1. The concept of Diabetes & CV risk: A lifetime risk challenge
Cardio Diabetes Master Class
European chapter
Munich, Germany
May 6-8, 2011
Presentation topic
RAS blockade in the real world: Clinical lessons from recent trials
Slide lecture prepared and held by:
Peter Meredith PhD
University of Glasgow,
Department of Medicine and Therapeutics,
Gardiner Institute
Western Infirmary
Glasgow, United Kingdom

2. The Cardiovascular Continuum
Coronary Artery
Disease
Angiotensin II
Plaque Rupture
Atherosclerosis
Myocardial Infarction
Endothelial Dysfunction
Dilatation/Remodeling
Angiotensin II has many pathophysiologic effects, mediated by stimulation of the AT1 and AT2 receptors.
It is a powerful vasoconstrictor that stimulates the secretion of two other potent vasoconstrictors, vasopressin and endothelin.
Angiotensin II also:
Increases salt and water retention directly, and indirectly via increased aldosterone secretion.
Activates the sympathetic nervous system and has a direct inotropic effect on the myocardium.
Stimulates cell growth and hypertrophy, apoptosis, interstitial fibrosis, and collagen synthesis influencing vascular and cardiac remodeling.
Causes platelet aggregation, promotes the production of tissue factor, induces the expression of PAI-1, and stimulates the formation of superoxide radical (1)
All of these pathophysiologic effects of angiotensin II result in pivotal, and potentially deleterious, effects throughout the cardiovascular continuum
(1) Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet. 2000;355:637–645.
Risk Factors
Heart Failure
Hypertension
Hyperlipidemia
Diabetes
End-Stage Heart Disease

3. RAS Blockade Across the CV Continuum
Hypertension
Vascular MI
ELITE II
Val-HeFT
CHARM
CONSENSUS I
SOLVD
PEP-CHF
I-PRESERVE
LIFE
SCOPE
VALUE
KYOTO HEART
CAPPP
ANBP-2
ALLHAT
CASE-J
OPTIMAAL
VALIANT
CONSENSUS II
ISIS-4
GISSI-3
SMILE
SAVE
AIRE
TRACE
Diabetes - Renal
RENAAL
IDNT
ABCD-2V
AASK
MARVAL
ADVANCE
DETAIL
DIRECT
ROADMAP
CAD
Heart Failure
EUROPA
PEACE
IMAGINE
ELITE II
Val-HeFT
CHARM
CONSENSUS I
SOLVD
PEP-CHF
I-PRESERVE
2o Stroke Prevention
ACCESS
PROGRESS
PRoFESS
SCAST
Pre-Diabetes
NAVIGATOR
DREAM 3

4. 2007 ESH/ESC Guidelines: Choice of Antihypertensive Drugs
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

5. VALUE : Odds Ratios Over Time
Primary Endpoint
Time D SBP
(months) (mmHg)
all study 2.2
study end 1.7
Favours Valsartan
Favours Amlodipine
0.5
1.0
Odds Ratio
2.0

6. Myocardial Infarction
VALUE: Endpoints while on Monotherapy
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.
Myocardial Infarction
Heart Failure
0.5 1 2
favours valsartan
favours amlodipine
hazard ratio
Months on monotherapy 12 18 24 30 36 42 48
favours valsartan
favours amlodipine
0.5 1 2
hazard ratio
Julius et al 2006

7. LIFE: Primary Composite Endpoint
0.16
Intention-to-Treat Analysis
Atenolol
0.14
BP losartan vs atenolol:
-1.1 mmHg SBP/ +0.2 mmHg DBP
-0.3 mmHg MAP
0.12
Losartan
0.10
Endpoint rate
0.08
0.06
0.04
Adjusted Risk Reduction 13·0%, p=0·021
Unadjusted Risk Reduction 14·6%, p=0·009
0.02
0.00 6 12 18 24 30 36 42 48 54 60 66
Month
Losartan
4605
4524
4460
4392
4312
4247
4189
4112
4047
3897
1889
901
Atenolol
4588
4494
4414
4349
4289
4205
4135
4066
3992
3821
1854
876
Dahlöf et al 2002 7

8. Risk Reduction: ARB versus Control
major CV event
CV death
fatal/non-fatal stroke
fatal/non-fatal MI
total mortality
SCOPE
LIFE
Relative Risk
Adapted from Dahlöf et al 2002 & Lithell et al 2003 8

9. MOrbidity and Mortality after Stroke – Eprosartan vs
MOrbidity and Mortality after Stroke – Eprosartan vs. Nitrendipine in Secondary Prevention
500
1000
1500
days 50
100
150
200
250
300
Events (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 9

10. SCOPE: First Major Cardiovascular Events
in Patients with a Previous Stroke
66%
62%
64%
Non-fatal
stroke
All
Major
CV event
Relative
risk reduction
Control
Events/1000 patient years 20 40 60 80
100
Candesartan
Trenkwalder et al 2005

11. Antagonism of Angiotensin II-Induced Effects by Candesartan and Losartan
125
Candesartan
125
Irbesartan
100
100
0.003nM
10 nM 75
Control 75
Control
0.03 nM
1 nM 50 50 25 25
1nM
0.1 M
-10 -9 -8 -7 -6 -5
-10 -9 -8 -7 -6 -5
125
Losartan
125
EXP-3174
100
100
0.01 nM 75
Control
Control 75 50
10 nM 50
1 nM
0.1 M
0.1 nM 25 25
-10 -9 -8 -7 -6 -5
-10 -9 -8 -7 -6 -5
Angiotensin II (nM)
Morsing et al 1998 11

12. Insurmountable and Surmountable
Antagonism: Relation to Duration of Binding
100
candesartan 80
telmisartan
olmesartan
EXP 3174 60
Insurmountability (%)
valsartan 40
irbesartan 20
losartan 20 40 60 80
100
120
Dissociation t1/2
Van Liefde et al 2009 12

13. A Placebo Controlled ABPM Comparison of Candesartan 8 mg and Losartan 50 mg
Systolic BP
Diastolic BP 4 2 -2 -4 -6 -8
-10
Change in BP (mmHg) -4 -8 * * * *
* #
-12
* # * *
day
night
day
night
*p<0.001 vs placebo
candesartan cilexetil 8 mg
#p<0.05 vs losartan
losartan 50 mg
placebo
Mallion et al 1999 13

14. Candesartan Cilexetil vs Losartan : Mean Change From Baseline to Week 8 in Systolic ABP
Hours after dose 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 -2
Losartan 100mg
Candesartan cilexetil 16mg
p=0.004 -4 -6 -8
-10
-12
-14
-16
-18
Change in SBP (mm Hg)
Lacourcière & Asmar 1999 28 28 28 31 31 31 28

15. 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

16. Candesartan & Losartan-Antihypertensive Effects: Systolic BP in Direct Comparator Trials
Study or
Subgroup
OVERALL
Heterogeneity: Tau
= 1.06; Chi
= 19.19, df
= 14 (P = 0.16); I
= 27%
Test for overall effect: Z = 5.92 (P < )
Mean SD
Total
2038
2028
Weight
100.0%
Candesartan
Losartan
95% CI
Mean Difference
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]
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
Manolis et al 2000
Matsuda et al 2003
Nishimura et al 2005
Ohman et al 2000
Rayner et al 2006
Vidt
et 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
12.8
12.1
10.7
11.8
12.2
9.7 10
18.3
15.1 82 84 87
322
162 81 31
109
106
462 17 12
151 25
307
8.8
9.8
23.8
22.7
8.4
10.3
14.4
15.2
7.9
13.7
17.7
10.1
8.9
14.6
12.7
12.4
10.5
11.5
11.7
10.4
8.1
17.4
15.6
14.9 83 89
332
170 79 32
100
449 15 11
148 27
304
2.1%
8.7%
12.6%
8.2%
5.8%
2.8%
9.4%
8.0%
17.5%
1.9%
5.9%
1.3%
11.7% 20
-10
Favours Candesartan
Favours Losartan
Meredith et al 2009 16

17. Candesartan & Losartan-Antihypertensive Effects: Systolic BP in Direct Comparator Trials
95% CI
Mean Difference
Favours Candesartan 10
-10
Favours Losartan
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 < )
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 < )
“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 < )
Meredith et al 2009 17

18. Candesartan & Losartan-Antihypertensive Effects: Diastolic BP in Direct Comparator Trials
Candesartan Losartan WMD % CI Test of Overall Effect (n=) (n=) (mmHg) (mmHg) Z= p=
All Trials ,
Monotherapy ,
“Low-Dose” ,
“High-Dose” ,
“HCTZ ,
Combination”
Meredith et al 2009 18

19. 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:-
an additional 1.8 mmHg reduction in diastolic BP can be predicted to result in:-
-10
-20
-30
-40
% reduction in events
CHD
Stroke
Prospective Studies Collaboration 2002 & Law et al 2009

20. 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 20

21. Selection Method
24,943 patients started on either losartan or candesartan from 1999–2007
Losartan ,771 (48.0%)
Follow-up average years (36,339 patient years)
Included 14,100
Candesartan 7,329 (52.0%)
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
REAL-LIFE 21

22. The “Real-Life” Study: Candesartan v Losartan
Losartan Candesartan p
(n=6771) (n=7329)
Age (years) (12) (12)
Women, n (%) (55.0) (56.1)
Body mass index (kg/m2) (5.3) (5.4)
Systolic BP(mmHg) 159 (20) 160 (19)
Diastolic BP (mmHg) 89 (10) 90 (10) <0.0001
Total cholesterol (mmol/L) 5.7 (1.0) 5·7 (1.1)
LDL cholesterol (mmol/L) (0.81) 3·39 (0.81)
HDL cholesterol (mmol/L) (0.32) 1·37 (0.31)
Triglycerides (mmol/L) (0.81) 1·62 (0.78)
Glucose (mmol/L) 6.3 (2.4) 6·2 (2.3)
HbA1c (%) 5.9 (1.4) 5·8 (1.4)
Diabetes, n (%) (17.9) (15.2) <0.0001
Serum creatinine (μmol/L) 84 (21) 84 (19)
Potassium (mmol/L) 4.0 (0.4) 4·0 (0.4)
Thiazides, n (%) 848 (12.5) (14.8)
Calcium channel blockers*, n (%) 968 (14.3) (15.1)
Beta-blockers, n (%) (23.7) (25.7)
Oral glucose lowering , n (%) 628 (9.3) 559 (7.6)
Statins, n (%) 727 (10.7) 688 (9.4)
Antithrombotics, n (%) 421 (6.2) 395 (5.4)
ARBs, n (%) 101 (1.5) 120 (1.6)
ACEIs, n (%) (20.1) (19.9)

23. Blood Pressure Reduction
REAL-LIFE
Blood Pressure Reduction
Losartan
180
Candesartan
160
140
Systolic
120
mmHg
100
Mean arterial 80
Diastolic 60 12 24 36 48 60 72 84 96
Months
Kjeldsen et al 2009

24. Concomitant Medication
REAL-LIFE
Months
Thiazides
losartan candesartan 90 80 70 60 50 40 30 20 10
Index 12 24 36 48 72 84 96
Calcium channel blockers
Betablockers
Statins
Oral glucose lowering drugs
Antithrombotics
Kjeldsen et al 2009

25. Primary Outcome: Candesartan v Losartan
The primary composite end-point: CVD morbidity, CVD mortality and elective coronary revascularisation 30 25 20 15 5 10
losartan
candesartan
Cumulative incidence (%)
Adjusted* risk reduction 14.4% (p=0.0062)
Unadjusted risk reduction 20.6% (p<0.0001) 24 12 36 48 72 60 84 96
time (months)
Number at risk
Los
6771
4548
3165
2090
1458
923
526
259 96
Can
7329
4860
3385
2242
1580
1021
592
257 76
*Adjusted for age, gender, diabetes & prescription & index year
Kjeldsen et al 2009

26. Risk of Separate Endpoints
Heart failure
Arrhythmias
Peripheral artery disease 12
losartan 12
losartan 12
losartan
candesartan
candesartan
candesartan 10 10 10 8
-35.9% p=0.0004 8 8
Cumulative incidence (%) 6
Cumulative incidence (%) 6 6
Cumulative incidence (%)
-38.8% p=0.0140 4 4 4
-20.0% p=0.0330 2 2 2 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
Time (months)
Time (months)
Chronic ischemic heart disease
Myocardial infarction
Stroke 12
candesartan
losartan 12
losartan 12
losartan 10
candesartan 10 10
candesartan 8 8 8
Cumulative incidence (%) 6
Cumulative incidence (%) 6
Cumulative Incidence (%) 6 4 4 4 2
-14.3% p=0.1400 2
-7.0% p=0.5600 2
-5.2% p=0.6400 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
Time (months)
Time (months)
*Adjusted for age, gender, diabetes and prescription & index year
Kjeldsen et al 2009 26

27. Candesartan v Losartan: Mortality in Heart Failure Patients
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
Eklind-Cervenka et al 2011

28. Candesartan v Losartan: Mortality in Heart Failure Patients
Losartan(n=2500) Candesartan (n=2639) p‐value
Mean age (years) ±SD ± ±
Women (40.7%) 1006(38.1%)
NYHA:
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:
>40% (42.3%) (41.6%)
<40% 1215(57.7%) 1393(58.4%)
Mean creatinine (mmol/L) ±SD 120± ±
Mean MAP (mmHg) ±SD ± ±
Hypertension 1296(53.7%) 1411(55.0%)
IHD (60.6%) 1286(50.7%)
Diabetes mellitus 844(34.0%) (29.2%)
ACE inhibitor 76(3.1%) 420(16.0%)
Beta blocker (82.3%) 2295(87.1%)
Aldosterone (36.4%) (30.6%)
Eklind-Cervenka et al 2011

29. Candesartan v Losartan: Mortality in Heart Failure Patients
82% one year
survival
90% one year
1.0
0.8
0.6
0.4
0.2
candesartan
51% five year
survival
72% five year
survival proportion
losartan
Log-rank p<0.001 1 2 3 4 5
years
Number at risk
Candesartan
2639
1739
957
426
125 30
Losartan
2500
1692
1097
646
359
178
Eklind-Cervenka et al 2011