White_STABILITY - Clinical Trial Results

Report
STABILITY
Stabilization of Atherosclerotic plaque By
Initiation of darapLadIb TherapY
Harvey D White
on behalf of
The STABILITY Investigators
Lipoprotein- associated Phospholipase A2
(Lp-PLA2) activity: Background
native LDL
carrier of Lp-PLA2
Lp-PLA2
Leukocyte
Lumen
Atheroma
Lp-PLA2
Sustained
Inflammation
Intima
Necrotic Core
Expansion
Oxidized LDL
substrate for Lp-PLA2
Macphee, Biochem J 1999; Zalewski and Macphee, ATVB 2005; Shi Atherosclerosis 2007; Kolodgie, ATVB 2006
Characteristics of Stable versus Ruptured Plaques
Modest Lipid Pool
Thick Fibrous Cap
Large Lipid Pool
Thin Fibrous Cap
Lumen
Lp-PLA2
Lumen
Lp-PLA2
Stable Plaque
 Low Lp-PLA2 content (dark staining)
 May have significant stenosis
 Thick fibrous cap / high collagen
content
 Modest lipid pool
 Few inflammatory cells
Ruptured Plaque
 High Lp-PLA2 content (dark staining)
 May have minimal stenosis
 Thin fibrous cap / low collagen
content
 Large lipid pool
 Many inflammatory cells
Corson et al. Am J Card 2008;101(Suppl):41F-50F
Rationale for STABILITY
Association
studies
EPIDEMIOLOGY
Higher Lp-PLA2 levels
predict CV events
GENETICS
Deficiency in Lp-PLA2
due to null allele results
in decreased CHD
PATHOLOGY
Up-regulation of LpPLA2 in vulnerable
plaques
Darapladib is a
selective oral inhibitor
that decreases
Lp-PLA2 by ~60%
Intervention with
darapladib
PRECLINICAL
Reduces Lp-PLA2 in
plaque and necrotic
core area (pig)
HUMAN ATHEROMA
Reduces carotid plaque
Lp-PLA2 activity
CORONARY
IMAGING
IBIS-2
Halts progression of
coronary artery
necrotic plaque core
volume
STABILITY Trial Study Design
Patients with chronic CHD
(prior MI >1 mth, prior coronary revascularization, multivessel CAD)
Enrichment criteria: ≥60 years of age, diabetes mellitus, low HDL,
current smoking, significant renal dysfunction, polyvascular disease
15,828 patients randomized
Darapladib 160mg daily
Placebo
Optimized guideline-recommended treatment
Median follow-up 3.7 years, 1588 events
Primary endpoint: composite of CV death, MI, stroke
Secondary endpoints: major coronary events, total coronary events
Design paper reference: White H, et al. Am Heart J 2010;160:655-61.
Global Recruitment (N=15,828)
North America (25%)
USA
Canada
Mexico
3102
780
141
Western Europe (22%)
Belgium
Denmark
France
Greece
Germany
202
102
250
187
1089
Italy
256
Netherlands 444
Norway
113
Spain
474
Sweden
299
UK
184
Eastern Europe (22%)
Bulgaria
222
Cz Republic 774
Estonia
77
Hungary
410
Poland
Romania
Russia
Slovakia
Ukraine
510
411
654
120
353
E & SE Asia
India
398
Pakistan 250
South America
Argentina
Brazil
Chile
Peru
542
384
195
78
South Africa 386
Asia-Pacific/Latina (31%)
China
Korea
Hong Kong
Taiwan
Japan
369
503
117
200
318
Thailand
Philippines
Australia
New Zealand
207
219
306
202
Demographics
Placebo
(N=7904)
Darapladib
(N=7924)
65.0
65.0
14%
14%
19%
18%
White
78%
79%
Black
2%
2%
Central/South/South East Asian
8%
7%
East Asian/Japanese
10%
10%
Other
2%
2%
Age (median in years)
≥75 years
Female
Race or Ethnic Group
Chronic Coronary Heart Disease
Qualifying Diagnosis
Placebo
(N=7904)
Darapladib
(N=7924)
Prior MI
59%
59%
Coronary revascularization
75%
75%
PCI
50%
50%
CABG
33%
33%
15%
15%
Multi-vessel CAD
Enrichment Criteria
Placebo
(N=7904)
Darapladib
(N=7924)
Age ≥ 60 years
73%
73%
Diabetes
34%
34%
HDL < 40 mg/dL (1.03 mmol/L)
35%
33%
Smoker
21%
20%
30%
30%
15%
15%
(Requiring pharmacotherapy)
(Current or former smoker
within 3 months; ≥5 cigs/day)
Significant renal dysfunction
(eGFR 30 to 59 mL/min/1.73 m2 or
urine ACR ≥3 mg albumin/g creatinine)
Polyvascular disease
(cerebrovascular disease or peripheral
arterial disease)
High Standard of Care
Time Point
Placebo
Darapladib
Aspirin
Baseline
Study end
93%
91%
92%
90%
Statins
Baseline
Study end
97%
96%
97%
96%
Beta-Blockers
Baseline
Study end
79%
79%
79%
78%
ACE inhibitor
Baseline
Study end
56%
54%
57%
54%
Angiotensin II
receptor blocker
Baseline
Study end
23%
27%
22%
26%
Patient Follow-up
Placebo
(N=7904)
Darapladib
(N=7924)
Study Drug Discontinuation
26.8%
32.7%
Study Withdrawal
3.5%
3.5%
Missing CV Endpoint at Study End
3.5%
3.6%
Missing Vital Status at Study End
0.7%
0.6%
Percentage of Patients
Primary Endpoint:
Time to First Occurrence of CV Death, MI, Stroke
Placebo events = 819 (10.4%)
Darapladib events = 769 (9.7%)
HR = 0.94 (95% CI, 0.85 - 1.03)
P-value = 0.199
Placebo
HR (95% CI) P-value Placebo
Darapladib
0.92 (0.82, 1.03) 0.395 672 (10.0%) 620 (9.2%)
(0.80,
(8.8%)
182 (8.6%)
1.030.98
(0.82,
1.29)1.20) 0.613
147 191
(12.3%)
149 (12.4%)
0.92 (0.82, 1.03)
628 (10.9%) 587 (10.1%)
0.91 (0.80, 1.03) 0.422 477 (9.1%) 435 (8.3%)
(0.83,
(10.5%)
624 (9.7%)
0.980.92
(0.85,
1.14)1.03) 0.500
342 670
(12.7%)
334 (12.5%)
1.01 (0.80, 1.26)
149 (9.9%) 145 (9.9%)
0.94 (0.83, 1.07) 0.951 502 (9.8%) 486 (9.2%)
(0.80,
(10.9%)
610 (9.8%)
0.930.90
(0.80,
1.10)1.00) 0.077
316 675
(11.3%)
281 (10.6%)
1.13 (0.90, 1.41)
144
(8.3%)
159 (%)
(9.4%)
Events
0.99 (0.89, 1.11)Interaction
0.044 619 Number
(10.0%) of625
(9.9%)
HR0.87
(95%
CI)
P-value
Darapladib
(0.74,
0.295
314
(9.6%)
274
(8.4%)
0.77
(0.62,
0.96)1.03)
192Placebo
(11.6%)
140
(8.9%)
0.98
(0.86,
1.10)
505
(10.9%)
495
(10.6%)
0.98 (0.77,
(0.80, 0.99)
1.20) 0.104
0.613 482
191 (8.7%)
(8.8%) 420
182 (7.6%)
(8.6%)
0.87
0.920.95
(0.82,
1.03)
628244
(10.9%)
587(14.5%)
(10.1%)
(0.80,
1.14) 0.837
(12.2%)
229
(11.6%)
1.03
(0.89,
1.19)
337
(14.2%)
349
0.93
(0.83,
1.05)
575
(9.7%)
540
(9.1%)
0.92 (0.83, 1.03) 0.500 670 (10.5%) 624 (9.7%)
0.93
(0.83,
1.04)
0.796 626
(9.3%)
584
(8.7%)
1.010.92
(0.80,
1.26)
149
(9.9%)
145
(9.9%)
(0.82, 1.03) 0.395 672 (10.0%) 620 (9.2%)
0.961.03
(0.78,
1.17)
193 (16.3%)
185 (15.6%)
(0.82,
1.29)
(12.3%)
(12.4%)
0.90 (0.80,
1.00)
0.077 675147
(10.9%)
610149
(9.8%)
0.88
(0.72,
1.08)
0.481
194
(10.2%)
173
(9.1%)
1.130.91
(0.90,
1.41)
144477
(8.3%)
159435
(9.4%)
(0.80,
1.03) 0.422
(9.1%)
(8.3%)
0.96
(0.86,
1.07)
623
(10.4%)
596
(9.9%)
0.98
(0.85,
1.14)
342
(12.7%)
334
(12.5%)
0.87 (0.74, 1.03) 0.295 314 (9.6%) 274 (8.4%)
0.980.94
(0.86,
1.10)
505
(10.9%)
495
(10.6%)
(0.83,
1.07)
0.951
(9.8%)
486
(9.2%)
0.79
(0.46,
1.38)
0.544
29 502
(13.0%)
22 (10.7%)
0.93
(0.80,
1.10)
316
(11.3%)
281
(10.6%)
0.94
(9.7%)
0.95 (0.85,
(0.80, 1.04)
1.14) 0.837 790
244(10.3%)
(12.2%) 747
229 (11.6%)
0.930.99
(0.83,
1.05)
575619
(9.7%)
540625
(9.1%)
(0.89,
1.11) 0.044
(10.0%)
(9.9%)
0.900.77
(0.73,
1.10)
0.575 191 192
(17.0%)
165 (15.2%)
(0.62,
0.96)
(11.6%)
140
(8.9%)
0.92 (0.86,
(0.82, 1.07)
1.03) 0.395 625
672 (10.0%)
620 (8.9%)
(9.2%)
0.96
(9.2%) 604
1.030.87
(0.82,
1.29)
147482
(12.3%)
149420
(12.4%)
(0.77,
0.99) 0.104
(8.7%)
(7.6%)
1.03
(0.89,
1.19)
337
(14.2%)
349
(14.5%)
1.03
(0.87,
1.23)
0.238
245
(8.7%)
251
(9.0%)
0.91 (0.80, 1.03) 0.422 477 (9.1%) 435 (8.3%)
0.95
1.12)
291
(9.6%) 278
(9.1%)
0.98 (0.81,
(0.85,
1.14)
342 (12.7%)
334584
(12.5%)
(0.83,
(9.3%)
(8.7%)
0.840.93
(0.71,
1.00)1.04) 0.796
281 626
(13.7%)
240 (11.6%)
(0.78,
1.17)
(16.3%)
(15.6%)
0.940.96
(0.83,
1.07)
0.951 502193
(9.8%)
486185
(9.2%)
1.00
(7.6%) 209
(7.6%)
0.93 (0.83,
(0.80, 1.22)
1.10) 0.604 209
316 (11.3%)
281 (10.6%)
0.88
(0.72,
1.08) 0.481
194
(10.2%)
173
(9.1%)
0.89
(0.75,
1.05)
(10.8%)
253
(9.7%)
0.990.96
(0.89,
1.11)
0.044 283
619623
(10.0%)
625596
(9.9%)
(0.86,
1.07)
(10.4%)
(9.9%)
0.90
(0.75,
1.08)
249
(13.6%)
225
(12.2%)
0.77 (0.62, 0.96)
192 (11.6%) 140 (8.9%)
(0.46,
1.38)
0.544
29
(13.0%)
22
(10.7%)
0.90
(0.74,
1.09)
0.863
213
190
0.870.79
(0.77,
0.99)
0.104
482(10.6%)
(8.7%)
420 (9.5%)
(7.6%)
0.94
(0.77,
1.15)
193
(10.9%)
181
(0.85,
1.04)
(10.3%)
747
(9.7%)
1.030.94
(0.89,
1.19)
337790
(14.2%)
349(10.2%)
(14.5%)
0.89 (0.73, 1.09)
207 (10.5%) 187 (9.3%)
(0.73,
1.10)
0.575
(17.0%)
165
(15.2%)
0.930.90
(0.83,
1.04)
0.796
626
(9.3%)
584
(8.7%)
1.02
(0.74,
1.41)
73 191
(12.2%)
74 (12.3%)
0.96
(0.86,
1.07)
625
(9.2%)
604
(8.9%)
1.03
133
(8.6%) 137
(8.9%)
0.96 (0.81,
(0.78, 1.31)
1.17)
193 (16.3%)
185 (15.6%)
Subgroup Analyses for CV Death, MI, Stroke
Baseline Status
Baseline Status
Baseline Status
Darapladib
No
Yes No
Yes
Diabetes req. pharmacotherapy: No
Gender:
YesMale
Female
HDL-C level <40 mg/dL:
No
Race collapsed:
White
Yes
Non-White Favors
Smoker:
No
Prior myocardial infarction: Yes No Darapladib
Yes
Age
≥60:
No
Renal
dysfunction:
No
Yes
Prior coronary revascularization:
Yes No
Male Yes
Gender:
Polyvascular
Disease:
No No
Multivessel CHD:
Female
YesYes
Race collapsed:
White
Pre-Study
CHD
Recent No
Non-White
Diabetes
req.Event:
pharmacotherapy:
Prior myocardial infarction: Remote
No Yes
Yes
HDL-C
Statin
use:level <40 mg/dL:
No No
Yes
Prior coronary revascularization:No Yes
Smoker:
Yes2 No
eGFR:
<60 ml/min/1.73m Yes
Multivessel CHD:
No
≥60 ml/min/1.73m 2
Yes
Renal dysfunction:
No
Yes
Baseline
LDL:
<70
mg/dL
Diabetes req. pharmacotherapy: No
≥70 - <100 mg/dL
Yes
Polyvascular Disease:
≥100 mg/dL No
HDL-C level <40 mg/dL:
No Yes
Yes
hs C-reactive protein:
<1.0 mg/L
Pre-Study CHD Event:
Recent
1.0 - 3.0 mg/L
Smoker:
No
Remote
>3.0 mg/L
Yes
Region:
North America
Statin
use:
Renal
dysfunction:
No No
Eastern Europe
Yes Yes
Western Europe 2
eGFR:
ml/min/1.73m
Polyvascular
Disease:<60
No
South
America
≥60Asia/Pacific
ml/min/1.73m
Yes 2
Multivessel CHD:
Age ≥60:
Baseline
LDL:
Pre-Study
CHD
Event:
<70 mg/dL
Recent
0.25
≥70 - <100
mg/dL
Remote
≥100 mg/dL
Statin use:
No
hs C-reactive protein:
<1.0
Yesmg/L
1.0 - 3.0 mg/L
2
>3.0 mg/L
eGFR:
<60 ml/min/1.73m
2
≥60 ml/min/1.73m
Region:
North America
Eastern
Europe
Baseline LDL:
<70 mg/dL
0.50
1.00
Favors
Placebo
2.00
Hazard Ratio
1.03 (0.87, 1.23) 0.238 245 (8.7%) 251 (9.0%)
4.00 0.88 (0.72, 1.08) 0.481 194 (10.2%) 173 (9.1%)
(0.81,
1.12)
(9.6%)
(9.1%)
0.960.95
(0.86,
1.07)
623291
(10.4%)
596278
(9.9%)
0.84 (0.71, 1.00)
281 (13.7%) 240 (11.6%)
0.79 (0.46, 1.38) 0.544 29 (13.0%) 22 (10.7%)
(0.83,
1.22) 0.604
(7.6%)
(7.6%)
0.941.00
(0.85,
1.04)
790209
(10.3%)
747209
(9.7%)
0.89 (0.75, 1.05)
283 (10.8%) 253 (9.7%)
0.900.90
(0.73,
1.10)
0.575 191249
(17.0%)
165225
(15.2%)
(0.75,
1.08)
(13.6%)
(12.2%)
0.96 (0.86, 1.07)
625 (9.2%) 604 (8.9%)
0.90 (0.74, 1.09) 0.863 213 (10.6%) 190 (9.5%)
(0.77,
1.15)
(10.9%)
(10.2%)
1.030.94
(0.87,
1.23)
0.238 245193
(8.7%)
251181
(9.0%)
Yes
No No
YesYes
Smoker:
NoMale
Gender:
Yes
Female
Renal
dysfunction:
No
Race collapsed:
White
Yes
Non-White
Prior myocardial
infarction: No No Favors
Polyvascular
Disease:
YesYes Darapladib
Prior coronary revascularization:No
Pre-Study
Recent
Age
≥60: CHD Event:
NoYes
Yes
Remote
Multivessel CHD:
No
Male
Gender:
Statin use:
NoYes
Female
Yes No
Diabetes req. pharmacotherapy:
Race collapsed:
White2Yes
eGFR:
<60 ml/min/1.73m
Non-White
HDL-C level <40
≥60mg/dL:
ml/min/1.73m 2 No
Prior myocardial infarction:
NoYes
Yes
Baseline LDL:
<70 mg/dL
Smoker:
No
≥70 - <100 mg/dL
Prior coronary revascularization:
NoYes
≥100 mg/dL
Yes
Renal dysfunction:
No
Multivessel
CHD:
NoYes
hs C-reactive
protein:
<1.0 mg/L
Yes
1.0 - 3.0 mg/L
>3.0
mg/L
Polyvascular
Disease:
Diabetes
req. pharmacotherapy:
No No
Yes
Region:
North AmericaYes
Placebo
HDL-C
Agelevel
≥60: <40 mg/dL:
Baseline Status
Baseline Status
Darapladib
0.98 HR
(0.85,
1.14)
(95%
CI)
342 (12.7%)
(12.5%)
P-value
Placebo334 Darapladib
0.940.98
(0.83,
1.07)
0.951
502191
(9.8%)
486182
(9.2%)
(0.80,
1.20)
0.613
(8.8%)
(8.6%)
0.930.92
(0.80,
1.10)
316628
(11.3%)
281587
(10.6%)
(0.82,
1.03)
(10.9%)
(10.1%)
0.990.92
(0.89,
1.11)
0.044
619670
(10.0%)
625624
(9.9%)
(0.83,
1.03)
0.500
(10.5%)
(9.7%)
0.771.01
(0.62,
0.96)
192149
(11.6%)
140145
(8.9%)
(0.80,
1.26)
(9.9%)
(9.9%)
0.870.90
(0.77,
0.99)
0.104
482
(8.7%)
420
(7.6%)
(0.80, 1.00) 0.077 675 (10.9%) 610 (9.8%)
1.031.13
(0.89,
1.19)
337144
(14.2%)
349159
(14.5%)
(0.90,
1.41)
(8.3%)
(9.4%)
Baseline Status
Subgroup Analyses for CV Death, MI, Stroke
Eastern Europe
HDL-C
level <40
mg/dL:
No
Pre-Study
CHD
Event:
Recent
Western Europe
Yes
Remote
South America
Smoker:
No
Asia/Pacific No
Statin use:
Yes
Yes
Renal dysfunction:
No0.252
eGFR:
<60 ml/min/1.73m
Yes
≥60 ml/min/1.73m 2
Polyvascular Disease:
No
Baseline LDL:
<70Yes
mg/dL
≥70 - <100 mg/dL
Pre-Study CHD Event:
Recent
≥100
mg/dL
Remote
hs C-reactive protein:
<1.0 mg/L
1.0 - 3.0No
mg/L
Statin use:
>3.0
mg/L
Yes
(0.74,
1.03)
0.295
314
(9.6%)
274
(8.4%)
0.930.87
(0.83,
1.04)
0.796
626Number
(9.3%)
(8.7%)
Interaction
of584
Events
(%)
0.98
(0.86,
1.10)
505
(10.9%)
495
(10.6%)
0.96
1.17) P-value 193Placebo
(16.3%) 185
(15.6%)
HR (0.78,
(95% CI)
Darapladib
Placebo
0.95 (0.80, 1.14) 0.837 244 (12.2%) 229 (11.6%)
0.88
(0.72,
1.08)
0.481
(10.2%)
173
(9.1%)
0.980.93
(0.80,
1.20)
0.613 194
191575
(8.8%)
182540
(8.6%)
(0.83,
1.05)
(9.7%)
(9.1%)
0.92
(0.82,
1.03)
628
(10.9%)
587
(10.1%)
0.96 (0.86, 1.07)
623 (10.4%) 596 (9.9%)
0.92 (0.82, 1.03) 0.395 672 (10.0%) 620 (9.2%)
0.921.03
(0.83,
1.03)
0.500 670
(10.5%)
624
(9.7%)
(0.82,
1.29)
(12.3%)
(12.4%)
0.79
(0.46,
1.38)
0.544
29147
(13.0%)
22149
(10.7%)
1.01
(0.80,
1.26)
149
(9.9%)
145
(9.9%)
0.940.91
(0.85,
1.04)
790
(10.3%)
747
(9.7%)
(0.80, 1.03) 0.422 477 (9.1%) 435 (8.3%)
0.900.98
(0.80,
1.00)
0.077 675342
(10.9%)
610334
(9.8%)
(0.85,
1.14)
(12.7%)
(12.5%)
0.90
1.13 (0.73,
(0.90, 1.10)
1.41) 0.575 191
144 (17.0%)
(8.3%) 165
159 (15.2%)
(9.4%)
0.960.94
(0.86,
1.07)
625502
(9.2%)
604486
(8.9%)
(0.83,
1.07) 0.951
(9.8%)
(9.2%)
0.870.93
(0.74,
1.03)
0.295 314316
(9.6%)
274281
(8.4%)
(0.80,
1.10)
(11.3%)
(10.6%)
0.98 (0.87,
(0.86, 1.23)
1.10) 0.238 245
505 (10.9%)
495 (10.6%)
1.03
(8.7%) 251
(9.0%)
0.99
(0.89,
1.11)
0.044
619
(10.0%)
625
(9.9%)
0.95
(0.81,
1.12)
291
(9.6%)
278
(9.1%)
0.950.77
(0.80,
1.14)
0.837 244192
(12.2%)
229140
(11.6%)
(0.62,
0.96)
(11.6%)
(8.9%)
0.84
281
0.93 (0.71,
(0.83, 1.00)
1.05)
575 (13.7%)
(9.7%) 240
540 (11.6%)
(9.1%)
0.87 (0.77, 0.99) 0.104 482 (8.7%) 420 (7.6%)
1.00
(0.83,
1.22)
0.604
(7.6%)
209
(7.6%)
0.921.03
(0.82,
1.03)
0.395 209
672337
(10.0%)
620349
(9.2%)
(0.89,
1.19)
(14.2%)
(14.5%)
1.03 (0.75,
(0.82, 1.05)
1.29)
147 (10.8%)
(12.3%) 253
149 (12.4%)
0.89
283
(9.7%)
(0.83,
1.04)
0.796
(9.3%)
(8.7%)
0.90
(0.75,
1.08)
249
(13.6%)
225
(12.2%)
0.910.93
(0.80,
1.03)
0.422
477626
(9.1%)
435584
(8.3%)
(0.78,
1.17)
(16.3%)
(15.6%)
0.980.96
(0.85,
1.14)
342193
(12.7%)
334185
(12.5%)
0.90
(0.74,
1.09)
0.863 213
(10.6%)
190
(9.5%)
0.940.88
(0.77,
1.15)
193
(10.9%)
181
(10.2%)
(0.72,
1.08)
0.481
(10.2%)
(9.1%)
(0.83,
1.07)
0.951
502194
(9.8%)
486173
(9.2%)
0.89
(0.73,
1.09)
207
(10.5%)
187
(9.3%)
0.930.96
(0.80,
1.10)
316
(11.3%)
281
(10.6%)
(0.86, 1.07)
623 (10.4%) 596
(9.9%)
1.02 (0.74, 1.41)
73 (12.2%) 74 (12.3%)
0.990.79
(0.89,
1.11)
0.044
619 (10.0%)
625 22
(9.9%)
(0.46,
1.38)
0.544
29
(13.0%)
(10.7%)
1.03
133
(8.6%)
137
0.77 (0.81,
(0.62, 1.31)
0.96)
192 (11.6%)
140 (8.9%)
(8.9%)
0.94 (0.85, 1.04)
790 (10.3%) 747 (9.7%)
0.50
1.00
2.00
4.00 0.87 (0.77, 0.99) 0.104 482 (8.7%) 420 (7.6%)
(0.73,
1.10) 0.575
(17.0%)
(15.2%)
1.030.90
(0.89,
1.19)
337191
(14.2%)
349165
(14.5%)
Hazard Ratio
0.96 (0.86, 1.07)
625 (9.2%) 604 (8.9%)
0.93 (0.83, 1.04) 0.796 626 (9.3%) 584 (8.7%)
(0.87,
1.23) 0.238
(8.7%)
(9.0%)
0.961.03
(0.78,
1.17)
193245
(16.3%)
185251
(15.6%)
0.95 (0.81, 1.12)
291 (9.6%) 278 (9.1%)
0.880.84
(0.72,
1.08)
0.481 194281
(10.2%)
173240
(9.1%)
(0.71,
1.00)
(13.7%)
(11.6%)
0.96 (0.86, 1.07)
623 (10.4%) 596 (9.9%)
1.00 (0.83, 1.22) 0.604 209 (7.6%) 209 (7.6%)
0.790.89
(0.46,
1.38)
0.544 29283
(13.0%)
(10.7%)
(0.75,
1.05)
(10.8%)22253
(9.7%)
0.940.90
(0.85,
1.04)
790249
(10.3%)
747225
(9.7%)
(0.75,
1.08)
(13.6%)
(12.2%)
2
North America
<60 ml/min/1.73m
Eastern
Europe
≥60 ml/min/1.73m 2
(0.74,
1.09)
0.863
(10.6%)
(9.5%)
0.900.90
(0.73,
1.10)
0.575
191213
(17.0%)
165190
(15.2%)
(0.77,
1.15)
(10.9%)
(10.2%)
0.960.94
(0.86,
1.07)
625193
(9.2%)
604181
(8.9%)
Region:
eGFR:
Favors
Cardiovascular and Mortality Endpoints
HR
P
CV
CV Death,
Death, MI,
MI, Stroke
Stroke
CV Death
Myocardial Infarction
Stroke
All-Cause Mortality, MI, Stroke
All-Cause Mortality
Favors Darapladib
Favors Placebo
Placebo Darapladib
Time to First Occurrence Major Coronary Events
Percentage of Patients
(CHD Death, MI, Urgent Coronary Revascularization)
Placebo events = 814 (10.3%)
Darapladib events = 737 (9.3%)
HR = 0.90 (95% CI, 0.82 - 1.00)
P-value = 0.045
Time to First Occurrence Total Coronary Events
(CHD Death, MI, Any Coronary Revascularization,
Percentage of Patients
Hospitalization for Unstable Angina)
Placebo events = 1269 (16.1%)
Darapladib events = 1159 (14.6%)
HR = 0.91 (95% CI, 0.84 - 0.98)
P-value = 0.019
Coronary-Specific Endpoints
P
HR
Major Coronary Events
CHD Death1
Myocardial Infarction
Urgent Coronary Revasc2
Total Coronary Events
Any Coronary Revasc2
Hosp for Unstable Angina1
Favors Darapladib
Favors Placebo
1 - Component of pre-specified composite, but not a pre-specified endpoint
2 - Component of pre-specified composite, pre-specified as an endpoint of interest
Placebo Darapladib
Coronary-Specific Endpoints
These findings should be considered exploratory and of
uncertain significance in light of the lack of effect on the
primary endpoint
Adverse Events
Placebo
(N=7890)
Darapladib
(N=7912)
Any serious adverse event
44%
43%
Any adverse event leading to study drug
discontinuation
14%
20%
New cancer
6.7%
6.4%
Adjudicated new GI cancer
1.3%
1.3%
1.1%
1.5%
Cancer
Renal Effects
Serious adverse events of renal failure
eGFR Change from baseline treatment
difference (ml/min/1.73m2)
End of treatment (n=14820)
1 month after treatment end (n=2650)
-2.5 (-3.0, -2.1)
-0.1 (-1.4, 1.1)
Darapladib Side Effects
Leading to Study Drug Discontinuation
Diarrhea & Odor
Adverse Events
Placebo
(N=7890)
Darapladib
(N=7912)
n (%)
Rate per
100 PY
n (%)
Rate per
100 PY
Diarrhea
60 (0.8%)
0.21
254 (3%)
0.92
Abnormal feces
5 (<0.1%)
0.02
177 (2%)
0.64
Abnormal skin odor
4 (<0.1%)
0.01
174 (2%)
0.63
Abnormal urine odor
1 (<0.1%)
<0.01
113 (1%)
0.40
Conclusions
Darapladib in patients with stable CHD followed for 3.7 years
on a background of optimal medical therapy resulted in
 No significant reduction in the incidence of the primary
composite endpoint of CV death, MI or stroke
 A signal of efficacy on the pre-specified coronary-specific
secondary endpoints of major coronary events and total
coronary events with nominal significance (p<0.05)
 A safety profile that was well characterized
Implications
The STABILITY trial is the first large scale randomized
global trial to test a novel mechanism of inhibition of
inflammation in the atherosclerotic plaque
Further analyses of the trial results based on biomarkers
and genetics will explore if darapladib might be useful in
specific patient subsets

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