The concept of Diabetes & CV risk:A lifetime risk challenge

RAS blockade in the real world:

Clinical lessons from recent trials

Peter Meredith PhDUniversity of Glasgow,Department of Medicine and Therapeutics,Gardiner InstituteWestern InfirmaryGlasgow, United Kingdom

Cardio Diabetes Master ClassEuropean chapterMunich, GermanyMay 6-8, 2011

Slide lecture prepared and held by:

Presentation topic

The Cardiovascular Continuum

Myocardial Infarction

Heart Failure

End-Stage Heart Disease

Plaque Rupture

Risk Factors

HypertensionHyperlipidemia

Diabetes

Atherosclerosis

Endothelial Dysfunction

Coronary ArteryDisease

Dilatation/Remodeling

Angiotensin II

RAS Blockade Across the CV Continuum

Hypertension

• LIFE• SCOPE• VALUE• KYOTO HEART• CAPPP• ANBP-2• ALLHAT• CASE-J

• ELITE II• Val-HeFT• CHARM• CONSENSUS I • SOLVD• PEP-CHF• I-PRESERVE

Heart Failure

MI

• OPTIMAAL• VALIANT• CONSENSUS II• ISIS-4• GISSI-3• SMILE• SAVE • AIRE• TRACE

• EUROPA• PEACE• IMAGINE

CAD

• ELITE II• Val-HeFT• CHARM• CONSENSUS I • SOLVD• PEP-CHF• I-PRESERVE

Vascular

• RENAAL• IDNT• ABCD-2V• AASK• MARVAL• ADVANCE• DETAIL• DIRECT• ROADMAP

Diabetes - Renal

• ACCESS• PROGRESS• PRoFESS• SCAST

2o Stroke Prevention

• NAVIGATOR• DREAM

Pre-Diabetes

The main benefits of antihypertensive therapy are due to lowering of BP per se

Five major classes of antihypertensive agents – thiazide diuretics, CCBs, ACE inhibitors, angiotensin receptor blockers (ARBs) and b-blockers – are suitable for the initiation & maintenance of antihypertensive treatment, alone or in combination. b-blockers, especially in combination with a thiazide diuretic, should not be used in patients with the metabolic syndrome or at high risk of incident diabetes

Because in many patients more than one drug is needed, emphasis on identification of the first class of drugs to be used is often futile. Nevertheless, there are many conditions for which there is evidence in favour of some drugs versus others either as initial treatment or as part of a combination

2007 ESH/ESC Guidelines: Choice ofAntihypertensive Drugs

VALUE : Odds Ratios Over Time

0.5 1.0Odds Ratio

2.0

Time D SBP(months) (mmHg)

all study 2.2

0-3 3.8

3-6 2.3

6-12 2.0

12-24 1.8

24-36 1.6

36-48 1.4

study end

1.7

Primary Endpoint

Favours Valsartan Favours Amlodipine

Months on monotherapy

12

18

24

30

36

42

48

VALUE: Endpoints while on Monotherapy

hazard ratio

Myocardial Infarction

0.5 1 2

favours valsartan

favours amlodipine

Julius et al 2006

Heart Failure

0.5 1 2

favours valsartan

favours amlodipine

hazard ratio

Analysis of outcomes in 7080 patients who, at the end of the initial drug adjustment period, remained on monotherapy (data was censored when monotherapy was discontinued).

Between-group differences in MI and heart failure at various time points in the study.

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

En

dpo

int r

ate

Losartan 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901Atenolol 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876

Intention-to-Treat Analysis

Losartan

Atenolol

Month0 6 12 18 24 30 36 42 48 54 60 66

Adjusted Risk Reduction 13·0%, p=0·021Unadjusted Risk Reduction 14·6%, p=0·009

LIFE: Primary Composite Endpoint

Dahlöf et al 2002

D BP losartan vs atenolol:-1.1 mmHg SBP/ +0.2 mmHg DBP

-0.3 mmHg MAP

0.5 1.0 1.5

SCOPELIFE

major CV event

CV death

fatal/non-fatal stroke

fatal/non-fatal MI

total mortality

Relative Risk

Risk Reduction: ARB versus Control

Adapted from Dahlöf et al 2002 & Lithell et al 2003

MOrbidity and Mortality after Stroke – Eprosartan vs. Nitrendipine in Secondary Prevention

0 500 1000 1500days

0

50

100

150

200

250

300

Eve

nts

(n)

Eprosartan

Nitrendipine

Odd Ratio=0.79 (0.66, 0.96) p<0.014

Primary Endpoint: composite of total mortality + total number of cerebrovascular & cardiovascular events (including recurrent events)

Schrader et al 2004

Trenkwalder et al 2005

66% 62% 64%

Non-fatalstroke

Allstroke

MajorCV eventRelative

risk reduction

Control

Eve

nts/

1000

pat

ient

yea

rs

0

20

40

60

80

100

Candesartan

SCOPE: First Major Cardiovascular Eventsin Patients with a Previous Stroke

-7-9 -8 -6-10 -5-9-10 -8 -7 -6 -5

125

100

75

50

25

0

EXP-3174

Control

0.01 nM

0.1 nM1 nM

125

100

75

50

25

0

Losartan

Control

10 nM0.1 M

125

100

-9 -8 -6

75

50

25

0

Irbesartan

-10 -7 -5

Control

1 nM

10 nM

0.1 M

Candesartan

0

125

100

75

50

25

-9-10

0.003nM

0.03 nM

1nM

-8 -7 -6 -5

Control

Angiotensin II (nM)

Antagonism of Angiotensin II-Induced Effects by Candesartan and Losartan

Morsing et al 1998

Insurmountable and Surmountable

Antagonism: Relation to Duration of Binding

telmisartan olmesartancandesartan

EXP 3174

valsartan

irbesartan

losartan

0 120Dissociation t1/2

0

100

Insu

rmou

ntab

ility

(%

)

80

10080

60

40

6040

20

20

Van Liefde et al 2009

A Placebo Controlled ABPM Comparison of Candesartan 8 mg and Losartan 50 mg

candesartan cilexetil 8 mg

losartan 50 mg

placebo

Cha

nge

in B

P (

mm

Hg)

day daynight night

Systolic BP Diastolic BP

* *

** #

*p<0.001 vs placebo#p<0.05 vs losartan

Mallion et al 1999

** *

4

0

-4

-8

-12

2

0

-2

-4

-6

-8

-10

* #

Candesartan Cilexetil vs Losartan : Mean Change From Baseline to Week 8 in Systolic ABP

0

-2

-4

-6

-8

-10

-12

-14

-16

-18

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36Hours after dose

Change in SBP (mm Hg)

Lacourcière & Asmar 1999

Losartan 100mg

Candesartan cilexetil 16mg

p=0.004

Comparison of the Efficacy of Candesartan & Losartan: Meta-Analysis of Trials in the Treatment of Hypertension

A systematic literature search of databases from 1980 to 1 October 2008 identified 13 studies in which candesartan and losartan (as mono-therapy or in fixed combination with HCTZ) were compared in randomised trials in hypertensive patients.

Data from 4066 patients were included in the statistical analysis which was performed using RevMan software (v5), provided by the Cochrane Information Management System using a random effect model.

Mean changes in SBP and DBP were compared for each drug alone and after stratification for dose and for combination with HCTZ.

Meredith et al 2009

Study or Subgroup

OVERALL

Heterogeneity: Tau ² = 1.06; Chi ² = 19.19, df = 14 (P = 0.16); I² = 27%

Test for overall effect: Z = 5.92 (P < 0.00001)

Mean SD Total

2038

Mean SD Total

2028

Weight

100.0%

Candesartan Losartan95% CI

Mean Difference95% CI

3.40 [-3.72, 10.52]

4.60 [ -2.44, 11.64]

2.00 [-1.01, 5.01]

3.50 [1.28, 5.72]

1.90 [-1.23, 5.03]

8.40 [4.45, 12.35]

-0.60 [-6.65, 5.45]

3.90 [1.07, 6.73]

4.20 [1.02, 7.38]

1.40 [-0.15, 2.95]

-1.00 [-8.00, 6.00]

3.50 [-3.91, 10.91]

5.70 [1.81, 9.59]

8.10 [-1.18, 17.38]

3.30 [0.92, 5.68]

3.22 [2.16, 4.29]

3.40 [-3.72, 10.52]

4.60 [-2.44, 11.64]

2.00 [-1.01, 5.01]

3.50 [1.28, 5.72]

1.90 [-1.23, 5.03]

8.40 [4.45, 12.35]

-0.60 [-6.65, 5.45]

3.90 [1.07, 6.73]

4.20 [1.02, 7.38]

1.40 [-0.15, 2.95]

-1.00 [-8.00, 6.00]

3.50 [-3.91, 10.91]

5.70 [1.81, 9.59]

8.10 [-1.18, 17.38]

3.30 [0.92, 5.68]

3.22 [2.16, 4.29]

Mean Difference 95% CI

Andersson et al 1998

Andersson et al 1998

Baguet et al 2006

Bakris et al 2001

Gradman et al 1999

Koenig et al 2000

Koh et al 2004

Lacourciere et al 1999

Lacourciere et al 1999

Manolis et al 2000

Matsuda et al 2003

Nishimura et al 2005

Ohman et al 2000

Rayner et al 2006

Vidtet al 2001

15.7

16.9

10.8

13.3

11.9

32.2

22.1

12.3

14.5

15.8

14.2

11.4

19.4

25.8

13.4

24.5

24.3

11.3

14.8

14.5

12.8

12.1

10.7

11.8

12.2

9.7

10

16.9

18.3

15.1

82

84

87

322

162

81

31

109

106

462

17

12

151

25

307

12.3

12.3

8.8

9.8

10

23.8

22.7

8.4

10.3

14.4

15.2

7.9

13.7

17.7

10.1

22.1

22.1

8.9

14.2

14.6

12.7

12.4

10.5

11.5

11.7

10.4

8.1

17.4

15.6

14.9

83

83

89

332

170

79

32

106

100

449

15

11

148

27

304

2.1%

2.1%

8.7%

12.6%

8.2%

5.8%

2.8%

9.4%

8.0%

17.5%

2.1%

1.9%

5.9%

1.3%

11.7%

Andersson et al 1998

Andersson et al 1998

Baguet et al 2006

Bakris et al 2001

Gradman et al 1999

Koenig et al 2000

Koh et al 2004

Lacourciere et al 1999

Lacourciere et al 1999

Manolis et al 2000

Matsuda et al 2003

Nishimura et al 2005

Ohman et al 2000

Rayner et al 2006

Vidtet al 2001

0 10 20-10

Favours CandesartanFavours Losartan

Meredith et al 2009

Candesartan & Losartan-Antihypertensive Effects: Systolic BP in Direct Comparator Trials

Meredith et al 2009

Candesartann=

Losartann= 95% CI

Mean Difference

Favours Candesartan

0 10-10

Favours Losartan

Mean Difference 95% CI

ALL TRIALS 2038 2028 3.22 [2.16, 4.29]Heterogeneity: Tau² = 1.06; Chi² = 19.19, df = 14 (P = 0.16); I² = 27%Test for overall effect: Z = 5.92 (P < 0.00001)

Monotherapy 1806 1801 2.57 [1.71, 3.44]Heterogeneity: Tau² = 0.00; Chi² = 9.24, df = 12 (P = 0.68); I² = 0%Test for overall effect: Z = 5.86 (P < 0.00001)

“Low Dose” 295 293 2.74 [0.83, 4.64]

Heterogeneity: Tau² = 0.00; Chi² = 2.01, df = 3 (P = 0.57); I² = 0%Test for overall effect: Z = 2.81 (P < 0.005)

“High Dose” 1427 1425 2.49 [1.52, 3.57]

Heterogeneity: Tau² = 0.00; Chi² = 6.86, df = 7 (P = 0.44); I² = 0%Test for overall effect: Z = 5.01 (P < 0.00001)

Candesartan & Losartan-Antihypertensive Effects: Systolic BP in Direct Comparator Trials

Candesartan Losartan WMD 95% CI Test of Overall Effect (n=) (n=) (mmHg) (mmHg) Z= p=

All Trials 2038 2028 2.21 1.34, 3.07 4.99

0.0001

Monotherapy 1806 1801 1.76 1.03, 2.50 4.70

0.0001

“Low-Dose” 295 293 2.02 0.81, 3.23 3.27

0.001

“High-Dose” 1427 1425 1.63 0.59, 2.67 3.06

0.002

“HCTZ 232 227 4.34 0.82, 7.87 2.41

0.02 Combination”

Candesartan & Losartan-Antihypertensive Effects: Diastolic BP in Direct Comparator Trials

Meredith et al 2009

Potential Benefits of Additional BP Reductions

Meta-analysis of 61 cohort studies and 147 randomised trials suggests that in a 65 year old, monotherapy with a standard dose of an

antihypertensive, reduces diastolic BP by approximately 5mmHg resulting in:-

Prospective Studies Collaboration 2002 & Law et al 2009

0

-10

-20

-30

-40

% r

ed

uctio

n in

eve

nts

CHD Stroke

an additional 1.8 mmHg reduction in diastolic BP can be predicted to result in:-

Hypothesis and Aim

Losartan and candesartan have different pharmacological properties and blood pressure lowering abilities

The aim of the Real Life study was to test the hypothesis that losartan and candesartan have different primary preventive effects on CVD risk

The hypothesis was tested by setting up a large retrospective observation study in 72 Health Care Centres in Sweden

REAL-LIFE

Selection Method

24,943 patients started on either

losartan or candesartan

from 1999–2007

10,843 (44%) patients were excluded:

1. CV-disease or prescription of warfarin/digitalis/nitrates

2. Malignancy

3. Another RAS-inhibitor in the first week after inclusion

Losartan 6,771 (48.0%)

Candesartan 7,329 (52.0%)

Follow-up average 2.0 years (36,339 patient years)

Incl

uded

14,

100

REAL-LIFE

Losartan Candesartan p(n=6771) (n=7329)

Age (years) 61.7 (12) 62.4 (12) 0.001Women, n (%) 3723 (55.0) 4109 (56.1) 0.2030Body mass index (kg/m2) 30.2 (5.3) 30.2 (5.4) 0.8463Systolic BP(mmHg) 159 (20) 160 (19) 0.0124Diastolic BP (mmHg) 89 (10) 90 (10) <0.0001Total cholesterol (mmol/L) 5.7 (1.0) 5·7 (1.1) 0.2243LDL cholesterol (mmol/L) 3.34 (0.81) 3·39 (0.81) 0.0647HDL cholesterol (mmol/L) 1.38 (0.32) 1·37 (0.31) 0.4826Triglycerides (mmol/L) 1.64 (0.81) 1·62 (0.78) 0.2965Glucose (mmol/L) 6.3 (2.4) 6·2 (2.3) 0.0024HbA1c (%) 5.9 (1.4) 5·8 (1.4) 0.0342Diabetes, n (%) 1215 (17.9) 1112 (15.2) <0.0001Serum creatinine (μmol/L) 84 (21) 84 (19) 0.6895Potassium (mmol/L) 4.0 (0.4) 4·0 (0.4) 0.7452Thiazides, n (%) 848 (12.5) 1087 (14.8) 0.0001Calcium channel blockers*, n (%) 968 (14.3) 1104 (15.1) 0.2071Beta-blockers, n (%) 1605 (23.7) 1883 (25.7) 0.0066Oral glucose lowering , n (%) 628 (9.3) 559 (7.6) 0.0005Statins, n (%) 727 (10.7) 688 (9.4) 0.0084Antithrombotics, n (%) 421 (6.2) 395 (5.4) 0.0386ARBs, n (%) 101 (1.5) 120 (1.6) 0.5301ACEIs, n (%) 1361 (20.1) 1459 (19.9) 0.7906

The “Real-Life” Study: Candesartan v Losartan

Blood Pressure Reduction

REAL-LIFE

mm

Hg

Months

180

160

140

120

100

80

60

012 24 36 48 60 72 84 96 0

Losartan

Candesartan

Systolic

Mean arterial

Diastolic

Kjeldsen et al 2009

Concomitant Medication

Months

Thiazides

losartancandesartan

90

80

70

60

50

40

30

20

10

0

Inde

x 12 24 36 48 60 72 84 96

Calcium channel blockers

Months

losartancandesartan

90

80

70

60

50

40

30

20

10

0

Inde

x 12 24 36 48 60 72 84 96

Betablockers

losartancandesartan

Months

90

80

70

60

50

40

30

20

10

0

Inde

x 12 24 36 48 60 72 84 96

Months

Statins

losartancandesartan

90

80

70

60

50

40

30

20

10

0

Inde

x 12 24 36 48 60 72 84 96

Oral glucose lowering drugs

losartancandesartan

Months

90

80

70

60

50

40

30

20

10

0

Inde

x 12 24 36 48 60 72 84 96

Months

losartancandesartan

90

80

70

60

50

40

30

20

10

0

Inde

x 12 24 36 48 60 72 84 96

Antithrombotics

REAL-LIFE

Kjeldsen et al 2009

Primary Outcome: Candesartan v Losartan

The primary composite end-point: CVD morbidity, CVD mortality and elective coronary revascularisation

Cum

ulat

ive

inci

denc

e (%

)

Kjeldsen et al 2009

Adjusted* risk reduction 14.4% (p=0.0062)

Unadjusted risk reduction 20.6% (p<0.0001)

24120 36 48 7260 84 96

30

25

20

15

0

5

10

time (months)

candesartan

losartan

*Adjusted for age, gender, diabetes & prescription & index year

Number at risk

Los 6771 4548 3165 2090 1458 923 526 259 96Can 7329 4860 3385 2242 1580 1021 592 257 76

Risk of Separate Endpoints

*Adjusted for age, gender, diabetes and prescription & index year

Heart failure

0

2

4

6

8

10

12

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

candesartanlosartan

Cum

ulat

ive

inci

denc

e (%

)

Time (months)

-35.9% p=0.0004

Arrhythmias

0

2

4

6

8

10

12

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Cum

ulat

ive

inci

denc

e (%

)

Time (months)

-20.0% p=0.0330

candesartanlosartan

Peripheral artery disease

0

2

4

6

8

10

12

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Cum

ulat

ive

inci

denc

e (%

)

Time (months)

-38.8% p=0.0140

candesartanlosartan

Chronic ischemic heart disease

0

2

4

6

8

10

12

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Cum

ulat

ive

inci

denc

e (%

)

Time (months)

-14.3% p=0.1400

candesartanlosartan

Myocardial infarction

0

2

4

6

8

10

12

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Cum

ulat

ive

inci

denc

e (%

)

Time (months)

-7.0% p=0.5600

candesartanlosartan

Stroke

0

2

4

6

8

10

12

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96C

umul

ativ

e In

cide

nce

(%)

Time (months)

-5.2% p=0.6400

candesartanlosartan

Kjeldsen et al 2009

Data from 30,254 unique patients registered from 62 hospitals and 60 outpatient clinics was extracted from the Swedish Heart Failure Registry between 2000 and 2009

A total of 5139 patients (mean [SD] age, 74 [11] years; 39% women) were treated with candesartan (n=2639) or losartan (n=2500)

Survival as of 14 December, 2009, by ARB agent was analyzed by Kaplan-Meier method

Predictors of survival determined by univariate and multivariate proportional hazard regression models, with and without adjustment for propensity scores and interactions

Stratified analyses and quantification of residual confounding were also performed

Candesartan v Losartan: Mortality in Heart Failure Patients

Eklind-Cervenka et al 2011

Losartan(n=2500) Candesartan (n=2639) p‐value

Mean age (years) ±SD 75.3±10.2 72.0±11.5 0.001Women 1017(40.7%) 1006(38.1%) 0.061NYHA: 0.001

I 164(9.0%) 234(10.9%) II 734(40.3%) 1068(50.0%)III 840(46.2%) 770(36.0%)IV 82(4.5%) 65(3.1%)

EF: 0.035>40% 892(42.3%) 992(41.6%)<40% 1215(57.7%) 1393(58.4%)

Mean creatinine (mmol/L) ±SD 120±13.4 111.0±56.4 0.001Mean MAP (mmHg) ±SD 91.5±13.4 92.6±13.9 0.003Hypertension 1296(53.7%) 1411(55.0%) 0.365IHD 1461(60.6%) 1286(50.7%) 0.001Diabetes mellitus 844(34.0%) 764(29.2%) 0.001ACE inhibitor 76(3.1%) 420(16.0%) 0.001Beta blocker 2049(82.3%) 2295(87.1%) 0.001Aldosterone 904(36.4%) 802(30.6%) 0.001

Eklind-Cervenka et al 2011

Candesartan v Losartan: Mortality in Heart Failure Patients

30

candesartan

losartan

1.0

0.8

0.6

0.4

0

0.2 Log-rank p<0.001

surv

iva

l pro

port

ion

10 2 3 4 5years Number at riskCandesartan 2639 1739 957 426 125Losartan 2500 1692 1097 646 359 178

82% one yearsurvival

90% one yearsurvival

51% five yearsurvival

72% five yearsurvival

Eklind-Cervenka et al 2011

Candesartan v Losartan: Mortality in Heart Failure Patients