vitamin-k-semiquinone-radical and Acute-Coronary-Syndrome

Vitamin-K antagonists (VKA) have been the standard for oral anticoagulation. However, they carry several problems in older patients: frequent bleeding complications, complex management, risk of interactions with multiple drugs. Two classes of direct oral anticoagulants (DOA) are currently available in France: (a) direct thrombin inhibitors: dabigatran; and (b) direct factor Xa inhibitors: rivaroxaban, apixaban and others. Their management is easier: quickly effective after administration, they are given at fixed doses and do not need regular laboratory monitoring. Several randomized trials have shown that DOA are non-inferior to VKA for treating venous thromboembolic disease (prophylactic or curative treatment) and atrial fibrillation (prevention of associated embolisms). DOA might be also effective for long-term treatment of coronary disease, in some cases. No trial has specifically studied older patients. In the context of atrial fibrillation, subgroup analysis show similar results between patients above and below 75-years-old. Lower doses of dabigatran and apixaban should be used in many older people. All DOA are eliminated at least partly by kidneys. Their dose must be reduced in moderate renal failure (filtration glomerular rate (FGR) 30 to 50mL/min) and they are contraindicated in older patients with severe renal failure (FGR<30mL/min). DOA also have other problems: (a) important drug interactions are still possible, (b) the clinical application of specific coagulation tests need to be defined, (c) their safety in some subgroups of elderly patients, very different from patients included in clinical trials, is not known.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Antithrombins; Atrial Fibrillation; Contraindications, Drug; Dose-Response Relationship, Drug; Drug Interactions; Factor Xa Inhibitors; Heart Valve Prosthesis; Hemorrhage; Humans; Renal Insufficiency, Chronic; Risk Factors; Secondary Prevention; Stroke; Thromboembolism; Vitamin K; Warfarin

The present article provides an update on anticoagulant treatment in patients with atrial fibrillation in distinct clinical scenarios requiring particular considerations, such as ischaemic heart disease, electrical cardioversion, pulmonary vein ablation, the presence of valvular disease with or without prosthetic valves, and renal insufficiency, as well as old age and frailty. In patients with non-valvular atrial fibrillation, the presence of renal insufficiency increases both thrombotic and haemorrhagic risk. In mild and moderate stages, direct-acting anticoagulants confer a greater benefit than warfarin, although they usually require dose adjustment. In renal failure/dialysis, there is no solid evidence that warfarin is beneficial and the use of direct-acting anticoagulants is not recommended. Because of its pathophysiology, oral anticoagulation could have a beneficial effect in patients with heart disease. However, vitamin K antagonists have not shown a satisfactory risk-benefit ratio. In contrast, direct-acting anticoagulants, at reduced doses, could have a beneficial effect in this scenario in association with antiplatelet agents. The use of direct-acting anticoagulants prior to electrical cardioversion in patients with non-valvular atrial fibrillation seems to be associated with a risk of cardioembolic events that is at least comparable to that of vitamin K antagonists. Their use avoids delay in the application of electrical cardioversion in patients without adequate INR levels. In the context of their use before and after atrial fibrillation ablation, dabiga-tran and rivaroxaban have demonstrated at least non-inferiority with vitamin K antagonists in terms of safety. In patients with any type or grade of valvular disease and atrial fibrillation, the indication of antithrombo-tic treatment must be evaluated in the same way as in patients with atrial fibrillation and no valvular di-sease. Whenever anticoagulation is required, direct-acting anticoagulants are the treatment of choice in nearly all situations, except in patients with mechanical valves or who have significant rheumatic mitral disease, who should be treated with vitamin K antagonists. The choice of appropriate antithrombotic stra-tegy in frail elderly patients is complex and involves multiple factors beyond assessment of embolic and haemorrhagic risk. Comprehensive geriatric assessment is essential for an individualised final decision. Moreover, any such decision should be consensus-based

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Electric Countershock; Fibrinolytic Agents; Heart Valve Diseases; Hemorrhage; Humans; International Normalized Ratio; Meta-Analysis as Topic; Multicenter Studies as Topic; Myocardial Ischemia; Renal Insufficiency; Risk Assessment; Secondary Prevention; Thromboembolism; Thrombophilia; Vitamin K; Warfarin

The direct oral anticoagulants (DOACs) represent a major advance in oral anticoagulant therapy and have replaced the vitamin K antagonists as the preferred treatment for many indications. By simplifying long-term anticoagulant therapy and improving its safety, the DOACs have the potential to reduce the global burden of thrombosis. Postmarketing studies suggest that the favorable results achieved with DOACs in the randomized controlled trials can be readily translated into practice, but highlight the need for appropriate patient, drug and dose selection, and careful follow-up. Leveraging on their success to date, ongoing studies are assessing the utility of DOACs for the prevention of thrombosis in patients with embolic stroke of unknown source, heart failure, coronary artery disease, peripheral artery disease, antiphospholipid syndrome, and cancer. The purpose of this article is to (1) review the pharmacology of the DOACs, (2) describe the advantages of the DOACs over vitamin K antagonists, (3) summarize the experience with the DOACs in established indications, (4) highlight current challenges and limitations, (5) highlight potential new indications; and (6) identify future directions for anticoagulant therapy.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Humans; Prothrombin; Randomized Controlled Trials as Topic; Venous Thrombosis; Vitamin K

Venous thromboembolism (VTE) is a disease state that carries significant morbidity and mortality, and is a known cause of preventable death in hospitalized and orthopedic surgical patients. There are many identifiable risk factors for VTE, yet up to half of VTE incident cases have no identifiable risk factor and carry a high likelihood of recurrence, which may warrant extended therapy. For many years, parenteral unfractionated heparin, low-molecular weight heparin, fondaparinux, and oral vitamin K antagonists (VKAs) have been the standard of care in VTE management. However, limitations in current drug therapy options have led to suboptimal treatment, so there has been a need for rapid-onset, fixed-dosing novel oral anticoagulants in both VTE treatment and prophylaxis. Oral VKAs have historically been challenging to use in clinical practice, with their narrow therapeutic range, unpredictable dose responsiveness, and many drug-drug and drug-food interactions. As such, there has also been a need for novel anticoagulant therapies with fewer limitations, which has recently been met. Dabigatran etexilate is a fixed-dose oral direct thrombin inhibitor available for use in acute and extended treatment of VTE, as well as prophylaxis in high-risk orthopedic surgical patients. In this review, the risks and overall benefits of dabigatran in VTE management are addressed, with special emphasis on clinical trial data and their application to general clinical practice and special patient populations. Current and emerging therapies in the management of VTE and monitoring of dabigatran anticoagulant-effect reversal are also discussed.

Topics: Acute Coronary Syndrome; Anticoagulants; Antithrombins; Comorbidity; Dabigatran; Hemorrhage; Humans; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Venous Thromboembolism; Vitamin K

Acute coronary syndrome affects more than 750,000 Americans per year, and antiplatelet agents are the cornerstones of treatment. Atrial fibrillation affects 2.4 million patients in the United States, and venous thromboembolism occurs in 1 to 2 per 1,000 adults per year. Anticoagulants are commonly prescribed to affected patients. Surgeons are commonly called upon to care for patients taking medications that affect normal coagulation. It is important that the surgical community has a fundamental understanding of these agents' pharmacology, which may impact patients' clinical course.. A review of recent literature on pharmacologic agents that affect coagulation was performed.. A number of medications that alter normal coagulation were reviewed in this article including their pharmacologic properties and reversal strategies.. There are a variety of medications that affect a patient's coagulation ability, including many newer agents on the market. This review provides surgeons with the knowledge needed to assist in caring for individuals receiving these drugs.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Thromboembolism; United States; Vitamin K

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.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Azepines; Azetidines; Benzamides; Benzimidazoles; Benzylamines; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Vitamin K

Cardiovascular disease remains a major cause of morbidity and mortality in developed countries. New treatments, in the form of novel oral anticoagulants (NOAC) that reduce thrombotic risk are now available for patients with atrial fibrillation (AF) or acute coronary syndrome (ACS). Warfarin has been the cornerstone of thromboprophylaxis in patients with AF, but treatment is cumbersome, inconvenient and often unreliable, with fluctuating time in therapeutic range. Thrombotic events also continue to occur in a significant number of ACS patients despite antiplatelet therapy. Thus there is an unfilled need to reduce thrombotic events in ACS and AF patients. NOAC comprise direct factor Xa inhibitors (apixaban, rivaroxaban, darexaban, edoxaban), direct thrombin inhibitors (dabigatran) and PAR-1 antagonists (vorapaxar, atopaxar). In this review, we compare and contrast NOACs and review their individual and specific clinical trial database in ACS and AF. In the setting of ACS, the role of NOAC is unclear, as any reduction in ischemic events appears to be offset by hemorrhagic risk. However, NOAC have a definite place in the treatment of patients with non-valvular AF, where they are at least as effective, if not superior to warfarin.

Topics: Acute Coronary Syndrome; Administration, Oral; Animals; Anticoagulants; Antithrombins; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Thrombosis; Vitamin K

The recent introduction of new oral anticoagulants or novel target specific oral anticoagulants (TSOA's) is likely to have a major impact in the years ahead. Many large clinical trials have been published in the past few years showing these agents are generally safe and effective in several clinical settings including acute venous thromboembolic disease, prophylaxis in the postoperative setting, prevention of thromboembolism in patients with atrial fibrillation, and in the management of acute coronary syndromes. Reported rates of overall and intracranial bleeding are lower compared to oral vitamin K antagonists. Other major advantages of oral direct thrombin inhibitors (dabigatran) and Xa inhibitors (rivaroxaban and apixaban) include rapid onset and offset of action and predictable pharmacodynamics with relatively wide therapeutic window allowing for unmonitored drug use. The relatively short half-life, rapid onset of action, and predictable pharmacokinetics should simplify periprocedural use of these agents. In this review we focus on some practical issues related to TSOA's including some limitations, potential complications, considerations to be made for certain patient populations, periprocedural management and issues pertaining to transition to and from these novel agents.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Drug Delivery Systems; Factor Xa Inhibitors; Female; Half-Life; Humans; Male; Postoperative Care; Thromboembolism; Vitamin K

Vitamin K antagonists have been used as oral anticoagulants (OACs) for over five decades, yet their use in real-world practice is problematic primarily because of their narrow therapeutic window, exacerbated by extensive food and drug interactions, necessitating regular coagulation monitoring and dose adjustment. Around half of patients receiving warfarin are within the therapeutic range, exposing them to the dangers of under-anticoagulation (i.e. thrombosis formation) or over-anticoagulation (i.e. bleeding). A new generation of OACs with improved pharmacology promises to revolutionize antithrombotic management. Rivaroxaban, apixaban (both oral direct Factor Xa inhibitors) and dabigatran (a direct thrombin inhibitor) all exhibit predictable anticoagulant responses and few drug-drug interactions and do not require routine coagulation monitoring.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Food-Drug Interactions; Hemorrhage; Humans; Thrombosis; Vitamin K

Venous thromboembolism (VTE) is a major public health concern since the incidence of VTE rises substantially with age. Furthermore, the diagnosis can be elusive since patients can present differently, causing delay in diagnosis and initiation of treatment and resulting in major morbidity and mortality. In addition to accuracy and precision in diagnosis, antithrombotic therapies are the cornerstones of VTE management. In traditional paradigm, vitamin K antagonists (warfarin), indirect factor Xa inhibitors, and heparin are the foundation in management of VTE. Warfarin has been the only available oral anticoagulant therapy for several decades. Although warfarin is effective in both treatment and prophylaxis against VTE, there are several limitations. Therefore, the novel anticoagulation therapies, including rivaroxaban, apixaban, and dabigatran etexilate, have apparent advantages over warfarin in terms of clinical efficacy and adverse effects. The objective of this review is to describe the background and clinical implications of these novel anticoagulants.

Topics: Acute Coronary Syndrome; Administration, Oral; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism; Vitamin K; Warfarin

The last decade has seen the evaluation of several new oral anticoagulants that directly target thrombin or activated factor X (FXa). All demonstrate a rapid onset of action, a low potential for food and drug interactions, and a predictable anticoagulant effect that obviates the need for routine coagulation monitoring. Those agents at the most advanced stages of clinical development are a direct thrombin inhibitor, dabigatran, and direct FXa inhibitors, rivaroxaban and apixaban. Dabigatran and rivaroxaban are approved in more than 70 countries for prevention of venous thromboembolism in patients undergoing elective hip or knee arthroplasty, and apixaban is being considered for approval by regulatory agencies for this indication. Dabigatran was shown in a large phase III trial to be more effective and safer than warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and has recently been approved for this indication. Edoxaban, an oral FXa inhibitor, is also being evaluated in phase III clinical trials. This review summarizes the pharmacology, clinical trial results, and future role of the new oral anticoagulants in clinical practice.

Topics: Acute Coronary Syndrome; Amidines; Anticoagulants; Atrial Fibrillation; Azetidines; Benzimidazoles; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thrombin; Thromboembolism; Treatment Outcome; Vitamin K

There remains uncertainty over optimal antithrombotic management strategy for patients with atrial fibrillation (AF) presenting with an acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting. Clinicians need to balance the risk of stroke and thromboembolism against the risk of recurrent cardiac ischaemia and/or stent thrombosis, and the risk of bleeding. This consensus document comprehensively reviews the published evidence and presents a consensus statement on a 'best practice' antithrombotic therapy guideline for the management of antithrombotic therapy in such AF patients.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Atrial Fibrillation; Benchmarking; Evidence-Based Medicine; Female; Fibrinolytic Agents; Hemorrhage; Humans; Male; Patient Selection; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Recurrence; Risk Assessment; Risk Factors; Stents; Stroke; Thrombosis; Treatment Outcome; Vitamin K

Arterial and venous thromboembolism account for significant morbidity and mortality worldwide. Warfarin, and other vitamin K antagonists (VKAs), have been the only class of oral anticoagulants currently in clinical use and have been so for over 50 years. Although warfarin is effective in preventing thromboembolism, its use is limited by its narrow therapeutic index that necessitates frequent monitoring and dose adjustments resulting in considerable inconvenience to patients and clinicians. There are now several orally administered anticoagulants in late stages of clinical development that may offer effective, safer, and more convenient anticoagulation. This review summarizes and compares data on novel anticoagulants in the prophylaxis and treatment of venous thromboembolism, acute coronary syndromes, and the prevention of stroke in patients with atrial fibrillation.

Topics: Acute Coronary Syndrome; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Stroke; Thrombin; Thromboembolism; Vitamin K; Warfarin

The article concerns the policy of anti-platelet treatment in patients with coronary heart disease exposed to transcutaneous coronary interventions. Patients with cardiac fibrillations are specially considered. International trials are reviewed.

Topics: Acute Coronary Syndrome; Anticoagulants; Arrhythmias, Cardiac; Contraindications; Coronary Angiography; Coronary Occlusion; Coronary Thrombosis; Disease Progression; Humans; Randomized Controlled Trials as Topic; Stents; Vitamin K; Warfarin

Drugs that inhibit platelet function are widely used to decrease the risk of occlusive arterial events in patients with atherosclerosis. There are three families of anti-platelet agents with proven clinical efficacy: (1) cyclo-oxygenase inhibitors, such as aspirin; (2) adenosine diphosphate receptor antagonists, such as the thienopyridine compounds ticlopidine and clopidogrel; and (3) glycoprotein IIb/IIIa antagonists. All these drugs are used during coronary interventions and in the medical management of acute coronary syndromes, while only aspirin and thienopyridine compounds are used in the long-term prevention of cardiovascular and cerebrovascular events in patients at risk. Despite the good risk-to-benefit ratio of anti-platelet agents, the risk of severe bleeding complications, including cerebral haemorrhage, is slightly increased, albeit to a much lesser extent than that associated with the use of other antithrombotic drugs, such as anticoagulants or thromobolytic agents. In addition, it must be noted that the increased incidence of haemorrhagic stroke is usually outweighed by a significant decrease in the incidence of ischaemic strokes. The combination of aspirin and vitamin K antagonists may be associated with the heightened risk of cerebral haemorrhage, compared to treatment with either drug alone.

Topics: Acute Coronary Syndrome; Aspirin; Cerebral Hemorrhage; Clinical Trials as Topic; Humans; Intracranial Hemorrhages; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Purinergic P2 Receptor Antagonists; Randomized Controlled Trials as Topic; Risk; Treatment Outcome; Vitamin K

Managing antithrombotic therapy in patients with atrial fibrillation (AF) and an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) is challenging and can be affected by prior oral anticoagulant (OAC) treatment. We examined the relationship between prior OAC use and outcomes in the AUGUSTUS trial.. This prespecified secondary analysis is from AUGUSTUS, an open-label, 2-by-2 factorial, RCT to evaluate the safety of apixaban versus vitamin K antagonist (VKA) and aspirin versus placebo in patients with AF and ACS and/or PCI. The primary endpoint, major or clinically relevant non-major bleeding and clinical outcomes were compared in patients receiving (n=2262) or not receiving (n=2352) an OAC prior to enrolment.. Patients with prior OAC use had more comorbidities, higher CHA. In AUGUSTUS, prior OAC use was associated with fewer ischaemic events but not more bleeding. In patients with AF and ACS and/or undergoing PCI, clinicians can be assured that the trial results can be applied to patients regardless of their prior OAC status.. NCT02415400.

Topics: Acute Coronary Syndrome; Aspirin; Atrial Fibrillation; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Ischemia; Male; Medication Therapy Management; Middle Aged; Outcome and Process Assessment, Health Care; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Preoperative Period; Pyrazoles; Pyridones; Vitamin K

We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI).. ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web-based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1-12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed.. From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2-76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65-1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority).. In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events.. Daiichi Sankyo.

Topics: Acute Coronary Syndrome; Aged; Atrial Fibrillation; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Pyridines; Stents; Stroke; Thiazoles; Vitamin K

The safety and efficacy of antithrombotic regimens may differ between patients with atrial fibrillation who have acute coronary syndromes (ACS), treated medically or with percutaneous coronary intervention (PCI), and those undergoing elective PCI.. Using a 2×2 factorial design, we compared apixaban with vitamin K antagonists and aspirin with placebo in patients with atrial fibrillation who had ACS or were undergoing PCI and were receiving a P2Y. An antithrombotic regimen consisting of apixaban and a P2Y. URL: https://www.clinicaltrials.gov. Unique identifier: NCT02415400.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Cardiovascular Agents; Combined Modality Therapy; Disease Management; Drug Therapy, Combination; Elective Surgical Procedures; Female; Fibrinolytic Agents; Hemorrhage; Hospitalization; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Purinergic P2Y Receptor Antagonists; Pyrazoles; Pyridones; Treatment Outcome; Vitamin K

Appropriate antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear.. In an international trial with a two-by-two factorial design, we randomly assigned patients with atrial fibrillation who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y. Enrollment included 4614 patients from 33 countries. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P<0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P = 0.002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the placebo group.. In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Atrial Fibrillation; Double-Blind Method; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Pyrazoles; Pyridones; Vitamin K

In the AUGUSTUS trial (An Open-Label, 2×2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban Versus Vitamin K Antagonist and Aspirin Versus Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention), apixaban resulted in less bleeding and fewer hospitalizations than vitamin K antagonists, and aspirin caused more bleeding than placebo in patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention treated with a P2Y. In 4456 patients, the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was used to calculate baseline estimated glomerular filtration rate (eGFR). The effect of apixaban versus vitamin K antagonists and aspirin versus placebo was assessed across kidney function categories by using Cox models. The primary outcome was International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and ischemic events (death, stroke, myocardial infarction, stent thrombosis [definite or probable], or urgent revascularization). Creatinine clearance <30 mL/min was an exclusion criterion in the AUGUSTUS trial.. Overall, 30%, 52%, and 19% had an eGFR of >80, >50 to 80, and 30 to 50 mL·min. The safety and efficacy of apixaban was consistent irrespective of kidney function, compared with warfarin, and in accordance with the overall trial results. The risk of bleeding with aspirin was consistently higher across all kidney function categories. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02415400.

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Kidney; Male; Middle Aged; Percutaneous Coronary Intervention; Pyrazoles; Pyridones; Vitamin K

In AUGUSTUS (Open-Label, 2×2 Factorial, Randomized, Controlled Clinical Trial to Evaluate the Safety of Apixaban vs Vitamin K Antagonist and Aspirin vs Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention), patients with atrial fibrillation and a recent acute coronary syndrome and those undergoing percutaneous coronary intervention had less bleeding with apixaban than vitamin K antagonist (VKA) and with placebo than aspirin. However, the number of ischemic events was numerically higher with placebo. The aim of this analysis is to assess the tradeoff of risk (bleeding) and benefit (ischemic events) over time with apixaban versus VKA and aspirin versus placebo.. In AUGUSTUS, 4614 patients with atrial fibrillation and recent acute coronary syndrome or percutaneous coronary intervention on a P2Y. Compared with VKA, apixaban had either a lower or a similar risk of bleeding and ischemic outcomes from randomization to 30 days and from 30 days to 6 months. From randomization to 30 days, aspirin caused more severe bleeding (absolute risk difference, 0.97% [95% CI, 0.23-1.70]) and fewer severe ischemic events (absolute risk difference, -0.91% [95% CI, -1.74 to -0.08]) than placebo. From 30 days to 6 months, the risk of severe bleeding was higher with aspirin than placebo (absolute risk difference, 1.25% [95% CI, 0.23-2.27]), whereas the risk of severe ischemic events was similar (absolute risk difference, -0.17% [95% CI, -1.33 to 0.98]).

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Coronary Thrombosis; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Hemorrhage; Humans; Ischemia; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Recurrence; Retrospective Studies; Risk Assessment; Risk Factors; Stroke; Time Factors; Treatment Outcome; Vitamin K

Topics: Acute Coronary Syndrome; Acute Disease; Aspirin; Atrial Fibrillation; Clopidogrel; Combined Modality Therapy; Cyclophosphamide; Dabigatran; Drug Therapy, Combination; Fibrinolytic Agents; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Stents; Stroke; Vitamin K

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Cardiovascular Agents; Combined Modality Therapy; Drug Therapy, Combination; Elective Surgical Procedures; Female; Fibrinolytic Agents; Hemorrhage; Hospitalization; Humans; Length of Stay; Male; Middle Aged; Multicenter Studies as Topic; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Purinergic P2Y Receptor Antagonists; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome; Vitamin K

Clinicians struggle daily with the optimal regimen for patients with an indication for antiplatelet therapy after stenting and in patients needing oral anticoagulation treatment for atrial fibrillation (AF). This is not only difficult in patients with acute coronary syndrome (ACS) but also in the large number of patients with AF undergoing elective percutaneous coronary intervention (PCI). The challenge is to strike a balance between the increasing risk of bleeding events and ischemic or thrombotic events. Until recently, guidelines were based on expert consensus and a few small, many of them retrospective, trials. A so-called triple therapy with a vitamin K antagonist (VKA) and dual antiplatelet therapy (DAPT) with aspirin and clopidogrel was recommended for patients with AF undergoing PCI in stable coronary artery disease or for those with ACS. However, severe bleeding complications remain a major issue during triple therapy, particularly in the growing aging population. In the past year, randomized controlled trials (RCT) with direct-acting oral anticoagulants (DOACs) have modified the standard use of care, now favoring dual therapy with DOACs. This review elucidates the current influential RCTs on the new antiplatelet and anticoagulation strategies for patients with AF undergoing PCI or with ACS, and discusses whether triple therapy is still required.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Aspirin; Atrial Fibrillation; Clopidogrel; Drug Therapy, Combination; Guideline Adherence; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Randomized Controlled Trials as Topic; Risk Factors; Stents; Stroke; Thrombosis; Vitamin K

Essentials Acute coronary syndrome (ACS) with atrial fibrillation (AF) is a therapeutic challenge. Dual and triple antithrombotic therapy showed a similar thrombotic risk in ACS patients with AF. The omission of aspirin during the first month did not increase the rate of ischemic events. Replacement of vitamin K antagonist by dabigatran leads to an increased thrombotic risk.. Background Dual antithrombotic therapy comprising a vitamin K antagonist (VKA) plus clopidogrel reduces the incidence of major bleeding compared with triple therapy (VKA + clopidogrel + aspirin) in acute coronary syndrome (ACS) patients with atrial fibrillation (AF), with a similar thrombotic risk. The oral thrombin inhibitor dabigatran (150 mg twice a day) showed superiority over VKA in non-valvular AF, but data supporting its use in AF patients presenting with ACS are limited. Objective We sought to evaluate the efficacy of dabigatran vs. VKA in the management of AF patients undergoing percutaneous coronary intervention for an ACS. Methods In this open-label study, 133 consecutive patients received dabigatran plus clopidogrel. Another cohort of 133 patients treated with VKA plus clopidogrel was used as the control group. Results After propensity score adjustment, the cumulative incidence of major adverse cardiovascular events over 24 months was higher with dabigatran vs. VKA (adjusted hazard ratio, 2.28; 95% confidence interval, 1.46-3.56). Similar rates of major bleeding were found (adjusted hazard ratio, 1.17; 95% confidence interval, 0.46-2.96). Conclusions In AF patients presenting with ACS, replacement of VKA by dabigatran concurrently with clopidogrel is associated with an increased thrombotic risk, without a reduction in major bleeding.

Topics: Acute Coronary Syndrome; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Atrial Fibrillation; Blood Platelets; Clopidogrel; Cohort Studies; Coronary Angiography; Dabigatran; Female; Glomerular Filtration Rate; Hemorrhage; Humans; Incidence; Ischemia; Kaplan-Meier Estimate; Male; Middle Aged; Outcome Assessment, Health Care; Patient Safety; Phenindione; Propensity Score; Proportional Hazards Models; Risk; Treatment Outcome; Vitamin K

The efficacy and tolerability of vitamin K antagonists (VKAs) depends on the quality of anticoagulant control, reflected by the mean time in therapeutic range (TTR) of international normalized ratio 2.0 to 3.0. In the present study, we aimed to investigate the association between TTR and change in TTR (ΔTTR) with the risk of mortality and clinically significant events in a consecutive cohort of atrial fibrillation (AF) patients.. We included 1361 AF patients stable on VKAs (international normalized ratio 2.0-3.0) during at least the previous 6 months. After 6 months of follow-up we recalculated TTR, calculated ΔTTR (ie, the difference between baseline and 6-month TTRs) and investigated the association of both with the risk of mortality and "clinically significant events" (defined as the composite of stroke or systemic embolism, major bleeding, acute coronary syndrome, acute heart failure, and all-cause deaths).. The median ΔTTR at 6 months of entry was 20% (interquartile range 0-34%), 796 (58.5%) patients had a TTR reduction of at least 20%, while 330 (24.2%) had a TTR <65%. During follow-up, 34 (2.5% [4.16% per year]) patients died and 61 (4.5% [7.47% per year]) had a clinically significant event. Median ΔTTR was significantly higher in patients who died (35.5% vs 20%; P = 0.002) or sustained clinically significant events (28% vs 20%; P = 0.022). Based on Cox regression analyses, the overall risk of mortality at 6 months for each decrease point in TTR was 1.02 (95% CI, 1.01-1.04; P = 0.003), and the risk of clinically significant events was 1.01 (95% CI, 1.00-1.03; P = 0.028). Patients with TTR <65% at 6 months had higher risk of mortality (hazard ratio = 2.96; 95% CI, 1.51-5.81; P = 0.002) and clinically significant events (hazard ratio = 1.71; 95% CI, 1.01-2.88; P = 0.046).. Our findings suggest that in AF patients anticoagulated with VKAs, a change in TTR over 6 months (ie, ΔTTR) is an independent risk factor for mortality and clinically significant events. Even in a cohort with good anticoagulation control, the risk for mortality and clinically significant events increases with every point deterioration of TTR.

Topics: Acenocoumarol; Acute Coronary Syndrome; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Heart Failure; Hemorrhage; Humans; International Normalized Ratio; Male; Regression Analysis; Risk Factors; Stroke; Vitamin K

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Consensus; Coronary Artery Disease; Drug Substitution; Fibrinolytic Agents; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Risk Factors; Stents; Thrombosis; Vitamin K

Topics: Acute Coronary Syndrome; Anticoagulants; Clinical Trials, Phase III as Topic; Factor Xa Inhibitors; Humans; Vitamin K

This study aimed to describe the real-life incidence of bleeding, arterial thrombotic events and death during vitamin K antagonist (VKA) treatment in atrial fibrillation (AF).. This was a cohort study in Echantillon Généraliste de Bénéficiaires, the 1/97 sample of the French national healthcare claims and hospitalization database, of new VKA users with definite or probable AF and no other indication, and of patients without AF, from 2007 to 2011. Prespecified outcomes were all-cause death, hospitalization for bleeding, arterial thrombotic event (ATE), or acute coronary syndrome (ACS) or any of the above (composite outcome).. Of 8894 new VKA users, 3345 had probable or certain AF, 51.7% were male, mean age was 75.1 years, 87.1% had a CHA2 DS2 -VASc score ≥ 2 and 11.6% a HAS-BLED score > 3. Among AF patients, during VKA exposure the incidence rate of bleeding was 2.8 [95% confidence interval (CI) 2.2, 3.4] per 100 patient-years, including 0.6 (95% CI 0.3, 0.8) cerebral, 1.0 (95% CI 0.7, 1.3) digestive and 1.4 (95% CI 1.0, 1.7) other bleeds. There were 1.6 (95% CI 1.2, 2.0) ACS, 1.5 (95% CI 1.1, 1.8) ATE and 3.8 (95% CI 3.2, 4.4) deaths per 100 patient-years. The incidence rate of the composite outcome was 9.1 per 100 patient-years (95% CI 8.2, 10.0). When patients stopped VKA, bleeding decreased (RR 0.67, 95% CI 0.43, 1.04)), but death or thrombosis increased (RR 3.06, 95% CI 2.46, 3.81 and 1.75, 95% CI 1.14, 2.70, respectively). During VKA exposure non-AF patients had similar rates of bleeding, but fewer deaths, ACS and ischaemic events.. Real-life rates for bleeding, arterial thrombotic events, ACS and deaths in AF patients treated with VKA were similar to those observed in clinical trials.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Atrial Fibrillation; Databases, Factual; Female; France; Hemorrhage; Hospitalization; Humans; Incidence; Male; Middle Aged; Thrombosis; Vitamin K

In patients with atrial fibrillation, oral anticoagulation with oral thrombin inhibitors (OTIs), in contrast to vitamin K antagonists (VKAs), associates with a modest increase in acute coronary syndromes (ACSs). Whether this observation is causatively linked to OTI treatment and, if so, whether OTI action is the result of a lower antithrombotic efficacy of OTI compared to VKA or reflects a yet undefined prothrombotic activity of OTI remain unclear. We analyzed platelet function in patients receiving OTI or dose-adapted VKA under static and flow conditions. In vivo, we studied arterial thrombosis in OTI-, VKA-, and vehicle-treated mice using carotid ligation and wire injury models. Further, we examined thrombus formation on human atherosclerotic plaque homogenates under arterial shear to address the relevance to human pathology. Under static conditions, aggregation in the presence of ristocetin was increased in OTI-treated blood, whereas platelet reactivity and aggregation to other agonists were only marginally affected. Under flow conditions, firm platelet adhesion and thrombus formation on von Willebrand factor, collagen, and human atherosclerotic plaque were increased in the presence of OTI in comparison to VKA. OTI treatment was associated with increased thrombus formation in injured carotid arteries of mice. Inhibition or ablation of GPIbα-thrombin interactions abolished the effect of OTI on thrombus formation, suggesting a mechanistic role of the platelet receptor GPIbα and its thrombin-binding site. The effect of OTI was also abrogated in the presence of aspirin. In summary, OTI treatment has prothrombotic activity that might contribute to the increase in ACS observed clinically in patients.

Topics: Acute Coronary Syndrome; Administration, Oral; Animals; Anticoagulants; Arteries; Aspirin; Atherosclerosis; Binding Sites; Blood Platelets; Fibrinolytic Agents; Humans; Mice; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Thrombin; Thrombosis; Vitamin K

Uncertainty remains over optimal antithrombotic treatment of patients with atrial fibrillation presenting with myocardial infarction and/or undergoing percutaneous coronary intervention. We investigated the risk and time frame for bleeding following myocardial infarction/percutaneous coronary intervention in patients with atrial fibrillation according to antithrombotic treatment.. Patients with atrial fibrillation and admitted with myocardial infarction or for percutaneous coronary intervention between 2000 and 2009 (11 480 subjects, mean age 75.6 years [SD ±10.3], males 60.9%) were identified by individual level linkage of nationwide registries in Denmark. Fatal or nonfatal (requiring hospitalization) bleeding was determined according to antithrombotic treatment regimen: triple therapy (TT) with vitamin K antagonist (VKA)+aspirin+clopidogrel, VKA+antiplatelet, and dual antiplatelet therapy with aspirin+clopidogrel. We calculated crude incidence rates and adjusted hazard ratios by Cox regression models. Within 1 year, 728 bleeding events were recorded (6.3%); 79 were fatal (0.7%). Within 30 days, rates were 22.6, 20.3, and 14.3 bleeding events per 100 person-years for TT, VKA+antiplatelet, and dual antiplatelet therapy, respectively. Both early (within 90 days) and delayed (90-360 days) bleeding risk with TT exposure in relation to VKA+antiplatelet was increased; hazard ratio 1.47 (1.04;2.08) and 1.36 (0.95;1.95), respectively. No significant difference in thromboembolic risk was observed for TT versus VKA+antiplatelet; hazard ratio, 1.15 (0.95;1.40).. High risk of bleeding is immediately evident with TT after myocardial infarction/percutaneous coronary intervention in patients with atrial fibrillation. A continually elevated risk associated with TT indicates no safe therapeutic window, and TT should only be prescribed after thorough bleeding risk assessment of patients.

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Aspirin; Atrial Fibrillation; Clopidogrel; Cohort Studies; Comorbidity; Denmark; Drug Therapy, Combination; Female; Fibrinolytic Agents; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Registries; Risk Factors; Stroke; Ticlopidine; Vitamin K

Although currently available anticoagulants are effective for the prevention and treatment of thromboembolic disorders, they have several drawbacks. Low molecular weight heparin and fondaparinux produce a predictable level of anticoagulation that obviates the need for coagulation monitoring, but they must be given parenterally, which renders them inconvenient for long-term use. Vitamin K antagonists, such as warfarin, are administered orally, but produce a variable anticoagulant response because genetic polymorphisms, dietary vitamin K intake and multiple drug-drug interactions affect their metabolism. Consequently, coagulation monitoring and frequent dose adjustments are needed to ensure that a therapeutic level of anticoagulation is achieved. This is burdensome for patients and physicians, and costly for the healthcare system. These limitations have prompted the development of new oral anticoagulants that target thrombin or factor Xa. The new agents produce such a predictable anticoagulant response that they can be given in fixed doses without monitoring. This paper focuses on the new oral anticoagulants in the most advanced stages of development.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Clinical Trials as Topic; Dabigatran; Drug Discovery; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thrombin; Venous Thromboembolism; Vitamin K

Vitamin K antagonists (VKA) are the only registered oral anticoagulants for the treatment of venous thromboembolism (VTE). VKA have an unpredictable and highly variable effect on coagulation, with a high risk of under- and over-treatment. Novel anticoagulants, such as dabigatran and rivaroxaban, could be a very welcome replacement for VKA, as they show a predictable anticoagulant effect. Results of several phase II and III studies have shown the efficacy and safety of dabigatran and rivaroxaban in the prophylaxis and treatment of VTE, and for the prevention of stroke in atrial fibrillation. It remains to be shown whether these new anticoagulants have the same safety profile in daily clinical practice, where more vulnerable patients will be treated. Lack of information on the proper monitoring method or antidote in case of bleeding may also hinder the translation from science to clinical practice.

Topics: Acute Coronary Syndrome; Anticoagulants; Arthroplasty, Replacement, Hip; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Diet; Drug Interactions; Factor VIIa; Factor Xa Inhibitors; Humans; Kidney; Life Style; Monitoring, Physiologic; Morpholines; Recombinant Proteins; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism; Vitamin K

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Venous Thromboembolism; Vitamin K

Topics: Acute Coronary Syndrome; Aspirin; Cardiovascular Diseases; Clinical Trials as Topic; Clopidogrel; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Prognosis; Ticlopidine; Vitamin K