Cardio Diabetes Master Class
Asian chapter
January 28-30 2011, Shanghai
Presentation topic
RAS blockade in the real world:
Clinical lessons from recent trials
Slide lecture prepared and held by:
Sverre Kjeldsen, MD
Ullevaal University Hospital
Oslo, Norway
P H Y S I C IAN S ’ A CAD E M Y F O R CAR D I O VAS C U LAR E D U CAT I O N
LIFE: Primary Composite Endpoint
0.16
Intention-to-treat
Endpoint rate
0.14
Atenolol
0.12
0.10
Losartan
0.08
0.06
0.04
0.02
Adjusted Risk Reduction 13·0%, p=0·021
Unadjusted Risk Reduction 14·6%, p=0·009
0.00
Study Day
Study Month
Losartan (n)
Atenolol (n)
0
180 360 540 720
0
6
12
18
24
4605 4524 4460 4392 4312
4588 4494 4414 4349 4289
January 2011
Presented at Cardio Diabetes Master Class Shanghai
900 1080 1260 1440 1620 1800 1980
30
36
42
48
54
60
66
4247 4189 4110 4045 3895 1888 901
4205 4135 4066 3992 3821 1854 876
Dahlöf B, Devereux RB, Kjeldsen SE et al. Lancet 2002
CHARM-Overall:
CV death or CHF hosp.
50
40
1310 (34.5%)
Placebo
1150 (30.2%)
30
Candesartan
%
20
10
HR 0.84 (95% CI 0.77-0.91), p<0.0001
HR 0.82, p<0.0001 (Adjusted)
0
Number at risk
Candesartan
Placebo
0
1
2
3
3.5
3803
3796
3563
3464
3271
3170
2215
2157
761
743
years
Pfeffer MA, Swedberg K, Granger CB, et al. Lancet. 2003;362:759-766
Binding Ability to the AT1 Receptor
Candesartan and losartan
have significant
pharmacological
differences*
– Candesartan binds harder to the AT1receptor
– Candesartan binds longer to the AT1receptor
Insurmountability (%)
100
candesartan
telmisartan
80
olmesartan
EXP 3174
60
valsartan
40
irbesartan
20
losartan
0
0
20
40
60
80
100
120
Dissociation t1/2
Large outcome trials comparing different ARBs for CV outcomes
will probably never be done!
*Van Liefde I, et al. Molecular and Cellular Endocrinology. 2008
The Real Life Study: Hypothesis and Aim
• Candesartan binds longer and harder to the AT1 receptor and may be
hypothesized to have a superior cardiovascular protection than other
ARBs
• The aim of the Real Life study was to test the hypothesis that losartan
and candesartan have different primary preventive effects on CVD risk,
beyond BP reduction
• The hypothesis was tested by setting up a large retrospective registration
study in 72 Health Care Centres in the southern part of Sweden
1. Van Liefde I, et al. Molecular and cellular endocrinology 2008. 2. Bhuiyan MA, et al. Life Sci. 2009. 3. Bakris G, et al. J Clin
Hypertens. 2001. 4. Lacourcière Y, et al. Am J Hypertens 1999 5. Meredith PA et al, J Hum Hypertens. 2009 [Epub ahead of print]
Health Care in Sweden
• All residents in Sweden have a unique identifiction number
• Long traditions with mandatory national health registers
• Wide use of electronic patient journals in primary care
• A patient is followed up by one and the same primary care physician
• The regulatories give permissions to use the registries
January 2011
Presented at Cardio Diabetes Master Class Shanghai
Data Extraction in Primary Care
• Every primary care center had to be visited
– Patients were extracted if they had an ARB precription
– Computer specialists assessed all visits with diagnosis, all drug
precriptions and available laboratory data
– The computer programme and it’s use has been validated in
previous published studies1,2
• Patients were excluded if they had
– History of known CVD
– Any CVD suspected drug
Lindgren P et al. Eur J Cardiovasc Prev Rehabil 2005; 12(6): 530–534;
Ringborg A et al. Int J Clin Pract 2008; 62(5): 708–716; Ringborg A et al. Diabet Med 2008; 25(10): 1178–1186
Prescription Patterns at Study Centers
100%
90%
80%
Losartan
70%
60%
50%
40%
30%
20%
Candesartan
10%
January 2011
Study Centre Number
Presented at Cardio Diabetes Master Class Shanghai
1378
2158
2553
1512
1063
1359
1608
1604
1461
1303
2550
1362
1502
3134
2350
1377
2221
1405
1520
1190
1154
1194
1546
2348
3116
1073
1463
1600
1093
2249
3386
1065
1579
0%
Included Patients Per Year
10%
Candesartan
9%
Losartan
8%
7%
6%
5%
4%
3%
2%
1%
0%
1999
2000
2001
January 2011
Presented at Cardio Diabetes Master Class Shanghai
2002
2003
2004
2005
2006
2007
Flow Chart
24,943 patients started prescription of losartan (13,001)
or candesartan (11,942) from 1999 to 2007
10,843 patients were excluded:
• 5792 (44.6%) losartan and 4144 (34.7%) candesartan patients
with a history of cardiovascular disease and/or prescription of
warfarin / digitalis / nitrates before index prescription
• 386 (3.2%) losartan and 379 (2.9%) candesartan patients with
malignancy
• Prescribed another RAAS* inhibitor in the first week after index
prescription, losartan 59 (0.5%) and candesartan 83 (0.7%)
6771 (52.1%) losartan patients
January 2011
Presented at Cardio Diabetes Master Class Shanghai
7329 (61.4%) candesartan patients
Two similar groups?
Primary care history
5.8 years
Drug history
Hospital care history
1.3 years
Inclusion
~15 years
No patients
hospitalised
No of days in hospital
per patient
Losartan
3,286 (48.6%)
~15
years
5.9 days
Candesartan
3,560 (48.5%)
5.9 days
Baseline Characteristics
Age (years)
Women, n (%)
Body mass index (kg/m2)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Total cholesterol (mmol/L)
LDL-C (mmol/L)
HDL-C (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 drugs, n (%)
Statins, n (%)
Antithrombotics, n (%)
Angiotensin receptor blockers, n (%)
Angiotensin converting enzyme inhibitors, n
(%)
Losartan (n=6771)
Candesartan (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)
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)
1361 (20.1)
1459 (19.9)
Up-titration of ARB
70,00
60,00
55,11
56,28
58,33
60,75
58,71
60,67
62
59,89
51,95
50,00
40,00
30,00
20,00
10,00
9,64
10,92
11,33
11,79
11,8
12,1
12,43
12,64
12,75
0,00
Index
6
12
January 2011
Presented at Cardio Diabetes Master Class Shanghai
24
36
Losartan mg/pas:
48
60
Candesartan mg/pas:
72
84
Ratio
(candesartan/losartan)
0.25
0.20
0.19
0.20
0.20
0.20
0.20
0.20
0.20
0.21
0.21
6
12
24
36
48
60
72
84
0.15
0.10
0.05
0.00
Index
Ratio (mg candesartan / mg losartan)
January 2011
Presented at Cardio Diabetes Master Class Shanghai
Follow-up Time (months)
7000
Losartan
6000
Candesartan
5000
4000
3000
2000
1000
0
6
12
24
36
48
60
72
84
Follow-up to 9 years (median 2.0 years; 36,339 patient years)
January 2011
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Blood Pressure Reduction
180
Losartan
Candesartan
160
Systolic
140
120
100
Mean arterial
80
Diastolic
60
40
0
12
24
January 2011
Presented at Cardio Diabetes Master Class Shanghai
36
48
60
72
84
96
% Losartan
dose titration
ARB Titration
70
60
50
40
30
20
10
0
50 mg
100 mg
% Candesartan
dose titration
Index
12
24
50 mg/12.5 mg
36
48
60
72
100 mg/25 mg
84
96 months
70
60
50
40
30
20
10
0
4 mg
8 mg
Index
12
January 2011
Presented at Cardio Diabetes Master Class Shanghai
24
16 mg
36
48
60
72
16 mg/12.5 mg
84
96 months
Concomitant Medication
Calcium channel blockers†
Thiazides*
90
80
70
60
50
40
30
20
10
0
Losartan
Candesartan
90
80
70
60
50
40
30
20
10
0
Losartan
Candesartan
Months
Losartan
Candesartan
90
80
70
60
50
40
30
20
10
0
Months
Statins
90
80
70
60
50
40
30
20
10
0
Betablockers
Months
Antithrombotics
90
80
70
60
50
40
30
20
10
0
Months
January 2011
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Losartan
Candesartan
Months
Losartan
Candesartan
Oral glucose lowering drugs
90
80
70
60
50
40
30
20
10
0
Losartan
Candesartan
Months
Limitations
•
The study was not randomized
– Imbalance in baseline characteristics not seen
– No evidence of “confounding by indication”
(in case, candesartan was considered as “heart failure
medication”)
•
Imbalance in use of HCTZ
– May have favored losartan*
•
Prescription behavior may change over time (marketing, scientific
publications)
– Adjustment for index year
*Okin PM, Hille DA, Kjeldsen SE, Lindholm LH, Edelman JM, Dahlöf B, Devereux RB. Greater regression of electrocardiographic left
ventricular hypertrophy during hydrochlorothiazide therapy in hypertensive patients and the interaction with losartan vs. atenolol therapy:
The LIFE Study. Am J Hypertens 2010; online April 15.
Conclusion – Conduct of Real Life
•
The method used is cost effective and feasible
•
It is possible to identify two similar groups from a large number of
patient when applying identical selection and exclusion criteria
•
Blood pressure treatment achieved identical reductions in both groups
•
Average follow up was 2 years with maximal follow-up 9 years and
accumulation of a total of 36,339 treatment years
•
We detected 1251 patients with a primary CV event defined as a
composite of heart failure, arrhythmias, coronary events, stroke,
peripheral artery disease and CV death
January 2011
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Cumulative incidence (%)
CVD Risk
35
Primary composite endpoint
Losartan
Candesartan
30
25
20
15
10
5
Adjusted risk reduction 14.4% p=0.0062
Unadjusted risk reduction 20.6% p<0.0001
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
Number at risk
Los.
Can.
January 2011
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Risk of Separate Endpoints
A Heart failure
6
4
2
Adjusted risk reduction 35.9% p=0.0004
Unadjusted risk reduction 41.9% p<0.0001
0
6
Cumulative incidence (%)
Cumulative incidence (%)
8
0
Losartan
Candesartan
12
10
8
6
4
2
Adjusted risk reduction 20.0% p=0.0330
Unadjusted risk reduction 26.7% p=0.0029
0
Time (months)
0
6
Number at risk
10
8
6
4
2
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
0
Los.
Can.
Can.
Can.
10
10
10
4
2
Adjusted risk reduction 14.3% p=0.1400
Unadjusted risk reduction 19.6% p=0.0350
0
0
6
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Number at risk
Time (months)
6
4
2
Adjusted risk reduction 7.0% p=0.5600
Unadjusted risk reduction 15.5% p=0.1800
0
0
6
Number at risk
Cumulative Incidence (%)
12
6
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
6
4
2
Adjusted risk reduction 5.2% p=0.6400
Unadjusted risk reduction 12.0% p=0.2600
0
0
Los.
Los.
Can.
Can.
Can.
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Time (months)
8
6
Number at risk
Los.
January 2011
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
F Stroke
12
Cumulative incidence (%)
Cumulative incidence (%)
E Myocardial infarction
12
8
6
Number at risk
Los.
8
Adjusted risk reduction 38.8% p=0.0140
Unadjusted risk reduction 44.1% p=0.0035
0
Los.
D Chronic ischemic heart disease
Losartan
Candesartan
12
10
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Number at risk
C Peripheral artery disease
Cumulative incidence (%)
Losartan
Candesartan
12
B Arrhythmias
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
Hazard Ratio
Losartan
(n=6771)
Candesartan Hazard ratio
(n=7329)
(unadjusted)
p
Hazard ratio
(adjusted*)
p
Primary composite endpoint
676 (10.0)
575 (7.8)
0.79 (0.71–0.89)
<0.0001
0·86 (0.77–0.96)
0.0062
Heart failure
164 (2.4)
101 (1.4)
0.58 (0.45–0.74)
<0.0001
0·64 (0.50–0.82)
0.0004
Cardiac arrhythmias
210 (3.1)
163 (2.2)
0.73 (0.60–0.90)
0.0029
0·80 (0.65–0.98)
0.0330
Peripheral artery disease
68 (1.0)
40 (0.5)
0.61 (0.38–0.83)
0.0035
0·61 (0.41–0.91)
0.0140
202 (3.0)
172 (2.3)
0.80 (0.66–0.99)
0.0350
0·86 (0.70–1.05)
0.1400
138 (2.0)
123 (1.7)
0.85 (0.66–1.08)
0.1800
0·93 (0.73–1.19)
0.5600
Stroke
157 (2.3)
146 (2.0)
0.88 (0.70–1.10)
0.2600
0·95 (0.76–1.19)
0.6400
Hosp. for unstable angina
26 (0.4)
21 (0.3)
0.77 (0.43–1.36)
0.3600
0·80 (0.45–1.42)
0.4500
Elective PCI
18 (0.3)
14 (0.2)
0.74 (0.37–1.48)
0.3900
0·78 (0.39–1.58)
0.4900
Cardiovascular mortality
75 (1.1)
66 (0.9)
0.83 (0.60–1.16)
0.2800
0·93 (0.66–1.29)
0.6500
Total mortality
155 (2.3)
156 (2.1)
0.96 (0.77–1.20)
0.7100
1·06 (0.85–1.32)
0.6200
New onset diabetes
318 (4.7)
309 (4.2)
0.92 (0.79–1.08)
0.3000
0·90 (0.77–1.05)
0.1900
Chronic ischemic heart
disease
Myocardial infarction
January 2011
Presented at Cardio Diabetes Master Class Shanghai
REAL LIFE: Conclusions
•
No difference in blood pressure was observed during follow-up
•
Frequently more use of thiazides in the losartan group
•
The risk of CVD was reduced by 14.4% when treated with candesartan
compared to losartan (NNT=45)
•
The primary result was driven by the risk reduction of arrhythmias (20%) and
heart failure (-36%)
January 2011
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What was the main driver of the results?
 Heart failure
 Candesartan prevents the negative property of
angiotensin II more effective than losartan
 Less hypertrophy, increased cardiac remodelling
 Arrhythmias
 90% of all arrhythmias were atrial fibrillation.
 Atrial fibrillation is a common complication to
heart failure.
 Late development of arrhythmias
Figure 4, page 6
January 2011
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No difference in CIHD, MI or stroke?
 Why didn´t we observe differences in chronic ischemic heart disease,
myocardial infarction or stroke?
 Atherosclerotic disease takes longer time to develop
January 2011
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Real Life – Outcomes in Subgroups
J Clin Hypertens 2011; in press (online a head of print)
Tabell 1
Losartan ( n=2500)
Candesartan ( n=2639)
p-value
Mean age (yrs) ±SD
75.3±10.2
72.0±11.5
p<0.001
women
NYHA
I
II
III
IV
1017(40.7%)
1006(38.1%)
p=0.061
p<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%)
EF
>40%
892(42.3%)
<40%
1215(57.7%)
Mean creatinine (mmol/l) ±SD 120±13.4
992(41.6%)
1393(58.4%)
111.0±56.4
p<0.001
Mean MAP (mmHg) ±SD
Hypertension
IHD
Diabetes mellitus
91.5±13.4
1296(53.7%)
1461(60.6%)
844(34.0%)
92.6±13.9
1411(55.0%)
1286(50.7%)
764(29.2%)
p=0.003
p=0.365
p<0.001
p<0.001
ACE inhibitor
76(3.1%)
420(16.0%)
p<0.001
Betablocker
Aldosterone
2049(82.3%)
904(36.4%)
2295(87.1%)
802(30.6%)
p<0.001
p<0.001
January 2011
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p=0.035
Overall Survival (JAMA 2011; 305: 175-182
90% one year survival
candesartan
82% one year
survival
losartan
72% five year survival
51% five year survival
p<0,0001
Survival in Days
January 2011
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Survival Men
Survival Women
90%
89%
candesartan
candesartan
81%
82%
losartan
losartan
p<0.0001
Survival in Days
January 2011
Presented at Cardio Diabetes Master Class Shanghai
p<0.0001
Survival in Days
EF >40%
EF<40%
91%
85%
candesartan
candesartan
85%
82%
losartan
losartan
p<0.0001
Survival in Days
January 2011
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p<0.0001
Survival in Days
NYHA I
NYHA II
96%
94%
candesartan
candesartan
94%
89%
losartan
losartan
p=0.0230
NYHA III
p<0.0001
NYHA IV
87%
63%
candesartan
79%
52%
candesartan
losartan
losartan
p<0.0001
January 2011
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p=0.0672
Conclusions Swedish Heart Failure
Registry Study
Candesartan is associated with longer survival than losartan:
• In univariate analysis
• In multivariate analysis, adjusted for age, gender, creatinine,
EF, NYHA, diabetes, drug treatment
• Benefit of candesartan was seen in both genders, across NYHA
classes and EF