Transcript In patients with type 2 diabetes, are the clinical effects

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
The Cardiovascular Continuum
Coronary Artery
Disease
Plaque Rupture
Atherosclerosis
Endothelial
Dysfunction
Angiotensin II
Myocardial Infarction
Dilatation/Remodeling
Risk Factors
Heart Failure
Hypertension
Hyperlipidemia
Diabetes
End-Stage Heart Disease
RAS Blockade Across the CV Continuum
Hypertension
• LIFE
• SCOPE
• VALUE
• KYOTO HEART
• CAPPP
• ANBP-2
• ALLHAT
• CASE-J
Heart Failure
• ELITE II
• Val-HeFT
• CHARM
• CONSENSUS I
• SOLVD
• PEP-CHF
• I-PRESERVE
Vascular
• ELITE II
• Val-HeFT
• CHARM
• CONSENSUS I
• SOLVD
• PEP-CHF
• I-PRESERVE
Diabetes - Renal
• RENAAL
• IDNT
• ABCD-2V
• AASK
• MARVAL
• ADVANCE
• DETAIL
• DIRECT
• ROADMAP
Pre-Diabetes
• NAVIGATOR
• DREAM
MI
• OPTIMAAL
• VALIANT
• CONSENSUS II
• ISIS-4
• GISSI-3
• SMILE
• SAVE
• AIRE
• TRACE
CAD
• EUROPA
• PEACE
• IMAGINE
2o Stroke Prevention
• ACCESS
• PROGRESS
• PRoFESS
• SCAST
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
VALUE : Odds Ratios Over Time
Time
(months)
all study
D SBP
(mmHg)
Primary Endpoint
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
Favours Valsartan
0.5
Favours Amlodipine
1.0
Odds Ratio
2.0
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
Months on
monotherapy
12
18
24
30
36
42
48
favours
valsartan
0.5
favours
valsartan
favours
amlodipine
1
hazard ratio
2
0.5
favours
amlodipine
1
hazard ratio
2
Julius et al 2006
LIFE: Primary Composite Endpoint
0.16
Intention-to-Treat Analysis
D BP losartan vs atenolol:
-1.1 mmHg SBP/ +0.2 mmHg DBP
-0.3 mmHg MAP
0.14
0.12
Endpoint rate
Atenolol
Losartan
0.10
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
0
Losartan 4605
Atenolol 4588
6
12
18
24
4524 4460 4392 4312
4494 4414 4349 4289
30
36
42
48
4247 4189 4112 4047
4205 4135 4066 3992
54
60
3897 1889
3821 1854
66 Month
901
876
Dahlöf et al 2002
Risk Reduction: ARB versus Control
SCOPE
LIFE
major CV event
CV death
fatal/non-fatal stroke
fatal/non-fatal MI
total mortality
0.5
1.0
Relative Risk
1.5
Adapted from Dahlöf et al 2002 & Lithell et al 2003
MOrbidity and Mortality after Stroke – Eprosartan vs.
Nitrendipine in Secondary Prevention
Primary Endpoint: composite of total mortality + total number of
cerebrovascular & cardiovascular events (including recurrent events)
Events (n)
300
250
Nitrendipine
200
Eprosartan
150
100
Odd Ratio=0.79 (0.66, 0.96) p<0.014
50
0
0
500
1000
1500
days
Schrader et al 2004
SCOPE: First Major Cardiovascular Events
in Patients with a Previous Stroke
100
Events/1000 patient years
Control
80
Candesartan
60
40
20
0
Relative
risk reduction
Non-fatal
stroke
All
stroke
Major
CV event
66%
62%
64%
Trenkwalder et al 2005
Antagonism of Angiotensin II-Induced Effects
by Candesartan and Losartan
Candesartan
125
Irbesartan
125
100
100
0.003nM
75
75
Control
10 nM
Control
0.03 nM
1 nM
50
50
25
25
0.1 M
1nM
0
0
-10
-9
-8
-7
-6
-5
Losartan
125
-10
-9
Control
50
10 nM
1 nM
0.1 M
0.1 nM
25
25
0
0
-10
-9
-8
-7
-6
-5
Control
75
50
-6
0.01 nM
100
75
-7
EXP-3174
125
100
-8
-5
-10
-9
-8
-7
-6
-5
Angiotensin II (nM)
Morsing et al 1998
Insurmountable and Surmountable
Antagonism: Relation to Duration of Binding
100
candesartan
Insurmountability (%)
80
telmisartan
olmesartan
EXP 3174
60
valsartan
40
irbesartan
20
losartan
0
0
20
40
60
80
100
120
Dissociation t1/2
Van Liefde et al 2009
A Placebo Controlled ABPM Comparison of
Candesartan 8 mg and Losartan 50 mg
Systolic BP
Change in BP (mmHg)
4
Diastolic BP
2
0
0
-2
-4
-4
-8
*
-12
*
day
*
* night
-8
-10
*#
*#
day
*p<0.001 vs placebo
candesartan cilexetil 8 mg
#p<0.05
losartan 50 mg
vs losartan
placebo
*
*
-6
night
Mallion et al 1999
Candesartan Cilexetil vs Losartan : Mean Change
From Baseline to Week 8 in Systolic ABP
0
Hours after dose
12 14 16 18 20 22 24 26 28 30 32 34 36
-2
-4
-6
-8
Losartan 100mg
p=0.004
-10
-12
-14
-16
Candesartan cilexetil 16mg
-18
Change in SBP (mm Hg)
Lacourcière & Asmar 1999
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
Candesartan & Losartan-Antihypertensive Effects:
Systolic BP in Direct Comparator Trials
Study or
Subgroup
Candesartan
Mean SD Total
Losartan
Mean SD Total
Mean Difference
95% CI
Weight
Andersson et al 1998
15.7 24.5
82
12.3 22.1
83
2.1%
3.40 [-3.72, 10.52]
Andersson et al 1998
16.9 24.3
84
12.3 22.1
83
2.1%
4.60
4.60 [[-2.44,
-2.44, 11.64]
Baguet et al 2006
10.8 11.3
87
8.9
89
8.7%
2.00 [-1.01, 5.01]
Bakris et al 2001
13.3 14.8
322
9.8 14.2
332
12.6%
3.50 [1.28, 5.72]
Gradman et al 1999
11.9 14.5
162
10 14.6
170
8.2%
1.90 [-1.23, 5.03]
Koenig et al 2000
32.2 12.8
81
23.8 12.7
79
5.8%
8.40 [4.45, 12.35]
Koh et al 2004
22.1 12.1
31
22.7 12.4
32
2.8%
-0.60 [-6.65, 5.45]
Lacourciere et al 1999
12.3 10.7
109
8.4 10.5
106
9.4%
3.90 [1.07, 6.73]
Lacourciere et al 1999
14.5 11.8
106
10.3 11.5
100
8.0%
4.20 [1.02, 7.38]
Manolis et al 2000
15.8 12.2
462
14.4 11.7
449
17.5%
1.40 [-0.15, 2.95]
Matsuda et al 2003
14.2
9.7
17
15.2 10.4
15
2.1%
-1.00 [-8.00, 6.00]
Nishimura et al 2005
11.4
10
12
8.1
11
1.9%
3.50 [-3.91, 10.91]
Ohman et al 2000
19.4 16.9
151
13.7 17.4
148
5.9%
5.70 [1.81, 9.59]
Rayner et al 2006
25.8 18.3
25
17.7 15.6
27
1.3%
8.10 [-1.18, 17.38]
Vidtet al 2001
13.4 15.1
307
10.1 14.9
304
11.7%
3.30 [0.92, 5.68]
2028
100.0%
3.22 [2.16, 4.29]
OVERALL
2038
8.8
7.9
Heterogeneity: Tau ² = 1.06; Chi ² = 19.19, df = 14 (P = 0.16); I ² = 27%
Test for overall effect: Z = 5.92 (P < 0.00001)
Favours Losartan
Favours Candesartan
-10
0
10
Mean Difference 95% CI
20
Meredith et al 2009
Candesartan & Losartan-Antihypertensive Effects:
Systolic BP in Direct Comparator Trials
ALL TRIALS
Candesartan
n=
Losartan
n=
Mean Difference
95% CI
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
2.57 [1.71, 3.44]
1801
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
2.74 [0.83, 4.64]
293
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
2.49 [1.52, 3.57]
1425
Heterogeneity: Tau² = 0.00; Chi² = 6.86, df = 7 (P = 0.44); I² = 0%
Test for overall effect: Z = 5.01 (P < 0.00001)
Favours Candesartan
Favours Losartan
-10
0
10
Mean Difference 95% CI
Meredith et al 2009
Candesartan & Losartan-Antihypertensive Effects:
Diastolic BP in Direct Comparator Trials
Candesartan Losartan
(n=)
(n=)
WMD
(mmHg)
95% CI
(mmHg)
Test of Overall Effect
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
232
227
4.34
0.82, 7.87
2.41
0.02
“HCTZ
Combination”
Meredith et al 2009
Potential Benefits of Additional BP Reductions
Meta-analysis of 61 cohort studies and 147 randomised trials suggests
in a 65
old, reduction
monotherapy
with a standard
dose
of an to
an that
additional
1.8year
mmHg
in diastolic
BP can be
predicted
antihypertensive, reduces diastolic
BP by approximately 5mmHg
result in:resulting in:-
CHD
Stroke
% reduction in events
0
-10
-20
-30
-40
Prospective Studies Collaboration 2002 & Law et al 2009
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
24,943 patients
started on either
losartan or
candesartan
from 1999–2007
Included 14,100
Selection Method
Losartan
6,771 (48.0%)
Follow-up average
2.0 years
(36,339 patient years)
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
The “Real-Life” Study: Candesartan v Losartan
Age (years)
Women, n (%)
Body mass index (kg/m2)
Systolic BP(mmHg)
Diastolic BP (mmHg)
Total cholesterol (mmol/L)
LDL cholesterol (mmol/L)
HDL cholesterol (mmol/L)
Triglycerides (mmol/L)
Glucose (mmol/L)
HbA1c (%)
Diabetes, n (%)
Serum creatinine (μmol/L)
Potassium (mmol/L)
Thiazides, n (%)
Calcium channel blockers*, n (%)
Beta-blockers, n (%)
Oral glucose lowering , n (%)
Statins, n (%)
Antithrombotics, n (%)
ARBs, n (%)
ACEIs, n (%)
Losartan
Candesartan
(n=6771)
(n=7329)
61.7 (12)
3723 (55.0)
30.2 (5.3)
159 (20)
89 (10)
5.7 (1.0)
3.34 (0.81)
1.38 (0.32)
1.64 (0.81)
6.3 (2.4)
5.9 (1.4)
1215 (17.9)
84 (21)
4.0 (0.4)
848 (12.5)
968 (14.3)
1605 (23.7)
628 (9.3)
727 (10.7)
421 (6.2)
101 (1.5)
1361 (20.1)
62.4 (12)
4109 (56.1)
30.2 (5.4)
160 (19)
90 (10)
5·7 (1.1)
3·39 (0.81)
1·37 (0.31)
1·62 (0.78)
6·2 (2.3)
5·8 (1.4)
1112 (15.2)
84 (19)
4·0 (0.4)
1087 (14.8)
1104 (15.1)
1883 (25.7)
559 (7.6)
688 (9.4)
395 (5.4)
120 (1.6)
1459 (19.9)
p
0.001
0.2030
0.8463
0.0124
<0.0001
0.2243
0.0647
0.4826
0.2965
0.0024
0.0342
<0.0001
0.6895
0.7452
0.0001
0.2071
0.0066
0.0005
0.0084
0.0386
0.5301
0.7906
Blood Pressure Reduction
Losartan
180
Candesartan
160
mmHg
140
Systolic
120
100
Mean arterial
80
Diastolic
60
0
0
REAL-LIFE
12
24
36
48
60
72
84
96
Months
Kjeldsen et al 2009
Concomitant Medication
REAL-LIFE
Calcium channel blockers
Thiazides
90
80
losartan
candesartan
90
80
losartan
candesartan
Betablockers
90
80
70
70
70
60
60
60
50
50
50
40
40
40
30
30
30
20
20
20
10
10
10
0
0
0
Months
Months
Statins
80
70
Months
Antithrombotics
90
90
losartan
candesartan
80
70
Oral glucose lowering drugs
90
losartan
candesartan
80
70
60
60
60
50
50
50
40
40
40
30
30
30
20
20
20
10
10
10
0
0
0
Months
losartan
candesartan
Months
losartan
candesartan
Months
Kjeldsen et al 2009
Primary Outcome: Candesartan v Losartan
The primary composite end-point: CVD morbidity, CVD mortality
and elective coronary revascularisation
Cumulative incidence (%)
30
25
losartan
20
candesartan
15
10
5
Adjusted* risk reduction 14.4% (p=0.0062)
Unadjusted risk reduction 20.6% (p<0.0001)
0
0
12
24
36
6771
7329
60
72
84
96
259
257
96
76
time (months)
Number at risk
Los
Can
48
4548
4860
3165
3385
2090
2242
*Adjusted for age, gender, diabetes & prescription & index year
1458
1580
923
1021
526
592
Kjeldsen et al 2009
Risk of Separate Endpoints
Heart failure
12
6
4
2
0
10
6
4
-20.0% p=0.0330
2
0
6
4
2
-14.3% p=0.1400
0
Cumulative incidence (%)
Cumulative incidence (%)
8
2
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
10
8
6
4
-7.0% p=0.5600
2
Stroke
12
losartan
candesartan
-38.8% p=0.0140
4
Myocardial infarction
12
losartan
candesartan
6
Time (months)
Chronic ischemic heart disease
losartan
candesartan
8
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
10
10
8
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
12
12
losartan
candesartan
Cumulative incidence (%)
-35.9% p=0.0004
8
Peripheral artery disease
Cumulative Incidence (%)
10
losartan
candesartan
Cumulative incidence (%)
Cumulative incidence (%)
12
Arrhythmias
10
losartan
candesartan
8
6
4
2
-5.2% p=0.6400
0
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
Time (months)
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
*Adjusted for age, gender, diabetes and prescription & index year
Kjeldsen et al 2009
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
Candesartan v Losartan:
Mortality in Heart Failure Patients
Mean age (years) ±SD
Women
NYHA:
I
II
III
IV
EF:
>40%
<40%
Mean creatinine (mmol/L) ±SD
Mean MAP (mmHg) ±SD
Hypertension 1296(53.7%)
IHD
Diabetes mellitus
ACE inhibitor 76(3.1%)
Beta blocker
Aldosterone
Losartan(n=2500)
Candesartan (n=2639)
p‐value
75.3±10.2
1017(40.7%)
72.0±11.5
1006(38.1%)
0.001
0.061
0.001
164(9.0%)
734(40.3%)
840(46.2%)
82(4.5%)
234(10.9%)
1068(50.0%)
770(36.0%)
65(3.1%)
0.035
892(42.3%)
1215(57.7%)
120±13.4
91.5±13.4
1411(55.0%)
1461(60.6%)
844(34.0%)
420(16.0%)
2049(82.3%)
904(36.4%)
992(41.6%)
1393(58.4%)
111.0±56.4
92.6±13.9
0.365
1286(50.7%)
764(29.2%)
0.001
2295(87.1%)
802(30.6%)
0.001
0.003
0.001
0.001
0.001
0.001
Eklind-Cervenka et al 2011
Candesartan v Losartan:
Mortality in Heart Failure Patients
90% one year
survival
1.0
candesartan
survival proportion
0.8
72% five year
survival
82% one year
survival
0.6
losartan
0.4
51% five year
survival
0.2
Log-rank p<0.001
0
Number at risk
Candesartan
Losartan
0
1
2
2639
2500
1739
1692
957
1097
years
3
4
5
426
646
125
359
30
178
Eklind-Cervenka et al 2011