Post on 19-Jul-2020
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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• Summarize current JNC8 guidelines.
• Present recent results from the SPRINT trial.
Agenda
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• Summarize current JNC8 guidelines.
• Present recent results from the SPRINT trial.
• Evaluate SPRINT in the subset of elderly patients.
Agenda
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• Evaluate SPRINT in the subset of elderly patients.
• Summarize current JNC8 guidelines.
• Present recent results from the SPRINT trial.
• Evaluate SPRINT in the subset of elderly patients.
Agenda
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• Evaluate SPRINT in the subset of elderly patients.
• 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
Systolic PRessure INtervention Trial
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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.
SPRINT Investigators, NEJM 2015; 373: 2103-2116
Systolic PRessure INtervention Trial
134.6 mmHg, 1.8 meds
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121.5 mmHg, 2.8 meds
SPRINT Investigators, NEJM 2015; 373: 2103-2116
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)
Number Needed to Treat for 3.26 Years
12 SPRINT Investigators, NEJM 2015; 373: 2103-2116
Number Needed to Treat for 3.26 Years
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
13 SPRINT Investigators, NEJM 2015; 373: 2103-2116
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
14 SPRINT Investigators, NEJM 2015; 373: 2103-2116
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)
15 SPRINT Investigators, NEJM 2015; 373: 2103-2116
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
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 102 148 0.66 (0.51, 0.85) 0.001
25 Williamson,… Ix,… Pajewski. JAMA 2016; 315: 2673-2682
Death (Secondary)Endpoint
73 107 0.67 (0.49, 0.91) 0.009
All SAEs
Injurious Falls
Hypotension
Syncope
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 102 148 0.66 (0.51, 0.85) 0.001
26 Williamson,… Ix,… Pajewski. JAMA 2016; 315: 2673-2682
Death (Secondary)Endpoint
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:
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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.
Outcomes in Participants Aged ≥ 75
Event Intensive(1317)
Standard(1319)
Fit (FI < 0.10; N=349) 121.4 134.9
28 Williamson,… Ix,… Pajewski. JAMA 2016; 315: 2673-2682
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
Event Intensive(1317)
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)
29 Williamson,… Ix,… Pajewski. JAMA 2016; 315: 2673-2682
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
Event Intensive(1251)
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
30 Williamson,… Ix,… Pajewski. JAMA 2016; 315: 2673-2682
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.
• joeix@ucsd.edu
Thank You
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Antihypertensives Used in SPRINT
36 SPRINT Investigators, NEJM 2015; 373: 2103-2116
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)