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STABILITY St abilization of A therosclerotic plaque B y Initiation of darap L ad I b T herap Y Harvey D White on behalf of The STABILITY Investigators. Lipoprotein- associated Phospholipase A 2 (Lp-PLA 2 ) activity: Background. native LDL carrier of Lp-PLA 2. Lp-PLA 2. Leukocyte.

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STABILITYStabilization of Atherosclerotic plaque By Initiation of darapLadIbTherapYHarvey D White on behalf of The STABILITY Investigators


Lipoprotein associated phospholipase a 2 lp pla 2 activity background
Lipoprotein- associated Phospholipase A2(Lp-PLA2) activity: Background

native LDL

carrier of Lp-PLA2

Lp-PLA2

Leukocyte

Lumen

Atheroma

Sustained Inflammation

Lp-PLA2

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
Characteristics of Stable versus Ruptured Plaques

Thick Fibrous Cap

Thin Fibrous Cap

Modest Lipid Pool

Large Lipid Pool

Lumen

Lumen

Lp-PLA2

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
Rationale for STABILITY

Darapladib is a selective oral inhibitor that decreases

Lp-PLA2 by ~60%

Association studies

Intervention with darapladib

EPIDEMIOLOGY

Higher Lp-PLA2 levels predict CV events

PRECLINICAL

Reduces Lp-PLA2 in plaque and necrotic core area (pig)

GENETICS

Deficiency in Lp-PLA2 due to null allele results in decreased CHD

HUMAN ATHEROMA

Reduces carotid plaque Lp-PLA2 activity

CORONARY IMAGING

IBIS-2

Halts progression of coronary artery necrotic plaque core volume

PATHOLOGY

Up-regulation of Lp-PLA2 in vulnerable plaques


Stability trial study design
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%)

Western Europe (22%)

Eastern Europe (22%)

USA 3102

Canada 780

Mexico 141

Belgium 202

Denmark 102

France 250

Greece 187

Germany 1089

Italy 256

Netherlands 444

Norway 113

Spain 474

Sweden 299

UK 184

Bulgaria 222

CzRepublic 774

Estonia 77

Hungary 410

Poland 510

Romania 411

Russia 654

Slovakia 120

Ukraine 353

E & SE Asia

China 369

Korea 503

HongKong 117

Taiwan 200

Japan 318

India 398

Pakistan 250

Thailand 207

Philippines 219

Australia 306

NewZealand 202

South America

Argentina 542

Brazil 384

Chile 195

Peru 78

SouthAfrica 386

Asia-Pacific/Latina (31%)







Primary endpoint time to first occurrence of cv death mi stroke
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

Percentage of Patients




Cardiovascular and mortality endpoints
Cardiovascular and Mortality Endpoints

P

Placebo

Darapladib

HR

CV Death, MI, Stroke

CV Death, MI, Stroke

CV Death

Myocardial Infarction

Stroke

All-Cause Mortality, MI, Stroke

All-Cause Mortality

Favors Placebo

Favors Darapladib


Time to first occurrence major coronary events chd death mi urgent coronary revascularization
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, 0.82- 1.00)

P-value = 0.045

Percentage of Patients


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, 0.84- 0.98)

P-value = 0.019

Percentage of Patients


Coronary specific endpoints
Coronary-Specific Endpoints

P

HR

Placebo

Darapladib

Major Coronary Events

CHD Death1

Myocardial Infarction

Urgent Coronary Revasc2

Total Coronary Events

Any Coronary Revasc2

Hosp for Unstable Angina1

Favors Placebo

Favors Darapladib

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


Coronary specific endpoints1
Coronary-Specific Endpoints

These findings should be considered exploratory and of uncertain significance in light of the lack of effect on the primary endpoint



Darapladib side effects leading to study drug discontinuation
Darapladib Side Effects Leading to Study Drug Discontinuation


Conclusions
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
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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