joint esh/ash session j-curve...

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)


INVEST(CAD pts)


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


100

90

80

70

600 10 20 30 40


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

joint esh/ash session j-curve...

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