wright JA, JAMA 2014; 160: 499-503.

Age-Adjusted Death Rates from CardiovascularDisease in the US 1990 - 2008

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http://www.cdc.gov/nchs/datawh/statab/unpubd/mortabs.htm.

Trend in Mean SBP in the US Population Over PastHalf Century

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Adapted from Wright JA, JAMA 2014; 160: 499-503.

Outcomes in Participants Aged ≥ 75

Event Intensive(1317)

Standard(1319)

HR (95% CI) P-value

Achieved SBP 123.4 134.8 < 0.001

CVD (Primary) Endpoint

24 Williamson,… Ix,… Pajewski. JAMA 2016; 315: 2673-2682

Death (Secondary)Endpoint

All SAEs

Injurious Falls

Hypotension

Syncope



Standard(1319)

HR (95% CI) P-value

Achieved SBP 123.4 134.8 < 0.001

CVD (Primary) Endpoint 102 148 0.66 (0.51, 0.85) 0.001



73 107 0.67 (0.49, 0.91) 0.009

All SAEs

Injurious Falls

Hypotension

Syncope



Standard(1319)

HR (95% CI) P-value

Achieved SBP 123.4 134.8 < 0.001

CVD (Primary) Endpoint 102 148 0.66 (0.51, 0.85) 0.001



73 107 0.67 (0.49, 0.91) 0.009

All SAEs 640 638 1.00 0.93

Injurious Falls 158 193 0.79 0.03

Hypotension 36 24 1.49 0.13

Syncope 46 37 1.24 0.33

Number Needed to Treat for 3.26 Years:

To Prevent 1 CVD Event:

27To Prevent 1 Death:

41

Outcomes in Participants Aged ≥ 75;Developed a Frailty Index

• A Frailty Index (FI) had been developed in the HYVET trial, which wasmodeled similarly in SPRINT.

• The Frailty Index was constructed from 37 data points, including:

• Global cognitive function (Montreal Cognitive Assessment).• Self rated health status (RAND 12-Item Health Survey).• Self rated depressive symptoms (9 items in the PHQ-9).• Two additional cognitive screening instruments.• 4 meter walk test.

27 Pajewski N, et al. J Gerontol. 2016; 71: 649-55.

• 4 meter walk test.• Laboratory measurements.• Baseline blood pressure.• Comorbidities at baseline.

• The FI was validated internally and shown to be highly predictive of:

• Self reported falls• Injurious fall admissions (SAEs)• All hospitalizations.



Standard(1319)

Fit (FI < 0.10; N=349) 121.4 134.9


Less Fit (FI 0.10-0.20; N=1456) 123.3 134.7

Frail (FI > 0.20; N=815) 124.3 135.0

Outcomes in Participants Aged ≥ 75 by Frailty Status


Standard(1319)

HR (95% CI) P-valueInteraction

CVD

Fit (N=349) 4 10 0.47 (0.13, 1.39)0.84Less Fit (N=1456) 48 77 0.63 (0.43, 0.91)

Frail (N=815) 50 61 0.68 (0.45,1.01)


Frail (N=815) 50 61 0.68 (0.45,1.01)

Death

Fit (N=349) 5 6 0.95 (0.27, 3.15)0.52Less Fit (N=1456) 26 52 0.48 (0.29, 0.78)

Frail (N=815) 40 49 0.64 (0.41, 1.01)

Outcomes in Participants Aged ≥ 75 by Walking Speed


Standard(1262)

HR (95% CI) P-valueInteraction

CVD

Gait Speed ≥ 8 m/sec. 59 86 0.67 (0.47, 0.94)0.85Gait Speed < 8 m/sec. 34 54 0.63 (0.40, 0.99)

Death


Death

Gait Speed ≥ 8 m/sec. 40 60 0.65 (0.43, 0.98)0.68Gait Speed < 8 m/sec. 29 40 0.75 (0.44, 1.26)

Frailty Index StrokeHR (95% CI)

CVDHR (95% CI)

DeathHR (95%CI)

0.1 0.75 (0.40, 1.38) 0.62 (0.42, 0.92) 0.89 (0.63, 1.25)

0.2 0.66 (0.43, 1.01) 0.60 (0.45, 0.78) 0.84 (0.66, 1.07)

0.3 0.59 (0.36, 0.96) 0.57 (0.42, 0.79) 0.80 (0.61, 1.04)

Relationship of Frailty with BP Treatment in theElderly – Secondary Analysis from the HYVET Trial

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0.3 0.59 (0.36, 0.96) 0.57 (0.42, 0.79) 0.80 (0.61, 1.04)

0.4 0.52 (0.25-1.09) 0.55 (0.34, 0.89) 0.76 (0.50, 1.14)

0.5 0.47 (0.16, 1.33) 0.53 (0.26, 1.06) 0.72 (0.40, 1.29)

0.6 0.41 (0.10, 1.65) 0.50 (0.20, 1.27) 0.68 (0.32, 1.48)

P-interaction 0.52 0.73 0.61

Warwick J, et al. BMC Medicine 2015; In Press

• Participants in SPRINT and HYVET were trial participants, and thusnot representative of all hypertensive patients in clinical practice.

• Patients with diabetes, prior stroke, and proteinuria > 1 g / g Cr wereexcluded from SPRINT.

Caveats

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• Safety data represents that in a randomized trial with follow-up ofparticipants every 3 months.

• Data on cognitive function is not yet available.

• Among hypertensive persons aged > 50 years with high risk for CVD,intensive blood pressure lowering to < 120mmHg:

• Prevents CVD Events• Saves Lives• Induces more rapid loss of eGFR in those with high baseline eGFR• Increases risk for AKI.

• Effect estimates were similar in patients with:

• CKD

Conclusions

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• CKD• Aged ≥ 75 years.

• Although the relative benefit of intensive blood pressure control is similarin the elderly, the absolute benefit is higher.

• Benefits of intensive blood pressure control were evident even in thefrailest elderly participants in SPRINT and HYVET.

• In patients older than 50 years at high risk for CVD, SBP levels<120mmHg should be targeted.

• In hypertensive patients older than 75 years:

• SBP targets of < 150mmHg (US) are difficult to justify in light ofnew trial data.

Conclusions

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new trial data.

• SBP targets of at least < 140mmHg, and perhaps < 120mmHgshould be sought.

• [email protected]

Thank You

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Antihypertensives Used in SPRINT


Trial (N) “Intensive” Less Intensive HR (95% CI)

SHEP (4736) 213 242 0.87 (0.73, 1.05)

HYVET (3845) 196 235 0.79 (0.65, 0.95)

SPRINT (9361) 155 210 0.73 (0.63, 0.90)

ACCORD (4733) 150 144 1.07 (0.85, 1.35)

JATOS (4418) 54 42 1.28 (0.86, 1.93)

VALISH (3260) 24 30 0.78 (0.46, 1.33)

Mortality in Prior “Intensive” Blood Pressure Trials

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VALISH (3260) 24 30 0.78 (0.46, 1.33)

Cardio-Sys (1111) 4 5 0.77 (0.21, 2.88)

CKD

SPRINT (2646) 70 95 0.73 (0.53, 1.00)

AASK (1094) 38 44 0.85 (0.54, 1.34)

MDRD (840) 12 7 1.64 (0.64, 4.20)

sprinting to treat hypertension: have the goals for ...€¦ · • participants in sprint and...

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