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CardioPulse ArticlesNew oral anticoagulants for non-valvular atrial fibrillation: harder to handle than expectedOnce-daily edoxaban: a safer option than well-managed warfarin for patients with atrial fibrillation?The Quick Test: 80 years onApixaban: a new direct oral anticoagulant for stroke prevention in atrial fibrillationNovel oral anticoagulants in the emergency room

DOI: http://dx.doi.org/10.1093/eurheartj/ehu250 1825-1830 First published online: 21 July 2014

New oral anticoagulants for non-valvular atrial fibrillation: harder to handle than expected

Many clinicians who manage coagulation therapy have long had a love–hate relationship with the vitamin K antagonist warfarin. The complexity of its use, the intricacies of INR—as well as its use as a rat poison!—have also done little to endear it to patients.

Physicians with a passion for pharmacokinetics, and especially food and drug interactions, may have been happily engaged with the drug, but others who want to help their patients with minimum complication have long sought agents like the new oral anticoagulants (NOACs): apixaban, rivaroxaban, and edoxaban are direct Factor Xa inhibitors and dabigatran is a direct thrombin (Factor IIa) inhibitor. With the exception of edoxaban, they have all been approved in Europe for non-valvular atrial fibrillation.

The hope was that the cardiologist could prescribe the appropriate dose of the appropriate NOAC and then hand the patient over to primary care for long-term management. But this scenario seems likely to be far from reality in many parts of the world. Some argue that the cost–benefit vis-à-vis warfarin is not sufficient and that NOACs are in any event not so easy to handle as expected.

General practitioners in countries those in northern Europe, including Germany, and especially Belgium, seem set to embrace NOACs for non-valvular atrial fibrillation, but in the south, and the UK, there is a reluctance to take them on. In fact, doing so is quite a challenge: it is a field that is moving extremely fast—even the acronym NOAC is being redefined as ‘non-vitamin-K-antagonist oral anticoagulants’.

To support clinicians learning how best to use NOACs for non-valvular atrial fibrillation, the European Heart Rhythm Association has produced a practical guide/executive summary, with the full text published in Europace and a short version in this journal European Heart Journal. In addition, the latest information from all sources is being posted continuously on the website www.NOACforAF.eu.

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A cardiologist who has been at the forefront of coagulation therapy for a long while is Prof. John Camm, who holds the Chair of Clinical Cardiology at St George's University of London. He chaired the ESC Guidelines for the Management of Atrial Fibrillation and its update published 2 years ago in 2012 and played a major role in the EHRA Practical Guide.

Recently back from the ACC annual scientific session in Washington DC, he gave his views on the current status of NOACs. He said: ‘They are undoubtedly better than warfarin in reducing intracranial haemorrhage and haemorrhagic stroke, with about a 50% relative reduction, but it's worth noting that the absolute risk reduction is small.

‘Warfarin is known to have a major risk reduction compared to placebo, and NOACs are presumed to do so, though no trials (against placebo) have been carried out. Also, NOACs are not as easy to use as originally envisaged. They do have some interactions, not with food, but with inhibitors of P-glycoprotein transporters, and with a number of drugs widely used in cardiology – such as verapamil and amiodarone – which will increase to various degrees the plasma concentration of a NOAC, so a lower dose of NOAC might have to be used. In primary practice if you were to concentrate on one NOAC you could manage it – but most GPs don’t want to do it. Cost is also a major factor, with NOACs costing a few Euros a day, compared with the few cents required for warfarin’.

He also outlined management of patients with kidney disease: ‘All NOACs are excreted by the kidney, so for patients with severe chronic kidney disease [CKD] the use of warfarin is still advocated. For less severe CKD lower doses of a NOAC can be used. The dose of 75 mg of dabigatran, for example, is specifically recommended for a creatinine clearance rate of 15–30 mL/minute in the United States although this dose is not approved in Europe. Similarly, the 20 mg daily dose of rivaroxaban can be downgraded to 15 mg daily and the 5 mg twice a day dose of apixaban can be reduced to 2.5 mg times a day. The situation as regards CKD with edoxaban, which has not yet been approved for use in Europe, has not been clarified’.

Prof. Camm pointed out other problems associated with NOACs, including non-compliance: ‘Because they have relatively short half-lives – about 12 hours versus about 5 days for warfarin – if patients miss 1 or 2 doses they will be unprotected, though the time to maximum plasma concentration is only 2-3 hours, so missed doses can be quickly made up. There are rules for each NOAC about what to do in these situations. Also, it should be noted that dabigatran causes dyspepsia in about 10% of patients. And, the INR test is of no use for these agents – instead, centres need to be able to use more specific and potentially expensive tests. Finally, none of the NOACs have reversal agents at present, though work is under way to devise them, but until then there are risks associated with an overdose or impaired excretion’.

One key expectation for NOACs was that the testing essential for warfarin would not to be required at all. In fact, it seems that for dabigatran at least, this may not be entirely true, as differences in excretion rates in the elderly may mean that testing is required. Much controversy has surfaced in the USA about findings that seem to point in this direction in a paper based on the RE-LY trial recently published by Dr Paul Reilly, Clinical Program Director of dabigatran's manufacturer, Boehringer Ingelheim, and others, in the Journal of the American College of Cardiology (2014; 63321–63328). They concluded: ‘Ischaemic stroke and bleeding outcomes were correlated with dabigatran plasma concentrations. Age was the most important covariate’.

It seems clear that the clinical development of NOACs is by no means complete. There are many ongoing studies likely to report within the next few years, including their possible use for cardioversion and coronary artery disease in association with AF. Until then, cardiologists with a passion for pharmacokinetics are assured of many opportunities to exercise their skills.

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Conflict of interest: Prof. A. John Camm has, in the context of NOACs, received honoraria and research grants from Bayer, Boehringer Ingelheim, Pfizer, BMS and Daiichi Sankyo.

Once-daily edoxaban: a safer option than well-managed warfarin for patients with atrial fibrillation?

Although warfarin is highly effective to reduce the incidence of ischaemic stroke in patients with atrial fibrillation (AF), it causes bleeding and has a number of practical limitations.

The introduction of target-specific oral anticoagulants (TSOACs) or novel oral anticoagulants (NOACs) in 2009 has been rightly heralded as a major therapeutic breakthrough. In a meta-analysis of the four AF trials comparing warfarin with NOACs, a >50% reduction in intracranial bleeding and 10% reduction in mortality were reported with the newer agents.1

Edoxaban is a direct-acting oral factor Xa inhibitor administered once daily with a terminal half-life of 10–14 h and 50% renal clearance.2 Like other NOACs, the onset of action is rapid, and no routine monitoring is required. Pharmacokinetic analyses demonstrated that bleeding was most strongly associated with nadir edoxaban levels, and that once-daily dosing reduced bleeding compared with the same total daily dose given twice daily.3 A phase III randomized, blinded trial of 8292 patients with symptomatic venothrombo-embolism demonstrated that edoxaban 60 mg once daily was as effective as warfarin and reduced bleeding.4

The ENGAGE AF-TIMI 48 trial5 was the largest (21 105 patients) and longest (median follow-up 2.8 years) study comparing a target-specific anticoagulant with warfarin in patients with AF at moderate risk for stroke. In a double-blind fashion patients were randomized to either a high-dose or low-dose once-daily edoxaban regimen (60 or 30 mg) or warfarin. In 25% of patients, the edoxaban dose was reduced by 50% for factors that reduced clearance, with another 9.2% undergoing dose modification after randomization. Warfarin was well-managed with a median time-in-therapeutic range (TTR) of 68.4%, with >25% of patients achieving a TTR of >77%. Only one patient was lost-to-follow-up and 1% withdrew consent to follow-up.

The primary non-inferiority analysis on-treatment showed that both regimens of edoxaban were non-inferior to warfarin in reducing stroke or systemic embolic events (SEE), with the higher dose reducing stroke/SEE by 21%. In the superiority analysis counting all events (whether on or off drug), there was a favourable trend (13% relative reduction, P = 0.08) with high-dose edoxaban vs. warfarin, and an unfavourable trend with low-dose edoxaban (13% relative increase, P = 0.10). Both high-dose and low-dose edoxaban regimens significantly reduced major bleeding (20 and 53%), intracranial haemorrhage (53 and 70%), and cardiovascular mortality (14 and 15%) when compared with warfarin. The high-dose edoxaban and warfarin groups had identical rates of ischaemic stroke, while patients receiving low-dose edoxaban experienced significantly more ischaemic strokes (41% relative).

There are several attributes of edoxaban and trial design that distinguish ENGAGE AF-TIMI 48 from prior studies. Two dose-regimens of this once-daily factor Xa inhibitor were found to be safer than and as efficacious as warfarin. Dose modifications were performed at randomization as well as afterwards, resulting in a four-fold range of doses (15, 30, and 60 mg) studied. This permitted more individualized dosing depending on patient characteristics. The high TTR achieved with warfarin, which exceeded other trials and most registries (outside of Scandinavia), lends further credibility of the superior safety profile of edoxaban vs. well-managed warfarin. Low rates of missing data further support the robustness of the data.

Further studies investigating methods to rapidly measure and reverse the anticoagulant effect of NOACs are needed. Direct comparisons would help clinicians decide which TSOAC is preferred for which patients. In the meantime, edoxaban represents a far safer and simpler alternative to warfarin for the majority of patients with AF who are at moderate-to-high risk of stroke.

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Conflict of interest: In the last 12 months, Dr. Robert P. Giugliano reports receiving consulting fees from Daiichi Sankyo, Janssen Pharmaceuticals, and Pfizer; CME lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, and Sanofi; and grant support through his institution from Daiichi Sankyo, Johnson & Johnson, Sanofi.


The Quick Test: 80 years on

Few procedures have lasted as long as the Quick Test and its later variants, but cardiologists should not accept anticoagulation data without first checking that reliable methods are being used, according to haematologist Prof. Leon Poller MD, Faculty of Life Sciences, Manchester, UK

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Leon Poller

Some believe that the advent of the new oral anticoagulants (NOACs)—recently renamed ‘non-vitamin K-antagonist oral anticoagulants’—means that the days of warfarin therapy and prothrombin time (PT) tests are numbered. Although a simple test to perform, PT measurement has been fraught with difficulties over the years and both clinicians and patients have often been anxious that the warfarin dose is not appropriate for walking the knife-edge between thrombus formation and bleeding. And yet NOACs may also be problematic, with anecdotes of patients suffering life-threatening bleeds without recourse to antidotes (though they are expected to be available in the near future).

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It is 80 years since Armand Quick first realized the value of measuring the time for plasma to clot on 6 January 1934. He observed a prolonged PT in a patient with jaundice, but ‘the results were often erratic’ (plus ça change!). After experimenting with various sources of thromboplastin, he developed a more reliable method using an extract of rabbit brain. Writing in 1959,1 he recalled: ‘Gradually I began to recognize the possible importance of the new test and was anxious to apply it clinically. In a short time we had a series of cases of obstructive jaundice with definitely prolonged clotting times as measured by the new test’.

Although Quick had chanced upon a test that was to bear his name, he acknowledged that he was benefiting from ideas that had been around for many years. A key finding, by Arthus and Pagès in 1890,2 was that blood would not coagulate if mixed with sodium oxalate, but addition of calcium restored its coagulability. However, within a decade of these promising findings the field had been hampered by ‘confused theories and poor experimental work’, according to Quick. He complained: ‘Such simple instruments of precision as the pipet [pipette] and stopwatch had not generally found their way into the physiologic and clinical laboratory …’

When 40 years later in1932, he took up the challenge, he went to work with key researchers, Drs F. Bancroft and M. Stanley-Brown, in the Pathology Department of the Fifth Avenue Hospital in New York City. He later admitted that he ‘knew nothing about blood coagulation’ and had to learn ‘the technic [technique] of the clotting time of recalcified plasma’ from a technician. To get up to speed on the subject he spent many evenings in the library, where he struggled with ‘a maze of theories’ on blood clotting. He recalled: ‘To say that the current literature of that period was bewildering is to understate the facts, A few investigators denied even the existence of prothrombin’.

Even when he had the data to show prolonged clotting times in jaundiced patients, three editors of the American Journal of Physiology unanimously rejected his paper (although Quick notes rather tartly that 10 years later ‘the material contained in that article’ won him a gold medal from the American Medical Association). A year later, however, the same journal did publish the work. The ‘Quick Test’ had been born, though it was to undergo many developments and extensions, including the use of the prothrombin ratio (PR) and the international normalized ratio (INR), based on the ISI (International Sensitivity Index) assigned by each manufacturer of the tissue factor being used.

The main driver for these developments was to make PT testing and coagulation therapy as effective and as safe as possible. For the past 20 years much has been done to improve matters in this direction by European Action on Anticoagulation (EAA), a cooperative of haematologists in 34 centres, chaired by Prof. Jørgen Jespersen (University of South Denmark, Esbjerg, Denmark) with project leader Prof. Leon Poller (Central Facility, Faculty of Life Sciences, University of Manchester, UK).

Commenting on current measurements of coagulability, and describing the latest development of a test, called the PT/INR Line (alby.pattison{at}hartbio.co.uk), Prof. Poller said: ‘PT testing is still done badly. It's getting the right result that is the problem. Technicians often assume that the manufacturers’ value of ISI for INR measurement are correct and there is very little quality control. Even with the same manufacturer in the same lab the data can be different! An attempt by the WHO to improve matters some years ago, based on plasma tests from 20 centres, failed – it was too complex! So, we have now come up with a method based on only 5 plasma samples, from which every laboratory can calibrate its coagulometer by drawing a regression line. It will probably be some while before the PT/INR Line method is widely taken up, as people don't yet know how easy it is to use. Another development that would improve the safety of anticoagulation therapy is the use of variance growth analysis (VGA) instead of the traditional “time in therapeutic range”. Of the several statistical formulae proposed for this, we have carried out trials showing that VGA is the most accurate′.3

An editorial in April 2014, a forum paper by Prof. Poller and others in the Journal of Thrombosis and Haemostasis4 compared the rates of adverse events in the warfarin arm of the RE-LY study and a similar study of atrial fibrillation with warfarin carried out by EAA with much more rigorous PT testing. The authors wrote: ‘Only in the EAA study was the reliability of reported INR at participant centres checked by centrally organized local ISI calibrations and by external quality control of reported INR’.

They point out that the different results between the warfarin arms of the EAA and RE-LY studies are quite marked, suggesting that although adverse events in the dabigatran arm of the RE-LY study were lower than in the warfarin arm, those achieved in the EAA study were very much lower, though the EAA authors offer no statistical comparisons (Table 1).

View this table:
Table 1

Comparison of warfarin results in the RE-LY and EAA studies

The implication is that greater attention to calibrating PT tests with warfarin might deliver better outcomes than NOACs, though more studies are required.

Armand Quick might be amused. His earliest work was bedevilled by erratic results and it seems that rather than coming to an end, his test might be due for a new life, once laboratories have grasped the significance of rigorous calibration procedures.

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Apixaban: a new direct oral anticoagulant for stroke prevention in atrial fibrillation

Dr Stefan H. Hohnloser reports on the results of the ARISTOTLE and AVERROES trials

Atrial fibrillation is the most common heart rhythm disorder encountered in clinical practice and is associated with significant morbidity and mortality, mostly due to thrombo-embolic complications. Hence, the most important therapeutic goal is stroke prevention (SP). For this purpose, a vitamin K antagonist (VKA) has been used in the past, but this medication is difficult to apply, has a small therapeutic window, and is often underused due to its perceived inherent bleeding risk. Therefore, several new direct oral anticoagulants have been developed to overcome the limitations of VKAs.

Apixaban is a novel oral direct factor Xa inhibitor which has been evaluated in two major phase III trials, the ARISTOTLE trial, comparing apixaban to warfarin for SPAF and the AVERROES trial against aspirin.

In ARISTOTLE, apixaban was superior to warfarin in reducing stroke or embolism [HR: 0.79; 95% confidence interval (CI), 0.66–0.95; P < 0.001 for non-inferiority; P = 0.01 for superiority] and safer than VKA therapy (HR for major bleeding 0.69; 95% CI: 0.60–0.80; P < 0.001). There was an 11% reduction in total mortality in the apixaban relative to the warfarin group (P = 0.047). As one of the most important results, it was noted that apixaban was associated with a 58% reduction in the risk for intracranial bleeding complications (P < 0.001) underscoring the vastly improved safety profile of this direct anticoagulant over VKA.

The AVERROES trial had to be stopped prematurely due to the overwhelming efficacy of apixaban over aspirin: the HR for stroke/peripheral embolism was 0.45 (95% CI: 0.32–0.62; P < 0.001) favouring apixaban over aspirin. Concerning the primary safety endpoint, major bleeding, there was no significant difference between both treatment arms (HR with apixaban, 1.13; 95% CI: 0.74–1.75; P = 0.57).

Subsequent post hoc subgroup analyses from these two pivotal trials confirmed the consistency of the primary study outcomes. For instance, the superior efficacy but particularly the reduced bleeding risk with apixaban relative to warfarin was maintained irrespective of the quality of INR control (measured as time in therapeutic range) in the warfarin arm of the ARISTOTLE trial. It was also demonstrated that the beneficial effects of apixaban were preserved across all ranges of stroke risk (estimated by the CHADS2 or the CHA2DS2VASc risk scores) both with respect to SP and to reduction in bleeding complications.

Two additional substudies from ARISTOTLE deserve mention; the first one concerned patients with mild-to-moderate renal insufficiency. These patients had better efficacy (SP) but particularly much less risk of major bleeding complications when they were randomized to apixaban relative to warfarin. Finally, given the large number of patients enrolled in the two pivotal apixaban trials, the efficacy and safety of the new compound could be determined not only for primary SPAF but also for secondary SP in subjects who had a prior history of stroke or TIA at randomization. In these patients, the effect size in reducing subsequent stroke or peripheral embolism with apixaban was even larger than that observed in primary prevention. Importantly, the risk of intracranial bleeding continued to be significantly lower for apixaban than for warfarin in secondary prevention patients.

Apixaban, therefore, now belongs to the best studied new direct oral anticoagulants. There remains the need for further studies to elucidate the efficacy and safety of this compound in specific subsets of patients. Consequently, studies are in the planning phase to examine AF patients scheduled for pacemaker/ICD surgery, cardioversion, or catheter ablation. These studies should help to further define the therapeutic potential of apixaban.

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Conflict of interest: S.H.H. has served as a consultant, advisor, or speaker for: Bayer Healthcare, BMS, Boehringer Ingelheim, Boston Scientific, Cardiome, Forest RI, Gilead, J&J, Medtronic, Otsuka, Pfizer, Portola, Sanofi aventis, Servier, St. Jude Medical.

Novel oral anticoagulants in the emergency room

Hans-Christoph Diener presented essential information for the management of patients with acute events whilst taking novel oral anticoagulants, at the American Heart Association/American Stroke Association International Stroke Conference in 2014

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Hans-Christoph Diener

Novel (NOACs) or direct (DOACs) oral anticoagulants will replace warfarin in the new future for stroke prevention in patients with atrial fibrillation. This poses a particular challenge when patients treated with DOACs are admitted to an emergency room because of an ischaemic stroke, an intracerebral bleed, or a major extracerebral bleed.

If a patient on a NOAC suffers a transient ischaemic attack or minor stroke, treatment can be continued. In patients with moderate or severe ischaemic stroke, the anticoagulation should be interrupted for 6–12 days. Resumption of the anticoagulation is dependent on a control CT or MRI excluding significant haemorrhagic transformation or a bleeding into the ischaemic area.

In patients with intracerebral or subarachnoid haemorrhage anticoagulation has to be stopped. Systemic thrombolysis with rt-PA, the only approved drug treatment for ischaemic stroke in a 4.5 h window is contraindicated in patients on a NOAC. In cases where the last intake is >48 h earlier, rt-PA might be considered in patients with normal renal function. A normal TT or a PTT in a patient on dabigatran would indicate that it might be safe to perform thrombolysis. A normal PT is a possible indicator for patients on rivaroxaban that rt-PA might be given. A biomarker reflecting that the biological activity of apixaban or edoxaban in the ER is not available at present.1

During the RE-LY trial 154 intracranial bleeds occurred.2 Some 46% of the haemorrhages were parenchymal bleeds, 45% traumatic or spontaneous subdural haematoma, and 8% subarachnoid haemorrhages. The rate of intracranial bleeds was dramatically reduced compared with warfarin. This is also true for the other NOACs, apixaban, edoxaban, and rivaroxaban.3 Despite the fact that most patients with intracranial bleeds on warfarin were treated with vitamin K, the mortality was similar in patients on warfarin or dabigatran (35–41%).

An important development is the implementation of a specific antidote against the new anticoagulants. A humanized antibody against dabigatran has been investigated successfully in animal models and healthy human volunteers.4 There are several small molecules that block the activity of factor Xa inhibitors.5

Dr Diener concluded, ‘At present we have no scientific data on how to best treat major bleeding complications in patients treated with NOACs. Possible options include prothrombin complex or recombinant factor VIIa. A big advantage of the NOACs is their short half-life and elimination if intake is discontinued’.

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Conflict of interest: Prof. Hans-Christoph Diener received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from: Abbott, Allergan, AstraZeneca, Bayer Vital, BMS, Boehringer Ingelheim, CoAxia, Corimmun, Covidien, Daiichi-Sankyo, D-Pharm, Fresenius, GlaxoSmithKline, Janssen-Cilag, Johnson & Johnson, Knoll, Lilly, MSD, Medtronic, MindFrame, Neurobiological Technologies, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, Syngis, Talecris, Thrombogenics, WebMD Global, Wyeth and Yamanouchi. Financial support for research projects was provided by AstraZeneca, GSK, Boehringer Ingelheim, Lundbeck, Novartis, Janssen-Cilag, Sanofi-Aventis, Syngis and Talecris. The Department of Neurology at the University Duisburg-Essen received research grants from the German Research Council (DFG), German Ministry of Education and Research (BMBF), European Union, NIH, Bertelsmann Foundation and Heinz-Nixdorf Foundation. HCD has no ownership interest and does not own stocks of any pharmaceutical company.