Joint ESH/ASH Session
J-Curve Revisited
Director Cardiology Department, Asklepeion Hospital, Athens,Greece
Athanasios J. Manolis
The Cardiovascular Continuum in Hypertension and the Relative
Preventive Effect of BP Lowering and Ancillary Actions of
Antihypertensive Agents
BP +
SpecificAncillaryActions
BP +
SpecificAncillaryActions
BP +
SpecificAncillaryActions BP
+SpecificAncillaryActions
Metabolic Syndrome
Dyslipidemia
LVH
IMT
Microalb.
Mild Renal Disease
Recent Diabetes
Endothelial Dysfunction
MI
Stroke
CHF
ESRD
Angina
TIA
Claudicatio
Proteinuria
Moderate Renal Disease
Established Diabetes
SubclinicalOrgan
Damage
RiskFactors
ClinicalDisease
Cardio-vascular
Event
Death
Hypertension
Zanchetti J Hypertens 2005;23:1113-20
Event Reduction in Patients on Active Antihypertensive
Treatment versus Placebo or No Treatment
-50
-40
-30
-20
-10
0
%
-50
-40
-30
-20
-10
0
%
Stroke CHD
All
cause CV
Non
CV
Fatal and
non fatal events
Mortality
Systolic-diastolic hypertension
Stroke CHD
All
cause CV
Non
CV
Fatal and
non fatal events
Mortality
Isolated systolic hypertension
< 0.001
< 0.01 < 0.01
< 0.001
NS NS
< 0.001
< 0.001
0.02
0.01
ESH-ESC Hypertension guidelines J Hypertens 2003
2007 ESH/ESC Guidelines
BP Thresholds / Targets (mmHg)
General HT population
≥ 140/90
< 140/90
High risk patients
(CAD/Cerebrovasc. disease/
Diabetes/Renal dysfunction)
≥ 130/85
< 130/80
Threshold
Target
Concept of flexible threshold/target
for treatment in relation to total CV risk
Rosendorff C et al., Circulation 2007,115:2761-2788
2007 AHA Guidelines:
Treatment of Hypertension in the Prevention and
Management of Ischemic Heart Disease
In achieving a target BP < 130/80 mmHg for secondary
prevention, the BP should be lowered slowly and
caution is advised in inducing falls of diastolic
BP below 60mmg.
Reappraisal of European guidelines on hypertension
management: a European Society of Hypertension
Task Force document
Recently, there has been some withdrawal from a perhaps excessive
enthusiasm for aggressive lowering of BP, based on the data of some
trials as well as post hoc analyses of the results of other trials on
high-risk patients. These data have raised the doubt that in patients
at high cardiovascular risk, antihypertensive treatment regimens that
reduce SBP to values close or below 120–125mmHg and DBP below
70–75mmHg may be accompanied by an increase (rather than a
further reduction) in the incidence of coronary events, that is, by a
J-curve phenomenon.
J. Hypertens 2009
History
The J-curve debate started with
Over a 6-years follow-up period, a DBP of <90 mm Hg was
associated with a 5-fold greater risk of MI vs DBP 100 t0 109
mm Hg
Stewart's Lancet 1979; 861-865
strong J-curve relationship between death from MI and treated
DBP only in patients with CAD
Cruickshank JM, Lancet 1987; 581-584.
Farnett et al, JAMA, 1991,265: 265:489
0
10
20
30
40
50
Treated DBP (mm Hg)
Per
1000 P
ati
en
t-Y
ears
95% Upper
Predicted
95% Lower
70 75 80 85 90 95 100 105 110 115
13 studies, 48473 patients
The J- Curve: Ischemic Heart Disease Events
Hypertension and J-Curve
J-curve: describes the shape of the relathionship between BP and the
risk of cardiovascular morbidity and/or mortality
J-shape: reflects increased risk at high levels of BP, with risk falling in
parallel to BP reduction until a nadir is reached, below which further
BP reduction begins to increase risk
Most of coronary blood flow to the LV occurs in diastole. In patients with
CHD a fall in DBP might lower perfusion pressure distal to a stenosis
below the critical level at which autoregulation is effective
Questions to be Answered
How low can BP be lowered and remain both safe and beneficial?
What is the lowest safe level of BP beyond which potential harm
offsets the benefits of treatment?
Whether the J-curve relationship is equally significant for SBP as
it is for DBP and whether its impact is more relevant for stroke,
renal events, myocardial infarction and heart failure
Prospective Studies Collaboration. Lancet. 2002;360:1903-1913
Str
oke M
ort
ality
(Flo
ati
ng
Ab
so
lute
Ris
k a
nd
95
% C
I)
Usual Systolic BP (mm Hg)
50-59 ys
60-69 ys
70-79 ys
80-89 ys
Systolic Blood Pressure Diastolic Blood Pressure
Usual Diastolic BP (mm Hg)
50-59 ys
60-69 ys
70-79 ys
80-89 ys
Age at risk: Age at risk:
120 140 160 180
256
128
64
32
16
8
4
2
1
0
70 80 90 110100
256
128
64
32
16
8
4
2
1
0
Stroke Mortality vs Usual BP by Age
PROGRESS Trial: Stroke by baseline BP
SBP ≥ 160
SBP 140-159
SBP < 140
DBP ≥ 95
DBP 85-94
DBP < 85
Total
active
57
54
39
27
65
58
150
placebo
106
87
62
68
99
88
255
Events Favours
active
Favours
placebo
Risk reduction
(95% CI)
47% (27 to 62%)
41% (16 to 58%)
39% ( 9 to 59%)
62% (41 to 76%)
36% (12 to 53%)
37% (12 to 55%)
43% (30 to 54%)
Hazard ratio
0.4 1.0 2.0
Stroke rates and hazard risk for in-trial SBP in
the INVEST trial
Coca A, et al. Stroke 2008; 39: 343-348
4
3
2
1
0
RR%
Stroke incidence (%)
Stroke relative risk (RR)
n = 22,576 follow-up 2.7 years
110 110-119 120-129 130-139 140-149 150-159 160-169 170-179 180
Average SBP during follow-up (mm Hg)
0
1
2
3
4
5
6
7
8
9
10
14214b M
Annual patient event rate (%)
Achieved systolic blood pressure (mmHg)
100 110 120 130 140 150 160 170
10
9
8
7
6
5
4
De Galan, Chalmers, Mancia et al., J Am Soc Nephrol 2009; 20: 883
Renal events (adjusted)All renal events
All participants
Baseline SBP (mmHg)
< 120
120-139
140-159
≥ 160
Baseline DBP (mmHg)
< 70
70-79
80-89
≥ 90
Median
BP (mmHg)
113
131
149
172
66
75
84
95
P for
trend
0.75
0.85
0.5 1.0 2.0
Hazard Ratio
(95% CI)
Risk of Renal Events according to Baseline SBP and DBP and Achieved SBP in ADVANCE
TNT(CAD pts)
0
5
10
15
20
25
30
35
0
1
2
3
4
5
≤ 60 61-70 71-80 81-90 91-100 > 100
On-treatment DBP (mmHg)
CV
eve
nts
(%
)
Ad
juste
d H
R
ONTARGET (high risk pts, mainly with CAD)
On-treatment SBP (mmHg)
112 121 126 130 133 136 140 144 149 160
0
10
20
30
0
1
2
3
CV
eve
nts
(%
)
Ad
juste
d H
R
VALUE(High risk pts)
On-treatment SBP (mmHg)
INVEST(CAD pts)
On-treatment SBP (mmHg)
110 >110to 120
>120to 130
>130to 140
>140to 150
>150to 160
>1600
10
20
30
40
50
60C
V e
ve
nts
(%
)C
ard
iac e
ven
ts (
%)
0
10
20
30
< 120 >120to 130
>130to 140
>140to 150
>150to 160
>160to 170
>170to 180
≥ 180
Safety and Efficacy of Low BP Among Patients with Diabetes
Subgroup Analysis from the ONTARGET
Redon J et al. J Am Coll Cardiol 2012;59:74
0
10
20
30
40
50
Inc
ide
nc
e (
%)
of
Pri
ma
ry O
utc
om
e
0
1
2
3
4
5
6
Es
tim
ate
d H
aza
rd R
ati
oPrimary Outcome
DBP & Risk for Primary Outcome: INVEST Subanalysis
DBP (mm Hg)
Total patients 176 2239 11306 7376 1230 248
0
1
2
3
4
5
6
Es
tim
ate
d H
aza
rd R
ati
oHazard Ratio
Nadir = 84.1 mm Hg
Messerli FH et al. Ann. Int. Med. July 2006
J-Shaped Relationship :
New Insights from a Meta-Analysis
N = 40,023
Mean F/U 3.9 years
Mean age:57.5
Male 48.9%
Total Deaths:1655
CV deaths: 926
INDANA (Individual Data ANalysis of Antihypertensive intervention) database
Ann Intern Med. 2002;136:438-448
Study (Reference) Patients Mean-Follow
n
Coope and Warrender (13) 859 3.6
EWPHE (19) 732 4.2
HDFP (23) 10819 3.9
MRC1 (24) 17307 4.0
MRC2 (20) 4334 4.8
SHEP (21) 4678 3.4
STOP (22) 1504 1.3
All studies 40233 3.9
J-Shaped Relationship: New Insights from a Meta-Analysis: Conclusions
The authors conclude:
The increased risk for events observed in patients with low blood pressure was not related to antihypertensive treatmentand was not specific to blood pressure–related events.
Poor health conditions leading to low blood pressure and an increased risk for death probably explain the J-shaped curve
Ann Intern Med. 2002;136:438- 448
Kaplan-Meier Curves for Time of Death, First Morbid Event, and
Hospitalization for HF by Quartile of Baseline SBP in Val-HeFT
Anand et al., Circ Heart Fail 2008; 1: 34-42
Time to death Time to first morbid event Time to hospitalization
100
90
80
70
600 10 20 30 40
% S
urv
iva
l
Months since randomization
100
90
80
70
600 10 20 30 40
Months since randomization
100
90
80
70
600 10 20 30 40
Months since randomization
SBP <110 mmHg
SBP >110 <121 mmHg
SBP >121 <135 mmHg
SBP >135 mmHg
Baseline Characteristics
Patients with low blood pressure tended to have a higher incidence of:
Myocardial infarction
Cancer
Heart failure
Diabetes
Pulse pressure
Role of increased central aortic and pulse pressures
in the increase of cardiovascular events
Decreased Coronary ArteryPerfusion Pressure in Diastole increased risk of MI
Increase in left ventricular load (LV
load) accelerates increase in LV mass
increased risk of LV hypertrophy
PP
Increase in the central pulse pressure that
drives cerebral blood flow
increased stroke risk..
Stroke
LVH
Coronary
Events (MI..)
Chronic
kidney
disease
16307 M
ONTARGET VALUE
60
80
100
120
140
160
0
1
2
3
4
5
6
0
1
2
3
4
5
6
0
1
2
3
4
5
6
145.5
133.0
124.8
116.3
144.0
131.3126.1
120.4
5.5
4.6
2.9 2.8
4.3
2.8
1.72.0
4.1
5.3 5.3
4.8 4.7
2.7
4.3
5.3
4.23.9
4.84.5
5.1
3.6
4.75.1
81.675.9
71.967.5
82.376.4 74.5
71.1
mm
Hg
% %
%
< 25
25-49
50-74
≥ 75
% of time with BP
at target
Stroke
MI CHF (hosp.)
BP mean
ONTARGET VALUE
S
D
Mancia et al., unpublished
Stroke and Cardiac Events by % of Time with BP < 130/80 mmHg
in ONTARGET (N = 19631) and VALUE (N = 15244)
ACCOMPLISH
SBP over time Kaplan-Meier for primary endpoint
mmHg
Month5731 5387 5206 4999 4804 4285 2520 1045
5709 5377 5154 4980 4831 4286 2594 1075Pts.
*Mean values are taken at 30 months F/U visit
129.3 mmHg
130 mmHg
Difference of 0.7 mmHg p<0.05*
DBP: 71.1 DBP: 72.8
ACEI / HCTZN=5733
CCB / ACEIN=5713
Cumulative event rate
HR (95% CI): 0.80 (0.72, 0.90)
20% Risk Reduction
Time to 1st CV morbidity/mortality (days)
p = 0.0002
ACEI / HCTZ
CCB / ACEI650
526
13018 M
Risk for a second CV event
Degree of vascular occlusion (coronary, other areas)
Integrity of hemodynamic mechanisms (LV function, baroreceptor
activity)
Degree of vascular stiffness
Renal dysfunction
Underlying treatment with vascular vasoprotective drugs (statins,
antiplatelet drugs, beta-blockers)
Heterogeneous conditions at high CV risk
Disease
DeathLow on-treatment
BP
?
So What??
The answer can only come from Prospective randomized Trials
As of today we only have two such studies:
Hypertension Optimal Treatment (HOT) study
ACCORD
0
1
2
3
4
5
6
7
8
9
10
< 80 < 85 < 90
MI
pe
r 1
00
0 P
ati
en
t Y
ea
rs
Non-Ischemic
Ischemic
DBP (mmHg)
CruickshankJM, Hannson L CV Drugs Therapy 2000;14,373
J-Curve HOT Study
“There was no evidence of a J-shaped curve for the relation of major cardiovascular events, all
myocardial infarction, all stroke, and cardiovascular mortality with achieved blood
pressures.”
HOT Study. Lancet 1998;351:1755-1762
15721 M The ACCORD Study Group, NEJM 2010; March 14
140
130
120
110
0
0 1 2 3 4 5 6 7 8
Years since randomization
(mmHg)Standard
Mean 133.5 mmHg
Intensive
Mean 119.3 mmHg
Mean no. of
medications
prescribed
Intensive
Standard
No. of patients
Intensive
Standard
3.2
1.9
2174
2208
3.4
2.1
2071
2136
3.4
2.1
1973
2077
3.5
2.2
1792
1860
3.5
2.2
1150
1241
3.5
2.3
445
504
3.4
2.3
156
203
3.4
2.3
156
201
1.0
0.8
0.6
0.4
0.2
0.00 1 2 3 4 5 6 7 8
0 1 2 3 4 5 6 7 8
0.0
0.1
0.2 Standard
Intensive
Proportion with events
Years
P = 0.20
BP and CV Events in ACCORD
SBP Primary outcome
DBP: 70 vs 62 mm Hg
15626 M
Nonfatal MI
Stroke
HR
0.5 1.0 2.0
Favours standard therapyFavours intensive therapy
RR
0.87
0.59
P
0.25
0.01
Intensive: SBP 119.3 mmHg
Standard: SBP 133.5 mmHg
The ACCORD Study Group, NEJM 2010
Relative Risk of Stroke / MI in ACCORD
What is the evidence to lower SBP < 130 in high/very
high risk hypertensives ?
132
129130
124
136
130130
122
140
136
130
124
133
128
138
135
140
136
150
150
141
132
149
143
100
110
120
130
140
150
160
136
133133
119
144
141
145
143144
140
137
128
138
132
140
134
143
134
162
153
143
139
154
144
155
145
148
145
110
120
130
140
150
160
170
Diabetes Previous CVD
BP Benefit No benefit
Zanchetti, Grassi, Mancia J Hypert 2009; 27: 923
SBP (mmHg)
HOTSHEP
UKPDS S. Eur ADV ABCDRENHOPE PROG
HT
IDNT
AMNT IR
IDNT
PL
Active
SBP (mmHg)
PATS
PL
Active
PROG
ACC
PROF
HOPE
EU
CAM-AM PREV
ACT
CAM-EN
PEATR
Stroke CHD
ACRDNAV
preDM
Achieved BP in Trials
1617 Z
0
10
20
30
50
40
Majo
r card
iovascu
lar
even
ts
(% in
5 y
ears
)
ACC
68
60
23
13
-
13
68
65
0
132
CAM
57
18
38
4
100
-
86
94
139
124
PEA
64
17
55
7
100
-
70
90
109
129
EU
60
-
65
3
100
-
57
92
102
128
INV
66
28
32
5
100
22
37
57
0
131
JM
65
22
42
-
100
-
28
55
0
136
ALL
67
36
23
52
16.5
25
36
0
135
ACT
64
15
52
-
100
-
68
86
37
130
ONT
64
37
49
21
91
13.6
62
81
118
133
TR
67
36
46
22
91
13
55
79
131
136
HOP
66
38
52
11
88
8.5
28
76
101
135
VAL
67
32
46
20
60
15
46
73
0
139
PROG
64
13
16
100
100
-
7
60
50
132
PROF
66
28
-
100
100
15.5
47
100
103
136
PATS
60
-
-
100
100
-
-
-
0
143
MOS
68
37
8
100
100
31
78
0
136
Trial
Age (y)
DM (%)
MI (%)
Stroke (%)
Any CVD (%)
LVH (%)
LLT (%)
APT (%)
AHT (%)
SBP (mmHg)
}
TIA
65
5
6
100
100
11
-
49
0
150
8.08.3
10.5 10.6 11.0
11.5
11.7
11.4 12.213.9 13.9 14.0
16.1
19.2
25.6 25.4
34.3
40.0
10.511.7 11.2
13.0
11.012.4
12.114.0
12.5
14.115.8
17.816.8
25.4
26.9 27.0
43.5
50.0
8.512.0
LIFE
67
36
16*
8
25
100
-
-
0
144
Zanchetti J Hypertens 2009
Trials in High-Risk Patients
Residual
Risk
1636 Z
30%
20%
10%
5%
CV risk
% in 10 years
40%
50%
Treatment Benefits -25%
50
37.5
3022.5
20
15
10
7.5 CV
risk
Death
Zanchetti A. Nat Rev Cardiol 2010;7:66-7
The Cardiovascular Continuum :
Treatment Benefits and Residual Risk at Increasing CV Risk
Advanced CV disease is a mixture of different clinical
conditions which require individualization of decisions
Despite the need to reduce CV risk by BP reduction, BP
control is more difficult to achieve due to the presence of
underlying vascular and renal organ damage
Clearly, there is a point at which both DBP and SBP
become too low to sustain life. The challenge is to better
define the limits of intervention and to define groups of
people who are particularly vulnerable to over-aggessive
lowering of BP
Prospective randomized trials needed to this aim
Conclusions