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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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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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Current status of lipid management in acute coronary syndrome.
Fujisue, K, Tsujita, K
Journal of cardiology. 2017;(2):101-106
Abstract
The development of coronary revascularization has dramatically improved early cardiovascular outcomes in patients with acute coronary syndrome (ACS). However, patients who have experienced myocardial infarction (MI) are at high risk of recurrence of cardiovascular events compared with those who are healthy or have stable coronary artery disease. Acute coronary events induce further inflammatory responses and plaque vulnerability in either a coronary culprit or whole vessels. The majority of data have supported the importance of coronary risk management to prevent secondary events. Dyslipidemia is common and one of the therapeutic targets in patients with ACS. Statins can reduce coronary plaque burden and lower the risk of cardiovascular death, recurrent MI, stroke, and coronary revascularization in patients with ACS. Growing evidence from clinical trials and meta-analyses supports early, intensive, and continuous therapy with statins in patients with ACS. Statins are accepted worldwide as the first-line lipid-lowering therapy as guidelines recommend. However, some patients do not reach the target level of low-density lipoprotein cholesterol by statins alone or are contra-indicated for statins. Recently, several clinical trials showed the further benefit of ezetimibe combined with statins on cardiovascular outcomes and coronary plaque regression in patients with ACS. In addition, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, novel and powerful lipid-lowering agents, have been developed and used in clinical settings. In this review, we summarize the present statin therapy, and refer to ezetimibe and PCSK9 as novel or additional non-statin strategies in the management of ACS.
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Utilization of and Adherence to Guideline-Recommended Lipid-Lowering Therapy After Acute Coronary Syndrome: Opportunities for Improvement.
Hirsh, BJ, Smilowitz, NR, Rosenson, RS, Fuster, V, Sperling, LS
Journal of the American College of Cardiology. 2015;(2):184-92
Abstract
In addition to aggressive lifestyle and nonlipid risk factor modification, statin therapy improves cardiovascular disease outcomes following acute coronary syndromes. Despite established benefits of treatment, contemporary registries reveal substantial underutilization of and nonadherence to statin therapy for secondary prevention. In randomized controlled trials investigating statin therapy, including moderate-intensity statin plus ezetimibe therapy, rates of nonadherence are reported in up to 40% of subjects. Durable strategies to address gaps in lipid lowering for secondary prevention are essential to maximize reduction in cardiovascular disease risk.
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Kounis syndrome secondary to amoxicillin/clavulanic acid administration: a case report and review of literature.
Ralapanawa, DM, Kularatne, SA
BMC research notes. 2015;:97
Abstract
BACKGROUND Kounis syndrome is the concurrence of acute coronary syndromes with mast cells activation induced by hypersensitivity and anaphylactoid insults and is increasingly encountered in clinical practice. The main pathophysiological mechanism is vasospasm of the epicardial coronary arteries due to increased inflammatory mediators that are released during a hypersensitivity reaction. CASE PRESENTATION A 74-year -old Sinhalese man with diabetes mellitus was admitted with four day history of high fever with chills and rigors. His urine analysis and blood investigations revealed evidence of urinary tract infection. After excluding allergic conditions, he was given amoxicillin/clavulanic acid intravenously. About 20 minutes after the first dose he felt severe itching of body, nausea , dizziness and sever retrosternal chest pain. Urgent electrocardiogram was taken and it showed widespread ST segment elevations. He was treated for anaphylactic shock as well as acute coronary syndrome and was able to be discharged within a few days. CONCLUSION This case highlights the occurrence of acute coronary syndrome following drug induced anaphylaxis. Acute coronary syndrome of this nature may be completely atypical and overlooked. Kounis syndrome should be borne in mind in the event of anaphylactic episode wherein the electrocardiogram becomes essential.
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New antithrombotics for secondary prevention of acute coronary syndrome.
Goto, S, Tomita, A
Clinical cardiology. 2014;(3):178-87
Abstract
Patients with acute coronary syndrome (ACS) usually receive acetylsalicylic acid plus an adenosine diphosphate (ADP) receptor inhibitor to reduce the long-term risk of recurrent events. However, patients receiving standard antiplatelet prophylaxis still face a substantial risk of recurrent events. Strategies involving 3 antithrombotic agents with different modes of action have now been tested. In Thrombin Receptor Antagonists for Clinical Event Reduction (TRA-CER), compared with standard care alone, bleeding complications including intracranial hemorrhage (ICH) were increased with the addition of vorapaxar, without efficacy benefit. In Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis (TRA 2°P-TIMI 50), the addition of vorapaxar reduced recurrent events compared with standard care in stable patients with prior myocardial infarction. This study was terminated early in patients with prior stroke owing to excess ICH, though an increased risk of ICH or fatal bleeding was not detected in patients with prior myocardial infarction. The Apixaban for Prevention of Acute Ischemic and Safety Events 2 (APPRAISE-2) trial of standard-dose apixaban added to standard care in patients with ACS was also stopped early owing to excess serious bleeding. However, in Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Patients With Acute Coronary Syndromes (ATLAS ACS 2 TIMI 51), fatal bleeding or fatal ICH did not increase with low-dose rivaroxaban added to low-dose acetylsalicylic acid-based standard care compared with standard care alone. In that trial, a significant reduction of recurrent vascular events was shown with 3 antithrombotic regimens compared with standard care. Therefore, depending on drug dose and patient population, further reductions in recurrent vascular events after ACS may be possible in future clinical practice, with a favorable benefit-risk profile.
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The "dual-pathway" strategy after acute coronary syndrome: rivaroxaban and antiplatelet agents in the ATLAS ACS 2-TIMI 51 trial.
Cohen, M, Iyer, D
Cardiovascular therapeutics. 2014;(5):224-32
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Abstract
Acute coronary syndrome (ACS) is a medical emergency often associated with an occlusive coronary event with consequent myocardial underperfusion. Patients require immediate antiplatelet therapy and long-term antithrombotic prophylaxis to reduce the risk of recurrence. Acetylsalicylic acid (ASA) alone or in combination with a platelet P2Y12 inhibitor (dual antiplatelet therapy [DAPT]) has become the clinically accepted antithrombotic prophylaxis for patients post-ACS. Historically, studies assessing the utility of adding oral anticoagulants (OACs) have not demonstrated a clinical benefit with regard to acceptable bleeding risk. Studies with vitamin K antagonists (VKAs) such as warfarin demonstrated a potential to reduce the risk of subsequent death by reinfarction but this benefit was offset by increases in bleeding. Results from studies of two targeted non-VKA OACs also proved disappointing, with little or no apparent reduction in the rate of ischemic events seen. However, the recent ATLAS studies assessing rivaroxaban (an oral factor Xa inhibitor) in patients with ACS demonstrated a reduction in the composite endpoint of deaths from cardiovascular causes, myocardial infarction (MI), or stroke, and a reduction in the rate of stent thrombosis. This review provides an overview of the pivotal studies in which the addition of OACs to antiplatelet therapy (the so-called "dual-pathway" approach) has been investigated for the management of patients post-ACS and considers the results of the ATLAS studies and their potential impact on the management of patients after an acute event.
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Secondary prevention of acute coronary syndrome. Socio-economic and lifestyle determinants: a literature review.
Notara, V, Panagiotakos, DB, Pitsavos, CE
Central European journal of public health. 2014;(3):175-82
Abstract
Although cardiovascular disease mortality rates seem to decline, especially among middle-aged people in developed countries, the prevalence of acute coronary syndrome (ACS) increases, representing the most common cause of morbidity in both developed and developing countries and generating large economic burden. It is estimated that one fifth of the ACS patients die suddenly and half of them belong to a fast growing popula- tion age-group, i.e., those between 70 and .80 years. A substantial number of these deaths has been attributed to various lifestyles, modifiable factors; therefore, it can be prevented. However, factors such as dietary habits and behaviours, physical activity, life stress and smoking habits, although thoroughly discussed, are not well understood and appreciated in the spectrum of secondary ACS prevention. The latter deserves further attention under the prism of socio-economic status that has changed dramatically in the last years in some populations. The aim of this review was to discuss the role of lifestyle factors on secondary ACS prevention under the prism of individual's socio-economic status. Based on the retrieved information it was revealed that there is vast evidence that secondary prevention of cardiovascular events cannot be accomplished simply through medical treatment, but it requires a multifaceted approach incorporating lifestyle modifications, too. Therefore, public health policy endeavours should be directed towards multifocal strategies, i.e., to motivate and support cardiac patients to consistently follow treatment regimens and to establish more effective and efficient community lifestyle interventions.
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Anticoagulation and antiplatelet therapy in acute coronary syndromes.
Singh, D, Gupta, K, Vacek, JL
Cleveland Clinic journal of medicine. 2014;(2):103-14
Abstract
Antiplatelet and anticoagulant drugs are the mainstay of treatment of acute coronary syndrome (ACS). The last 30 years have seen the development of various agents, a deeper understanding of the pathobiology of this disease, and an evolution in its treatment. We review the role of contemporary agents in ACS and highlight key clinical trials of these agents.
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Novel oral anticoagulants in acute coronary syndrome: re-evaluating the thrombin hypothesis.
Bassand, JP
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2014;(11):1333-41
Abstract
Despite widespread adoption of acetylsalicylic acid and P2Y12 receptor inhibitor therapy as the standard of care for secondary event prevention in patients with acute coronary syndrome (ACS), the rate of cardiovascular death or myocardial infarction following discharge is approximately 24-31% over five years, indicating an important unmet need to reduce further the risk of recurrent ACS events. Because thrombin has a role in arterial thrombus generation, a mechanistic rationale exists for adding an anticoagulant to dual antiplatelet therapy to reduce cardiovascular event rates and mortality. The direct thrombin inhibitor dabigatran and the direct Factor Xa inhibitors rivaroxaban and apixaban have been investigated for this application, with only rivaroxaban successfully completing a phase III trial. These results suggest that dose selection is of paramount importance in this indication, with lower anticoagulant doses (relative to those used in other indications, such as stroke prevention in atrial fibrillation) plus low-dose acetylsalicylic acid potentially improving cardiovascular outcomes. This article reviews clinical trial data of anticoagulants for secondary event prevention in patients with ACS; it also discusses the mechanistic reasons that may underlie these observations and looks towards the potential impact of findings from the ATLAS ACS 2 TIMI 51 trial on clinical practice.