the sprint study - american college of physiciansodds ratio for cv events and systolic bp...
TRANSCRIPT
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THE SPRINT STUDY : IMPLICATIONS FOR
CARDIOLOGISTS
Vasilios Papademetriou, MD
Professor of Medicine
Georgetown University
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SYSTOLIC BLOOD PRESSURE
INTERVENTION TRIAL: SPRINT
Promised to change everything know in
hypertension management
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Reduced all Cv events
Safe for the heart
Reasonable for the kidney
Settled the J shape curve
Applicable to high risk patients
SPRINT FOR CARDIOLOGISTS
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0
10
20
30
40
50
60
1980 1985 1990 1995 2000 2005 2010 2013
Series 1
RATES OF BP CONTROL AND
MORTALITY
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EDWARD D. FREIS
At Georgetown The VA Medical Center
Author of landmark VA studies
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Severe HTN Mild to moderate HTN
VA CO-OP STUDIES: ED D. FREIS
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ED FREIS
Ed Freis;stoke 1974;5:76-79
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0
5
10
15
CV events
CV Events
<90mmHg <85mmHg <80mmHg
PRINCIPAL RESULTS OF THE HYPERTENSIONOPTIMAL TREATMENT (HOT) RANDOMISED TRIAL
SBP: 143,141,139
mmHg
Lancet 1998; 351: 1755–62
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THE SHEP STUDY
JAMA, 1991;265:3255
4736 pts >60 yo, SBP=160-219, DBP<90 Meds: Chlorthalidone, atenolol, etc
Matching placebo
Placebo
treatment
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Odds Ratio for CV Events and Systolic BP Difference: Recent and Older Trials
Staessen et al. J Hypertens. 2003;21:1055-1076.
Od
ds R
ati
o (
exp
eri
men
tal/re
fere
nce) 1.50
1.25
1.00
0.75
0.50
0.25
-5 0 5 10 15 20 25
P<.0001
Difference (reference minus experimental)
in Systolic BP (mm Hg)
Recent trials
Older trials placebo
STONE
UKPDS L vs. H
PROGRESSION/Com
STOP 1
RCT70-80
EWPHE
HEP
MRC2
SHEP
Syst-Eur
PART2/SCAT
HOPE
STOP2/ACEIs
ALLHAT/Dox
UKPDS C vs. A
MIDAS/NICS/VHAS
STOP2/CCBs
HOT M vs. H
INSIGHT
HOT
PROGRESS/Per
PATS
RENAAL
L vs. H
MRC
ATMH
Syst-China
OlderRecent
AASK L vs. H
ABCD/NT L vs. H
ALLHAT/Lis Blacks
ALLHAT/Lis 65
ALLHAT/Lis
ALLHAT/Aml
CONVINCE
DIABHYCAR
ANBP2
LIFE/ALL
ELSA
LIFE/DM
NICOLE
PREVENT
IDNT2
SCOPE
Older trials active
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CHANGE IN SYSTOLIC AND DIASTOLIC
BP WITH AGE
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Lower is better
Earlier is better
<140/90 in most, <130/85
<150 in pts >60yo
GUIDELINES
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BP TARGETS
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CONCERNS ABOUT J=SHAPE CURVE
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Incidence of total myocardial infarction (MI) and total stroke by diastolic blood pressure strata
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INCIDENCE OF THE PRIMARY
OUTCOME
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THE VA STUDY
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DEATH RATE BY LAST SYSTOLIC BP
N=477,730
162/84143/79
134/75124/72
114/67
104/62
Papademetriou et al 2013, AHA
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DEATH RATE BY LAST DIASTOLIC BP
N=477,730
Follow up > 10 years
Papademetriou et al: AHA ,2013
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Death Rate for HypertensivesUsing Last BP
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
>= 150 140-149 130-139 120-129 110-119 < 110
Mo
rtality
Systolic
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
>= 100 90-99 80-89 70-79 60-69 50-59 < 50
Mo
rtality
Last Diastolic BP
<55 55- <70 70- <80 >= 80Fletcher et al
Diastolic
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>40 years after the publication of the landmark VA
studies we still do not have definite treatment
targets
Indications that optimal systolic is 130-140 mmHg
and diastolic 80-90 mmHg
The Guidelines suggest higher BPs in people >60
years of age
The threat of J shape Curve is looming!!
SPRINT to the resque
BP TREATMENT TARGETS ?
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SYSTOLIC BLOOD PRESSURE
INTERVENTION TRIAL: SPRINT
Promised to change everything we know in
hypertension management
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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.
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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)
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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
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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
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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
-27%
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Primary Outcome in the Six Pre-specified Subgroups of Interest
*Treatment by subgroup interaction
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All-cause Mortality in the Six Pre-specified Subgroups of Interest
*
*p=0.34, after Hommeladjustment for multiplecomparisons
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Primary and Secondary Outcomes and Renal Outcomes
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SPRINT: Adverse events
SAE, serious adverse event SPRINT Research Group. N Engl J Med 2015;373:2103–2116
Intensive treatment(N=4678)
Standard treatment(N=4683)
Hazard ratio P-value
SAE, n (%) 1793 (38.3) 1736 (37.1) 1.04 0.25
Conditions of interest – SAE only, n (%)HypotensionSyncopeBradycardiaElectrolyte abnormalityInjurious fallAcute kidney injury or acute renal failure
110 (2.4)107 (2.3)87 (1.9)
144 (3.1)105 (2.2)193 (4.1)
66 (1.4)80 (1.7)73 (1.6)
107 (2.3)110 (2.3)117 (2.5)
1.671.331.191.350.951.66
0.0010.050.280.020.71
<0.001
11
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SPRINT: Adverse renal outcomes
SPRINT Research Group. N Engl J Med 2015;373:2103–2116
Intensive treatment Standard treatmentHR
(95% CI) P-valueEvents %/year Events %/year
Participants with CKD at baseline (N=1330) (N=1316)
Primary CKD outcome≥50% reduction in eGFR*
Secondary CKD outcomeIncident albuminuria†
1410
49
0.330.23
3.02
1511
59
0.360.26
3.90
0.89 (0.42–1.87)0.87 (0.36–2.07)
0.72 (0.48–1.07)
0.760.75
0.11
Participants without CKD at baseline (N=3332) (N=3345)
Secondary CKD outcomes≥30% reduction in eGFR*
Incident albuminuria†
127110
1.212.00
37135
0.352.41
3.49 (2.44–5.10)0.81 (0.63–1.04)
<0.0010.10
*Confirmed on a second occasion ≥90 days apart†Doubling of urinary albumin/creatinine ratio from <10 to >10 mg/g
12
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BP AND WITH KIDNEY DISEASEGFR
CHANGES
2.1 2.0 2.0 2.0 2.1 2.0 2.1 2.1 2.1
2.1 2.9 3.0 3.0 3.0 3.0 2.9 2.9 3.0
Mean Number of Meds
Standard:
Intensive:
1316 1215 1156 1117 1087 1022 766 480 230
1330 1246 1194 1145 1136 1054 804 515 268
Number With Data
Standard:
Intensive:
0 12 24 36 48
Follow-up Month
116
121
126
131
136
141
Sy
sto
lic
Blo
od
Pre
ss
ure
(m
mH
g)
BP eGFR
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.
KAPLAN-MEIER CURVES FOR THE PRIMARY
CARDIOVASCULAR DISEASE (PANEL A) AND ALL-CAUSE
MORTALITY (PANEL B) OUTCOMES .
Years Follow-up
1316 1277 1227 865 269
1330 1279 1244 859 295
Panel B
1316 1241 1164 801 245
1330 1243 1181 808 278
Num at risk
Panel A
0 1 2 3 4 50 1 2 3 4 5
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Cu
mu
lati
ve
Ha
za
rd
Standard
Intensive
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RENAL OUTCOMES: PRIMARY END
POINT
1316 1265 1214 854 2661330 1268 1230 850 286
Number at risk
StandardIntensive
0 1 2 3 4 5
Years Follow-up
0.000
0.005
0.010
0.015
0.020
Cu
mu
lativ
e H
azar
d
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Gait Speed as an Incremental Predictor of
morbidity and Mortality
4 min walk
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Date of download: 10/16/2016 Copyright © The American College of Cardiology. All rights reserved.
From: Gait Speed as an Incremental Predictor of Mortality and Major Morbidity in Elderly Patients Undergoing
Cardiac SurgeryJ Am Coll Cardiol. 2010;56(20):1668-1676. doi:10.1016/j.jacc.2010.06.039
Figure Legend:
Predicted Probability of Mortality or Major Morbidity According to Gait Speed and the STS Risk Score
Slow gait speed (solid circles) conferred a 2- to 3-fold increase in risk for any given level of Society of Thoracic Surgeons (STS) predicted
mortality or major morbidity compared with normal gait speed (open circles). The adjusted odds ratio for mortality or major morbidity was 3.05
(95% confidence interval: 1.23 to 7.54).
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Intensive blood pressure control, gait speed, and mobility limitation: The Systolic Blood Pressure Intervention Trial (SPRINT)
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How do SPRINT results compare with ACCORD?
1. Cushman WC et al. N Engl J Med 2010;362:1575–1585 2. SPRINT Research Group. N Engl J Med 2015;373:2103–2116
ACCORD (Primary outcome: nonfatal MI
nonfatal stroke, CVD death)1
Standard treatment
Intensive treatment
Hazard ratio: 0.88(95% CI, 0.73–1.06)p=0.20
Pat
ien
ts w
ith
eve
nts
(%
)
Years post-randomization
20
15
10
5
00 1 2 3 4 5 6 7 8
Intensive treatment = SBP <120 mmHg; standard treatment = SBP <140 mmHg
SPRINT (Primary outcome: MI, non-MI ACS,
stroke, heart failure, CVD death)2
Hazard ratio with intensive treatment:0.75 (95% CI, 0.64–0.89)p<0.001
Standard treatment
Intensive treatment
Years post-randomization
0.10
0.08
0.04
0.02
0.00
0.06
0 1 2 3 4 5
Cu
mu
lati
ve h
azar
d
14
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How do SPRINT results compare with SPS-3?
1. Benavente OR, et al. Lancet 2013;382:507–15;2. SPRINT Research Group. N Engl J Med 2015;373:2103–2116
Hazard ratio: 0.81 (95% CI, 0.64–1.03)p=0.08
Time since randomization (years)
Pro
bab
ility
of
pri
mar
y ev
en
t
874310.0
0.2
0.4
0.6
0.8
1.0
2 5 60
Higher-target group
Lower-target group
SPS3: No difference in CV events† in prior stroke patients with BP <130 (lower-target
group) and <150 mmHg (higher-target group)1
†Recurrent stroke, MI, or vascular death BUT significant benefit of lower BP target in reducing risk of intracerebral haemorrhage. Mean baseline SBP: 144 ±SD 19 mmHg (higher-target); 142 ±SD 19 mmHg (lower-target)
SPRINT (Primary outcome: MI, non-MI ACS,
stroke, heart failure, CVD death)2
Hazard ratio with intensive treatment:0.75 (95% CI, 0.64–0.89)p<0.001
Standard treatment
Intensive treatment
Years post-randomization
0.10
0.08
0.04
0.02
0.00
0.06
0 1 2 3 4 5
Cu
mu
lati
ve h
azar
d
15
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How do SPRINT results compare with VALUE?
1. Mancia G, et al. Eur Heart J 2016;37:955-964;2. SPRINT Research Group. N Engl J Med 2015;373:2103–2116
VALUE: Primary endpoint† vs. mean SBP during the treatment period1
Note. VALUE was not a randomized trial between target pressures
†Time to first cardiac event (fatal or nonfatal MI, sudden cardiac death, death from revascularization procedures, HF requiring hospitalization, and emergency procedures to prevent MI
SPRINT (Primary outcome: MI, non-MI ACS,
stroke, heart failure, CVD death)2
Hazard ratio with intensive treatment:0.75 (95% CI, 0.64–0.89)p<0.001
Standard treatment
Intensive treatment
Years post-randomization
0.10
0.08
0.04
0.02
0.00
0.06
0 1 2 3 4 5
Cu
mu
lati
ve h
azar
d
16
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HOPE-3 evaluated antihypertensive therapy in a low-risk population
Objective:
Evaluate the following in preventing major CV events in patients at low risk* (N=12,705; 21 countries):
– LDL-C–lowering with rosuvastatin 10 mg/day vs placebo
– BP-lowering with candesartan/hydrochlorothiazide (HCTZ) 16/12.5 mg/day vs placebo
– The combination of both vs double placebo
Primary outcomes:
Composite of CV death, nonfatal MI, and nonfatal stroke
Composite of CV death, nonfatal MI, nonfatal stroke, resuscitated cardiac arrest, heart failure, and revascularization
CVD, cardiovascular disease; HOPE-3, Heart Outcomes Prevention Evaluation; MI, myocardial infarction Lonn EM, et al. N Engl J Med 2016; 374:2009-2020
*No previous CVD, no strictly defined cholesterol or BP levels upon entry, and having received lifestyle advice.
17
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SPRINT vs ACCORD
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CKD group
Non-CKD group
INTENSIVE VS STANDARD TREATMENT OF BP
IN ACCORD CKD AND NON-CKD PATIENTS
Papademetriou. Tsioufis..…Doumas; AJN 2016
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CKD group Non-CKD group
CHANGE IN ANY STROKE IN ACCORD
CKD AND NON-CKD PATIENTS
P<0.001
Papademetriou. Tsioufis..…Doumas; AJN 2016
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CKD group Non-CKD group
CHANGE IN NON-FATAL STROKE IN
ACCORD CKD AND NON-CKD PATIENTS
P<0.))!
Papademetriou. Tsioufis..…Doumas; AJN 2016
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GENERALIZABILITY OF SPRINT RESULTS
TO THE U.S. ADULT POPULATION
Bress AP et al..; JACC 2016; 67:464-472
.
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SPRINT-MIND
Mini-mental test at closing---underway
SPRINT ABPM
Correlation with events
Correlation with office BP
Details of gait, fragility, fractures, renal function
Visit to visit variability
Intensive Rx in pre-diabetics
Assessment by diastolic BP
Renal outcomes etc
More that 104 proposals for manuscripts
MORE DATA FROM SPRINT ARE
COMING
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Intensive treatment of bp works and saves lives
Intensive treatment is safe and low BPs are
achievable in most pts
Low BPs are well tolerated even in the very old
Effects on the kidney seem to be due to
hemodynamic changes
Benefits from BP control are not drug specific
BP control should be achieved by the least
intrusive means
TRANSLATE SPRINT INTO CLINICAL
PRACTICE
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Use drugs that are effective
Use drugs that are safe and well tolerated
Combinations with complementary mechanism of action
Try to establish and maintain compliance
Be aware of cost
Expensive is not necessarily better.
See patients frequently
Use the SPRINT approach
HOW TO CONTROL BP
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Services are provided through a network of 151 Medical Centers, 300 Vet Centers, 827 Community-based Outpatient Clinics (CBOC), 135 Community Living Centers, 6 Independent Outpatient Clinics, and 103 Residential Rehabilitation Centers 56
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15 Cities – 478,199 hypertensive patients
Systolic and Diastolic BP by Age
130
135
140
1451999-1
0
2000-4
2000-1
0
2001-4
2001-1
0
2002-4
2002
-10
20
03-4
20
03-1
0
2004
-4
2004
-10
2005
-4
2005
-10
2006-4
2006-1
0
2007
-4
20
07-1
0
Month
Sys
toli
c B
P
65
70
75
80
85
Dia
sto
lic
BP
<55 55 - <70 70 - <80 80+
Fletcher , Papademetriou AHA
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58
40%
45%
50%
55%
60%
65%
70%
75%
80%
20
00
-1
20
00
-6
20
00
-11
20
01
-4
20
01
-9
20
02
-2
20
02
-7
20
02
-12
20
03
-5
20
03
-10
20
04
-3
20
04
-8
20
05
-1
20
05
-6
20
05
-11
20
06
-4
20
06
-9
20
07
-2
20
07
-7
20
07
-12
20
08
-5
20
08
-10
20
09
-3
20
09
-8
20
10
-1
20
10
-6
20
10
-11
20
11
-4
20
11
-9
< 55
55 - <70
70 - <80
>=80
Hypertension Control by Age
Me
an P
erc
en
t C
on
tro
lled
Year-monthFletcher , Papademetriou AHA
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45%
50%
55%
60%
65%
70%
75%
80%
20
00
-1
20
00
-6
20
00
-11
20
01
-4
20
01
-9
20
02
-2
20
02
-7
20
02
-12
20
03
-5
20
03
-10
20
04
-3
20
04
-8
20
05
-1
20
05
-6
20
05
-11
20
06
-4
20
06
-9
20
07
-2
20
07
-7
20
07
-12
20
08
-5
20
08
-10
20
09
-3
20
09
-8
20
10
-1
20
10
-6
20
10
-11
20
11
-4
20
11
-9
Me
an P
erc
en
t C
on
tro
lled
Year-month
4,353,383 Hypertensive Patients
Hypertensive Patients Controlled
59Fletcher , Papademetriou AHA
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40%
45%
50%
55%
60%
65%
70%
75%
80%2
00
0-1
200
0-5
200
0-9
200
1-1
200
1-5
200
1-9
200
2-1
200
2-5
200
2-9
200
3-1
200
3-5
200
3-9
200
4-1
200
4-5
200
4-9
200
5-1
200
5-5
200
5-9
200
6-1
200
6-5
200
6-9
200
7-1
200
7-5
200
7-9
200
8-1
200
8-5
200
8-9
200
9-1
200
9-5
200
9-9
201
0-1
201
0-5
201
0-9
201
1-1
201
1-5
201
1-9
Me
an
pe
rcen
t co
ntr
olle
d
Year-month
Washington DC
All centers
Blood Pressure Control in the VA
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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 be cost-effective?
It will
Save lives
Improve morbidity
Decrease hospitalizations and
May save money
HOW WILL SPRINT AFFECT YOUR
PRACTICE
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PCSK9 INHIBITORS:
SECOND REVOLUTION IN
CV DISEASE
(THE FIRST WAS THE REVOLUTION OF STATINS)
Vasilios Papademetriou, MD
Professor of Medicine
Georgetown University
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Almost two decades the 4S first showed that simvastatin effectively improve survival in patients with cardiovascular disease (CVD), and initiated a revolution in the treatment of atherosclerotic heart disease
Results with other statins confirmed and enhanced these results
Other newer and/or novel compounds were abandoned either because of lack of efficacy or unacceptable side effects
Recently ezetimibe-in the IMPROVE-IT study- showed further improvement of outcomes when added to a statin.
Yet the incremental reduction of LDL -C was modest and additional
benefits small, but the study confirmed the impression that “ Lower is better”
That’s where PCSK9 in come into play
MANAGEMENT OF DYSLIPIDEMIAS
AND PCSK9 INHIBITORS
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PCSK9 INHIBITORS: THE NEW
REVOLUTION
Recently the Food and Drug Administration (FDA)
approved alirocumab and evolocumab, PCSK9
inhibitors, for the treatment of hyperlipidemia.
More specifically these to be used as an:
“adjunct to diet and maximally tolerated statin therapy for the
treatment of adults with heterozygous familial hypercholesterolemia
or clinical atherosclerotic cardiovascular disease,
who require additional lowering of LDL [low-density lipoprotein]-
cholesterol.”
A third PCSK9 inhibitor-Bococizumab- is under intensive investigation
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Why is this so important?
Are very potent LDL reducing agents
Lower LDL to levels we have never seen before
Their mechanism of action is favorable, work well with
statins and work like statins
Have the potential of eliminating CV events ??
Have the potential of eliminating atherosclerosis ??
BUT
Have issues and Limitations:
They are injectable proteins/antibodies
May cause side effects
Are expensive ( $14,000.00/year in the US)
PCSK9 INHIBITORS: THE NEW
REVOLUTION
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PCSK9 is a protein
Proprotein convertase subtil isin kexin 9 (PCSK9) is
produced predominantly in the liver
Its job is to tag the LDL receptors for destruction
PCSK9 inhibitors prevent that by binding PCSK9
Another small molecule the “interfering RNA (siRNA)”, can
cause direct degradation of messenger RNA that leads to
production of PCSK9
It is currently under intense investigation. A single dose of
siRNA resulted in 70% reduction of circulating PCSK9 and
40% reduction in LDL cholesterol
WHAT ARE THE PCSK9 INHIBITORS
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The first suggestion of a link between PCSK9
and hypercholesterolemia was published in
2003
The progress from PCSK9 discovery to the
development of targeted treatment has been
unprecedented in terms of scale and speed
PCSK9 inhibition is now considered an exciting
and revolutionary approach in the reduction of
residual risk of cardiovascular disease.
Can reduce LDL ti its infancy levels
PCSK9 INHIBITORS
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Are considered a breakthrough in
the management of dyslipidemias
because”
Are safe and
Very-very effective
WHY ARE PSCK9 INHIBITORS
IMPORTANT?
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SAFE BECAUSE ARE HUMANIZED
MONOCLONAL ANTIBODIES
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ANOTHER CAVEAT: STATINS
INCREASE PCSK9 LEVELS
-Meta-analysis from 15 studies with 19 treatment arms
-A total of 2691 subjects, with 1973 in the statin arm and 718 inthe control arm. d-Changes in PCSK9 levels were irrespective of the type of statin
Diabetes, Obesity and Metabolism 17: 1042–1055, 2015.
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CHANGE IN PCSK9 LEVELS AFTER
STATIN THERAPY
Study name
Grouped by
Type os statin
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PSCK9 INHIBITORS HAVE BEEN
APPROVED FOR ASCVD AND FH
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GUIDELINES ARE CONFUSING
>50% reduction
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28%Achieving LDL-C < 70 mg/dL
72%Not achieving
LDL-C < 70 mg/dL
Treated Patients From NHANES
NHANES = National Health and Nutrition
Examination Survey
*NHANES defined CHD based on answers to
questions about CHD, angina, and MI from
patient surveys
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HOW LDL PARTICLES ARE CLEARED
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PSCK9 TAGS LDL-R FOR
DESTRUCTION
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EVOLOCUMAB BINDS TO PCSK9PREVENTING IT FROM BINDING THE LDL RECEPTORS
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Characteristic All patients with HoFH
(n=49)
Age (years), mean 31
Female (%) 49
Male (%) 51
Race: White (%) 90
LDL-C (mg/dL), mean 349
Statin (atorvastatin or rosuvastatin) (%) 100
Ezetimbe (%) 92
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Long term studies and
Studies in Familiar
hypercholesterolemia
STUDIES WITH ALIROCUMAB
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CALCULATED LDL-C LEVELS
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LONG TERM EFFICACY IN FH
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EFFICACY AND SAFETY OF EVOLOCUMAB INREDUCING LIPIDS AND CV EVENTS
The New England Journal of Medicine, March 15th, 2015
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CHANGE IN LDL CHOLESTEROL
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CUMULATIVE INCIDENCE OF
CV EVENTS
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EFFICACY AND SAFETY OF ALIROCUMABIN REDUCING LIPIDS AND CV EVENTS
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CALCULATED LDL CHOLESTEROL LEVELS OVER TIME:
ALIROCUMAB VS PLACEBO
NEJM March 15 2015
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0
1
2
3
4
5
6
7
site inj react Myalgia Neurogon.ev opthal even CV event
Alirocumab Placebo
P<0.2
ADVERSE AND CV EVENTS
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Trial
name
Study drug Patient population Primary outcome Follow-
up
FOURIERN
CTEvolocumab n = 27,000; h/o CVD high risk of
CV;LDL-C ≥70 mg/dL on statin therapy
Time to
cardiovascular
death, CV event
5 years
ODYSSEY OUTCOME
Alirocumab n = 18,000; ACS <52 weeks earlier; LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL; on statin therapy
Time to cardiovascular death CV event
64 months
SPIRE-1
NCTBococizumab n = 17,000; high risk of CVD
event, background lipid-lowering treatment;LDL-C 70–100 mg/dL
Time to composite major CV event
60 months
SPIRE-2
NCTBococizumab n = 9000; high risk of CVD
event;background lipid-lowering treatment; LDL-C ≥100 mg/dL
Time to composite major CV event
60 months
ONGOING CLINICAL OUTCOME TRIALS OF PCSK9 INHIBITORS
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EFFECTS OF PCSK9 INHIBITORES IN
ADULTS WITH HYPERCHOLESTEROLEMIA
Data from 22 phase 2 or 3 randomized, controlled trials (RCTs) comparing treatment using PCSK9 antibodies with no anti-PCSK9 therapy in adults with hypercholesterolemia were included.
A total of 10 159 patients were randomized to PCSK9 antibody or no antibody
Ann Intern Med. 2015;163:40-51.
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-56
-54
-52
-50
-48
-46
-44
-42
-47.5%
-55%
-50%
TREATMENT WITH PCSK9
ANTIBODIES (N=10,159 PTS)
LDL-C reduction All cause mortality CV mortality Myocarial Inf
-51%
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compared with no anti-PCSK9 treatment, use of PCSK9 antibodies is associated with:
Lower odds of all-cause mortality and myocardial infarction and a statistically nonsignificant reduction in cardiovascular mortality;
Marked reduction of LDL-C and Lp (a)
Lower increase in the serum creatine kinase level;
No increase in serious adverse events; and
A marked reduction in atherogenic lipid fractions.
Improvements in clinical outcomes were consistent in multiple sensitivity analyses that used different methods of analysis.
IN SUMMARY
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……..A second revolution is
happening in cardiology today
…….It is happening “RIGHT HERE and
RIGHT NOW”
…..Thank you very much!!!!!
I CAN AFFIRM TO YOU