Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy

doi:10.1378/chest.126.3_suppl.234S

Chest

Volume 126, Issue 3, Supplement, September 2004, Pages 234S-264S

https://doi.org/10.1378/chest.126.3_suppl.234S Get rights and content

This article discusses platelet active drugs as part of the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. New data on antiplatelet agents include the following: (1) the role of aspirin in primary prevention has been the subject of recommendations based on the assessment of cardiovascular risk; (2) an increasing number of reports suggest a substantial interindividual variability in the response to antiplatelet agents, and various phenomena of “resistance” to the antiplatelet effects of aspirin and clopidogrel; (3) the benefit/risk profile of currently available glycoprotein IIb/IIIa antagonists is substantially uncertain for patients with acute coronary syndromes who are not routinely scheduled for early revascularization; (4) there is an expanding role for the combination of aspirin and clopidogrel in the long-term management of high-risk patients; and (5) the cardiovascular effects of selective and nonselective cyclooxygenase-2 inhibitors have been the subject of increasing attention.

Section snippets

1.0 Aspirin and Other COX Inhibitors

Aspirin has been thoroughly evaluated as an antiplatelet drug, and it has been found to prevent vascular death by approximately 15% and to prevent nonfatal vascular events by about 30% in a meta-analysis¹⁹ of > 100 randomized trials in high-risk patients.

2.0 Reversible COX Inhibitors

A variety of NSAIDs can inhibit TXA₂-dependent platelet function through competitive, reversible inhibition of platelet COX-1.¹⁵⁹ In general, these drugs, when used at a conventional analgesic dosage, inhibit reversibly platelet COX activity by 70 to 90%. This level of inhibition may be insufficient to block adequately platelet aggregation in vivo, because of the very substantial biosynthetic capacity of human platelets to produce TXA₂.¹⁶⁰¹⁶¹ Population-based observational studies¹⁶²¹⁶³¹⁶⁴ have

3.0 Dipyridamole

Dipyridamole is a pyrimidopyrimidine derivative with vasodilator and antiplatelet properties. The mechanism of action of dipyridamole as an antiplatelet agent has been a subject of controversy.¹⁸² Both the inhibition of cyclic nucleotide phosphodiesterase (the enzyme that degrades cyclic adenosine monophosphate [AMP] to 5′-AMP, resulting in the intraplatelet accumulation of cyclic AMP, a platelet inhibitor) and blockade of the uptake of adenosine (which acts at A₂ receptors for adenosine to

4.0 Thienopyridines

Ticlopidine and clopidogrel are structurally related thienopyridines with platelet-inhibitory properties. Both drugs selectively inhibit ADP-induced platelet aggregation with no direct effects on arachidonic acid metabolism.¹⁸⁵ Although ticlopidine and clopidogrel also can inhibit platelet aggregation induced by collagen and thrombin, these inhibitory effects are abolished by increasing the agonist concentration and, therefore, are likely to reflect the blockade of ADP-mediated amplification of

5.0 Integrin αIIbβ3 (GPIIb/IIIa) Receptor Antagonists

Given the redundance of discrete pathways leading to platelet aggregation, it is not surprising that the clinical efficacy of aspirin, ticlopidine, and clopidogrel is only partial. These drugs, while inhibiting TXA₂-mediated or ADP-mediated platelet aggregation, leave the activity of other platelet agonists such as thrombin largely unaffected. Following recognition that the expression of functionally active integrin αIIbβ3 (GPIIb/IIIa) on the platelet surface is the final common pathway of

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Chest

Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy

Section snippets

1.0 Aspirin and Other COX Inhibitors

2.0 Reversible COX Inhibitors

3.0 Dipyridamole

4.0 Thienopyridines

5.0 Integrin αIIbβ3 (GPIIb/IIIa) Receptor Antagonists

Chest

Am J Cardiol

Am J Cardiol

Lancet

Lancet

J Biol Chem

Thromb Res

Lancet

Lancet

J Neurol Sci

Lancet

Lancet

J Thorac Cardiovasc Surg

Am J Cardiol

Am Heart J

Blood

J Am Coll Cardiol

Thromb Res

Blood

FEBS Lett

Aspirin for the primary prevention of cardiovascular events: recommendation and rationale

Ann Intern Med

Aspirin for primary prevention of coronary events

N Engl J Med

AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update; consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases

Circulation

Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-assessing ultegra) multicenter study

Circulation

Individual variations of platelet inhibition after loading doses of clopidogrel

J Intern Med

Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity

Circulation

Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events

Circulation

Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement

Thromb Haemost

Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction

Circulation

Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function: a flow cytometry study

Eur Heart J

Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial

Lancet

Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation

N Engl J Med

Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial

JAMA

The coxibs, selective inhibitors of cyclooxygenase-2

N Engl J Med

Risk of cardiovascular events associated with selective COX-2 inhibitors

JAMA

Selective cyclooxygenase-2 inhibitors, aspirin and cardiovascular disease: a reappraisal

Arthritis Rheum

Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients

BMJ

The mechanism of the effect of aspirin on human platelets: I. Acetylation of a particulate fraction protein

J Clin Invest

Acetylation of prostaglandin synthase by aspirin

Proc Natl Acad Sci U S A

Inhibition of platelet prostaglandin synthetase by oral aspirin

J Clin Invest

Arachidonate metabolism in vascular disorders

J Clin Invest

The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2synthase

Nat Struct Biol

Differential suppression of thromboxane biosynthesis by indobufen and aspirin in patients with unstable angina

Circulation

Inhibition of prostacyclin and platelet thromboxane A2after low-dose aspirin

N Engl J Med

Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects

J Clin Invest

Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man

J Clin Invest

The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H₂synthase

Inhibition of prostacyclin and platelet thromboxane A₂after low-dose aspirin

Suppression of thromboxane A₂but not systemic prostacyclin by controlled-release aspirin