Contemporary Antiplatelet Pharmacotherapy in the Management of Acute Coronary Syndromes

Purpose of review

Antiplatelet therapies are pivotal treatments in the management of acute coronary syndrome (ACS) with or without revascularization. In recent years, the use of P2Y12 antagonists prior to catheterization, so-called pretreatment, has been questioned, particularly in patients who may be at higher bleeding risks. The purpose of this review was to evaluate the current literature on contemporary and novel antiplatelet therapy in the pretreatment and treatment of ACS.

Recent findings

The P2Y12 receptor antagonists are associated with substantial reductions in morbidity and mortality for all types of ACS but only clopidogrel and ticagrelor have sufficient evidence for use in the pretreatment setting. The data regarding prasugrel support the use in patients undergoing percutaneous intervention (PCI). The glycoprotein IIa/IIIb antagonists are the most optimal for use in high-risk ACS as an adjuvant therapy during and after PCI.

Summary

In summary, although all P2Y12 antagonists have morbidity- and mortality-reducing effects in ACS, only clopidogrel and ticagrelor have sufficient evidence in the pretreatment setting. Newer antiplatelet therapies, most notably the protease-activated receptor 1 antagonists, are evolving and promising but are associated with greater bleeding risks.

     

Antiplatelet Therapy in Acute Coronary Syndromes without Persistent ST-Segment Elevation

The treatment of ACS without persistent ST-segment elevation is evolving. Antiplatelet and antithrombin therapy forms the mainstay of medical management. The antiplatelet agents studied can be pharmacologically classified as GP IIb/IIIa receptor antagonists, ADP receptor antagonists, thromboxane inhibitors, and cyclo-oxgenase inhibitors. While aspirin, a cyclo-oxygenase inhibitor, is well entrenched in the treatment (and thus will not be reviewed here), other drugs have been subjects of intense study and large-scale clinical trials in the last decade. In this article we will explore the rationale of using antiplatelet agents, describe the platelet biology and mechanism of action of these drugs, narrate the major phase III trials, and attempt to draw conclusions from the clinical experience. Important trials which have been presented at principal international scientific meetings and which have not yet been published are also cited.     

Acute Coronary Syndromes

Acute coronary syndromes represent a broad spectrum of ischemic myocardial events including unstable angina, non-ST elevation myocardial infarction and acute ST elevation myocardial infarction, which are associated with high morbidity and mortality. They constitute the most frequent cause of hospital admission related to cardiac disease. Early diagnosis and risk stratification are essential for initiation of optimal medical and invasive management. Therapeutic measures comprise aggressive antiplatelet, antithrombotic, and anti-ischemic agents. In addition, patients with high-risk features, notably positive troponin, ST segment changes and diabetes, benefit from an early invasive as compared to a conservative strategy. Importantly, lifestyle interventions, modification of the risk factor profile, and long-term medical treatment are of pivotal importance in reducing the long-term risk of recurrence.     

Antiplatelet Strategies: Evaluating Their Current Role in the Setting of Acute Coronary Syndromes

Numerous clinical trials have established the value of antiplatelet therapies for acute coronary syndromes (ACS). Aspirin (ASA), thienopyridines (i.e., clopidogrel and ticlopidine) and GP IIb/IIIa antagonists comprise the major classes of antiplatelet therapies demonstrated to be of benefit in the treatment of ACS and for the prevention of thrombotic complications of percutaneous coronary intervention (PCI). Clopidogrel is beneficial when administered before and after PCI, and is more effective when combined with either ASA or GP IIb/IIIa inhibitors in preventing post‐PCI complications, coronary subacute stent thrombosis, and thrombotic events in general. It is currently unclear whether a higher loading dose of clopidogrel (600 mg) is better than the standard loading dose (300 mg), how long therapy should continue, and which maintenance dose is optimal. The role of the GP IIb/IIIa antagonists in ACS is less clear due to conflicting data from several studies with different patient populations. Currently, it appears that the use of GP IIb/IIIa antagonists might be most beneficial in high‐risk ACS patients scheduled to undergo PCI, who demonstrate non‐ST‐segment elevation myocardial infarction and elevated troponin levels. Copyright © 2008 Wiley Periodicals, Inc.     

Thrombogenesis in Acute Coronary Syndromes

It is well-established that intracoronary thrombosis, which may be associated with plaque fissure and enhanced coronary vasoconstriction, is the immediate cause of a sudden impairment of regional myocardial perfusion, which is transient in unstable angina and is, eventually, irreversible in acute myocardial infarction. It is also well-known that increased platelet reactivity, increased procoagulant activity, and reduced endogenous fibrinolysis are risk factors for acute coronary events. Nevertheless, the primary causes responsible for sudden intracoronary thrombosis and for coronary vasoconstriction causing acute coronary syndromes are still largely speculative. Recent studies have shown activated inflammatory cells both in the coronary arterial wall and in the systemic circulation of patients with unstable angina. Furthermore, the intensity of the inflammatory response is correlated with an adverse prognosis. This inflammatory component may have important pathogenetic and prognostic roles because an outburst of inflammatory cytokines has the potential to increase the sensitivity of platelets to agonists, to turn the anticoagulant and vasodilator physiological properties of the endothelium into procoagulant and vasoconstrictor properties, and to cause plaque fissure by the release of proteolytic enzymes.     

Apixaban in Acute Coronary Syndromes

Apixaban is an orally active, selective, direct‐acting, reversible inhibitor of factor Xa that is under evaluation for the management of acute coronary syndromes (ACS). This article critically reviews the rationale and evidence for the use of anticoagulants in the long‐term management of ACS, preliminary data for apixaban from the phase 2 apixaban for prevention of acute ischemic and safety events (APPRAISE) trial, and the potential future role of apixaban for this indication.     

rFVIIai in Acute Coronary Syndromes

Following vessel wall injury, tissue factor (TF) is exposed and forms complexes with already activated factor VII (FVIIa) present in the circulating blood, thereby initiating the hemostatic process. After the first FXa is formed, the TF pathway inhibitor (TFPI) forms a complex with FXa, and a quaternary complex is formed, TF/FVIIa/ FXa/TFPI, which inhibits the first step of the hemostatic pathway. Recombinant activated FVII (rFVIIa) has been developed for use as a hemostatic agent (NovoNordisk A/S, Denmark). Active site-inactivated rFVIIa (rFVIIai) has also been prepared and was shown to have a faster association to and a slower dissociation from TF than rFVIIa, resulting in a lower calculated Kd of rFVIIai compared with rFVIIa. In various animal models rFVIIai has been demonstrated to prevent or diminish immediate thrombus formation at the site of vessel wall injury (athroplasty or other forms of mechanical injury) as well as the development of long-term intima thickening. The inflammatory response following endotoxin-induced sepsis was shown to decrease after administration of rFVIIai. Also, survival increased in the rFVIIai-treated animals in this study. In addition, ischemia-reperfusion injury was mitigated by rFVIIai. In a limited number of patients undergoing percutaneous transluminal coronary angioplasty (PTCA), rFVIIai was observed to allow PTCA to be performed at lower doses of heparin than what has been reported previously.     

Coronary Stenting Without Predilatation in Acute Coronary Syndromes

We report on the procedural outcome in 30 patients with acute coronary syndromes in whom stent implantation was attempted without predilatation. Elective stent implantation in infarct related coronary arteries after myocardial infarction might be superior to agioptasty alone. We retrospectively analyzed the result from 88 patients who had stent implantation for myocardial infarction or unstable angina. In 30 of these patients we attempted to implant a stem without predilating the vessel. Successful stent deployment was possible in 26 (87%). In four patients where it was not possible to cross the lesion, we could withdraw the stent to predilate the lesion. We did not attempt direct stent implantation if the lesion was calcified, long, involved major side branches or a tortuous proximal segment, or where the length of the lesion and diameter of the distal vessel could not be measured. A low profile, premounted stent was used. Procedural success was 100% in the group of 30 patients with direct stent implantation— not significantly different from the 93% success in the group of 58 patients whose lesions were predilated first but had more complex lesions. The incidence of complications did not differ significantly between the two groups and no instances of stent loss or displacement occurred in the direct implantation group. Stent implantation without predilatation is feasible and not associated with a higher incidence of complications, provided lesions that allow easy positioning of the stent are selected. It can shorten the procedure and duration of ischemic occlusion of the vessel, which would be of particular advantage in unstable patients or where a large area of myocardium is jeopardized.     

Coronary Atherosclerotic Precursors of Acute Coronary Syndromes

Background

The association of atherosclerotic features with first acute coronary syndromes (ACS) has not accounted for plaque burden.

Risk Stratification in Acute Coronary Syndromes

Accurate and readily available systems for risk stratification and a wide array of antithrombotic agents, on top of classical anti-ischemic drugs, provide the noninvasive cardiologist admitting the patient in the CCU with an effective and reliable armamentarium for the safe management of most patients with ACS. From the interventionalist’s perspective, the immediate knowledge of the coronary anatomy yields the most valuable information to address the most appropriate treatment. The sooner angiography is performed the higher the benefit for patients at moderate to high risk, but if performed by expert teams and with the correct use of modern drugs and devices, the invasive approach has the potential to reduce costs and length of hospital stay also in low-risk patients. Although still some reluctance remains to equalize treatment strategies for patients with STEMI to those with NSTEMI, such differences will likely disappear in the near future with upcoming new evidence. Cardiac surgery may represent a life-saving alternative for patients presenting with NSTEMI evolving in cardiogenic shock or with mechanical complications, or in patients unsuitable for PCI or with failed PCI attempts. In stabilized conditions after the treatment of the culprit lesion, patients with severe multivessel disease may benefit from cardiac surgery to complete myocardial revascularization. Indications for CABG in this setting should be evaluated in the context of a local “heart team” or through prespecified protocols in centers without cardiac surgery on site.     

Reconstituted HDL in Acute Coronary Syndromes

Objectives: The strong inverse relationship between plasma high‐density lipoprotein (HDL)‐cholesterol and atherosclerotic cardiovascular disease provides the epidemiological basis that HDL is atheroprotective. Since HDL enhances cholesterol efflux and exhibits potent antiinflammatory properties, the aim of the present study was to investigate whether infusion of reconstituted HDL (rHDL) impacts on vascular function, a well‐established surrogate of atherosclerotic vascular disease, as well as markers of inflammation and oxidative stress in patients with acute coronary syndromes (ACS). Methods: Twenty‐nine patients with ACS were randomized to double‐blind treatment with rHDL or albumin. Endothelium‐dependent and independent vasodilatation to intraarterial acetylcholine and sodium nitroprusside were measured by forearm venous occlusion plethysmography. In addition, oxidized LDL and high‐sensitivity C‐reactive protein were determined as markers of oxidative stress and vascular inflammation. Results: rHDL infusion increased plasma HDL (P < 0.0001) and decreased LDL (P < 0.0001). Oxidized LDL (P= 0.11), high‐sensitivity C‐reactive protein (P= 0.12) and the response to endothelium‐dependent and ‐independent vasodilatators remained unchanged after rHDL compared to albumin infusion (14.9 ± 9.2 versus 14.5 ± 12.4, P= 0.93 and 12.8 ± 7.1 versus 13.2 ± 9.6, P= 0.27, respectively). Conclusions: An increase of HDL and a reduction of LDL notwithstanding, human rHDL did not improve vascular function in patients with ACS thus further challenging the clinical benefit of interventions, which rapidly raise HDL in ACS, particularly with the infusion of reconstituted HDL.     

Elderly Patients with Acute Coronary Syndromes: Higher Risk and Greater Benefit from Antithrombotic and Interventional Therapies

In elderly patients with acute coronary syndromes, outcomes are poorer than in younger patients and, disappointingly, some therapies—including thrombolysis for ST elevation myocardial infarction—confer less benefit than in younger patients. In contrast, in unstable angina and non-ST elevation myocardial infarction, the elderly appear to derive greater relative and absolute benefit from the newer, more potent antithrombotic therapies. In both the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events and Thrombolysis in Myocardial Infarction 11B trials, the low molecular weight heparin enoxaparin, compared with unfractionated heparin, appeared to have greater relative and absolute benefit in patients aged 65 years and older, as compared with younger patients. For the glycoprotein IIb/IIIa inhibitors, an equivalent relative benefit has been observed, which translated into a greater absolute benefit in older vs. younger patients. Similarly, in the FRagmin and Fast Revascularisation during InStability in Coronary Artery Disease II trial, patients 65 years and older derived significantly greater benefit from an invasive than from a conservative strategy, whereas there was no difference in outcome by strategy in younger patients. A similar trend was observed in the Thrombolysis in Myocardial Infarction IIIB trial. Thus, in unstable angina and non-ST elevation myocardial infarction, elderly patients are at higher risk and appear to derive particular benefit from the more aggressive antithrombotic and interventional therapies.     

Novel Antiplatelet Therapies

Advances in antiplatelet therapy have significantly improved outcomes in patients with ischemic heart disease. Thienopyridines remain a cornerstone of therapy along with aspirin. Recently, concerns have been raised about the use of clopidogrel due to its pharmacokinetic and pharmacogenetic interpatient variability. A third-generation thienopyridine, prasugrel, overcomes some of these problems by improving inhibition of platelet aggregation, but increasing the risk of peri-procedural bleeding. Other novel antiplatelet agents, such as ticagrelor, have shown improved efficacy in recent trials and require further investigations. The field of pharmacotherapy continues to rapidly evolve as newer agents, such as thrombin receptor antagonists, along with older agents, such as cilostazol and glycoprotein IIb/IIIa inhibitors, are being explored.