The new oral anticoagulants

In patients with nonvalvular atrial fibrillation oral anticoagulation with the vitamin K antagonists acenocoumarol, phenprocoumon and warfarin reduces the risk of stroke by more than 60%, whereas single or double antiplatelet therapy is much less effective and sometimes associated with a similar bleeding risk as vitamin K antagonists. Besides bleeding, INR monitoring and high interindividual variability remain the largest drawbacks of vitamin K antagonists. In the last decade oral agents have been developed that directly block the activity of thrombin (factor IIa), as well as drugs that directly inhibit activated factor X (Xa), which is the first protein in the final common pathway to the activation of thrombin. These agents have huge advantages in that they do not need monitoring and have a fast onset and offset of action. This survey addresses the role of classical and modern anticoagulation in stroke prevention in atrial fibrillation. (Neth Heart J 2010;18:314-8.)     

New oral anticoagulant drugs: dabigatran, rivaroxaban and apixaban. Present and future

For years, prevention and treatment of thromboembolic events have been restricted to the use of heparins and vitamin K antagonists. These treatments, in spite of their unquestioned efficacy, present numerous limits (hemorrhagic risk, need for regular laboratory controls). These limits call for the development of new antithrombotic drugs. This review briefly reports on three new molecules, in very advanced phases of clinical research: dabigatran (Pradaxa?), rivaroxaban (Xarelto?) and apixaban. These molecules represent new oral anticoagulants, which directly inhibit a coagulation factor (thrombin for dabigatran, factor Xa for rivaroxaban and apixaban) and do not need regular anticoagulant monitoring or dose adjustment. The approval is still restricted in France to the prophylaxis of venous thromboembolism in orthopaedics. Dabigratran will be soon available in the prevention of stroke in atrial fibrillation. With the forthcoming phase III studies to prevent and treat venous thromboembolism, anticoagulant therapy management will be most probably improved in the coming years.     

Optimal long-term antithrombotic management of atrial fibrillation: life cycle management

Optimal antithrombotic management of atrial fibrillation equals balancing between prevention of arterial thromboembolism, predominantly ischaemic stroke, and haemorrhagic complications. Over time different antithrombotic agents and strategies have been developed. At present, non-vitamin K antagonist oral anticoagulants (NOACs) are the first-line therapy for stroke prevention in patients with non-valvular atrial fibrillation (i.e. without a mechanical valve prosthesis or rheumatic heart disease). Considering the impact of the suboptimal adoption of recommended oral anticoagulant therapy, as experienced with the previous first-line vitamin K antagonists, this review focuses on adequate use of NOACs. As such, we address the most important and clinically challenging issues in the antithrombotic life cycle management for long-term stroke prevention in atrial fibrillation.     

Anticoagulación en población anciana con fibrilación auricular no valvular. Artículo de revisión

Aging is an important risk factor for patients with atrial fibrillation. The estimated prevalence of atrial fibrillation in patients aged ≥80 years is 9–10%, and is associated with a four to five fold increased risk of embolic stroke, and with an estimated increased stroke risk of 1.45-fold per decade in aging. Older age is also associated with an increased risk of major bleeding with oral anticoagulant therapy. This review will focus on the role of oral anticoagulation with new oral anticoagulants, non-vitamin K antagonist in populations with common comorbid conditions, including age, chronic kidney disease, coronary artery disease, on multiple medication, and frailty. In patients 75 years and older, randomised trials have shown new oral anticoagulants to be as effective as warfarin, or in some cases superior, with an overall better safety profile, consistently reducing rates of intracranial haemorrhages. Prior to considering oral anticoagulant therapy in an elderly frail patient, a comprehensive assessment should be performed to include the risks and benefits, stroke risk, baseline kidney function, cognitive status, mobility and fall risk, multiple medication, nutritional status assessment, and life expectancy.     

Complex clinical scenarios with the use of direct oral anticoagulants in patients with atrial fibrillation: a multidisciplinary expert advisory board

The risk of developing atrial fibrillation (AF) and the risk of stroke both increase with advancing age. As such, many individuals have, or will develop, an indication for oral anticoagulation to reduce the risk of stroke. Currently, a large number of anticoagulants are available, including vitamin K antagonists, direct thrombin or factor Xa inhibitors (the last two also referred to as direct oral anticoagulants or DOACs), and different dosages are available. Of the DOACs, rivaroxaban can be obtained in the most different doses: 2.5 mg, 5 mg, 15 mg and 20 mg. Many patients develop co-morbidities and/or undergo procedures that may require the temporary combination of anticoagulation with antiplatelet therapy. In daily practice, clinicians encounter complex scenarios that are not always described in the treatment guidelines, and clear recommendations are lacking. Here, we report the outcomes of a multidisciplinary advisory board meeting, held in Utrecht (The Netherlands) on 3 June 2019, on decision making in complex clinical situations regarding the use of DOACs. The advisory board consisted of Dutch cardiovascular specialists: (interventional) cardiologist, internist, neurologist, vascular surgeon and general practitioners invited according to personal title and specific field of expertise.

     

Also the very elderly benefit from warfarin in atrial fibrillation

Warfarin therapy is the cornerstone in the prevention of thromboembolism in patients with atrial fibrillation. It reduces the risk of stroke by two thirds in comparison with no anticoagulation. 1 A weak alternative to warfarin is aspirin, which is also effective over placebo in the prevention of stroke in atrial fibrillation. 1 Aspirin is safer than warfarin in general use. The incidence of atrial fibrillation sharply increases with age, but also the risk of bleeding from warfarin shows the same pattern.     

Antithrombotic management of patients with atrial fibrillation—Dutch anticoagulant initiatives anno 2020

In recent years, as more and more experience has been gained with prescribing direct oral anticoagulants (DOACs), new research initiatives have emerged in the Netherlands to improve the safety and appropriateness of DOAC treatment for stroke prevention in patients with atrial fibrillation (AF). These initiatives address several contemporary unresolved issues, such as inappropriate dosing, non-adherence and the long-term management of DOAC treatment. Dutch initiatives have also contributed to the development and improvement of risk prediction models. Although fewer bleeding complications (notably intracranial bleeding) are in general seen with DOACs in comparison with vitamin K antagonists, to successfully identify patients with high bleeding risk and to tailor anticoagulant treatment accordingly to mitigate this increased bleeding risk, is one of the research aims of recent and future years. This review highlights contributions from the Netherlands that aim to address these unresolved issues regarding the anticoagulant management in AF in daily practice, and provides a narrative overview of contemporary stroke and bleeding risk assessment strategies.

     

Aspirin Compared to Low Intensity Anticoagulation in Patients with Non-Valvular Atrial Fibrillation. A Systematic Review and Meta-Analysis

Background

Despite its lack of efficacy, aspirin is commonly used for stroke prevention in atrial fibrillation. Since prior studies have suggested a benefit of low-intensity anticoagulation over aspirin in the prevention of vascular events, the aim of this systematic review was to compare the outcomes of patients with non-valvular atrial fibrillation treated with low-intensity anticoagulation with Vitamin K antagonists or aspirin.

Methods

We conducted a systematic review searching Ovid MEDLINE, Embase and the Cochrane Central Register of Controlled Trials, from 1946 to October 14^th, 2015. Randomized controlled trials were included if they reported the outcomes of patients with non-valvular atrial fibrillation treated with a low-intensity anticoagulation compared to patients treated with aspirin. The primary outcome was a combination of ischemic stroke or systemic embolism. The random-effects model odds ratio was used as the outcome measure.

Results

Our initial search identified 6309relevant articles of which three satisfied our inclusion criteria and were included. Compared to low-intensity anticoagulation, aspirin alone did not reduce the incidence of ischemic stroke or systemic embolism OR 0.94 (95% CI 0.57–1.56), major bleeding OR 1.06 (95% CI 0.42–2.62) or vascular death OR 1.04 (95% CI 0.61–1.75). The use of aspirin was associated with a significant increase in all-cause mortality OR 1.66 (95% CI 1.12–2.48).

Conclusion

In patients with non-valvular atrial fibrillation, aspirin provides no benefits over low-intensity anticoagulation. Furthermore, the use of aspirin appears to be associated with an increased risk in all-cause mortality. Our study provides more evidence against the use aspirin in patients with non-valvular atrial fibrillation.     

Anticoagulation for non-valvular atrial aibrillation - towards a new beginning with ximelagatran

OBJECTIVES: Ximelagatran is a novel oral direct thrombin inhibitor. It has favorable pharmacodynamic properties, with a broad therapeutic range without the need for anticoagulation monitoring. We aimed to discover whether ximelagatran offers a genuine future replacement to warfarin for patients in persistent atrial fibrillation (AF). MATERIALS AND METHODS: We provide an evidence-based review of the relative merits and disadvantages of warfarin and aspirin. We subsequently present an overview of the evidence for the utility of ximelagatran in the treatment of AF. RESULTS: Adjusted dose warfarin is recommended over aspirin for patients in AF at high risk of future stroke. Some of this benefit is partially offset by the higher bleeding risks associated with warfarin therapy. The SPORTIF III and V studies have shown that ximelagatran is not inferior to warfarin in the prevention of all strokes in patients with AF (both persistent and paroxysmal). This benefit was partially offset by the finding of a significant elevation of liver transaminases (>3 x normal) in 6% of patients. CONCLUSIONS: Current data would suggest that ximelagatran might represent a future alternative to warfarin. The lack of need for anticoagulant monitoring has been partially offset by a need for regular monitoring of liver function. Further data from randomized clinical trials is clearly needed.     

Treatment of nonvalvular atrial fibrillation.

Nonvalvular atrial fibrillation is an increasingly common condition. It may cause disabling symptoms and is an important risk factor for stroke. The goals of treatment include the relief and prevention of rate- and rhythm-related symptoms and the prevention of stroke and systemic emboli. Three principal treatments should be considered: pharmacologic rate control, cardioversion and antiarrhythmic therapy to restore and maintain sinus rhythm, and prophylactic anticoagulation or antiplatelet therapy to reduce the risk of stroke. The risks and benefits of each of these therapies have been reviewed. Symptoms, if present, can often be managed safely with rate-directed therapy alone. Until issues regarding safety and long-term efficacy are resolved, cardioversion and antiarrhythmic therapy should be limited to those patients whose symptoms cannot otherwise be controlled. The benefits of warfarin anticoagulation for the primary and secondary prevention of stroke in nonvalvular atrial fibrillation have been demonstrated convincingly by several randomized clinical trials. These benefits must be weighed against the real risk of major hemorrhage. For patients at low risk of stroke, the use of aspirin may be an acceptable alternative to warfarin sodium therapy.     

Continuation of vitamin K antagonists as acceptable anticoagulation regimen in patients undergoing pulmonary vein isolation

Background

Recent studies have demonstrated that radiofrequency isolation of the pulmonary veins (PVI) is an effective treatment for symptomatic atrial fibrillation. Based on these positive results, non- pharmacological therapy has been incorporated in the guidelines for drug refractory atrial fibrillation, resulting in an increased popularity. The prevention of thromboembolic complications remains an important issue.

Methods

In January 2010, we adopted an anticoagulation strategy based on continuation of vitamin K antagonists (VKAs) and selective use of transoesophageal echocardiogram (TEE). We retrospectively analysed the results of this strategy in all patients referred for PVI treatment. VKAs were started for all patients 2 months prior to treatment. Discontinuation of oral anticoagulation was considered 3 months after treatment based on thromboembolic and bleeding risk profile. Bleeding and thromboembolic complications were registered during outpatient clinic follow-up up until 3 months.

Results

We performed 151 PVI procedures from January 2010 to March 2011. All patients were seen 6 weeks after discharge. No transient ischaemic accidents or ischaemic cerebrovascular incidents occurred pre-, peri- or postprocedure. Four (2.7%) procedures were complicated by tamponade requiring pericardiocentesis.

Conclusions

Our data support the increasing evidence for continuation of periprocedural administration of VKAs complemented by a selective TEE approach as a safe therapy for thromboembolic complications.     

Antiplatelet therapy in secondary stroke prevention – state of the art

Our objective is to provide the reader with an overview as well as an update on current antiplatelet therapy for secondary stroke prevention. Relevant journals were hand-searched by the authors to compile a broad but by far not comprehensive summary of innovative and clinically relevant studies. Aspirin, clopidogrel and the combination of dipyridamole plus aspirin are the cornerstone therapy in secondary prevention after non-cardio-embolic stroke or transient ischaemic attack. A head-to-head comparison showed no difference in the prevention of recurrent stroke between dipyridamole plus aspirin and clopidogrel. More potent antiplatelet drugs or the combination of aspirin and clopidogrel prevent more ischaemic events, but also lead to more bleeding complications. For secondary stroke prevention in patients with atrial fibrillation, oral anticoagulation is more effective than aspirin or the combination of aspirin and clopidogrel.     

Equivalence and noninferiority trials – are they viable alternatives for registration of new drugs? (III)

Objectives

Ximelagatran is a novel oral direct thrombin inhibitor. It has favorable pharmacodynamic properties, with a broad therapeutic range without the need for anticoagulation monitoring. We aimed to discover whether ximelagatran offers a genuine future replacement to warfarin for patients in persistent atrial fibrillation (AF).

Materials and methods

We provide an evidence-based review of the relative merits and disadvantages of warfarin and aspirin. We subsequently present an overview of the evidence for the utility of ximelagatran in the treatment of AF.

Results

Adjusted dose warfarin is recommended over aspirin for patients in AF at high risk of future stroke. Some of this benefit is partially offset by the higher bleeding risks associated with warfarin therapy. The SPORTIF III and V studies have shown that ximelagatran is not inferior to warfarin in the prevention of all strokes in patients with AF (both persistent and paroxysmal). This benefit was partially offset by the finding of a significant elevation of liver transaminases (>3 × normal) in 6% of patients.

Conclusions

Current data would suggest that ximelagatran might represent a future alternative to warfarin. The lack of need for anticoagulant monitoring has been partially offset by a need for regular monitoring of liver function. Further data from randomized clinical trials is clearly needed.     

Anticoagulants for nonvalvular atrial fibrillation (NVAF)--drug review

Vitamin K-inhibiting anticoagulants, especially warfarin, have become standard treatment for reducing the incidence of strokes and systemic emboli in patients with nonvalvular atrial fibrillation (NVAF). The randomized controlled trials that form the scientific basis for the efficacy of anticoagulants in prophylaxis of embolic events show small but statistically significant benefit with warfarin and other vitamin K inhibitors. The generalizability of these randomized trials to clinical practice is highly questionable because of the low percentage of NVAF patients from the participating institutions that entered the trials, the relatively young age of the patients, and the superior anticoagulation monitoring compared with that in general practice. Indirect comparisons of warfarin with aspirin by looking at separate meta-analyses of placebo-controlled randomized trials give potentially biased results. The meta-analyses of trials directly comparing warfarin with aspirin have diametrically opposing conclusions. In contrast to observational studies of general medical practice, randomized trials significantly underestimate the bleeding risks of warfarin. Anticoagulants for stroke prophylaxis for NVAF cause about 17,000 major bleeds in the United States per year, of which about 4000 are fatal. In 5 randomized trials with follow-up periods of 1.3-2.3 years, 10% to 38% of patients permanently discontinued anticoagulants. The 2-year average follow up of patients in the randomized trials is too short to predict the long-term impact of anticoagulation on the natural history of NVAF. Aspirin should be preferred over anticoagulants in prophylaxis against cardiogenic embolism in NVAF patients.     

Left atrial appendage closure: outcomes and challenges

Whereas the left atrial appendage plays a rather minor role under physiological circumstances, it gains an importance in patients with atrial fibrillation. Compelling evidence has revealed that the left atrial appendage is implicated as the source of thrombus in the vast majority of strokes in atrial fibrillation. Oral anticoagulation remains the standard of care for stroke prevention in atrial fibrillation; nevertheless, this treatment has several limitations and is often contraindicated, particularly in the elderly population in whom the risk of stroke is high. Therefore, occluding the left atrial appendage is a logical approach to prevent thrombus formation and subsequent cardioembolic events in these patients. We present a review of clinical outcomes of patients with atrial fibrillation undergoing left atrial appendage closure and the challenges faced in this field.     

Optimal antithrombotic treatment of patients with atrial fibrillation undergoing percutaneous coronary intervention: triple therapy is too much!

Patients with atrial fibrillation who undergo a coronary intervention are eligible for both anticoagulation and (dual) antiplatelet therapy ((D)APT). An optimal balance has to be found to reduce the thromboembolic risk (i.e. stroke, systemic embolism and myocardial infarction) and to minimise the increased risk of bleeding with concomitant use of an anticoagulant and (D)APT. Owing to a lack of evidence, the guideline recommendations are predominantly based on expert opinion. Current evidence indicates that the combination of a non-vitamin K oral anticoagulant (NOAC) and clopidogrel is safer than vitamin-K oral antagonists plus DAPT, which increases the risk of bleeding, without clear advantages in regard to efficacy. Concerning whether (N)OACs should be combined with single APT rather than DAPT, the findings of the WOEST, PIONEER AF-PCI and RE-DUAL PCI trials seem to favour a combination with clopidogrel only, thus omitting aspirin. Choosing the optimal treatment strategies for individual patients on NOACs and (D)APT will remain a challenge for clinicians, though triple therapy seems to be the less favourable option owing to the increased risk of bleeding.     

Organisation of care for patients using direct oral anticoagulants

Direct oral anticoagulants (DOACs) are recommended by several scientific societies as first-line therapy for the prevention of stroke and systemic embolism in patients with atrial fibrillation. However, there is uncertainty regarding the organisation of anticoagulation care, with various caregivers being involved. Patients and caregivers are often confronted by uncertainty about the coordination of treatment. With the functional resonance analysis method we visualised the process of anticoagulation care in daily practice in the Maastricht region. This resulted in recommendations on how to improve the organisation of anticoagulation care for DOAC patients.

     

Economic Evaluation of Apixaban for the Prevention of Stroke in Non-Valvular Atrial Fibrillation in the Netherlands

Background

Stroke prevention is the main goal of treating patients with atrial fibrillation (AF). Vitamin-K antagonists (VKAs) present an effective treatment in stroke prevention, however, the risk of bleeding and the requirement for regular coagulation monitoring are limiting their use. Apixaban is a novel oral anticoagulant associated with significantly lower hazard rates for stroke, major bleedings and treatment discontinuations, compared to VKAs.

Objective

To estimate the cost-effectiveness of apixaban compared to VKAs in non-valvular AF patients in the Netherlands.

Methods

Previously published lifetime Markov model using efficacy data from the ARISTOTLE and the AVERROES trial was modified to reflect the use of oral anticoagulants in the Netherlands. Dutch specific costs, baseline population stroke risk and coagulation monitoring levels were incorporated. Univariate, probabilistic sensitivity and scenario analyses on the impact of different coagulation monitoring levels were performed on the incremental cost-effectiveness ratio (ICER).

Results

Treatment with apixaban compared to VKAs resulted in an ICER of €10,576 per quality adjusted life year (QALY). Those findings correspond with lower number of strokes and bleedings associated with the use of apixaban compared to VKAs. Univariate sensitivity analyses revealed model sensitivity to the absolute stroke risk with apixaban and treatment discontinuations risks with apixaban and VKAs. The probability that apixaban is cost-effective at a willingness-to-pay threshold of €20,000/QALY was 68%. Results of the scenario analyses on the impact of different coagulation monitoring levels were quite robust.

Conclusions

In patients with non-valvular AF, apixaban is likely to be a cost-effective alternative to VKAs in the Netherlands.