Warfarin Versus New Agents: Interpreting the Data

AbstractStroke prevention in atrial fibrillation (AF) is a rapidly expanding indication for lifelong oral anticoagulation. The vitamin K antagonists (VKAs) effectively prevent stroke, but are notoriously difficult to manage and are associated with frequent adverse events. These factors account for the widespread underuse of warfarin for patients with AF who are qualified candidates for therapy. New oral anticoagulants with different mechanisms of action are beginning to exit phase III trials and may replace the VKAs for a number of indications, especially AF. The oral direct thrombin and Xa inhibitors are furthest along in development. Dabigatran etexilate, a thrombin inhibitor, has recently shown excellent outcomes in the prevention of stroke in patients with AF. The oral Xa inhibitors are still in phase III trials for stroke prevention in AF, but results from trials for other indications look promising. These short-acting, short-duration, unmonitored drugs are not without limitations and potential adverse effects. The perceived drawbacks of the VKAs may actually be assets in the management of patients with AF, and the pros and cons of each class of drug must be taken into account as physicians consider or patients request transition to a new class of oral anticoagulants.

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Stroke Prevention in Atrial Fibrillation: Understanding the New Oral Anticoagulants Dabigatran, Rivaroxaban, and Apixaban

Thrombosis ◽

10.1155/2012/108983 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Tan Ru San ◽

Mark Yan Yee Chan ◽

Teo Wee Siong ◽

Tang Kok Foo ◽

Ng Kheng Siang ◽

...

Keyword(s):

Atrial Fibrillation ◽

Stroke Prevention ◽

Primary Care Physicians ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

New Oral Anticoagulants ◽

Phase Iii ◽

Fixed Dose ◽

Thrombin Inhibitor ◽

Factor X

Unlike vitamin K antagonists (VKAs), the new oral anticoagulants (NOACs)—direct thrombin inhibitor, dabigatran, and direct activated factor X inhibitors, rivaroxaban, and apixaban—do not require routine INR monitoring. Compared to VKAs, they possess relatively rapid onset of action and short halflives, but vary in relative degrees of renal excretion as well as interaction with p-glycoprotein membrane transporters and liver cytochrome P450 metabolic enzymes. Recent completed phase III trials comparing NOACs with VKAs for stroke prevention in atrial fibrillation (AF)—the RE-LY, ROCKET AF, and ARISTOTLE trials—demonstrated at least noninferior efficacy, largely driven by significant reductions in haemorrhagic stroke. Major and nonmajor clinically relevant bleeding rates were acceptable compared to VKAs. Of note, the NOACs caused significantly less intracranial haemorrhagic events compared to VKAs, the mechanisms of which are not completely clear. With convenient fixed-dose administration, the NOACs facilitate anticoagulant management in AF in the community, which has hitherto been grossly underutilised. Guidelines should evolve towards simplicity in anticipation of greater use of NOACs among primary care physicians. At the same time, the need for caution with their use in patients with severely impaired renal function should be emphasised.

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Update on Edoxaban for the Prevention and Treatment of Thromboembolism: Clinical Applications Based on Current Evidence

Advances in Hematology ◽

10.1155/2015/920361 ◽

2015 ◽

Vol 2015 ◽

pp. 1-19 ◽

Cited By ~ 5

Author(s):

Ali Zalpour ◽

Thein Hlaing Oo

Keyword(s):

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Coagulation Factors ◽

Current Evidence ◽

Thrombin Inhibitor ◽

Prevention And Treatment ◽

Financial Impacts

Vitamin K antagonists (VKA) and heparins have been utilized for the prevention and treatment of thromboembolism (arterial and venous) for decades. Targeting and inhibiting specific coagulation factors have led to new discoveries in the pharmacotherapy of thromboembolism management. These targeted anticoagulants are known as direct oral anticoagulants (DOACs). Two pharmacologically distinct classes of targeted agents are dabigatran etexilate (Direct Thrombin Inhibitor (DTI)) and rivaroxaban, apixaban, and edoxaban (direct oral factor Xa inhibitors (OFXaIs)). Emerging evidence from the clinical trials has shown that DOACs are noninferior to VKA or low-molecular-weight heparins in the prevention and treatment of thromboembolism. This review examines the role of edoxaban, a recently approved OFXaI, in the prevention and treatment of thromboembolism based on the available published literature. The management of edoxaban in the perioperative setting, reversibility in bleeding cases, its role in cancer patients, the relevance of drug-drug interactions, patient satisfaction, financial impacts, and patient education will be discussed.

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RE-COVERY DVT/PE: Rationale and design of a prospective observational study of acute venous thromboembolism with a focus on dabigatran etexilate

Thrombosis and Haemostasis ◽

10.1160/th16-07-0566 ◽

2017 ◽

Vol 117 (02) ◽

pp. 415-421 ◽

Cited By ~ 6

Author(s):

Walter Ageno ◽

Ivan B. Casella ◽

Chee Kok Han ◽

Gary E. Raskob ◽

Sebastian Schellong ◽

...

Keyword(s):

Venous Thromboembolism ◽

Vitamin K ◽

Large Scale ◽

Vitamin K Antagonists ◽

Phase 1 ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Phase Iii ◽

Real World Data ◽

Phase Iii Studies

SummaryThe therapeutic management of venous thromboembolism (VTE) is rapidly evolving. Following the positive results of pivotal large-scale randomised trials, the non-vitamin K antagonist oral anticoagulants (NOACs) represent an important alternative to standard anticoagulation. In phase III studies, dabigatran was as effective as, and significantly safer than warfarin. Additional information on real-world data of dabigatran is now warranted. RE-COVERY DVT/PE is a multi-centre, international, observational (i. e. non-interventional) study enrolling patients with acute DVT and/or PE within 30 days after objective diagnosis. The study is designed with two phases. Phase 1 has a cross-sectional design, enrolling approximately 6000 patients independently of treatment choice, with the aim of providing a contemporary picture of the management of VTE worldwide. Phase 2 has a prospective cohort design, with follow-up of one year, enrolling 8000 patients treated with dabigatran or vitamin K antagonists (VKAs) with the aim of comparing their safety, defined by the occurrence of major bleeding, and effectiveness, defined by the occurrence of symptomatic recurrent VTE. RE-COVERY DVT/PE will complement both the results of other observational studies in this field and the results of phase III studies with dabigatran, in particular by assessing its clinical benefit in various patient subgroups treated in routine clinical practice.

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Ten years of non-vitamin K antagonists oral anticoagulants for stroke prevention in atrial fibrillation: is warfarin obsolete?

European Heart Journal Supplements ◽

10.1093/eurheartj/suaa177 ◽

2020 ◽

Vol 22 (Supplement_O) ◽

pp. O28-O41

Author(s):

Matthias Hammwöhner ◽

Andreas Goette

Keyword(s):

Atrial Fibrillation ◽

Clinical Data ◽

Vitamin K ◽

Stroke Prevention ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Study Data ◽

Phase Iii ◽

Clinical Settings ◽

Specific Patient

Abstract Currently, four non-vitamin K antagonists oral anticoagulants (NOACs) are available for stroke prevention in atrial fibrillation (AF). These have been in clinical use for up to 10 years now. Besides data of the initial phase III clinical trials, now clinical data, several sub-studies, meta-analyses, and studies in special clinical settings and specific patient populations are available. This review shall give an overview on the history of NOAC development, sum up study data and ‘real-world’ clinical data as well as discuss several special clinical settings like NOAC treatment in patients that require coronary artery stenting or cardioversion (CV). Furthermore, treatment considerations in special patient populations like patients with renal impairment, obesity, or patients requiring NOACs for secondary prevention are discussed. The significance of NOAC treatment will be discussed under consideration of the recently published 2020 ESC/EACTS Guidelines for the diagnosis and management of AF.

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New Issues in Oral Anticoagulants

Hematology ◽

10.1182/asheducation-2008.1.259 ◽

2008 ◽

Vol 2008 (1) ◽

pp. 259-265 ◽

Cited By ~ 15

Author(s):

Charles W. Francis

Keyword(s):

Knee Replacement ◽

Oral Anticoagulants ◽

Phase Iii ◽

Bleeding Complications ◽

Thrombin Inhibitor ◽

Oral Direct Thrombin Inhibitor ◽

Phase Iii Trials ◽

High Level ◽

Cytochrome P 450 ◽

Advanced Development

Abstract Polymorphisms in CYP2C9, a critical cytochrome P-450 enzyme in the metabolism of warfarin, alters its clearance and affects dosing. CYP*1 has higher activity than either the *2 or *3 variants, and patients with the *2 or *3 variants require a lower dose. VKORC1 is the enzyme inhibited by warfarin, and its levels are affected by several polymorphisms that can be divided into high or low level haplotypes, and patients with high level haplotypes require higher warfarin doses. The use of algorithms for dosing that incorporate pharmacogenomic information perform better than those using clinical data alone. Considerable effort is ongoing to develop new oral anticoagulants as alternatives to warfarin, and three agents are in advanced development. Dabigatran is an oral direct thrombin inhibitor that has been compared with enoxaparin for prevention of VTE following hip or knee replacement. Based on non-inferiority results in European trials, it has now been approved for marketing in Europe. Phase III trials with a new oral Xa inhibitor, rivaroxaban, have been completed in hip or knee replacement, and rivaroxaban was superior to enoxaparin in prevention of VTE with no increase in bleeding complications. Phase III studies with apixaban, another oral Xa inhibitor, are in progress. These agents are also being evaluated in large studies for prevention of stroke in atrial fibrillation and for VTE treatment.

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Direct Oral Anticoagulants in Patients with Obesity and Atrial Fibrillation: Position Paper of Italian National Association of Hospital Cardiologists (ANMCO)

Journal of Clinical Medicine ◽

10.3390/jcm10184185 ◽

2021 ◽

Vol 10 (18) ◽

pp. 4185

Author(s):

David Mocini ◽

Stefania Angela Di Fusco ◽

Edoardo Mocini ◽

Lorenzo Maria Donini ◽

Carlo Lavalle ◽

...

Keyword(s):

Atrial Fibrillation ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

High Body Mass Index ◽

Normal Weight ◽

Phase Iii ◽

Fixed Dose ◽

Pivotal Phase ◽

Phase Iii Trials

The use of the direct oral anticoagulants dabigatran, rivaroxaban, apixaban and edoxaban (DOACs) offers some major advantages over warfarin and other vitamin K antagonists (VKAs). One advantage is the possibility to use a fixed dose in normal-weight patients, overweight patients and patients with obesity. However, the “one size fits all” strategy raised a concern regarding the possibility to undertreat patients with a high body mass index. No randomized controlled trials (RCTs) have ever compared VKAs and DOACs in this population. We analyzed data from the literature on DOAC pharmacokinetics and pharmacodynamics, results from the four pivotal phase III trials on non-valvular atrial fibrillation, retrospective observational studies and metanalyses. While we are aware of the limitation imposed by the absence of specific RCTs, we propose the position of the Italian Association of Hospital Cardiologists (ANMCO) on the use of DOACs in patients with obesity based on the existing evidence.

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Treatment of Venous Thromboembolism in Special Populations with Direct Oral Anticoagulants

Thrombosis and Haemostasis ◽

10.1055/s-0040-1710314 ◽

2020 ◽

Vol 120 (06) ◽

pp. 899-911

Author(s):

Roisin Bavalia ◽

Saskia Middeldorp ◽

Gerhard Weisser ◽

Christine Espinola-Klein

Keyword(s):

Venous Thromboembolism ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Phase Iii ◽

Patients With Cancer ◽

Phase Iii Trials ◽

Guidance Documents ◽

Phase Iii Studies ◽

Dose Reductions

AbstractAs a result of the successful completion of their respective phase III studies compared with vitamin K antagonists (VKAs), four direct oral anticoagulants (DOACs) have been approved for the treatment and secondary prevention of venous thromboembolism (VTE). These DOACs—apixaban, dabigatran, edoxaban, and rivaroxaban—have subsequently seen a steady uptake among clinicians since their approval. Despite the suitability of DOACs for a broad range of patients, they are not appropriate in certain situations, whereas in others they require additional considerations such as dose reductions. Subanalyses of phase III trials and studies on specific VTE patient populations have been conducted to evaluate the safety and efficacy of the DOACs in a broad range of settings, such as patients with renal impairment, patients with cancer, patients of childbearing potential, patients with multiple comorbidities and pediatric patients. Furthermore, many recent guidance documents from important hematological societies and other specialists have incorporated several of these developments. These documents also identify the patients for whom DOACs are not suitable and where traditional anticoagulation options such as heparins or VKAs should be considered instead. This review provides an overview of key VTE patient subgroups, the clinical evidence supporting the use of anticoagulation in these patients, and a discussion of the most appropriate approaches to their management, including considerations such as dosing, acute and extended treatment durations, and DOAC selection.

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Novel oral anticoagulants - key messages for the angiologist

VASA ◽

10.1024/0301-1526/a000184 ◽

2012 ◽

Vol 41 (3) ◽

pp. 177-191 ◽

Cited By ~ 7

Author(s):

Haas ◽

Spannagl ◽

M. Schellong

Keyword(s):

Clinical Evidence ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Factor Xa ◽

Novel Oral Anticoagulants ◽

Bleeding Complications ◽

Thrombin Inhibitor ◽

Clinical Scenarios ◽

Major Orthopaedic Surgery

Novel oral anticoagulants (NOACs) have become available for different clinical indications such as the prevention of venous thromboembolism (VTE) after major orthopaedic surgery, for the treatment of VTE and stroke prevention in patients with atrial fibrillation (AF). One thrombin inhibitor (dabigatran etexilate) and two factor Xa-inhibitors (rivaroxaban and apixaban) are the most advanced NOACs and therefore, up-to-date information on their evidence and use in clinical practice appears timely. In this review we give a concise overview of the pharmacology and clinical evidence derived from phase 3 clinical trials. Then the meaningfulness of laboratory testing is discussed and recommendations are given for clinical scenarios that may necessitate adjustment of their use. We conclude that NOACs are valuable alternatives to heparins or vitamin K antagonists (VKA) in the prevention and treatment of VTE and for the prevention of stroke in patients with AF. Prescribers should however be aware of special situations and patient populations where the manufacturers instructions need to be carefully followed. In particular, patients with comorbidities and co-medications may require individual decision making in order to prevent bleeding complications.

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Pros and cons of new oral anticoagulants

Hematology ◽

10.1182/asheducation-2013.1.464 ◽

2013 ◽

Vol 2013 (1) ◽

pp. 464-470 ◽

Cited By ~ 106

Author(s):

Kenneth A. Bauer

Keyword(s):

Venous Thromboembolism ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Factor Xa ◽

Rapid Onset ◽

New Oral Anticoagulants ◽

Therapeutic Class ◽

Pros And Cons ◽

Additional Agent

Abstract The availability of new oral anticoagulants (NOACs) targeting either thrombin (dabigatran etexilate) or factor Xa (rivaroxaban and apixaban) for the prevention and treatment of thrombosis has been highly anticipated. NOACs have major pharmacologic advantages over vitamin K antagonists (eg, warfarin), including rapid onset/offset of action, few drug interactions, and predictable pharmacokinetics, eliminating the requirement for regular coagulation monitoring. Regulatory agencies have approved several NOACs for specific indications based on the results of clinical trials demonstrating efficacy and safety that are at least as good, if not better, than warfarin (for stroke prevention in atrial fibrillation and treatment and secondary prevention of venous thromboembolism) or low-molecular-weight heparin, which is injectable (for initial treatment of venous thromboembolism and thromboprophylaxis in patients undergoing hip or knee arthroplasty). However, the adoption of this new therapeutic class into clinical practice has been slower than expected due to several factors including concerns regarding medication adherence without laboratory monitoring, uncertainty about dosing in some patient populations (eg, renal dysfunction, marked extremes of body weight), and higher drug costs compared with warfarin. Other issues are the current absence of specific antidotes for NOACs and assays to measure drug levels at most centers. The indications for NOACs on the market will expand and at least one additional agent (edoxaban) will likely gain approval within the next 2 years. As practitioners gain familiarity with the drugs and healthcare systems adapt to their use, NOAC use will increase substantially over time. Warfarin, however, will continue to be an appropriate anticoagulant choice for many patients.

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DOACs vs Vitamin K Antagonists: a Comparison of Phase III Clinical Trials and a Prescriber Support Tool

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2019.289 ◽

2019 ◽

Vol 7 (7) ◽

pp. 1226-1232 ◽

Cited By ~ 1

Author(s):

Alina-Maria Pirlog ◽

Cristian Daniel Pirlog ◽

Marius Adrian Maghiar

Keyword(s):

Clinical Trials ◽

Vitamin K ◽

Primary Outcome ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Phase Iii ◽

Support Tool ◽

Phase Iii Clinical Trials

AIM: The purpose of this article was to systematically review the literature assessing the efficacy and safety of phase III clinical trials for each direct oral anticoagulant versus vitamin K antagonists and to design a ’’go-to’’ table for the prescriber. MATERIAL AND METHODS: A systematic review of specialist literature was conducted to identify RCTs which compared direct oral anticoagulants (DOACs) with standard warfarin treatment. Medline, Em-base, and the Cochrane databases were searched from January 2005- January 2019. The inclusion criteria were randomised controlled trials of oral anticoagulants in patients with non-valvular atrial fibrillation (NVAF). Four publications were phase III randomised control trials (RCTs) included in the final analysis. RESULTS: Regarding the primary outcome in RELY the results were 1.69% per 100-year patients (p/y) for Warfarin compared to 1.11% p/y dabigatran etexilate 150mg BD (twice daily). In ROCKET AF the rates of the primary outcome were 2.2% p/y for warfarin compared to 1.7% p/y for rivaroxaban 20 mg OD (once daily). In ARISTOTLE trial the rates of the primary outcome were 1.60% p/y for warfarin compared to 1.27% p/y for apixaban 5 mg BD. In ENGAGE AF TIMI, the rates of the primary outcome were 1.50% p/y for warfarin compared to 1.18% p/y for edoxaban 60mg BD. CONCLUSION: DOACs showed to be either noninferior or superior to warfarin with regards to the primary outcome with better safety patterns. Our ’’go-to’’ table provides a supportive tool for physicians in preventing medical errors when managing patients on oral anticoagulants.

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