Aspirinn doses in diabetics - AngiolilloSlide 1 Davide Capodanno, MD, Aasita Patel, MD, Kodlipet...

Aspirinn doses in diabetics - Angiolillo Slide 1

Davide Capodanno, MD, Aasita Patel, MD, Kodlipet Dharmashankar, MD, José Luis Ferreiro, MD, Masafumi Ueno, MD,

Murali Kodali, MD, Salvatore D. Tomasello, MD, Piera Capranzano, MD, Naveen Seecheran, MD, Andrew Darlington,

MD, Antonio Tello-Montoliu, MD, PhD, Bhaloo Desai, PhD, Theodore A. Bass, MD, Dominick J. Angiolillo, MD, PhD

University of Florida, College of Medicine, Jacksonville, USA

Pharmacodynamic Effects of Different Aspirin Dosing Regimens in Type 2 Diabetes Mellitus

Patients with Coronary Artery Disease

Circ Card Interv 2011 Ahead of print


The reduced life-span and increased turnover rates of platelets have been suggested to have a contributing role in the differential pharmacodynamic response profiles to antiplatelet therapy in type 2 diabetes mellitus (T2DM) patients.

Aspirin has only a 20-minute half-life and therefore the accelerated thrombopoiesis which characterizes T2DM patients does not allow newly generated platelets entering the circulation to be sufficiently exposed to aspirin.

Background

Winocour, et al. Eur J Clin Invest. 1994;24 (Suppl 1):34-7Di Minno G, et al Blood. 1983;61:1081-5

Patrono C. N Engl J Med. 1994;330:1287-94


It may be hypothesized that an increase in the frequency, rather than the dose, of aspirin administration may be a more effective strategy to inhibit platelet reactivity in diabetic patients as this may enable COX-1 blockade of newly generated platelets

Therefore, the aim of the present pilot investigation was to evaluate how increasing the frequency of aspirin administration, remaining within the daily recommended therapeutic doses, affects antiplatelet responsiveness in T2DM patients with coronary artery disease (CAD)

Rationale and objective


Schematic of circadian release of platelets into bloodstream from bone marrow and impact of a single daily dose of aspirin on newly generated platelets in type 2 diabetes mellitus

Platelets from patients with type 2 diabetes mellitus (T2DM) have a reduced life-span and increased turnover rates, leading to enhanced bone marrow megakaryocyte generation and release of new and hyper-reactive platelets into the bloodstream. Aspirin has only a 20-minute half-life and therefore the accelerated thrombopoiesis which characterizes T2DM patients does not allow newly generated platelets entering the circulation to be sufficiently exposed to aspirin if given once daily. This may lead to a considerable proportion of circulating platelets with uninhibited cyclooxigenase-1 (COX-1) activity that continue to generate high levels of serum thromboxane and therefore promote activation of circulating platelets (acetylated and non-acetylated) via thromboxane receptors (TP) on the platelet surface. A twice daily administration of aspirin may allow newly generated platelets released into the bloodstream to be COX-1 inhibited, thus achieving more optimal blockade of platelet activation processes in T2DM.


Visit 181 mg

od

Visit 281 mg

bid

Visit 3162 mg

od

Visit 4162 mg

bid

Visit 5325 mg

od

run-in phase

Screening phase

Patients modified their aspirin regimen on a weekly basis according to the following scheme

Pharmacodynamic assessments included:

light transmittance aggregometry (LTA) following arachidonic acid, collagen and adenosine diphosphate (ADP) stimuli

VerifyNow-Aspirin assay;

serum thromboxane B2 (TXB2) levels


• active bleeding or bleeding diathesis

• concomitant use of other antithrombotic drugs

• recent treatment (30 days) with a glycoprotein IIb/IIIa antagonist

• platelet count 100*106/l

• acute coronary or cerebrovascular event within 3 months;

• serum creatinine > 2 mg/dL;

• baseline ALT > 2.5 times the upper limit of normal

• HbA1C > 10%

Patient population

* Key exclusion criteria


(n = 20)

Age (years±SD) 59±7Male, n (%) 10 (50)BMI (Kg/m2±SD) 33±9Risk factors, n (%)Smoking 6 (30)Hypertension 19 (95)Dyslipidemia 17 (85)Insulin-treated 8 (40)

Medical history, n (%)Prior MI 1 (5)Prior stroke 0 (0)Prior CABG 2 (10)Multivessel CAD 6 (30)

Baseline clinical characteristics


(n = 20)

Beta-blockers 11 (55)ACE inhibitors 18 (90)Ca2+ antagonists 11 (55)Lipid-lowering agentsCYP 3A4 pathway metabolized 8 (40)Non-CYP 3A4 pathway metabolized 0 (0)Proton pump inhibitors 5 (25)

Medical therapy

Laboratory data(n = 20)

Platelet count (1,000/mm3±SD) 241±66Hematocrit (%±SD) 42±4HbA1C (%±SD) 7.1±1.3Creatinine (g/dl±SD) 1.0±0.3


Assay81 mg

od

162 md

od

325 mg

od

81 mg od vs.

162 mg od

P value

81 mg od vs.

325 mg od

P value

162 mg od vs.

325 mg od

P value

81 mg od vs.

162 mg od vs

325 mg od

P for trend

Arachidonic acid (1 mmol/L), % 2±0.9 2±0.7 2±0.7 1.000 1.000 1.000 1.000

Collagen (2 µg/mL), % 44±23 39±14 35±15 0.285 0.083 0.374 0.157

ADP (5 µmol/L), % 49±13 54±10 54±11 0.111 0.851 0.612 0.192

ADP (20 µmol/L), % 66±7 71±11 68±7 0.033 0.459 0.145 0.109

VN-ASA, ARU 455±51 432±62 431±58 0.087 0.126 0.922 0.121

Serum TXB2, pg/ml 107±143 41±79 22±21 0.008 0.030 0.328 0.008

Dose comparison in once daily administration

Data are expressed as means±SD. ADP indicates adenosine diphosphate; VN-ASA indicates VerifyNow-Aspirin assay; TXB2 indicates thromboxane B2


Assay 81 mg bid 162 mg bid P value

Arachidonic acid (1 mmol/L), % 2±0.5 2±1.4 0.106

Collagen (2 µg/mL), % 32±14 33±14 0.895

ADP (5 µmol/L), % 54±13 50±15 0.360

ADP (20 µmol/L), % 69±11 67±14 0.476

VN-ASA, ARU 420±41 423±52 0.777

Serum TXB2, pg/ml 34±50 19±21 0.165

Dose comparison in twice daily administration



Assay162 mg

od

81 mg

bidP

325 mg

od

162 mg

bidP

Arachidonic acid (1 mmol/L), % 2±0.7 2±0.5 0.772 2±0.7 2±1.4 0.094

Collagen (2 µg/mL), % 39±14 32±14 0.060 35±15 33±14 0.490

ADP (5 µmol/L), % 54±10 54±13 0.857 54±11 50±15 0.273

ADP (20 µmol/L), % 71±11 69±11 0.343 68±7 67±14 0.751

VN-ASA, ARU 432±62 420±41 0.345 431±58 423±52 0.551

Serum TXB2, pg/ml 41±79 34±50 0.716 22±21 19±21 0.579

Comparison of single versus staggered daily administration of the same aspirin dose



Comparison of different aspirin regimens by collagen induced light transmission aggregometry (A) and VerifyNow-ASA (B)

A

B


p = 0.003

Changes in thromboxane B2 levels across the study phases

Thromboxane B2 levels are expressed as pg/ml. Error bars indicate standard deviations of the mean. Error bars indicate standard deviations; od indicates once daily administration; bid indicates twice daily administration.


Conclusions

• Aspirin dosing regimens are associated with different pharmacodynamic effects in platelets from T2DM patients and stable CAD.

• In particular, a twice daily low-dose aspirin administration is associated with greater platelet inhibition than a once daily administration as assessed by aspirin sensitive assays, and a dose-dependent effect is observed on serum TXB2 levels.

• The clinical implications of a modified aspirin regimen tailored to T2DM patients warrants further investigation.


Circ Card Interv 2011 Ahead of print

Aspirinn doses in diabetics - AngiolilloSlide 1 Davide Capodanno, MD, Aasita Patel, MD, Kodlipet...

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