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The Role of Colchicine in Acute Coronary Syndromes.
Vaidya, K, Martínez, G, Patel, S
Clinical therapeutics. 2019;(1):11-20
Abstract
PURPOSE Because inflammation is a key process implicated in the pathogenesis of atherosclerosis at all stages, including plaque formation, progression, instability, and rupture, and because colchicine has unique anti-inflammatory properties, this review article summarizes the pathophysiologic mechanisms underpinning inflammation in atherosclerosis and acute coronary syndrome (ACS), outlines anti-inflammatory therapeutic approaches that have been tested thus far, and evaluates the evidence supporting the potential role of colchicine in improving outcomes and reducing cardiovascular morbidity and mortality in patients after ACS. METHODS PubMed was searched for publications on colchicine and ACSs and atherosclerosis, and www.clinicaltrials.org was searched for completed and ongoing trials of colchicine use in ACSs. FINDINGS Despite contemporary optimal medical therapy, patients remain at a high risk of future events after an ACS because of residual inflammation at culprit and nonculprit sites. Several attempts have been made to address this with targeted anti-inflammatory therapies, but until the recent promising results of canakinumab (an anti-interleukin-1β monoclonal antibody), most have failed to find any prognostic benefit in large clinical trials with hard end points. The pathogenic role of neutrophils and monocytes in atheroinflammation is well established, and a fundamental component in this process is the activation of the NOD-like receptor protein 3 inflammasome, a cytosolic multiprotein complex that, when activated by a stress signal such as cholesterol crystals, drives caspase-1-dependent release of 2 key proinflammatory cytokines, which are predictive of future adverse cardiovascular events: interleukin-1β and interleukin-18. Colchicine is a widely available, inexpensive, and well-tolerated medication that, among several anti-inflammatory mechanisms of action, inhibits activation of the NOD-like receptor protein 3 inflammasome complex. A seminal trial has found the beneficial properties of colchicine in reducing adverse cardiovascular events in the stable coronary artery disease population. IMPLICATIONS Despite promising results in small prospective observational and randomized trials, there is a need for more evidence evaluating the role of colchicine as a secondary preventive agent after ACSs.
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Low-Density Lipoprotein Cholesterol After an Acute Coronary Syndrome: How Low to Go?
Qamar, A, Libby, P
Current cardiology reports. 2019;(8):77
Abstract
PURPOSE OF REVIEW Recent advances in low-density lipoprotein cholesterol (LDL-C) lowering therapy have now enabled reducing LDL-C safely to very low levels. This review summarizes evidence from recent randomized clinical trials of intensive LDL-C lowering in patients with acute coronary syndrome (ACS) and provides a practical approach for LDL-C lowering to reduce the risk of recurrent ischemic events in this population. RECENT FINDINGS The risk of atherothrombotic events falls linearly with LDL-C level extending to very low achieved LDL-C levels (< 10 mg/dL) without apparent safety concerns. The addition of ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (i.e., evolocumab or alirocumab) to statin therapy lowers LDL-C to very low levels (≤ 30-50 mg/dL) with safety under the conditions studied and reduces the risk of recurrent cardiovascular events in patients with atherosclerotic cardiovascular disease. Current data support LDL-C lowering to levels below 70 mg/dL in patients post-ACS. Combination of high-intensity statins, ezetimibe, and if needed PCSK9 inhibitors merits consideration in such patients with ACS to optimize outcomes.
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Development of New Antithrombotic Regimens for Patients with Acute Coronary Syndrome.
George, S, Onwordi, ENC, Gamal, A, Zaman, A
Clinical drug investigation. 2019;(6):495-502
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Abstract
Patients with acute coronary syndrome (ACS) require long-term antithrombotic intervention to reduce the risk of further ischemic events; dual antiplatelet therapy with a P2Y12 inhibitor and acetylsalicylic acid (ASA) is the current standard of care. However, pivotal clinical trials report that patients receiving this treatment have a residual risk of approximately 10% for further ischemic events. The development of non-vitamin K antagonist oral anticoagulants (NOACs) has renewed interest in a 'dual pathway' strategy, targeting both the coagulation cascade and platelet component of thrombus formation. In the phase III ATLAS ACS 2 TIMI 51 trial, a 'triple therapy' approach (NOAC plus dual antiplatelet therapy) showed reduced ischemic events with rivaroxaban 2.5 mg twice daily, albeit at an increased risk of bleeding. Two studies have investigated the role of NOACs in combination with a P2Y12 inhibitor, with or without ASA, in reducing bleeding risk in patients with atrial fibrillation undergoing percutaneous coronary intervention; two further studies are underway. Although these trials will help to inform optimal treatment protocols for secondary prevention of ACS, an individualized approach to treatment will be needed, taking account of the high frequency of co-morbid conditions found in this patient population.
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[Is it necessary to prescribe oral anticoagulant therapy for paroxysmal atrial fibrillation during acute coronary syndrome, and for how long?].
Visconti, LO, Ferlini, M, Rordorf, R, Savastano, S
Giornale italiano di cardiologia (2006). 2019;(6):361-366
Abstract
There is limited knowledge on the occurrence of new-onset, transient atrial fibrillation during acute coronary syndromes; compared with patients in sinus rhythm, patients with paroxysmal atrial fibrillation have an increased risk of in-hospital and long-term recurrence of the arrhythmia, all-cause mortality and ischemic stroke. There is a lack of prospective, randomized studies on anticoagulant therapy modalities in this specific subset of patients. In the absence of a widely accepted anticoagulation algorithm, the international guidelines for the management of atrial fibrillation recommend to initiate anticoagulant treatment during acute coronary syndromes estimating in each patient the thrombotic and bleeding risk using the CHA2DS2-VASc and HAS-BLED scores, respectively. In the last updates of the guidelines for the management of atrial fibrillation, non-vitamin K oral anticoagulants are recommended over warfarin and, in patients with atrial fibrillation who have undergone percutaneous coronary intervention with stenting for acute coronary syndromes, dual antiplatelet therapy with rivaroxaban or dabigatran and clopidogrel is reasonable to reduce the risk of bleeding compared with triple therapy. Neither scientific evidences nor recommendations from the guidelines are available about the duration of anticoagulant therapy in case of paroxysmal atrial fibrillation during acute coronary syndromes.
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Bivalirudin during percutaneous coronary intervention in acute coronary syndromes.
Laine, M, Lemesle, G, Dabry, T, Panagides, V, Peyrol, M, Paganelli, F, Bonello, L
Expert opinion on pharmacotherapy. 2019;(3):295-304
Abstract
INTRODUCTION Anticoagulant therapy is critical to prevent ischemic recurrences and complications in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Unfractionated heparin (UFH), an injectable anticoagulant has several limitations: lack of predictability of its biological efficacy, platelets activation, heparin-induced thrombopenia and bleedings. Bivalirudin, a synthetic direct thrombin inhibitor has biological properties that promised better clinical outcome in ACS patients undergoing PCI. AREAS COVERED The present review aimed to summarize two decades of randomized clinical trials that compared bivalirudin to UFH in ACS patients treated with PCI. Early trials highlighted a reduction of bleedings with bivalirudin compared to UFH in combination with glycoprotein inhibitors (GPI). Recent studies questioned this reduction given that GPI are less and less used during PCI. Further, trials raised concerns about the risk of stent thrombosis in patients treated with bivalirudin. In light of this data, bivalirudin has been downgraded in international guidelines and appears as a second line anticoagulant agent after UFH. EXPERT OPINION The highly questioned reduction of bleedings under bivalirudin and the potential risk of stent thrombosis are unwarranted. Based on clinical trials, UFH has no equivalent in terms of anticoagulation in ACS patients undergoing PCI.
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Anticoagulation in Acute Coronary Syndrome: Review of Major Therapeutic Advances.
Pop, C, Matei, C, Petris, A
American journal of therapeutics. 2019;(2):e184-e197
Abstract
BACKGROUND In patients with acute coronary syndrome (ACS), a persistent hypercoagulable state has been demonstrated and antithrombin therapy in addition to platelet inhibition has been proposed. AREAS OF UNCERTAINTY Vitamin K antagonists (VKAs) were used as oral anticoagulant (OAC) therapy and produced mixed results whereas trials are still ongoing with non-vitamin K OACs (NOACs). DATA SOURCES A literature search regarding benefits and risks of different OAC therapies in ACS was conducted through MEDLINE and EMBASE (last 20 years until September 2018). THERAPEUTIC ADVANCES Patients receiving dual antiplatelet therapy (DAPT) in combination with NOAC are to be considered at high bleeding risk. Rivaroxaban 2.5 mg BID in triple therapy with DAPT, rivaroxaban 15 mg, or dabigatran 110/150 mg BID in dual therapy with P2Y12 inhibitor (mainly clopidogrel) is safer in terms of bleeding risk than triple therapy with VKA plus DAPT. The reduction in ischemic events by NOACs was most promising when added to single antiplatelet therapy. Ongoing trials with apixaban and edoxaban could clarify whether dual therapy NOACs with P2Y12 inhibitor sufficiently protect against stent thrombosis or myocardial infarction and are safer in terms of bleeding risk than a dual therapy with a VKA and clopidogrel. In the absence of randomized trials, it is unknown whether dual therapy with NOAC and aspirin could be an alternative to NOAC and a P2Y12 inhibitor. Thus, the overall benefit of adding NOAC to antiplatelet treatment after ACS in patients without clear indication for long-term OAC is still unknown. CONCLUSIONS Different OACs have been tested as antithrombotic therapy after ACS in combination with single or DAPT and led to a modest reduction in ischemic events. Further studies evaluating NOACs in combination with single antiplatelet therapy or shorter duration of triple antithrombotic therapy are warranted.
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Benefits and Risks of Anticoagulation in Acute Coronary Syndrome.
Pop, C, Matei, C
American journal of therapeutics. 2019;(2):e198-e207
Abstract
BACKGROUND Both antiplatelets and anticoagulants are necessary in the management of acute coronary syndrome (ACS), although the exact proportion of antithrombotic effect that each drug and class should ideally provide remains a matter of ongoing study. AREA OF UNCERTAINTY Defining the best combination between the antiplatelet agents and oral anticoagulants (OACs) can be challenging. The choice is particularly important for special categories of patients with ACS who have an indication of a long-term OAC. DATA SOURCES A literature search regarding benefits and risks of anticoagulation in ACS was conducted through MEDLINE and EMBASE (past 20 years until September 2018). THERAPEUTIC ADVANCES Many patients with ACS have an indication for long-term OACs. Those receiving dual antiplatelet therapy and anticoagulants are considered to be at a high bleeding risk. The addition of a vitamin K antagonist (VKA) imposes a target international normalized ratio of 2.0-3.0. When non-VKA oral anticoagulants are used, the lowest effective tested dose for stroke prevention should be applied. For most patients, triple therapy in the form of an OAC plus dual antiplatelet therapy [aspirin and P2Y12 inhibitors (usually clopidogrel)] should be considered for 3-6 months. Later, dual therapy (OAC plus aspirin or clopidogrel) should be considered for an additional 6 months. After 1 year, it is recommended that only the OAC is maintained. In cases of very high bleeding risk, triple therapy can be reduced to 1 month after ACS, continuing on dual therapy up to 1 year, and thereafter only anticoagulation. In general, the bleeding risk seems to be lower with non-VKA oral anticoagulants than VKA plus antiplatelet combination. CONCLUSIONS Many risk factors for ischemic events and bleeding overlap. The clinician's challenges include monitoring patients' adherence and global assessment of the antithrombotic effect that incorporates antiplatelet and anticoagulant effects.
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Clinical Pharmacokinetics and Pharmacodynamics of Dalcetrapib.
Black, DM, Bentley, D, Chapel, S, Lee, J, Briggs, E, Heinonen, T
Clinical pharmacokinetics. 2018;(11):1359-1367
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Abstract
The cholesterol ester transfer protein (CETP) inhibitor dalcetrapib has been under evaluation for its potential to prevent cardiovascular (CV) events for almost two decades. The current clinical development program, representing new advances in precision medicine and focused on a genetically defined population with acute coronary syndrome (ACS), is supported by a large body of pharmacokinetic and pharmacodynamic data as well as substantial clinical experience in over 13,000 patients and volunteers. Dalcetrapib treatment of 600 mg/day produces significant inhibition of CETP activity, and has been utilized in phase II and III studies, including CV endpoint trials. Numerous studies have investigated the interactions between dalcetrapib and most drugs commonly prescribed to CV patients and have not demonstrated any clinically significant effects. Evaluations in patients with renal and hepatic impairment demonstrate a greater exposure to dalcetrapib than in the non-impaired population, but long-term clinical studies including patients with mild to moderate hepatic and renal dysfunction demonstrate no increase in adverse events. Safety pharmacology and toxicology studies as well as the clinical safety experience support the continuing development of dalcetrapib as an adjunct to 'standard of care' for the ACS population. This article provides a full review of the pharmacokinetics, as well as pharmacodynamics and pharmacology, of dalcetrapib in the context of a large clinical program.
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Management of cardiogenic shock complicating myocardial infarction.
Mebazaa, A, Combes, A, van Diepen, S, Hollinger, A, Katz, JN, Landoni, G, Hajjar, LA, Lassus, J, Lebreton, G, Montalescot, G, et al
Intensive care medicine. 2018;(6):760-773
Abstract
Up to 10% of acute coronary syndromes are complicated by cardiogenic shock (CS) with contemporary mortality rates of 40-50%. The extent of ischemic myocardium has a profound impact on the initial, in-hospital, and post-discharge management and prognosis in this patient population. Individualized patient risk assessment plays an important role in determining appropriate revascularization, drug treatment with inotropes and vasopressors, mechanical circulatory support, intensive care support of other organ systems, hospital level of care triage, and allocation of clinical resources. This review will outline the underlying causes and diagnostic criteria, pathophysiology, and treatment of CS complicating acute coronary syndromes with a focus on (a) potential therapeutic issues from the perspective an interventional cardiologist, an emergency physician, and an intensive care physician, (b) the type of revascularization, and (c) new therapeutic advancements in pharmacologic and mechanical percutaneous circulatory support.
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[Antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome].
Tubaro, M, Falaschi, G, Colivicchi, F
Giornale italiano di cardiologia (2006). 2018;(10):552-562
Abstract
Antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome is a difficult challenge because of the need of taking into consideration three different issues: the cardiac ischemic risk related to coronary artery disease and its treatment with angioplasty and stenting; the thromboembolic risk associated with atrial fibrillation; and the hemorrhagic risk related to the combined use of antiplatelet therapy (with one or two agents) and oral anticoagulant therapy.Data from many trials and meta-analyses currently support a combination therapy with oral anticoagulants (vitamin K antagonists or direct oral anticoagulants) and antiplatelet agents (aspirin and clopidogrel in dual or single antiplatelet therapy).Recently completed and ongoing trials aim to tackle the still controversial issues of this therapy: the choice of the anticoagulant agent and its dosage; the choice of the antiplatelet agent; the use of single or dual antiplatelet therapy and its duration.