Transcript Number of events - LandmarkTrials.nl

Results
Preventive therapy in type 2 diabetes:
Unresolved issues in 2000
Does standard treatment with fixed combination
perindopril/indapamide on top of regular BP control:
 Produce additional benefits when systolic pressure is lowered
below 145 mmHg?
 Produce similar benefits for hypertensive and nonhypertensive patients?
 Add to the benefits produced by other cardiovascular
preventive therapies including ACE inhibitors ?
Follow-up and
adherence
ADVANCE
Trial profile
12877 with type 2
diabetes registered
1737 withdrew
during run-in
11140 randomised
5569 assigned perindoprilindapamide combination
4 lost to
follow-up
5571 assigned matching
placebo
11 lost to
follow-up
Scheduled end of follow-up: 4.3 years
Scheduled end of follow-up: 4.3 years
4908 (88%) assessed at final visit
4081 (73%) adherent to treatment
4863 (87%) assessed at final visit
4143 (74%) adherent to treatment
Reasons for discontinuation
Major reasons for discontinuation
Randomised treatment
Active
(n=5569)
Placebo
(n=5571)
Patient unable / unwilling to attend visits
521 (9.4%)
635 (11.4%)
Cough
184 (3.3%)
72 (1.3%)
Hypotension or dizziness
69 (1.2%)
22 (0.4%)
Serious adverse events
67 (1.2%)
66 (1.2%)
Other reasons
172 (3.1%)
195 (3.5%)
Reasons for discontinuation
Major reasons for discontinuation
Randomised treatment
Active
(n=5569)
Placebo
(n=5571)
Patient unable / unwilling to attend visits
521 (9.4%)
635 (11.4%)
Cough
184 (3.3%)
72 (1.3%)
Hypotension or dizziness
69 (1.2%)
22 (0.4%)
Serious adverse events
67 (1.2%)
66 (1.2%)
Other reasons
172 (3.1%)
195 (3.5%)
Reasons for discontinuation
Major reasons for discontinuation
Randomised treatment
Active
(n=5569)
Placebo
(n=5571)
Patient unable / unwilling to attend visits
521 (9.4%)
635 (11.4%)
Cough
184 (3.3%)
72 (1.3%)
Hypotension or dizziness
69 (1.2%)
22 (0.4%)
Serious adverse events
67 (1.2%)
66 (1.2%)
Other reasons
172 (3.1%)
195 (3.5%)
Adherence to study treatments
Follow-up visits
Randomised treatment
months
Active
(n=5569)
Placebo
(n=5571)
12
4950 (89%)
5081 (91%)
24
4676 (84%)
4776 (86%)
36
4403 (79%)
4518 (81%)
48
4164 (75%)
4287 (77%)
Final visit
4081 (73%)
4143 (74%)
Mortality and
morbidity
All-cause mortality
10
Placebo
Perindopril-Indapamide
5
Relative risk reduction
14%: 95% CI 2-25%
p=0.025
0
0
6
12
18
24
30
36
Follow-up (months)
42
48
54
60
Deaths
Cardiovascular
5%
Placebo
Perindopril-indapamide
Non-cardiovascular
5%
Placebo
Perindopril-indapamide
Relative risk reduction
18%; p=0.027
6
12 18 24 30 36 42 48 54 60
Follow-up (months)
Relative risk reduction
8%; p=0.41
6
12 18 24 30 36 42 48 54 60
Follow-up (months)
Combined primary outcomes
Major macro or microvascular event
20
Placebo
Perindopril-Indapamide
10
Relative risk reduction
9%: 95% CI: 0 to 17%
p=0.041
0
0
6
12
18
24
30
36
Follow-up (months)
42
48
54
60
Primary outcomes
Major macro or microvascular event
Number of events
Per-Ind
Placebo
(n=5,569) (n=5,571)
Favours Favours
Per-Ind Placebo
Relative risk
reduction (95% CI)
Combined macro+micro 861
938
9% (0 to 17)*
Macrovascular
480
520
8% (-4 to 19)
Microvascular
439
477
9% (-4 to 20)
0.5
1.0
2.0
Hazard ratio
*2P=0.04
Coronary events
Number of events
Per-Ind
Placebo
(n=5,569) (n=5,571)
Favours Favours
Per-Ind Placebo
Relative risk
reduction (95% CI)
All coronary heart disease 468
535
14% (2 to 24)*
Major coronary heart disease† 265
294
11% (-6 to 24)
Other coronary heart disease‡ 283
324
14% (-1 to 27)
0.5
1.0
Hazard ratio
†Non-fatal
MI or death from coronary heart disease
‡Unstable
angina requiring hospitalisation, coronary revascularisation or silent MI
2.0
*2P=0.02
Cerebrovascular events
Number of events
Per-Ind Placebo
(n=5,569) (n=5,571)
Favours Favours
Per-Ind Placebo
Relative risk
reduction (95% CI)
All cerebrovascular disease 286
303
6% (-10 to 20)*
Major cerebrovascular disease†
215
218
2% (-18 to 19)
Other cerebrovascular disease‡
79
99
21% (-6 to 41)
0.5
1.0
Hazard ratio
†Non-fatal
stroke or death from cerebrovascular disease
‡Transient
ischaemic attack or subarachnoid haemorrhage
2.0
*2P=0.40
Renal events
Number of events
Per-Ind Placebo
(n=5,569)(n=5,571)
Total renal events
Favours Favours
Per-Ind Placebo
Relative risk
reduction (95% CI)
1243
1500
21% (15 to 27)*
New or worsening nephropathy 181
216
18% (-1 to 32)
New microalbuminuria
1317
21% (14 to 27)
1094
0.5
1.0
Hazard ratio
2.0
*2P=<0.01
Eye events
Number of events
Per-Ind Placebo
(n=5,569) (n=5,571)
Total eye events
2531
2611
New or worsening eye disease
289
286
Visual deterioration
2446
2514
0.5
Favours Favours
Per-Ind Placebo
Relative risk
reduction (95% CI)
5% (-1 to 10)*
-1% (-18 to 15)
5% (-1 to 10)
1.0
2.0
Hazard ratio
*2P=0.09
Absolute benefits of routine treatment
with perindopril and indapamide
After 5 years, treatment
would prevent:
One major vascular event
One death
One coronary event
One renal event*
Among every
66 patients
79 patients
75 patients
20 patients
*mostly new onset microalbuminuria
Subgroups
Combined primary
outcome
Effects by age, sex, BP and HbA1c
Combined primary endpoint
Number of events
Per-Ind
Placebo
(n=5,569) (n=5,571)
Favours
Favours
Per-Ind
Placebo
Relative risk
reduction (95% CI)
Age (years)
< 65
≥ 65
325
536
346
592
6% (-10 to 19)
11% (0 to 21)
546
315
594
344
10% (-1 to 20)
8% (-7 to 21)
309
552
341
597
10% (-5 to 23)
9% (-2 to 19)
121
740
136
802
9% (-17 to 29)
9% (0 to 18)
406
451
456
481
9% (-4 to 20)
11% (-1 to 22)
861
938
9% (0 to 17)
Sex
Male
Female
SBP (mmHg)
< 140
≥ 140
History of hypertension
No
Yes
HbA1c (%)
≤ 7.5
> 7.5
All participants
0.5
1.0
Hazard ratio
2.0
Phomogeneity all >0.1
Effects by ancillary treatment
Combined primary endpoint
Number of events
Per-Ind Placebo
(n=5,569) (n=5,571)
Favours Favours
Per-Ind Placebo
Relative risk
reduction (95% CI)
Treatment with any BP lowering drug
No
177
183
6% (-15 to 24)
Yes
684
755
10% (0 to 19)
No
417
455
10% (-3 to 21)
Yes
444
483
8% (-4 to 20)
638
223
687
251
10% (0 to 19)
8% (-10 to 23)
408
453
454
484
11% (-2 to 22)
7% (-5 to 18)
861
938
9% (0 to 17)
Treatment with ACE inhibitor
Treatment with statins
No
Yes
Treatment with anti-platelet drug
No
Yes
All participants
0.5
1.0
Hazard ratio
2.0
Phomogeneity all >0.1
Subgroups
New onset
microalbuminuria
Effects by age, sex, BP and HbA1c
Microalbuminuria
Number of events
Per-Ind
Placebo
(n=5,569) (n=5,571)
Age (years)
< 65
≥ 65
Sex
Male
Female
SBP (mmHg)
< 140
≥ 140
History of hypertension
No
Yes
HbA1c (%)
≤ 7.5
> 7.5
All participants
Favours
Favours
Per-Ind
Placebo
Relative risk
reduction (95% CI)
448
646
522
795
16% (5 to 26)
24% (15 to 31)
601
493
724
593
21% (12 to 29)
20% (9 to 29)
465
629
535
782
16% (4 to 25)
24% (16 to 32)
178
916
218
1099
19% (1 to 34)
21% (14 to 28)
640
444
795
517
20% (11 to 28)
22% (11 to 31)
1094
1317
21% (14 to 27)
0.5
1.0
Hazard ratio
2.0
Phomogeneity all >0.1
Effects by ancillary treatment
Microalbuminuria
Number of events
Per-Ind Placebo
(n=5,569) (n=5,571)
Favours Favours
Per-Ind Placebo
Relative risk
reduction (95% CI)
Treatment with any BP lowering drug
No
Yes
264
830
312
1005
21% (7 to 33)
20% (13 to 27)
588
506
671
646
16% (6 to 25)
25% (16 to 33)
816
278
987
330
23% (15 to 30)
15% (1 to 28)
568
697
22% (13 to 30)
526
620
19% (9 to 28)
1094
1317
21% (14 to 27)
Treatment with open-label perindopril
No
Yes
Treatment with statins
No
Yes
Treatment with anti-platelet drug
No
Yes
All participants
0.5
1.0
Hazard ratio
2.0
Phomogeneity all >0.1
Summary
Routine treatment of type 2 diabetic patients
with perindopril-indapamide resulted in:
>
>
>
>
>
14% reduction in total mortality
18% reduction in cardiovascular death
9% reduction in major vascular events
14% reduction in total coronary events
21% reduction in total renal events
Similar benefits in all major subgroups.
Benefits additional to those produced by
other treatments, including ACE inhibitor.
Treatment very well tolerated.
Preventive therapy in type 2 diabetes:
Unresolved issues in 2000
Does standard treatment with fixed combination
perindopril/indapamide on top of regular BP control:
 Produce additional benefits when systolic pressure is lowered
below 145 mmHg? YES
 Produce similar benefits for hypertensive and nonhypertensive patients? YES
 Add to the benefits produced by other cardiovascular
preventive therapies including ACE inhibitors ? YES
Summary
In ADVANCE
Need for type 2 DM patients
Fixed combination perindopril/indapamide
Reduction of CV events
Reduces
 Mortality
 CV events
 renal failure
on top of current preventive treatments
on top of current preventive treatments
irrespective of usage of
 BP lowering agents including ACEi
 statines
Simple, safe and well tolerated treatment
Simple, safe and well tolerated treatment
Summary
Aim for guideline based BP goal
+
standard additition of fixed per/ind combination
(like statines post MI)
Is a more effective strategy than
Aim for guideline based BP goal
Discussie
Wat betekent ADVANCE voor de
dagelijkse diabeteszorg?