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STABILITY Stabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY Harvey D White on behalf of The STABILITY Investigators.

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Presentation on theme: "STABILITY Stabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY Harvey D White on behalf of The STABILITY Investigators."— Presentation transcript:

1 STABILITY Stabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY Harvey D White on behalf of The STABILITY Investigators

2 Lipoprotein- associated Phospholipase A 2 (Lp-PLA 2 ) activity: Background Lumen Intima native LDL carrier of Lp-PLA 2 Oxidized LDL substrate for Lp-PLA 2 Sustained Inflammation Necrotic Core Expansion Leukocyte Atheroma Lp-PLA 2 Macphee, Biochem J 1999; Zalewski and Macphee, ATVB 2005; Shi Atherosclerosis 2007; Kolodgie, ATVB 2006

3 Characteristics of Stable versus Ruptured Plaques Stable Plaque Low Lp-PLA 2 content (dark staining) May have significant stenosis Thick fibrous cap / high collagen content Modest lipid pool Few inflammatory cells Ruptured Plaque High Lp-PLA 2 content (dark staining) May have minimal stenosis Thin fibrous cap / low collagen content Large lipid pool Many inflammatory cells Modest Lipid PoolLarge Lipid Pool Lp-PLA 2 Thin Fibrous CapThick Fibrous Cap Lumen Corson et al. Am J Card 2008;101(Suppl):41F-50F

4 Rationale for STABILITY PRECLINICAL Reduces Lp-PLA 2 in plaque and necrotic core area (pig) HUMAN ATHEROMA Reduces carotid plaque Lp-PLA 2 activity EPIDEMIOLOGY Higher Lp-PLA 2 levels predict CV events Association studies PATHOLOGY Up-regulation of Lp- PLA 2 in vulnerable plaques GENETICS Deficiency in Lp-PLA 2 due to null allele results in decreased CHD CORONARY IMAGING IBIS-2 Halts progression of coronary artery necrotic plaque core volume Intervention with darapladib Darapladib is a selective oral inhibitor that decreases Lp-PLA 2 by ~60%

5 STABILITY Trial Study Design 15,828 patients randomized Patients with chronic CHD ( prior MI >1 mth, prior coronary revascularization, multivessel CAD) Darapladib 160mg daily Placebo Median follow-up 3.7 years, 1588 events Primary endpoint: composite of CV death, MI, stroke Secondary endpoints: major coronary events, total coronary events Enrichment criteria : ≥60 years of age, diabetes mellitus, low HDL, current smoking, significant renal dysfunction, polyvascular disease Optimized guideline-recommended treatment Design paper reference: White H, et al. Am Heart J 2010;160:

6 USA3102 Canada780 Mexico141 Argentina542 Brazil384 Chile195 Peru78 Belgium202 Denmark 102 France250 Greece187 Germany1089 Bulgaria222 Cz Republic774 Estonia77 Hungary410 China369 Korea503 Hong Kong 117 Taiwan200 Japan318 India 398 Pakistan 250 Italy256 Netherlands444 Norway113 Spain474 Sweden299 UK184 Western Europe (22%) Poland510 Romania411 Russia654 Slovakia120 Ukraine353 Eastern Europe (22%) E & SE Asia South America North America (25%) Global Recruitment (N=15,828) Asia-Pacific/Latina (31%) South Africa 386 Thailand 207 Philippines 219 Australia 306 New Zealand 202

7 Demographics Placebo (N=7904) Darapladib (N=7924) Age (median in years)65.0 ≥75 years14% Female19%18% Race or Ethnic Group White78%79% Black2% Central/South/South East Asian8%7% East Asian/Japanese10% Other2%

8 Chronic Coronary Heart Disease Qualifying Diagnosis Placebo (N=7904) Darapladib (N=7924) Prior MI59% Coronary revascularization75% PCI50% CABG33% Multi-vessel CAD15%

9 Enrichment Criteria Placebo (N=7904) Darapladib (N=7924) Age ≥ 60 years73% Diabetes (Requiring pharmacotherapy) 34% HDL < 40 mg/dL (1.03 mmol/L)35%33% Smoker (Current or former smoker within 3 months; ≥5 cigs/day) 21%20% Significant renal dysfunction (eGFR 30 to 59 mL/min/1.73 m 2 or urine ACR ≥3 mg albumin/g creatinine) 30% Polyvascular disease (cerebrovascular disease or peripheral arterial disease) 15%

10 High Standard of Care Time PointPlaceboDarapladib AspirinBaseline Study end 93% 91% 92% 90% StatinsBaseline Study end 97% 96% 97% 96% Beta-BlockersBaseline Study end 79% 78% ACE inhibitorBaseline Study end 56% 54% 57% 54% Angiotensin II receptor blocker Baseline Study end 23% 27% 22% 26%

11 Patient Follow-up Placebo (N=7904) Darapladib (N=7924) Study Drug Discontinuation26.8%32.7% Study Withdrawal3.5% Missing CV Endpoint at Study End3.5%3.6% Missing Vital Status at Study End0.7%0.6%

12 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, ) P-value = Percentage of Patients

13 Subgroup Analyses for CV Death, MI, Stroke

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15 Cardiovascular and Mortality Endpoints P HR Favors Darapladib Favors Placebo PlaceboDarapladib CV Death, MI, Stroke CV Death Myocardial Infarction Stroke All-Cause Mortality, MI, Stroke All-Cause Mortality

16 Time to First Occurrence Major Coronary Events (CHD Death, MI, Urgent Coronary Revascularization) Placebo events = 814 (10.3%) Darapladib events = 737 (9.3%) HR = 0.90 (95% CI, ) P-value = Percentage of Patients

17 Time to First Occurrence Total Coronary Events (CHD Death, MI, Any Coronary Revascularization, Hospitalization for Unstable Angina) Placebo events = 1269 (16.1%) Darapladib events = 1159 (14.6%) HR = 0.91 (95% CI, ) P-value = Percentage of Patients

18 Coronary-Specific Endpoints 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 Favors Darapladib Favors Placebo P HR PlaceboDarapladib Major Coronary Events CHD Death 1 Myocardial Infarction Urgent Coronary Revasc 2 Total Coronary Events Any Coronary Revasc 2 Hosp for Unstable Angina 1

19 Coronary-Specific Endpoints These findings should be considered exploratory and of uncertain significance in light of the lack of effect on the primary endpoint

20 Adverse Events Placebo (N=7890) Darapladib (N=7912) Any serious adverse event44%43% Any adverse event leading to study drug discontinuation 14%20% Cancer New cancer6.7%6.4% Adjudicated new GI cancer1.3% Renal Effects Serious adverse events of renal failure1.1%1.5% eGFR Change from baseline treatment difference (ml/min/1.73m 2 ) End of treatment (n=14820) 1 month after treatment end (n=2650) -2.5 (-3.0, -2.1) -0.1 (-1.4, 1.1)

21 Darapladib Side Effects Leading to Study Drug Discontinuation Diarrhea & Odor Adverse Events Placebo (N=7890) Darapladib (N=7912) n (%) Rate per 100 PYn (%) Rate per 100 PY Diarrhea60 (0.8%) (3%)0.92 Abnormal feces5 (<0.1%) (2%)0.64 Abnormal skin odor4 (<0.1%) (2%)0.63 Abnormal urine odor1 (<0.1%)< (1%)0.40

22 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

23 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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