Newer antiplatelet agents in acute coronary syndromes

doi:10.1053/hj.1999.v138.a102298

American Heart Journal

Volume 138, Issue 6, Supplement, December 1999, Pages s570-s576

https://doi.org/10.1053/hj.1999.v138.a102298 Get rights and content

Abstract

Aspirin is accepted as standard therapy in the management of acute coronary syndromes, but has significant limitations, including intolerance, allergy, resistance, peptic ulceration, and intracranial hemorrhage. Recent trials involving approximately 18,000 patients with unstable angina have investigated the efficacy and safety of glycoprotein IIb/IIIa receptor antagonists, which block the final common pathway of platelet aggregation. The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) trial compared tirofiban with heparin and found a 33% reduction in the composite end point of death, myocardial infarction, or refractory ischemia at 48 hours. In the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial, patients were randomly assigned to receive either heparin, tirofiban, or both. At 7 days, the patients who had received heparin and tirofiban had a 34% lower incidence of the composite end point of death, myocardial infarction, or refractory ischemia than those treated with heparin alone. The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial randomly assigned patients to receive either eptifibatide or placebo. At 30 days, the rate of death or myocardial infarction was reduced by 9.6% in the eptifibatide group compared with the placebo group. In the Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON) trial, patients were randomly assigned to receive either low- or high-dose lamifiban with or without heparin, or heparin alone. There were no differences between the treatment groups at 30 days, but at 6 months the patients randomly assigned to receive low-dose lamifiban had a 23% lower incidence of death or myocardial infarction, perhaps because of long-term passivation of the plaque. Overall, IIb/IIIa antagonists have been shown to be safe and beneficial in patients with unstable angina, particularly during the infusion period. However, there remain a number of unanswered questions concerning treatment with these agents, such as the appropriate dosing regimens and the safety and efficacy of combining intravenous antiplatelet therapy with other agents such as low-molecular-weight heparin, thrombolytic agents, and oral agents. (Am Heart J 1999;138:S570-S576.)

Section snippets

PRISM

The PRISM trial¹⁸ compared tirofiban (Aggrastat), a small, selective IIb/IIIa receptor antagonist, with heparin in the treatment of patients with unstable angina. The 3232 patients enrolled in PRISM had low- to intermediate-risk profiles,²¹ with 75% exhibiting electrocardiographic changes and 32% ST-segment depression. Patients were randomly assigned up to 24 hours after their last ischemic event to receive either tirofiban (0.6 μg/kg/min for 30 minutes followed by 0.15 μg/kg/min) or heparin

PRISM-PLUS

The aim of the PRISM-PLUS trial was to determine the clinical efficacy of tirofiban as part of a comprehensive strategy to prevent acute ischemic events in patients with unstable angina or non-Q-wave myocardial infarction.¹⁹ A total of 1915 patients were randomly assigned in a double-blind manner to 1 of 3 treatment arms consisting of tirofiban alone, tirofiban plus heparin, or heparin alone. All patients received aspirin unless it was contraindicated. The patient population in PRISM-PLUS was

PURSUIT

In the PURSUIT trial,²⁰ eptifibatide (Integrilin), a synthetic cyclic heptapeptide with selective high affinity for the IIb/IIIa receptor, was compared with placebo for the acute treatment of unstable angina and non-Q-wave myocardial infarction. The trial enrolled 10,948 patients who had had an episode of acute chest pain (with electrocardiographic changes or increased creatine kinase MB level) during the previous 24 hours was studied. This trial was an intermediate-risk study, with

PARAGON

The objective of the PARAGON study¹⁷ was to test the benefit of different doses of lamifiban, a nonpeptide IIb/IIIa receptor antagonist, alone and in combination with heparin in patients with unstable angina or nonQ-wave myocardial infarction, in order to select the most promising lamifiban regimen for subsequent evaluation. The study population consisted of 2282 patients from 273 hospitals in 20 countries. All patients received aspirin and were randomly assigned to receive either low-dose

Future directions

These drugs have clearly been shown to be beneficial in reducing myocardial infarction in patients with unstable angina, particularly during the infusion. A number of questions remain concerning intravenous therapy. Which patients should be targeted? What should the target be for platelet inhibition? For how long should the infusion be continued? Does low-molecular-weight heparin add to the benefit, and is this combination safe? How should an invasive strategy be integrated?

The coupling of

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Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study

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Cited by (14)

Synthesis and anti-platelet activity of novel arylsulfonate-acylhydrazone derivatives, designed as antithrombotic candidates
2008, European Journal of Medicinal Chemistry
Citation Excerpt :
This compound can be obtained by regioselective aromatic electrophilic substitution at the C-6 position of 3,4-methylenedioxytoluene (6), which was obtained in ca. 50% overall yield from natural safrole (5), an abundant natural product [12,13]. As previously described [10], simple distillation of sassafras oil generates 5 in 85% yield. Basic catalyzed isomerization of the double bond followed by oxidative cleavage and Wolff–Kishner reduction gave 6 in appropriated yield.
In this work, we describe a new class of promising anti-platelet drug candidates with significant antithrombotic activity in vivo. This new series of compounds was structurally planned by modification of known thrombin inhibitors based on the use of acylhydrazone subunit, as a nonpeptide scaffold, and variations at P1 moiety. Three different families of arylsulfonate–acylhydrazone derivatives were designed. The bioassays indicated the first class of derivatives represented by 4f (LASSBio-693) and 4j (LASSBio-743), which were active in inhibiting the platelet aggregation induced by thrombin. The second class represented by compounds 4e (LASSBio-774) and 4h (LASSBio-480) that selectively inhibit the platelet aggregation involving TXA₂ formation. Finally, the third class of derivatives was identified acting as a novel symbiotic agent able to inhibit the platelet aggregation induced by collagen or AA and by thrombin, represented by compounds 4b (LASSBio-694) and 4g (LASSBio-770).
Measurement and clinical significance of circulating PAPP-A in ACS patients
2007, Clinica Chimica Acta
The rupture of coronary atherosclerotic plaque and subsequent thrombus formation are major events underlying acute coronary syndromes (ACS). Pregnancy associated plasma protein A (PAPP-A), a biomarker of plaque rupture, has been studied in patients with ACS. This review aimed to provide an overview of clinical utility of PAPP-A in ACS patients and analytical issues adhering to immunological PAPP-A measurement.
The literature relating to PAPP-A in ACS, the molecular structure and immunodetection of PAPP-A was reviewed. PubMed was used to search the relevant articles published from 1974 to 2006.
Higher PAPP-A concentrations have been found in patients with ACS than in patients with stable angina and subjects without coronary artery disease. Elevated PAPP-A concentrations have also been shown to associate with adverse cardiac events in ACS patients. The prognostic value of PAPP-A appears to be independent of cardiac troponins. Noteworthy, the PAPP-A form that accounts for increase in ACS is uncomplexed with the proform of eosinophil major basic protein (proMBP). However, PAPP-A assays applied in clinical studies published thus far detect total PAPP-A. Consequently, the clinical value may be non-optimal when total PAPP-A is measured in ACS patients. In addition, the clinical value can also be affected by the analytical factors that exert an effect on the performance of PAPP-A assays.
PAPP-A appears to be a very promising biomarker useful in the clinical management of ACS patients. However, more prospective and interventional studies with carefully established immunoassays are required to validate its clinical utility.
Inhibition of tissue factor-activated platelets by low-molecular-weight heparins and glycoprotein IIb/IIIa receptor antagonist
2001, Thrombosis Research
Thrombotic disorders can lead to vascular distress and platelet activation eventually resulting in the rupture of the lesions where a sizable amount of tissue factor (TF) is generated during the pathogenesis of arterial diseases. Since low-molecular-weight heparins (LMWHs) and platelet glycoprotein (GP) IIb/IIIa inhibitors are clinically used for the management of acute coronary syndrome (ACS), studies were taken to determine the effects of these agents on TF-mediated activation of platelets. Freshly drawn native whole blood (WB) from normal healthy volunteers (n=6) supplemented with a predetermined amount of TF was incubated with equivalent anti-Xa adjusted amounts of various LMWHs at 0.01–1.0 U/ml and tirofiban from 10 to 100 ng/ml. Platelet activation was assessed by measuring the expression of P-selectin (CD62) and the generation of platelet aggregates. At 0.01 U/ml, enoxaparin exhibited a stronger inhibition of TF-induced platelet activation compared to ardeparin and dalteparin. At 0.1 U/ml, these LMWHs produced a comparable inhibition of total P-selectin expression, and at 1.0 U/ml, a marked inhibition was noted. Since enoxaparin produced the best concentration-dependent inhibition of P-selectin expression (saline: 76±10% vs. 1.0 U/ml enoxaparin: 18±7%; P<.02) and platelet aggregate formation (saline: 63±7% vs. 1.0 U/ml enoxaparin: 35±6%, P<.035), this agent was used for additional studies. Unlike enoxaparin, tirofiban produced a weak concentration-dependent inhibition of platelet activation. At 100 ng/ml, tirofiban produced a 40% inhibition of P-selectin expression and about 60% inhibition of platelet aggregate formation. To elucidate the potential interaction between tirofiban and enoxaparin, the effect of 10 and 100 ng/ml tirofiban was studied with enoxaparin-supplemented WB in a 0.01–1.0 U/ml range. Additive effects between these two agents were noted only at lower concentrations. Thus, at therapeutic concentrations (0.8–1.2 U/ml), enoxaparin itself was capable of inhibiting TF-mediated activation of platelets to >70%; whereas tirofiban failed to produce such concentration-dependent inhibition. This suggests that the simultaneous administration of GPIIb/IIIa receptor antagonist with LMWH may not have any added benefit in the clinical management of patients with ACS.
Medical therapy of unstable angina and non-Q-wave myocardial infarction
2000, American Journal of Cardiology
Citation Excerpt :
Treatment with low-molecular-weight heparin for >1 week was no better than placebo, but was associated with an increased risk of major bleeding.45 Platelet receptor blockers represent a therapeutic breakthrough.47–49 The IIb/IIIa agents interfere with the final common pathway of platelet aggregation and act at multiple sites of receptor-ligand binding, including fibrinogen and von Willebrand factor and other compounds that result in platelet adherence and the subsequent development of a platelet plug or platelet-fibrin rich thrombus.
Management of acute coronary syndromes has been the focus of increased interest in recent years. This has come about with the recognition that the majority of patients who present to the hospital with chest pain have unstable angina or non–Q-wave myocardial infarction (MI). Further, sensitive biochemical markers of myocardial necrosis, such as troponin and creatine kinase, have improved early diagnosis. Markers of inflammation such as C-reactive protein (CRP), although not in wide clinical practice, may provide an early and important marker of prognosis. The current approach to management of acute coronary syndromes is careful risk stratification so as to select appropriate medical therapies and to guide the clinician to appropriate interventions such as angiography or percutaneous coronary intervention (PCI). Established therapies such as aspirin, heparin, intravenous nitrates, and, in selected patients, β blockers or calcium antagonists, are being used concomitantly with, or are being supplanted by, newer therapies such as low-molecular-weight heparins and glycoprotein IIb/IIIa inhibitors. The role of hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) in patients with acute coronary syndromes is being investigated and shows promise.
A preliminary investigation of Mesoionic Xanthine analogues as inhibitors of platelet aggregation
2000, Bioorganic and Medicinal Chemistry
Citation Excerpt :
Ischemic stroke resulting from the transient or permanent reduction in cerebral blood is in most cases caused by the occlusion of a cerebral artery by either embolism or local thrombosis. The utility of anti-platelet agents in the treatment of cardiovascular disorders and stroke has recently been reviewed.1 A large number of agents such as papaverine2 and the methyl xanthine derivatives theophylline (1) and 1-isobutyl-3-methylxanthine (IBMX; 2) inhibit platelet aggregation through their activity as phosphodiesterase inhibitors.3,4
A series of mesoionic xanthines (e.g. mesoionic thiazolopyrimidines, 3, and thiadiazolopyrimidines, 5) and related analogues were examined as inhibitors of human platelet aggregation. Appropriately substituted compounds were found to fully inhibit platelet aggregation, and anhydro-(6-ethyl-8-isopentyl-7-oxo-5-hydroxy-1,3,4-thiadiazolo[3,2-a]pyrimidinium hydroxide) (5b) was 40 times more potent than the structurally related xanthine theophylline (1). Gel filtration studies suggest that compound 5b irreversibly inhibits aggregation and this might be due to its ability to act as a latent acylation agent.
Inflammation, hormones, the blood and the heart; Are cardiologists learning to be internists again?
2000, International Journal of Cardiology

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Newer antiplatelet agents in acute coronary syndromes

Abstract

Section snippets

PRISM

PRISM-PLUS

PURSUIT

PARAGON

Future directions

Lancet

Thromb Res

Prev Med

Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2

Lancet

Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: results of a Veterans Administration cooperative study

N Engl J Med

Collaborative overview of randomised trials of antiplatelet therapy. I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients

BMJ

Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men

N Engl J Med

The gastrointestinal toxicity of aspirin: an overview of randomised controlled trials

Br J Clin Pharmacol

Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty

N Engl J Med

Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization

N Engl J Med

Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study

Lancet