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ASPIRIN RESISTANCE. Oxford 1763. Paul RJ Ames, MD, MSc, PhD Immunoclot Ltd, Leeds, UK William Harvey Research Institute. Queen Mary University London Department of Haematology , St George’s Hospital, London, United Kindom. Introduction. Aspirin Resistance

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Aspirin resistance

ASPIRINRESISTANCE

Oxford 1763

Paul RJ Ames, MD, MSc, PhD

Immunoclot Ltd, Leeds, UK

William Harvey Research Institute.

Queen Mary University London

Department of Haematology,

St George’s Hospital, London,

United Kindom


Introduction
Introduction

  • Aspirin Resistance

  • Urinary 11-dehydro Thromboxane B2 measurement in Diabetes Mellitus and ACS


Aspirin and vascular disease
ASPIRIN AND VASCULAR DISEASE

  • ASA weak agent for prevention of vascular disease

    • Relative risk reduction in MI is 20-25%

    • Relative risk of cardiac death is 25%

    • Relative risk reduction in IS is 15-20%

      (low rates)

  • Re-stroke prevalence on ASA is 30-40%

  • ASA safe and inexpensive


ASA INHIBITION OF CYCLO-OXYGENASE

Sweeny JM et al. Nat Rev Cardiol 2009



ASPIRIN RESISTANCE

CLINICAL

ASA resistance

Persistent platelet reactivity despite ASA use

ASA failure

Thrombotic event despite ASA use

BIOCHEMICAL

ASA insensitive thromboxane generation


ASPIRIN RESISTANCE

  • DRUG RELATED

    • Pharmacokinetics

      • Insufficient bioavailability (low dose)

      • Prevention of access to COX-1 binding site by NSAIDS

    • Pharmacodynamics

      • Impaired sensitivity of platelet COX-1 (CABG)

      • COX-1 gene polymorphism


ASPIRIN RESISTANCE

  • DISEASE RELATED

    • PLT reactivity (residual PLT activity)

    • PLT stimulation by ASA insensitive mechanisms (ADP, shear stress)

    • PLT stimulation by COX-2 dependent TBX generation (PLT mediated)

    • PLT sensitising by isoprostanes



Cut off determination
Cut-off determination

  • Studied over 300 apparently healthy adults before and after receiving controlled doses of ASA

  • Based on the resulting frequency of 11dhTxB2 levels, a cut-off value was established to assess an adequate ASA response at 1,500 pg/mg of 11dhTxB2/creatinine

  • This cut-off has been re-confirmed in subsequent studies using both healthy and diseased populations before and after ASA ingestion [27].

  • Those individuals with urinary 11dhTxB2 levels after ASA ingestion below the cut-off of 1,500 pg/mg are considered good ASA responders while those with levels above 1,500 pg/mg are poor ASA responders (“ASA resistance”).


Atherosclerotic Cardio Vascular Disease (CVD)

Chronic, progressive (frequently asymptomatic) disease

that may start early in life. Multi-factorial with 2 main components:

  • Systemic (circulation)

  • Platelet activation/aggregation (thromboxane-mediated)

  • resulting in arterial (and venous) hypercoagulability,

  • endothelial dysfunction, clotting factor activation, etc.

  • Focal (tissue)

  • Oxidative & nitrativechronic inflammation (dyslipidemia, oxLDL) macrophage activation, foam cell fomation, lymphocytes (immune response) with plaque formation in arterial wall.


THROMBOXANE BIOSYNTHESIS BY

CYCLOOXYGENASE ACTIVATION PATHWAYS

Membranephospholipids

Inflammatory COX-2

Pathway

Platelet COX-1 Pathway

PLA2

PLC

Aspirin

TX-synthase/Peroxidase

Peroxidase/TX-synthase

Arachidonic

acid

TXA2

TXA2

PGH2/PGG2

PGG2/PGH2

COX-2

COX-1

Hydrolytic

inactivation

Hydrolytic

inactivation

Serum

TXB2

Urinary

11dhTXB2

AspirinWorks®

ELISA test measures

TxBCardio Assay


Key Publications on 11dhTxB2

HOPE Study (2002)

  • Multi-centre study in Canada

  • 976 aspirin-treated patients who had suffered a previous CVD event

  • Sub-study of a larger 5000 patient clinical trial on clopidogrel

  • 11dhTxB2 (Corgenix assay) measured at baseline, then patients followed for 5 years

  • 488 patients suffered another event (case), 488 did not (controls)


Key Publications on 11dhTxB2

HOPE Study (2002)

Results:

  • Increased 11dhTxB2 predicts increased composite risk of MI, stroke or death

  • For death in particular, the highest quartile of 11dhTxB2 concentrations equated to a 3.5 fold increased risk

  • 11dhTxB2 could be used to prospectively identify aspirin resistant patients who may benefit from additional aspirin doses or additional medication


Key Publications on 11dhTxB2

HOPE Study (2002)


Key Publications on 11dhTxB2

CHARISMA Study (2008)

  • Follow-up to HOPE (2002) study, in an attempt to validate the findings

  • Sub-study of main CHARISMA (multi-centre, multi-national 15,000 patient trial on clopidogrel)

  • Measured 11dhTxB2 (Corgenix assay) in 3261 aspirin-treated patients at least one month after being assigned to placebo or clopidogrel


Key Publications on 11dhTxB2

CHARISMA Study (2008)

Results:

  • Validated findings of HOPE study in this new cohort

  • 11dhTxB2 is an independent, modifiable predictor of CVD risk

  • Found that both increased aspirin & statin therapy reduced 11dhTxB2 & risk


PRE POST

81 mg ASA

PRE POST

325 mg ASA

ASPIRIN WORKS KIT: 1500 pg/mg cut-off to discriminate ASA responders from non-responders established on healthy volunteers post ASA ingestion (7 Days)


PRE

POST

ASPIRIN WORKS KIT: 1500 pg/mg cut-off to discriminate ASA responders from non-responders established on healthy volunteers post ASA ingestion (7 Days)


Females 50.9% higher than males


Healthy controls

Diabetes Melitus

DM 69.5%

higher than healthy controls


71.5% suppression

14.8% AR

75.1% suppression

8.4% AR

Level of 11dhTxB2 suppression equal, but DM more Aspirin “resistance” (8 vrs 15%).


2-DM: INFLAMMATORY/OXIDATIVE MARKERS UNAFFECTED BY ASA INDIVIDUALS

11dhTxB2 and 8-isoPGF2a pre & post ASA

PRE POST

81 mg ASA

PRE POST

81 mg ASA

DM significantly higher baseline and post-ASA TxB2 and PGF2a than controls.

But only TxB2 (COX-1) was affected by ASA.

Ames PRJ et al. Aspirin insensitive thromboxane generation is associated with oxidative stress in type 2 diabetes mellitus Thromb Res 2012; 130:350-354


3- ACS PCI STUDIES (BEFORE AND AFTER ASA INDIVIDUALS)

81.6% suppression

28.7% AR

Matsuura EE. On aspirin treatment but not baseline thromboxane B2 levels predict adverse outcomes in patients with acute coronary syndromes. J ThrombHeamost 2012;


SUMMARY 11DHTXB2 STUDIES OF DM AND ACS INDIVIDUALS

Baseline 11dhTxB2 levels

100,000

% ASA poor-responders

Upper range

20,000

10,000


MEAN URINARY EXCRETION OF 8-ISO-PGF2Α INDIVIDUALS

IN UNSTABLE ANGINA, CHRONIC STABLE ANGINA AND IN HEALTHY SUBJECTS.

Cipollone F et al. Circulation. 2000;102:1007-1013


URINARY 11-DEHYDRO-TXB2 IN MATCHED PATIENTS WITH INDIVIDUALS

UNSTABLE ANGINA AND CHRONIC STABLE ANGINA.

Cipollone F et al. Circulation. 2000;102:1007-1013


CORRELATION BETWEEN URINARY EXCRETION RATES OF 8-ISO-PGF2Α AND 11-DEHYDRO-TXB2 IN PATIENTS WITH SEVERE UNSTABLE ANGINA.

Cipollone F et al. Circulation. 2000;102:1007-1013


URINARY 8-ISO-PGF2a & 11-DEHYDRO-TXB2 IN PATIENTS WITH STABLE ANGINA WITH CHRONIC ASA THERAPY COMPARED WITH NON ASA REATMENT.

Cipollone F et al. Circulation. 2000;102:1007-1013


Assay key features
Assay Key Features STABLE ANGINA WITH CHRONIC ASA THERAPY COMPARED WITH NON ASA REATMENT.


TxB Cardio STABLE ANGINA WITH CHRONIC ASA THERAPY COMPARED WITH NON ASA REATMENT. vs Corgenix ELISA

Correlation Data

11dhTxB2 (pg/ml) – TxB Cardio ITA

11dhTxB2 (pg/ml) – Corgenix EIA


CLINICAL INTERPRETATION OF 11DHTXB2 LEVELS PRE & POST STABLE ANGINA WITH CHRONIC ASA THERAPY COMPARED WITH NON ASA REATMENT.

ASA TREATMENT AND DECISION MAKING ALGORITHM

11dhTxB2 levels before ASA

ASA effect for CVD risk assessment

<2,500

OK

ASA

i

n

g

e

s

t

I

o

n

<1,500

Good response

OK

Consider:

CVD risk factors and

ASA response

2,500-

10,000

“Increased Risk”

>1,500

Poor response

Evaluate:

CVD risk factors and

ASA response

>10,000

  • poor COX-1 TxA2 inhibition – modify ASA dose or add other anti-platelet drugs.

  • Non-platelet COX-2 TxA2 production from pro-atherogenic oxidative inflammation – modify/treat CVD risk factors.


Summary
Summary STABLE ANGINA WITH CHRONIC ASA THERAPY COMPARED WITH NON ASA REATMENT.

  • Up to 30% patients prescribed aspirin may still undergo vascular occlusions

  • Urinary 11-dehydro-Thromboxane excretion reflects platelet activity in vivo

  • Measured using TxBCardio assay

  • Correlates with ELISA assay

  • Available for automated clinical chemistry analysers.


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