Predictors of cardiovascular events in patients with ...download.xuebalib.com/5iuchB2d96Ll.pdf ·...

Blood Pressure. 2009; 18: 348–361

∗The LIFE study is registered at www.clinicaltrials.gov as NCT00338260.Correspondence: Sverre E. Kjeldsen, Department of Cardiology, University of Oslo Ullevaal Hospital, N-0407 Oslo, Norway. Tel: �47 22 119101. Fax: �47 22 119181. E-mail: [email protected]

(Received 25 September 2009; accepted 3 November 2009)

ISSN 0803-7051 print/ISSN 1651-1999 online © 2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)DOI: 10.3109/08037050903460590

ORIGINAL ARTICLE

Predictors of cardiovascular events in patients with hypertension and left ventricular hypertrophy: the Losartan Intervention For Endpoint reduction in hypertension study

SVERRE E. KJELDSEN1,5, RICHARD B. DEVEREUX2, DARCY A. HILLE3,PAULETTE A. LYLE3, BJÖRN DAHLÖF4, STEVO JULIUS5, JONATHAN M. EDELMAN3,STEVEN M. SNAPINN3, ULF DE FAIRE6, FREJ FYHRQUIST7, HANS IBSEN8,OLE LEDERBALLE-PEDERSEN9, LARS H. LINDHOLM10, MARKKU S. NIEMINEN7,PER OMVIK11, SUZANNE OPARIL12 & HANS WEDEL13; FOR THE LIFE STUDY GROUP∗

1University of Oslo, Ullevaal Hospital, Oslo, Norway, 2Weill Cornell Medical College, New York, NY, USA, 3Merck Research Laboratories, North Wales, PA, USA, 4Sahlgrenska University Hospital/Östra, Göteborg, Sweden, 5University of Michigan Medical Center, Ann Arbor, MI, USA, 6Karolinska University Hospital, Stockholm, Sweden, 7Helsinki University Central Hospital, Helsinki, Finland, 8Holbaek Hospital, Holbaek, Denmark, 9Viborg Hospital, Viborg, Denmark, 10Umeå University, Umeå, Sweden, 11Haukeland University Hospital, Bergen, Norway, 12University of Alabama Medical Center, Birmingham, AL, USA and 13Nordic School of Public Health, Göteborg, Sweden

AbstractObjective. We assessed readily available patient characteristics, including albuminuria (not included in traditional cardio-vascular risk scores), as predictors of cardiovascular events in hypertension with left ventricular hypertrophy (LVH) and developed risk algorithms/scores for outcomes. Methods. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study compared effects of losartan-based versus atenolol-based therapy on cardiovascular events in 9193 patients with hypertension and LVH. Univariate and multivariate analyses identifi ed baseline variables with signifi cant impact on development of the primary composite endpoint (cardiovascular death, stroke and myocardial infarction) and its components. Multivariate analysis used a Cox regression model with stepwise selection process. Risk scores were developed from coeffi cients of risk factors from the multivariate analysis, validated internally using naïve and jack-knife procedures, checked for discrimination and calibration, and compared with Framingham coronary heart disease and other risk scores. Results. LIFE risk scores showed increasing endpoint rates with increasing quintile (fi rst to fi fth quintile, composite endpoint 2.8–26.7%, cardiovascular death 0.5–14.4%, stroke 1.2–11.3%, myocardial infarction 1.4–8.1%) and were confi rmed with a jack-knife approach that adjusts for potentially optimistic bias. The Framingham coronary heart disease and other risk scores overestimated risk in lower risk patients and underestimated risk in higher risk patients, except for myocardial infarction. Conclusion. A number of patient characteristics predicted cardiovascular events in patients with hypertension and LVH. Risk scores developed from these patient characteristics, including albuminuria, strongly predicted outcomes and may improve risk assessment of patients with hypertension and LVH and planning of clinical trials.

Key Words: Cardiovascular disease, hypertension, left ventricular hypertrophy, risk factors

Introduction

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study compared effects of the angiotensin receptor antagonist losartan with the beta-blocker atenolol in 9193 patients with

hypertension and electrocardiographic (ECG) left ventricular hypertrophy (LVH) (1–4). The LIFE study, by far the largest study undertaken to date in LVH and one of the larger outcome studies in essential hypertension, utilized ECG–LVH criteria to

Predictors of CV events in hypertensives with LVH 349

stroke (n�443 from 8465 patients) and MI (n�331from 8624 patients) were analyzed.

Ordinal variables were included in univariate analyses by creating multiple indicator variables with a common reference category; in multivariate analy-ses, these variables were dichotomized. All univariate models were age adjusted.

Multivariate analysis used a stepwise selection pro-cess to select risk factors for the risk scores. Risk scores were developed from coeffi cients of risk factors (log hazard ratios). p � 0.001 was required to enter the fi nal multivariate model. Once this model was determined, interactions between selected variables and age were evaluated, and interactions with p � 0.001 were added. The approximate mean age in the study, 65, was sub-tracted from age to center the interaction term and facilitate interpretation of the parameter coeffi cients.

To verify that the model applied regardless of treatment, tests for interactions between treatment and the baseline parameters (individually and as a group) were performed. Separate models were run for each treatment group, and resulting coeffi cients were compared.

Calculation of risk from the risk scores is described in the Appendix, Section I.

Model validation and performance

To validate the risk score, patients were classifi ed into quintiles and deciles, and crude endpoint rates within these categories were calculated (naïve validation approach). Because of the potential optimistic bias of this approach, we also calculated endpoint rates using a jack-knife approach, in which the population was randomly split into 10 testing sets of approximately equal size, such that each of the 9193 patients fell into one of the testing sets. For each of the 10 testing sets, an entirely new score was calculated based on the remaining 90% of patients. That is, a separate multivariate model was run on the 90% sample and checked to see if interactions with age could enter the model. Then a score was calculated from the 90% sample, quintile and decile cut-points were deter-mined, and the 10% test set was classifi ed into quin-tiles and deciles. Therefore, all 9193 patients were classifi ed into quintiles or deciles based on a score that the patient had no part in developing.

Event rates predicted by quintiles and deciles of the naïve and jack-knife risk scores were compared with event rates predicted by the Framingham risk score for coronary heart disease (chosen a priori as a covari-ate for endpoint analyses in LIFE) (5). The LIFE risk scores for stroke and cardiovascular death were also compared with a Framingham risk score for stroke (10) and a risk score for cardiovascular death reported by Pocock et al. (11) (Appendix, Section II).

The ability of the LIFE risk scores to discrimi-nate between those who did or did not have an event

recruit a large population of high-risk patients with hypertension (5–9).

In a pre-specifi ed analysis, we assessed base-line demographic, clinical and laboratory variables (including albuminuria, which was not included in traditional cardiovascular risk scores) from the LIFE study as predictors of the primary composite end-point (cardiovascular death, stroke and myocardial infarction, MI) and its components and used them to develop risk algorithms/scores for patients with hypertension and LVH.

Methods

Patients and design

Eligible patients were aged 55–80 years with hyper-tension [diastolic blood pressure (BP) 95–115 mmHg and/or systolic BP 160–200 mmHg] and ECG–LVH (1). Detailed patient characteristics data have been published (2–4). Participants (n�9193) had base-line mean BP 174.4/97.8 mmHg, age 66.9 years, and body mass index (BMI) 28.0 kg/m2; 54% were women; and 12.5% had diabetes (3,4).

This randomized, double-blind study compared losartan-based versus atenolol-based therapy (both 50–100 mg daily) on cardiovascular morbidity and mortality (1). Additional treatment was given as open-label hydrochlorothiazide 12.5–25 mg and other antihypertensive medication (except beta-blockers, angiotensin receptor antagonists or angio-tensin-converting enzyme inhibitors) to reach BP �140/90 mmHg. Patients were followed for a mean of 4.8 years. The primary composite endpoint (fi rst occurrence of cardiovascular death, stroke or MI) occurred in 1096 patients. Endpoints were classifi ed by an independent committee.

Statistical methods

All analyses were conducted using SAS (version 8) and S-Plus (version 6). Univariate and multivariate Cox regression models evaluated demographic, clini-cal and laboratory variables at baseline that signifi -cantly predicted the risk of the primary composite endpoint and its components. Patients with miss-ing baseline data were excluded from the univari-ate analysis for that particular variable. However, for no variable missing data exceeded 10%, so for the multivariate analysis, missing data were interpolated with the median value of the missing variable in patients with non-missing data. The primary com-posite endpoint analysis included fi rst occurrence of cardiovascular death, stroke and MI (n�1096from 9193 patients). All cardiovascular deaths were analyzed (n�438 from 9193 patients). Patients with prestudy stroke (n�98) or MI (n�55) were excluded from analyses of these individual endpoints; incident

350 S. E. Kjeldsen et al.

was evaluated with receiver operating characteristic (ROC) curves (Appendix, Section III).

Results

Univariate analyses

In univariate analyses, we evaluated 45 categorical and continuous variables for each endpoint (Table I).

Multivariate analysis

Composite endpoint: In the multivariate model, 12 variables had signifi cant impact on development of the 1096 composite endpoints (Table IIa, Figure 1a), including an age–sex interaction term. Risk scorecomposite�0.365�log urinary albumin:creatinine ratio [UACR] (per 10-fold)�0.476 if current smoker�0.536 if history of stroke or transient isch-emic attack (TIA)�0.474 if history of diabetes�0.646if history of atrial fi brillation�0.387 if history of ischemic heart disease�0.115�total cholesterol (per mmol/l)−0.258 if exercise �30 min twice/week�0.116�LVH by Sokolow–Lyon voltage (SL) (per 10 mm)�0.086�LVH by Cornell product (CP)

(per 1000 mm·s). Additional terms were added to the risk score for women (0.786�[age−65]/10) and men (0.434�[age−65]/10�0.703).

Cardiovascular death, stroke, or MI: In the mul-tivariate model, 11 variables had signifi cant impact on development of the 438 cardiovascular deaths (Table IIb, Figure 1b), including an age–smoking interaction term. Risk scoreCVdeath�0.833 if his-tory of atrial fi brillation�0.690 if history of stroke or TIA�0.391�log UACR (per 10-fold)−0.489 if exercise �30 min twice/week�0.157�LVH by CP (per 1000 mm·s)�0.429 if male�0.059�serum glucose (mmol/l)�0.368 if history of ischemic heart disease�0.068�serum creatinine (per 10 μmol/l). Additional terms were added to the risk score for non-smokers (1.092�[age−65]/10) and smokers (0.501�[age−65]/10�1.006).

In the multivariate model, seven baseline variables had signifi cant impact on development of the 443 incident strokes (Table IIc, Figure 1c), including an age–smoking interaction term. Risk scorestroke�0.668if current smoker�0.359�log UACR (per 10-fold)�0.747 if history of atrial fi brillation�0.453if history of diabetes�0.021�serum uric acid

1.00.5 0.6 0.7 2.0 3.0Hazard Ratio (95% CI)

LVH by CP (per 1000 units)

LVH by SL (per 10 units)

Exercise

Total cholesterol

Ischemic heart disease

Atrial fibrillation

Diabetes

Stroke/TIA

Current smoker

Age (men, per 10 years)

UACR (per 10 fold)

Male sex at age 65

Age (women, per 10 years)

1.00.5 0.6 0.8 2.0 3.0Hazard Ratio (95% CI)

Serum creatinine (per 10 μmol/L)

Ischemic heart disease

Age (smoker, per 10 yrs)

Serum glucose (mmol/L)

Male sex

LVH by CP (per 1000 units)

Exercise

UACR (per 10 fold)

Stroke/TIA

Atrial fibrillation

Current smoker at age 65

Age (nonsmoker, per 10 yrs)

1.00.5 0.6 0.7 2.0 3.0Hazard Ratio (95% CI)

Age (smoker, per 10 yrs)

LVH by SL (per 10 units)

Uric Acid (per 10 μmol/L)

Diabetes

Atrial Fibrillation

UACR (per 10 fold)

Current smoker at age 65

Age (nonsmoker, per 10 yrs)

1.00.5 0.60.7 2.0 3.0Hazard Ratio (95% CI)

Pulse Pressure (per 10 mmHg)

Diabetes

Angina

UACR (per 10 fold)

Total cholesterol (per mmol/L)

Male Sex

(a) (b)

(c) (d)

Figure 1. Stepwise multivariate analyses: (a) primary composite endpoint (n�1096); (b) cardiovascular death (n�438); (c) incident stroke (n�443); (d) incident myocardial infarction (n�331). CI denotes confi dence interval, CP Cornell product, LVH left ventricular hypertrophy, SL Sokolow–Lyon voltage, TIA transient ischemic attack, and UACR urinary albumin:creatinine ratio.


Tab

le 1

. U

niva

riat

e an

alys

is o

f ba

selin

e de

mog

raph

ic,

clin

ical

, an

d la

bora

tory

var

iabl

es.

Tab

le 1

a. D

emog

raph

ic a

nd c

linic

al c

hara

cter

isti

cs. P

rim

ary

com

posi

te e

ndpo

int

(n�

1096

)C

ardi

ovas

cula

r de

ath

(n�

438)

Inci

dent

str

oke

(n�

443)

Inci

dent

myo

card

ial

infa

rcti

on

(n�

331)

Var

iabl

eH

R (

95%

CI)

PH

R (

95%

CI)

PH

R (

95%

CI)

PH

R (

95%

CI)

P

Age

(pe

r 10

yea

rs)

1.88

(1.

72–2

.06)

�0.

001

2.67

(2.

29–3

.11)

�0.

001

2.12

(1.

83–2

.44)

�0.

001

1.40

(1.

20–1

.64)

�0.

001

Mal

e se

x1.

80 (

1.59

–2.0

3)�

0.00

11.

86 (

1.54

–2.2

6)�

0.00

11.

45 (

1.20

–1.7

4)�

0.00

11.

88 (

1.51

–2.3

4)�

0.00

1R

ace

(rel

ativ

e to

whi

te)

0.00

1�

0.00

10.

051

0.55

3B

lack

1.53

(1.

21–1

.93)

2.13

(1.

52–2

.99)

1.60

(1.

10–2

.34)

0.97

(0.

58–1

.64)

Oth

er1.

27 (

0.79

–2.0

2)1.

86 (

0.96

–3.6

0)1.

07 (

0.48

–2.4

0)1.

51 (

0.71

–3.2

0)H

eigh

t (p

er 1

0 cm

)1.

25 (

1.17

–1.3

3)�

0.00

11.

25 (

1.13

–1.3

9)�

0.00

11.

15 (

1.04

–1.2

7)0.

007

1.24

(1.

10–1

.40)

�0.

001

Wei

ght

(per

10

kg)

1.09

(1.

05–1

.13)

�0.

001

1.12

(1.

05–1

.20)

�0.

001

1.08

(1.

01–1

.15)

0.02

11.

04 (

0.96

–1.1

2)0.

320

Bod

y m

ass

inde

x (k

g/m

2 )1.

00 (

0.99

–1.0

1)0.

799

1.01

(0.

99–1

.03)

0.43

51.

01 (

0.99

–1.0

3)0.

574

0.98

(0.

96–1

.01)

0.21

1S

ysto

lic B

P (

per

10 m

mH

g)1.

06 (

1.01

–1.1

1)0.

010

1.04

(0.

97–1

.11)

0.26

11.

15 (

1.08

–1.2

4)�

0.00

11.

11 (

1.02

–1.2

0)0.

011

Dia

stol

ic B

P (

per

10 m

mH

g)1.

05 (

0.98

–1.1

3)0.

138

1.04

(0.

93–1

.15)

0.51

81.

18 (

1.06

–1.3

2)0.

003

0.88

(0.

78–1

.00)

0.04

8P

ulse

pre

ssur

e (p

er 1

0 m

mH

g)1.

03 (

0.99

–1.0

8)0.

126

1.02

(0.

96–1

.09)

0.51

21.

07 (

1.00

–1.1

4)0.

045

1.15

(1.

06–1

.23)

�0.

001

Pul

se (

per

10 b

eats

)1.

05 (

0.99

–1.1

0)0.

100

1.17

(1.

08–1

.27)

�0.

001

0.99

(0.

91–1

.08)

0.83

00.

97 (

0.88

–1.0

7)0.

492

LVH

by

Cor

nell

(per

100

0 m

m·s

)1.

10 (

1.04

–1.1

6)�

0.00

11.

19 (

1.11

–1.2

8)�

0.00

11.

10 (

1.02

–1.0

0)0.

017

1.06

(0.

96–1

.17)

0.25

1LV

H b

y S

okol

ow–L

yon

volt

age

(per

10

mm

)1.

21 (

1.15

–1.2

8)�

0.00

11.

22 (

1.12

–1.3

3)�

0.00

11.

20 (

1.10

–1.3

1)�

0.00

11.

18 (

1.07

–1.3

1)0.

001

Alc

ohol

use

(re

lati

ve t

o no

ne)

1.10

(0.

93–1

.30)

0.27

81.

14 (

0.86

–1.5

0)0.

358

1.25

(0.

96–1

.62)

0.09

20.

67 (

0.46

–0.9

6)0.

030

Exe

rcis

e (r

elat

ive

to n

one)

�0.

001

�0.

001

0.02

40.

054

�30

min

tw

ice/

wee

k0.

96 (

0.82

–1.1

2)0.

80 (

0.63

–1.0

1)1.

04 (

0.81

–1.3

4)1.

10 (

0.82

–1.4

7)�

30 m

in t

wic

e/w

eek

0.70

(0.

60–0

.81)

0.48

(0.

38–0

.61)

0.79

(0.

62–1

.00)

0.81

(0.

62–1

.07)

Cur

rent

sm

oker

1.93

(1.

67–2

.22)

�0.

001

2.44

(1.

97–3

.03)

�0.

001

1.74

(1.

39–2

.20)

�0.

001

1.63

(1.

25–2

.13)

�0.

001

Sm

okin

g (p

er d

ay,

rela

tive

to

neve

r)�

0.00

1�

0.00

1�

0.00

1�

0.00

1E

x-sm

oker

1.41

(1.

23–1

.62)

1.35

(1.

09–1

.69)

1.40

(1.

14–1

.73)

1.53

(1.

20–1

.95)

1–5

1.82

(1.

42–2

.33)

2.11

(1.

45–3

.07)

1.54

(1.

02–2

.34)

1.67

(1.

05–2

.67)

6–10

2.60

(2.

06–3

.29)

3.81

(2.

76–5

.28)

1.87

(1.

23–2

.84)

2.61

(1.

73–3

.95)

10–2

02.

14 (

1.64

–2.7

8)2.

24 (

1.45

–3.4

8)2.

86 (

1.96

–4.1

5)1.

62 (

0.96

–2.7

3)�

202.

80 (

1.98

–3.9

6)3.

37 (

1.98

–5.7

2)1.

98 (

1.05

–3.7

5)1.

96 (

0.96

–4.0

2)C

ount

ry (

rela

tive

to

Uni

ted

Sta

tes)

�0.

001

�0.

038

�0.

001

�0.

001

Den

mar

k0.

85 (

0.70

–1.0

4)1.

09 (

0.80

–1.4

7)1.

09 (

0.80

–1.4

7)0.

60 (

0.39

–0.9

2)F

inla

nd0.

63 (

0.51

–0.7

9)0.

73 (

0.51

–1.0

3)0.

73 (

0.51

–1.0

3)0.

82 (

0.56

–1.2

0)N

orw

ay0.

91 (

0.76

–1.1

1)0.

88 (

0.64

–1.2

0)0.

88 (

0.64

–1.2

0)1.

03 (

0.72

–1.4

8)S

wed

en0.

75 (

0.63

–0.9

0)0.

86 (

0.65

–1.1

4)0.

86 (

0.65

–1.1

4)1.

05 (

0.76

–1.4

5)Ic

elan

d0.

68 (

0.40

–1.1

7)0.

38 (

0.12

–1.2

0)0.

38 (

0.12

–1.2

0)0.

93 (

0.37

–2.3

1)U

nite

d K

ingd

om0.

71 (

0.55

–0.9

1)0.

58 (

0.37

–0.9

1)0.

58 (

0.37

–0.9

1)0.

75 (

0.46

–1.2

3)

HR

, ha

zard

rat

io;

BP,

blo

od p

ress

ure.


Tab

le 1

b. M

edic

al h

isto

ry.

Pri

mar

y co

mpo

site

end

poin

t (n

�10

96)

Car

diov

ascu

lar

deat

h(n

�43

8)In

cide

nt s

trok

e(n

�44

3)In

cide

nt m

yoca

rdia

l in

farc

tion

(n

�33

1)

Var

iabl

eH

R (

95%

CI)

PH

R (

95%

CI)

PH

R (

95%

CI)

PH

R (

95%

CI)

P

Ane

urys

m,

aort

ic2.

06 (

1.24

–3.4

3)

0.0

053.

74 (

2.06

–6.8

1)�

0.00

10.

84 (

0.21

–3.3

8)0.

810

1.55

(0.

50–4

.84)

0.44

8A

ngin

a1.

67 (

1.42

–1.9

6)�

0.00

11.

51 (

1.17

–1.9

5)

0.0

011.

38 (

1.05

–1.8

0)0.

020

2.28

(1.

70–3

.05)

�0.

001

Ant

ihyp

erte

nsiv

e th

erap

y us

e1.

38 (

1.20

–1.6

0)�

0.00

11.

50 (

1.19

–1.8

9)�

0.00

11.

44 (

1.15

–1.8

0)0.

002

1.15

(0.

90–1

.47)

0.25

7A

rrhy

thm

ia1.

95 (

1.63

–2.3

2)�

0.00

12.

41 (

1.88

–3.1

0)�

0.00

12.

04 (

1.55

–2.6

8)�

0.00

11.

31 (

0.89

–1.9

2)0.

168

Asp

irin

use

1.36

(1.

19–1

.55)

�0.

001

1.44

(1.

18–1

.77)

�0.

001

1.11

(0.

88–1

.40)

0.37

41.

19 (

0.92

–1.5

4)0.

190

Atr

ial

fi bri

llati

on2.

61 (

2.12

–3.2

1)�

0.00

13.

42 (

2.58

–4.5

3)�

0.00

12.

80 (

2.03

–3.8

5)�

0.00

11.

15 (

0.66

–2.0

0)0.

632

Chr

onic

obs

truc

tive

pul

mon

ary

dise

ase

1.68

(1.

33–2

.13)

�0.

001

2.08

(1.

49–2

.92)

�0.

001

1.68

(1.

15–2

.45)

0.00

71.

70 (

1.09

–2.6

5)0.

018

Dia

bete

s1.

96 (

1.70

–2.2

7)�

0.00

11.

95 (

1.56

–2.4

4)�

0.00

11.

81 (

1.44

–2.2

9)�

0.00

12.

16 (

1.67

–2.7

9)�

0.00

1H

eart

fai

lure

2.40

(1.

78–3

.22)

�0.

001

2.86

(1.

91–4

.30)

�0.

001

1.19

(0.

61–2

.29)

0.61

42.

07 (

1.02

–4.1

9)0.

043

Isch

emic

hea

rt d

isea

se1.

84 (

1.61

–2.1

1)�

0.00

11.

94 (

1.58

–2.3

9)�

0.00

11.

46 (

1.17

–1.8

3)�

0.00

12.

17 (

1.65

–2.8

4)�

0.00

1M

yoca

rdia

l in

farc

tion

2.05

(1.

71–2

.46)

�0.

001

2.25

(1.

71–2

.95)

�0.

001

1.39

(0.

99–1

.95)

0.05

4N

AN

AP

erip

hera

l va

scul

ar d

isea

se1.

69 (

1.38

–2.0

7)�

0.00

11.

54 (

1.11

–2.1

2)

0.0

091.

74 (

1.27

–2.4

0)�

0.00

12.

05 (

1.43

–2.9

3)�

0.00

1S

trok

e2.

18 (

1.77

–2.6

8)�

0.00

12.

72 (

2.04

–3.6

3)�

0.00

1N

AN

A1.

76 (

1.15

–2.7

0)0.

009

Str

oke

or t

rans

ient

isc

hem

ic a

ttac

k2.

10 (

1.79

–2.4

8)�

0.00

12.

55 (

2.02

–3.2

3)�

0.00

1N

AN

A1.

80 (

1.30

–2.4

8)�

0.00

1T

rans

ient

isc

hem

ic a

ttac

k2.

06 (

1.66

–2.5

6)�

0.00

12.

41 (

1.77

–3.2

8)�

0.00

1N

AN

A1.

83 (

1.20

–2.8

0)0.

005

HR

, ha

zard

rat

io;

BP,

blo

od p

ress

ure.

Tab

le 1

c. L

abor

ator

y va

lues

.

Pri

mar

y co

mpo

site

end

poin

t (n

�10

96)

Car

diov

ascu

lar

deat

h (n

�43

8)In

cide

nt s

trok

e (n

�44

3)In

cide

nt m

yoca

rdia

l in

farc

tion

(n

�38

6)

Var

iabl

eH

R (

95%

CI)

PH

R (

95%

CI)

PH

R (

95%

CI)

PH

R (

95%

CI)

P

AL

AT

(IU

/l)0.

84 (

0.67

–1.0

6)0.

138

0.54

(0.

34–0

.86)

0.00

81.

03 (

0.81

–1.3

2)0.

787

0.94

(0.

66–1

.34)

0.73

9H

DL

cho

lest

erol

(m

mol

/l)0.

56 (

0.48

–0.6

5)�

0.00

10.

56 (

0.44

–0.7

2)�

0.00

10.

73 (

0.58

–0.9

2)0.

007

0.49

(0.

37–0

.65)

�0.

001

Hem

oglo

bin

(per

10

g/l)

1.10

(1.

04–1

.16)

�0.

001

1.01

(0.

93–1

.10)

0.8

021.

05 (

0.96

–1.1

4)0.

266

1.20

(1.

09–1

.33)

�0.

001

Ser

um c

reat

inin

e (p

er 1

0 μm

ol/l)

1.11

(1.

09–1

.13)

�0.

001

1.14

(1.

11–1

.16)

�0.

001

1.10

(1.

06–1

.14)

�0.

001

1.10

(1.

05–1

.14)

�0.

001

Ser

um g

luco

se (

mm

ol/l)

1.09

(1.

06–1

.11)

�0.

001

1.11

(1.

08–1

.15)

�0.

001

1.06

(1.

03–1

.10)

�0.

001

1.12

(1.

08–1

.15)

�0.

001

Ser

um p

otas

sium

(m

mol

/l)1.

11 (

0.95

–1.2

0)0.

186

1.20

(0.

95–1

.52)

0.11

70.

90 (

0.69

–1.1

7)0.

426

1.09

(0.

83–1

.44)

0.52

8S

erum

sod

ium

(m

mol

/l)0.

99 (

0.97

–1.0

2)0.

0535

0.98

(0.

95–1

.02)

0.32

41.

01 (

0.97

–1.0

5)0.

649

0.97

(0.

93–1

.02)

0.21

3S

erum

uri

c ac

id (

per

10 μ

mol

/l)1.

03 (

1.02

–1.0

4)�

0.00

11.

04 (

1.02

–1.0

5)�

0.00

11.

03 (

1.02

–1.0

4)�

0.00

11.

02 (

1.00

–1.0

3)0.

008

Tot

al c

hole

ster

ol (

mm

ol/l)

1.01

(0.

95–1

.06)

0.78

80.

97 (

0.89

–1.0

6)0.

524

0.95

(0.

87–1

.04)

0.28

01.

13 (

1.03

–1.2

5)0.

011

Tot

al c

hole

ster

ol/H

DL

rat

io1.

15 (

1.11

–1.2

0)�

0.00

11.

14 (

1.07

–1.2

0)�

0.00

11.

06 (

0.99

–1.1

3)0.

078

1.21

(1.

14–1

.29)

�0.

001

Uri

nary

cre

atin

ine

(per

10

mm

ol/l)

1.18

(1.

06–1

.31)

0.00

31.

04 (

0.89

–1.2

2)0.

635

1.23

(1.

05–1

.44)

0.01

00.

99 (

0.80

–1.2

3)0.

949

Uri

nary

alb

umin

(pe

r 10

0 m

g/l)

1.06

(1.

05–1

.08)

�0.

001

1.07

(1.

05–1

.09)

�0.

001

1.05

(1.

03–1

.08)

�0.

001

1.05

(1.

02–1

.08)

�0.

001

Uri

nary

alb

umin

:cre

atin

ine

rati

o (p

er 1

0-fo

ld)

1.79

(1.

64–1

.96)

�0.

001

2.08

(1.

81–2

.38)

�0.

001

1.73

(1.

51–2

.00)

�0.

001

1.69

(1.

44–2

.00)

�0.

001

p�0.

001

was

req

uire

d to

ent

er t

he s

ubse

quen

t m

ulti

vari

ate

mod

el.

Pat

ient

s w

ith

prio

r st

roke

or

myo

card

ial

infa

rcti

on w

ere

excl

uded

. All

vari

able

s, e

xcep

t ag

e, w

ere

age

adju

sted

. H

R,

haza

rd r

atio

; B

P,

bloo

d pr

essu

re; A

LA

T,

alan

ine

amin

otra

nsfe

rase

, H

DL

, hi

gh-d

ensi

ty l

ipop

rote

in;

LVH

, le

ft v

entr

icul

ar h

yper

trop

hy;

NA

, no

t ap

plic

able

.


Table 2. Stepwise multivariate analysis.

Table 2a. Primary composite endpoint (n�1096).

Variable Multiplier in risk score Chi-square HR (95% CI) P

Age (women, per 10 years) 0.786 108.5 2.19 (1.89–2.54) �0.001Male sex 0.703 73.0 2.02 (1.72–2.37) �0.001Log urinary albumin:creatinine ratio (per 10-fold) 0.365 61.7 1.44 (1.32–1.58) �0.001Age (men, per 10 years) 0.434 50.8 1.54 (1.37–1.74) �0.001Current smoker 0.476 41.6 1.61 (1.39–1.86) �0.001History of stroke or transient ischemic attack 0.536 40.7 1.71 (1.45–2.01) �0.001History of diabetes 0.474 38.9 1.61 (1.38–1.86) �0.001History of atrial fi brillation 0.646 36.2 1.91 (1.55–2.35) �0.001History of ischemic heart disease 0.387 30.9 1.47 (1.28–1.69) �0.001Total cholesterol (per mmol/l) 0.115 17.4 1.12 (1.06–1.18) �0.001Exercise �30 min twice/week −0.258 17.1 0.77 (0.68–0.87) �0.001LVH by Sokolow–Lyon voltage (per 10 mm) 0.116 16.7 1.12 (1.06–1.19) �0.001LVH by Cornell product (per 1000 mm·s) 0.086 11.3 1.09 (1.04–1.15) �0.001

HR, hazard ratio; LVH, left ventricular hypertrophy.

Table 2b. Cardiovascular death (n�438).


Age in non-smokers (per 10 years) 1.092 119.9 2.98 (2.45–3.62) �0.001Current smoker 1.006 54.2 2.73 (2.09–3.57) �0.001History of atrial fi brillation 0.833 32.5 2.30 (1.73–3.06) �0.001History of stroke or transient ischemic attack 0.690 32.1 1.99 (1.57–2.53) �0.001Log urinary albumin:creatinine ratio (per 10-fold) 0.391 28.8 1.48 (1.28–1.71) �0.001Exercise �30 min twice/week −0.489 23.0 0.61 (0.50–0.75) �0.001LVH by Cornell product (per 1000 mm·s) 0.157 18.1 1.17 (1.09–1.26) �0.001Male sex 0.429 16.8 1.54 (1.25–1.89) �0.001Serum glucose (mmol/l) 0.059 13.5 1.06 (1.03–1.10) �0.001Age in current smokers (per 10 years) 0.501 13.1 1.65 (1.26–2.17) �0.001Prior ischemic heart disease 0.368 11.7 1.44 (1.17–1.78) �0.001Serum creatinine (per 10 μmol/l) 0.068 11.5 1.07 (1.03–1.11) �0.001


Table 2c. Incident stroke (n�443).


Age in non-smokers (per 10 years) 0.873 98.5 2.40 (2.02–2.85) �0.001Current smoker 0.668 26.3 1.95 (1.51–2.52) �0.001Log urinary albumin:creatinine ratio (per 10-fold) 0.359 23.4 1.43 (1.24–1.66) �0.001History of atrial fi brillation 0.747 20.0 2.11 (1.52–2.93) �0.001History of diabetes 0.453 13.7 1.57 (1.24–2.00) �0.001Serum uric acid (per 10 μmol/l) 0.021 11.8 1.02 (1.01–1.03) �0.001LVH by Sokolow–Lyon voltage (per 10 mm) 0.138 10.0 1.15 (1.05–1.25) 0.002Age in current smokers (per 10 years) 0.291 3.7 1.34 (1.00–1.80) 0.053


Table 2d. Incident myocardial infarction (n�331).

Variable Multiplier in risk score Chi square HR (95% CI) P

Male sex 0.690 35.6 1.99 (1.59–2.50) �0.001Total cholesterol (per mmol/l) 0.238 24.2 1.27 (1.15–1.40) �0.001Log urinary albumin:creatinine ratio (per 10-fold) 0.409 23.6 1.51 (1.28–1.78) �0.001History of angina 0.723 23.5 2.06 (1.54–2.76) �0.001History of diabetes 0.559 16.8 1.75 (1.34–2.28) �0.001Pulse pressure (per 10 mmHg) 0.149 16.7 1.16 (1.08–1.25) �0.001



Table 3. Naïve and jack-knife internal validation and Framingham risk score approaches.

Table 3a. Primary composite endpoint and cardiovascular death.

Primary composite endpoint (n�1096) Cardiovascular death (n�438)

Naïve, n (%)

Jack-knife, n (%)

FraminghamCHD (5), n (%)

Naïve, n (%)

Jack-knife, n (%)


Quintile 1 51 (2.8) 55 (3.0) 100 (5.4) 9 (0.5) 11 (0.6) 43 (2.3)2 95 (5.2) 100 (5.4) 173 (9.4) 21 (1.1) 22 (1.2) 65 (3.5)3 177 (9.6) 181 (10.0) 190 (10.3) 44 (2.4) 51 (2.8) 76 (4.1)4 283 (15.4) 278 (14.8) 235 (12.8) 99 (5.4) 113 (6.2) 79 (4.3)5 490 (26.7) 482 (26.3) 398 (21.7) 265 (14.4) 241 (13.1) 175 (9.5)

Decile 1 19/920 (2.1) 20/950 (2.1) 46/920 (5.0) 4/920 (0.4) 4/907 (0.4) 18/920 (2.0)2 32/919 (3.5) 35/882 (4.0) 54/919 (5.9) 5/919 (0.5) 7/920 (0.8) 25/919 (2.7)3 37/919 (4.0) 43/933 (4.6) 85/919 (9.2) 7/919 (0.8) 9/943 (1.0) 36/919 (3.9)4 58/920 (6.3) 57/916 (6.2) 88/920 (9.6) 14/920 (1.5) 13/922 (1.4) 29/920 (3.2)5 87/919 (9.5) 80/940 (8.5) 84/919 (9.1) 21/919 (2.3) 25/885 (2.8) 32/919 (3.5)6 90/919 (9.8) 101/868 (11.6) 106/919 (11.5) 23/919 (2.5) 26/964 (2.7) 44/919 (4.8)7 120/920 (13.0) 127/928 (13.7) 111/920 (12.1) 50/920 (5.4) 49/899 (5.5) 34/920 (3.7)8 163/919 (17.7) 151/945 (16.0) 124/919 (13.5) 49/919 (5.3) 64/913 (7.0) 45/919 (4.9)9 212/919 (23.1) 216/931 (23.2) 160/919 (17.4) 108/919 (11.8) 101/937 (10.8) 59/919 (6.4)

10 278/919 (30.3) 266/900 (29.6) 238/919 (25.9) 157/919 (17.1) 140/903 (15.5) 116/919 (12.6)

Table 3b. Incident stroke and incident myocardial infarction.

Incident stroke (n�443) Incident myocardial infarction (n�331)

Naïve, n (%)

Jack-knife, n (%)

FraminghamCHD (5),n (%)

Naïve, n (%)

Jack-knife, n (%)


Quartile 1 21 (1.2) 25 (1.5) 48 (2.8) 61 (3.6) 25 (1.4) 28 (1.6)2 43 (2.5) 51 (3.1) 80 (4.7) 113 (6.7) 43 (2.5) 40 (2.4)3 79 (4.7) 86 (5.0) 73 (4.3) 63 (3.7) 48 (2.8) 55 (3.1)4 109 (6.4) 117 (6.9) 99 (5.8) 78 (4.6) 75 (4.3) 90 (5.1)5 191 (11.3) 164 (9.8) 143 (8.4) 128 (7.6) 140 (8.1) 118 (7.0)

Decile 1 8/847 (0.9) 12/835 (1.4) 24/847 (2.8) 11/863 (1.3) 12/882 (1.4) 10/863 (1.2)2 13/846 (1.5) 13/863 (1.5) 24/846 (2.8) 14/862 (1.6) 16/871 (1.8) 11/862 (1.3)3 15/847 (1.8) 20/819 (2.4) 36/847 (4.3) 16/863 (1.9) 16/833 (1.9) 27/863 (3.1)4 28/846 (3.3) 31/836 (3.7) 44/846 (5.2) 27/862 (3.1) 24/832 (2.9) 21/862 (2.4)5 34/847 (4.0) 36/867 (4.2) 34/847 (4.0) 21/862 (2.4) 24/881 (2.7) 26/862 (3.0)6 44/846 (5.2) 50/868 (5.8) 39/846 (4.6) 27/863 (3.1) 31/875 (3.5) 25/863 (2.9)7 53/847 (6.3) 47/840 (5.6) 52/847 (6.1) 28/862 (3.2) 40/860 (4.7) 44/862 (5.1)8 57/846 (6.7) 70/856 (8.2) 47/846 (5.6) 47/863 (5.4) 50/910 (5.5) 41/863 (4.8)9 78/847 (9.2) 65/830 (7.8) 63/847 (7.4) 55/862 (6.4) 51/841 (6.1) 58/862 (6.7)

10 113/846 (13.4) 99/851 (11.6) 80/846 (9.5) 85/862 (9.9) 67/839 (8.0) 68/862 (7.9)

(per 10 μmol/l)�0.138�LVH by SL (per 10 mm). Additional terms were added to the risk score for non-smokers (0.873�[age−65]/10) and smokers (0.291�[age−65]/10�0.668).

In the multivariate model, six variables had sig-nifi cant impact on the development of 331 incident MIs (Table IId, Figure 1d), without any interaction terms. Risk scoreMI�0.690 if male�0.238�totalcholesterol (per mmol/l)�0.409�log UACR (per 10-fold)�0.723 if history of angina�0.559 if history of diabetes�0.149�pulse pressure (per 10 mmHg).

Validation and p with Framingham coronary heart disease risk score (Table III, Figure 2): Thenaïve and jack-knife validation approaches indicated that the risk scores were able to effectively stratify risk of an endpoint. The two approaches gave similar

results, and good separation between low and high risks was achieved with the risk score models. The risk scores developed from the 10 different 90% sam-ples from the jack-knife approach were similar, but not identical (as one would expect). For the primary composite endpoint, most variables were selected all 10 times: age; sex; history of atrial fi brillation, stroke or TIA, diabetes, or ischemic heart disease; UACR; and smoking. In addition, either total cholesterol or total/high-density lipoprotein (HDL) cholesterol was selected each time. Exercise and LVH as measured by SL were selected nine times. For cardiovascular death, age, exercise, smoking, history of atrial fi bril-lation, history of stroke or TIA, and UACR were selected all 10 times; male sex and LVH by CP were selected nine times. For stroke, age, smoking, history of atrial fi brillation and UACR were selected all 10


times. For MI, male sex and UACR were selected all 10 times, and pulse pressure was selected nine times.

Actual rates of each endpoint were better sepa-rated by the naïve or jack-knife validation approaches for the risk scores developed in the LIFE study than by the Framingham coronary heart disease risk score (5) for the primary endpoint and cardiovascular death and the Framingham stroke risk score for stroke (10) The LIFE risk scoreMI and the Framingham coro-nary heart disease risk score (5) performed simi-larly with respect to MI. The Framingham coronary heart disease risk score overestimated risk in lower risk patients and underestimated risk in higher risk patients, except for MI. The LIFE risk score had sig-nifi cantly better sensitivity and specifi city as demon-strated by the ROC area under the curve (c-statistic) than the other risk scores for the primary composite endpoint, cardiovascular death, and stroke, without difference from the Framingham coronary disease score for the MI endpoint (Figure 3, Appendix, Section III, Table A1). The LIFE risk score had the best sensitivity and specifi city for the top quintiles for all endpoints. The sensitivity of the top quintile of the LIFE risk score was better than the Framing-ham coronary heart disease (5), jack-knife, and Framingham stroke (10) and Pocock cardiovascular death (11) risk scores (Appendix, Section II) for all endpoints. For the primary composite endpoint, the sensitivity of the top quintile of the LIFE risk score was 44.7%, compared with 36.3% for the Framing-ham coronary heart disease risk score. The specifi c-ity of the top quintile was at least 80% for all of the risk scores and all of the endpoints. The modifi ed

Hosmer–Lemeshow chi-square statistics did not indicate lack of fi t for any of the risk scores for any endpoint (Appendix, Section III, Table A1).

There was no signifi cant interaction between the risk score covariates and treatment for any endpoint. Separate models were run for each treatment group, which showed that effects of the risk score covariates were similar in both treatment groups.

Manuscript

The LIFE Steering Committee designed the LIFE study and monitored the gathering of the data and the conduct of the study. Members of the Steering Committee have the complete study data set. The ana-lyses reported here were performed by statisticians from Merck & Co., Inc., Ms Hille and Dr Snapinn. Drs Dahlöf, Devereux, Edelman, Kjeldsen, and Snapinn and Mss Hille and Lyle wrote the fi rst draft of the manuscript.

Discussion

The LIFE study used strict, but simple, ECG cri-teria to identify 9193 patients with hypertension and LVH who were treated with an antihypertensive regimen based on losartan or atenolol. Similar BPs were achieved in the treatment groups during the mean 4.8-year follow-up. The study population was at high risk for cardiovascular endpoints, with a cal-culated 5-year Framingham coronary heart disease risk score (5) of 0.221 (2). The subjects were middle-aged to elderly and, on average, overweight with high

Figure 2. Naïve and jack-knife internal validation approaches showing that the risk scores achieve good separation of risks; better predictions for the primary composite endpoint, cardiovascular death, and stroke; and similar prediction for myocardial infarction when comparedwith the Framingham coronary heart disease risk score (5). CV denotes cardiovascular, FRS Framingham coronary heart disease riskscore, and MI myocardial infarction.

Decile

0

4

9

13

17

1 2 3 4 5 6 7 8 9 101 2 3 4 5 6 7 8 9 10

2

0

5

7

10

0

3

7

10

13

0

8

15

23

30

Eve

nt R

ate

(%)

CV Death

MIStroke

Primary Composite

LIFE Risk ScoreJackknifeFRS


prevalences of diabetes, lipid disorders, coronary heart or cerebrovascular disease, and isolated systolic hypertension (3,4). However, the total cardiovascular event rate in the LIFE study (25.9 events per 1000 patient-years) was lower than the rate (33.5 events per 1000 patient-years) of the same primary compos-ite endpoint in the active treatment arm of the Swed-ish Trial in Old Patients with Hypertension (STOP) (12). The difference is likely caused by the higher mean baseline age (75.6 years vs 66.9 years in LIFE) and BP (195/102 mmHg vs 174.4/97.8 mmHg in LIFE) of the STOP population.

The present data show that in a population of older patients with hypertension and LVH most of the traditional risk factors for cardiovascular disease (CVD) signifi cantly predicted serious cardiovascular morbidity and mortality: age; male sex; UACR; smok-ing; history of stroke or TIA, diabetes, atrial fi bril-lation, or ischemic heart disease; total cholesterol; exercise; and LVH measured by SL or CP criteria.

The effect of BP at baseline was not signifi cant, most likely related to the narrow range in study-entry BP (as specifi ed by the protocol) and because BP was controlled to a common target irrespective of

BP at randomization. High heart rate is a cardiovas-cular risk factor (13) but baseline heart rate was not an independent predictor of outcome in the present analyses, possibly because of exclusion of patients with active heart failure or pulmonary disease, lim-iting beta-blocker use. BMI was not a signifi cant predictor of outcomes, perhaps because event rates in LIFE, especially of cardiovascular death, were elevated in patients with low BMI (�20 kg/m2) as well as in those with moderate-to-severe obesity (BMI 35 kg/m2) (14), excluding BMI as a linear predictor of events.

There are similarities between the LIFE study and the report of Gueyffi er et al. (15) in which data from 24,390 hypertensive participants who constituted the control groups from eight controlled trials (1726 deaths in over 5 years) were analyzed in multivariate survival models. ECG–LVH was confi rmed to be a powerful risk factor. Older age, male sex, smoking, prior stroke and total cholesterol were also signifi cant risk predictors. Height, glomerular fi ltration rate and serum uric acid showed some signifi cance, suggesting that they deserved further study. BMI and heart rate were not independent risk factors.

Figure 3. Receiver operating characteristics curves for LIFE risk scores, jack-knife scores, Framingham coronary heart disease risk score (FRS) (5) Framingham stroke risk score (Stroke Score) (10) and Pocock risk score (CVD Score) (11).

Risk Score (C=0.79)Jack-knife (C=0.73)FRS (C = 0.65)CVD Score (C=0.58)

CV Death

Risk Score (C=0.70)Jack-knife (C = 0.61)FRS (C=0.61)Stroke Score (C=0.56)

Stroke

Risk Score (C=0.68)FRS (C=0.66)Jack-knife (C = 0.61)

MI

0.0 0.2 0.4 0.6 0.8 1.0

1-Specificity

0.0 0.2 0.4 0.6 0.8 1.0

1-Specificity

0.0 0.2 0.4 0.6 0.8 1.0

1-Specificity

0.0 0.2 0.4 0.6 0.8 1.0

1-Specificity

0.0

0.2

0.4

0.6

0.8

1.0

Sen

sitiv

ity

0.0

0.2

0.4

0.6

0.8

1.0

Sen

sitiv

ity

0.0

0.2

0.4

0.6

0.8

1.0

Sen

sitiv

ity

0.0

0.2

0.4

0.6

0.8

1.0

Sen

sitiv

ity

Risk Score (C=0.73)Jack-knife (C=0.67)FRS (C=0.65)

Primary Composite


Risk scores that we developed from readily and commonly available hypertensive patient charac-teristics strongly predicted outcomes in the LIFE study and were better than Framingham coronary heart disease risk score (5) for predicting the com-posite endpoint, cardiovascular death and stroke. The Framingham coronary heart disease risk score overestimated risk in lower-risk patients and under-estimated risk in higher-risk patients, except for MI. The LIFEstroke and LIFECVD risk scores were simi-larly more effective than the Framingham stroke (10) and Pocock cardiovascular death (11) risk scores.

An important difference from Framingham risk scores (5,10,16) and most other cardiovascular risk scores (17–20) is that the LIFE models presented here include albuminuria (UACR), an increasingly used measure of systemic vascular disease (21). UACR was an important risk predictor in the LIFE study (22) and approximately one-fi fth of the dif-ference in the primary endpoint between treatments was explained by greater reduction in albuminuria in the losartan group (23). Improved prediction of cardiovascular outcomes by models that include UACR was also shown in a population-based sam-ple of American Indians (24), suggesting the utility of including albuminuria in risk models in different populations.

In view of the large number of patients with hypertension and ECG–LVH, estimated at 7.8 mil-lion in the fi rst 15 member states of the European Union (25) with similar or larger numbers in the remainder of Europe or the United States, improved risk stratifi cation by the models reported here may facilitate targeting interventions in a substantial seg-ment of the global population. Furthermore, these risk scores may be useful in clinical trial design.

Limitations of these analyses that pertain to the LIFE patient population should be taken into account when evaluating use of these results in other popula-tions. The LIFE study enrolled an older and princi-pally white population from northern Europe and the United States. The population was selected for hypertension and LVH at baseline and the Framing-ham and Pocock populations (5,10,11) were not, which makes the risk score comparisons not only a function of different risk factors studied, but also of cardiovascular status at data collection initiation. Therefore, the LIFE risk scores for the composite endpoint, cardiovascular death and stroke may be more predictive in patients with established CVD.The LIFE risk scores are rather complex, but their use could be facilitated by a Web-based calculator. Although we performed internal validations and comparisons with other risk scores (5,10,11) that increase our confi dence in the accuracy of the LIFE study risk scores, they remain to be validated in other patient sets. Strengths of our analyses include the evaluation of albuminuria as a variable, the large

patient sample, 4.8 years of follow-up, and adjudica-tion of endpoints by an independent committee.

In conclusion, we found a number of patient characteristics that independently predicted a com-posite endpoint of cardiovascular death, stroke, and MI and its components in patients with ECG–LVH being treated for hypertension with a BP goal of �140/90 mmHg. Risk scores developed from these readily and commonly available hypertensive patient characteristics strongly predicted outcomes in the LIFE study and were generally better at doing so than the Framingham coronary heart disease (5), Framing-ham stroke (10) or Pocock cardiovascular death (11) risk scores. These fi ndings may be relevant for risk assessment of patients with hypertension and LVH and for risk calculations in future clinical trials.

Disclosures

The LIFE study was sponsored by Merck & Co., Inc. Drs. Kjeldsen, Devereux, Dahlöf, Julius, Beevers, de Faire, Fyhrquist, Ibsen, Lederballe-Pedersen, Lindholm, Nieminen, Omvik, Oparil and Wedel are members of the LIFE Study Steering Committee and have received grant support from Merck. Drs Edelman and Snapinn and Mss Hille and Lyle are or have been employees of Merck. Declaration of interest: The authors alone are responsible for the content and writing of the paper.

References

Dahlöf B, Devereux R, de Faire U, Fyhrquist F, Hedner T, 1. Ibsen H, et al. The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study: Rationale, design, and methods. The LIFE Study Group. Am J Hypertens. 1997; 10:705–713.Dahlöf B, Devereux RB, Julius S, Kjeldsen SE, Beevers G, 2. de Faire U, et al. Characteristics of 9194 patients with left ventricular hypertrophy: The LIFE study. Losartan Interven-tion For Endpoint Reduction in Hypertension. Hypertension. 1998;32:989–997.Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, 3. de Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hyper-tension study (LIFE): A randomised trial against atenolol. Lancet. 2002;359:995–1003.Lindholm LH, Ibsen H, Dahlöf B, Devereux RB, Beevers G, 4. de Faire U, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For End-point reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet. 2002;359:1004–1010.Anderson KM, Wilson PW, Odell PM, Kannel WB. An 5. updated coronary risk profi le. A statement for health profes-sionals. Circulation. 1991;83:356–362.Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. 6. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990;322:1561–1566.Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. 7. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med. 1991;114:345–352.


Liao Y, Cooper RS, McGee DL, Mensah GA, Ghali JK. 8. The relative effects of left ventricular hypertrophy, coronary artery disease, and ventricular dysfunction on survival among black adults. JAMA. 1995;273:1592–1597.Otterstad JE, Smiseth O, Kjeldsen SE. Hypertensive left 9. ventricular hypertrophy: Pathophysiology, assessment and treatment. Blood Press. 1996;5:5–15.Wolf PA, D’Agostino RB, Belanger AJ, Kannel WB. Probabil-10. ity of stroke: A risk profi le from the Framingham Study. Stroke. 1991;22:312–318.Pocock SJ, McCormack V, Gueyffi er F, Boutitie F, Fagard 11. RH, Boissel JP. A score for predicting risk of death from cardiovascular disease in adults with raised blood pressure, based on individual patient data from randomised controlled trials. BMJ. 2001;323:75–81.Dahlöf B, Lindholm LH, Hansson L, Schersten B, Ekbom T, 12. Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lan-cet. 1991;338:1281–1285.Sandvik L, Erikssen J, Ellestad M, Erikssen G, Thaulow E, 13. Mundal R, et al. Heart rate increase and maximal heart rate during exercise as predictors of cardiovascular mortality: A 16-year follow-up study of 1960 healthy men. Coron Artery Dis. 1995;6:667–679.de Simone G, Wachtell K, Palmieri V, Hille DA, Beevers G, 14. Dahlöf B, et al. Body build and risk of cardiovascular events in hypertension and left ventricular hypertrophy: The LIFE (Losartan Intervention For Endpoint reduction in hyperten-sion) study. Circulation. 2005;111:1924–1931.Gueyffi er F, Boissel JP, Pocock S, Boutitie F, Coope J, Cutler 15. J,et al. Identifi cation of risk factors in hypertensive patients: Contribution of randomized controlled trials through an indi-vidual patient database. Circulation. 1999;100:e88–e94.D’Agostino RB Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain 16. M, Massaro JM, et al. General cardiovascular risk profi le for use in primary care. The Framingham Heart Study. Circula-tion. 2008;117;743–753.Conroy RM, Pyörälä K, Fitzgerald AP, Sans S, Menotti A, 17. De Backer G, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: The SCORE project. Eur Heart J. 2003;24:987–1003.Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J, 18. May M, Brindle P. Derivation and validation of QRISK, a

new cardiovascular disease risk score for the United King-dom: Prospective open cohort study. BMJ. 2007;335:136.Ridker PM, Buring JE, Rifai N, Cook NR. Development and 19. validation of improved algorithms for the assessment of global cardiovascular risk in women: The Reynolds risk score. JAMA. 2007;297:611–619.Woodward M, Brindle P, Tunstall-Pedoe H, for the SIGN 20. Group on Risk Evaluation. Adding social deprivation and family history to cardiovascular risk assessment: The ASSIGN score from the Scottish Heart Health Extended Cohort (SHHEC). Heart. 2007;93:172–176.Weir MR. Microalbuminuria and cardiovascular disease. Clin 21. J Am Soc Nephrol. 2007;2:581–590Wachtell K, Ibsen H, Olsen MH, Borch-Johnsen K, Lindholm 22. LH, Mogensen CE, et al. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: The LIFE study. Ann Intern Med. 2003;139:901–906.Ibsen H, Wachtell K, Olsen MH, Borch-Johnsen K, 23. Lindholm LH, Mogensen CE, et al. Does albuminuria predict cardiovascular outcome on treatment with losartan versus atenolol in patients with hypertension and left ven-tricular hypertrophy? A LIFE substudy. J Hypertens. 2004;22:1805–1811.Lee ET, Howard BV, Wang W, Welty TK, Galloway JM, Best 24. LG, et al. Prediction of coronary heart disease in a population with high prevalences of diabetes and albuminuria: The Strong Heart Study. Circulation. 2006;113:2897–2905.Dahlöf B, Burke TA, Krobot K, Carides GW, Edelman JM, 25. Devereux RB, et al. Population impact of losartan use on stroke in the European Union (EU): Projections from the Losartan Intervention For Endpoint reduction in hyperten-sion (LIFE) study. J Hum Hypertens. 2004;18:367–373.Mahoney, DW, Atkinson, EJ. Technical Report Series: Receiver 26. operating characteristic (ROC) curves using S-Plus. Roches-ter, MN: Department of Health Science Research, Mayo Clinic; 2004.Lemeshow S, Hosmer DW Jr. A review of goodness of fi t 27. statistics for use in the development of logistic regression models. Am J Epidemiol. 1982;115:92–106.D’Agostino R, Nam BH. Evaluation of the performance 28. of survival analysis models: Discrimination and calibration measures. In: Handbook of statistics. Amsterdam: Elsevier; 2004. p 1–25.


Appendix

Section I. Calculating risk from the risk scores

Because factor coeffi cients in the risk scores are log haz-ard ratios, the difference between two scores can be con-verted into relative risk by exponentiation. For example, consider a risk score that contains smoking as one of the factors. If two patients have identical risk factors except for smoking, the difference in scores is the coeffi cient for smoking (βsmoking) and the risk for the smoker is eβsmoking times higher than for the non-smoker. For the primary composite, the βsmoking�0.476. The risk for a smoker compared with a non-smoker, all other things being equal, is e0.476, or about 1.6 times higher.

It is possible to convert the LIFE risk scores into estimates of 5-year risk for an individual to develop any of the endpoints (cardiovascular death, stroke, MI or the composite) using the following formula:

Risk estimate � 1–S0(5)exp(X–M)

where S0 (5) is average survival at 5 years (survival rate at the mean values of the risk factors), X is the individu-

al’s risk score, and M is the risk score at mean values of the risk factors. S0 (5) and M are shown in Table A1.

Because S0 (5)�0.9044 and M�1.964 for the primary composite endpoint, the 5-year risk esti-mate is 1−0.9044exp(X−1.964). Consider a patient with the following characteristics: male; age 65 years; log UACR�0.20; current smoker; diabetic; no his-tory of stroke or TIA, atrial fi brillation, or ischemic heart disease; total cholesterol�6.0 mmol/l; exer-cises �30 min twice/week; LVH by Sokolow–Lyon criteria�30 mm; and LVH by Cornell product criteria�2800 mm·s. For this patient, X�2.749. The predicted 5-year risk of the primary composite end-point is 1−0.9044(2.749−1.964)�19.8%. For a patient with the same characteristics who is not a smoker, the 5-year risk of stroke is 12.8%.

Section II. Comparisons with the Framingham stroke and Pocock cardiovascular death risk scores

The LIFE stroke risk score was compared with the Framingham stroke risk score (Table A1, Figures 3

Table A1. Performance summary: LIFE risk scores versus jack-knife, Framingham coronary heart disease (5), Framingham stroke risk(10) and Pocock cardiovascular death risk scores (11).

LIFE Jack-knife FraminghamCHD (5) Framinghamstroke (10), PocockCVD (11)

Primary composite endpointC 0.733 0.670 0.647 –95% CI for C (0.718–0.748) (0.653–0.687) (0.629 0.664) –Chi-square 2.82 1.58 1.76 –Sensitivity of top quintile 44.71 38.78 36.31 –Specifi city of top quintile 83.35 82.55 82.22 –S0 (5) 0.9044 – – –M 1.964 – – –

Cardiovascular deathC 0.795 0.733 0.646 0.58395% CI for C (0.775–0.815) 0.710–0.756) (0.619–0.674) (0.553–0.613)Chi-square 3.37 1.35 0.77 2.57Sensitivity of top quintile 60.50 47.72 39.95 34.25Specifi city of top quintile 82.03 81.39 81.00 80.72S0 (5) 0.9719 – – –M 1.939 – – –

Incident strokeC 0.704 0.607 0.606 0.56095% CI for C (0.681–0.728) (0.581–0.633) (0.579–0.633) (0.532–0.589)Chi-square 2.65 1.24 2.08 3.04Sensitivity of top quintile 43.12 30.25 32.28 28.89Specifi city of top quintile 81.28 80.57 80.68 80.49S0 (5) 0.9565 – – –M 1.527 – – –

Incident myocardial infarctionC 0.677 0.609 0.658 –95% CI for C (0.647–0.706) (0.580–0.638) (0.629 ,0.687) –Chi-square 2.95 3.39 2.90 –Sensitivity of top quintile 42.30 27.19 38.07 –Specifi city of top quintile 80.90 80.30 80.73 –S0 (5) 0.9657 – – –M 3.116 – – –

C represents the c-statistic from the receiver operating characteristic curve. Chi-square indicates model fi t and is calculated with a modifi ed Hosmer–Lemeshow technique. A larger chi-square indicates lack of fi t; the critical chi-square value with nine degrees of freedom is 16.9. The sensitivity of the top quintile is the percent of events in the top quintile. The specifi city of the top quintile is the percent of non-events in the bottom four quintiles. S0(5) is the baseline survival rate (i.e. without an event) for 5 years for an individual with all mean values for the variables in the risk score. M represents the value of the risk score at all mean values for the variables.


and A1) (10). The Framingham stroke risk score was calculated separately for men and women. For men, the stroke risk score was defi ned as:

Stroke score (men) � 0.0505 (age)�0.0140(SBP)�0.3263(Hyp Rx)�0.3384(DM)�0.5147(Cigs)�0.5195(CVD)�0.6061(AF)�0.8415 (LVH),

and for women, the stroke risk function was defi ned as:

Stroke score (women)� 0.0657 (age)�0.0197 (SBP)�2.5432 (Hyp Rx) −0.0134 (SBP)�Hyp Rx interaction�0.5442 (DM)�0.5294 (Cigs)�0.4326 (CVD)�1.1497 (AF)�0.8488 (LVH),

where SBP is systolic blood pressure; Hyp Rx is use of antihypertensive therapy; DM is presence of diabetes mellitus; Cigs is cigarette smoking; CVD is previously diagnosed coronary heart disease, car-diac failure, or intermittent claudication; AF is pres-ence of atrial fi brillation; and LVH is left ventricular hypertrophy by electrocardiogram.

The LIFE cardiovascular death risk score was compared with the cardiovascular death risk score reported by Pocock et al. (Table A1, Figure 3) (11). The Pocock cardiovascular death risk score was cal-culated separately for men and women. For men, the cardiovascular death risk score was defi ned as:

CVD score (men)� 1.208�0.286 (age) �(Cigs)�0.359 (age)

� (No Cigs)�0.108(SBP)�0.180 (Chol)�0.060(Creat)−0.148 (height)�0.606(Cigs)�0.144 (DM) �0.808(CVATIA)�0.820 (MI)�0.332(LVH)−0.166 (Hyp Rx)

and for women, the cardiovascular death risk func-tion was defi ned as:

CVD score (women)� 0.381 (age) � (Cigs)�0.455(age) � (no Cigs)�0.108(SBP)�0.048 (Chol)�0.060(Creat)−0.148 (height)�1.046(Cigs)�0.911 (DM)�0.808(CVATIA)�0.820(MI)�0.332 (LVH)−0.166 (Hyp Rx),

where age is age per 5 years, Cigs is cigarette smoking, SBP is systolic blood pressure per 10 mmHg, Chol is cholesterol concentration per 1 mmol/l, Creat is serum creatinine concentration per 10 mol/l, Height is per 10 cm, DM is presence of diabetes mellitus, CVATIA is history of stroke, MI is history of MI, LVH is left ventricular hypertrophy by electrocardiogram, and Hyp Rx is use of antihypertensive therapy.

Section III. Discrimination and calibration

The ability of the LIFE risk scores to discriminate between those who did or did not have an event was evaluated with ROC curves (Table A1). The area under the ROC curves for the competing risk scores was compared with c-statistics (26). The calibration of each risk score was evaluated with a modifi ed Hosmer–Lemeshow chi-square statistic, which indicated lack of model fi t. For each risk score, the

1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10

Decile

0

4

9

13

17

0

3

7

10

13

Eve

nt R

ate

(%)

CV Death StrokeLIFE Risk ScoreFramingham Stroke Score

LIFE Risk ScorePocock CVD Score

Figure A1. Naïve and jack-knife internal validation approaches showing that the risk scores achieve good separation of risks; betterpredictions for the primary composite endpoint, cardiovascular death, and stroke; and similar prediction for myocardial infarction when compared with the Pocock cardiovascular death risk score (11) and Framingham stroke risk score (10).


patients were classifi ed into deciles by increasing risk score. The expected number of events in each decile was calculated via the Kaplan–Meier estimator, and compared with the observed number of events. The modifi ed chi-square calculation also compares the expected and observed number of non-events in each decile (27,28). Patients were also classifi ed into

quintiles by increasing risk score. The proportion of events that occurred in the top quintile were calcu-lated as a measure of the sensitivity of the top quintile of predicted risk, and the proportion of non-events that were not in the top quintile of predicted risk as a measure of the specifi city of the top quartile of predicted risk (16).

Copyright of Blood Pressure is the property of Taylor & Francis Ltd and its content may not be copied or

emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.

However, users may print, download, or email articles for individual use.

本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源，

提供一站式文献检索和下载服务”的24 小时在线不限IP

图书馆。

图书馆致力于便利、促进学习与科研，提供最强文献下载服务。

图书馆导航：

图书馆首页文献云下载图书馆入口外文数据库大全疑难文献辅助工具

http://www.xuebalib.com/cloud/

http://www.xuebalib.com/

http://www.xuebalib.com/cloud/


http://www.xuebalib.com/vip.html

http://www.xuebalib.com/db.php

http://www.xuebalib.com/zixun/2014-08-15/44.html


Predictors of cardiovascular events in patients with ...download.xuebalib.com/5iuchB2d96Ll.pdf ·...

Documents

Transcript of Predictors of cardiovascular events in patients with ...download.xuebalib.com/5iuchB2d96Ll.pdf ·...