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An Update on Anticoagulation in Atrial Fibrillation
REVIEW
Heart, Lung and Circulation (2017) 26, 911–917 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2017.05.131
An Update on Anticoagulation in Atrial Fibrillation John Amerena, MBBS, [5_TD$IF]FRACP, FCSANZ a*, Daryl Ridley, MBBS, FRACP, FCSANZ b[5_TD$IF] Deakin University, Geelong, [6_TD$IF]Vic, Australia University Hospital, Geelong, [6_TD$IF]Vic, Australia
a
b
Online published-ahead-of-print 3 June 2017
Cerebrovascular [9_TD$IF]accidents related to atrial fibrillation (AF) are potentially preventable with anticoagulation. Until recently, warfarin was the only proven anticoagulant to be effective in stroke prevention, however the novel, direct acting oral anticoagulants (DOACs) are now available, triggering a paradigm shift in treatment philosophy. Today, physicians need to consider in which patients anticoagulation should not be used rather than, as in the past, deciding in which patients it should be used. Although warfarin will continue to have a place [10_TD$IF]in managing some patients with AF, in the future, the DOACs should be the predominant therapy for stroke prevention in patients with non-valvular AF. Keywords
Anticoagulation Atrial fibrillation Warfarin Novel anticoagulants
Introduction Atrial fibrillation (AF) is the commonest cardiac arrhythmia and its prevalence is expected to increase globally, and in Australia, over the next 20 years [1]. The incidence of AF increases with age, and is present in around 15% of the population aged above 80 years, so is by far the commonest cause of stroke in this age group. Identification of AF and appropriate institution of anticoagulation is therefore the largest potential way to prevent stroke in this population. Ischaemic stroke is the most common cause of cerebrovascular accident in Australia and 75% of these strokes are directly related to atrial fibrillation [2]. The proportion of stroke from cardioembolic sources rises with age [3], so that 35% or more of stroke in patients over 80 years of age is [1_TD$IF] cardiac in origin, mostly due to AF. Atrial fibrillation causes incomplete and sluggish emptying of the left atrial appendage (LAA) and this is [12_TD$IF]the site where thrombus forms, although thrombus can occasionally be seen in the left atrium itself. These LAA thrombi tend to be large, and when they dislodge and embolise, stroke or peripheral embolisation are the common outcomes. Strokes associated with atrial fibrillation tend to be larger, and are more likely to be fatal or
disabling [4]. Given this mechanism, strokes related to AF are potentially preventable with anticoagulation.
Valvular or Nonvalvular Atrial Fibrillation? Atrial fibrillation is commonly classified as being either valvular or non-valvular in origin, which is an important distinction as it influences the choice of treatment options available for stroke prevention in these patients. The majority of patients with AF have non-valvular AF (NVAF) with the minority having AF associated with valvular heart disease. The definition of valvular/non-valvular AF has been a little confusing over recent years, as American and European definitions are somewhat different. The current AHA/ACC definition of valvular heart disease states that valvular AF is that which is associated with rheumatic mitral stenosis, prosthetic heart valves (metallic or bioprosthetic) and mitral valve repair [5]. This is a fairly broad definition and many clinicians would not agree that mitral valve repair or a bioprosthetic valve is truly valvular heart disease, as, after an initial period of anticoagulation,
*Corresponding author at: [8_TD$IF]4th Floor Kardinia House Bellerine Str Geelong 3220., Email: [email protected] © 2017 Published by Elsevier B.V. on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
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these valvular conditions do not require anticoagulation in their own right. According to these guidelines, anticoagulation with a vitamin K antagonist (VKA), such as warfarin, is recommended for stroke prevention in patients with valvular heart disease, whereas VKA or one of the direct acting oral anticoagulants (DOACs) can be used in patients with NVAF. The latest definition from the European Society of Cardiology (ESC) in 2016 is simpler, and states that valvular heart disease is confined to moderate to severe mitral stenosis or metallic prosthetic heart valves, and that everything else should be considered non-valvular [6]. The ESC recommended that VKAs be used for anticoagulation in patients with valvular heart disease, and that a VKA or DOAC can be used in patients when the valvular heart disease does not require anticoagulation in its own right. This includes patients with a mitral valve repair or bioprosthetic valves after the initial implantation, and also patients with mitral regurgitation, tricuspid regurgitation, aortic incompetence and aortic stenosis which are not haemodynamically significant enough to require intervention. This ESC definition has removed a lot of the confusion about what is valvular and non-valvular AF and we would encourage Australasian clinicians to follow these latest guidelines.
Who to Anticoagulate? All patients with AF associated with valvular heart disease should be considered for anticoagulation with a VKA, as the stroke risk is high without anticoagulation. The decision to anticoagulate patients with NVAF for stroke prevention depends on their risk of stroke, and there are several risk scores that can be used to evaluate stroke risk in these patients. The traditional stroke evaluation tool has been the CHADS2 score which assigns points to various risk factors (see [13_TD$IF]Table 1) and is good at evaluating the risk of stroke in relatively high risk patients but is not good at identifying patients who are at low risk of stroke and thus do not require anticoagulation [7].
Because of this lack of discrimination in low-risk patients, the CHA2DS2-VASc score has been developed [8], and has largely superseded the CHADS2 score. The authors of [14_TD$IF]these guidelines reviewed epidemiological and registry data looking at the risk of stroke related to various risk factors and have incorporated the CHADS2 risk factors in the score and have upgraded age >75 years to the same level of risk as previous stroke, and have also included vascular disease, age >65 years and female gender as significant risk factors for stroke, although the magnitude of gender associated risk has been questioned recently. The score has been validated in large populations and is now the most widely used tool for stroke risk assessment in UK, Europe and Asia Pacific. The real advantage of the CHA2DS2-VASc score is that it is better at identifying truly low-risk patients who would not benefit from anticoagulation and thus not be treated inappropriately. The current US guidelines advise that if the CHADS2 score is >/ = 2 for men or women anticoagulation is recommended but that if the CHADS2 score is 1, anticoagulation or aspirin can be considered depending on the individual patient characteristics and preferences [5]. In a patient with a CHADS2 score of 0, neither anticoagulation nor aspirin is recommended in these [15_TD$IF]American guidelines [5]. The most recent iteration of the European guidelines has recommended that, if men have a CHA2DS2-VASc score of >/ = 2, anticoagulation should be used for stroke prevention, but if the CHA2DS2-VASc score is 1, it should be considered, depending on patient characteristics and preferences [6]. For females, there has been a liberalisation of the recommendations for anticoagulation due to the recognition that female gender is a relatively weak risk factor for stroke. The latest guidelines advise that if a female has a CHA2DS2-VASc score of >/ = 3, anticoagulation is recommended, but if the score is 2, anticoagulation be considered. If the CHA2DS2-VASc score is 0 in men and women or is 1 in a woman, neither anticoagulation nor aspirin is necessary. Although these latest recommendations have been validated, the more liberal risk score for females has yet to be adopted in clinical practice in Australia. These guidelines have also stated that the DOACs are to be preferred over VKA for stroke prevention in NVAF. Australian guidelines for stroke prevention in NVAF are being currently written under the auspices of the CSANZ.
[4_TD$IF]Table 1 Risk score. Risk Score CHADS2
Risk Factors
Risk Score CHA2DS2-VASc
1
Chronic heart failure
1
1
Hypertension
1
1 1
Age ( 75) Diabetes
2 1
2
Stroke/TIA
2
Vascular disease (CAD/MI)
1
Age (65–74)
1
Sex category (female gender)
1
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The CHADS2 and CHA2DS2-VASc scores are good at quantifying the risk of stroke in patients with NVAF, but their ability to do so is far less than ideal. The C statistic for the CHA2DS2-VASc score in stroke prediction is around 0.68, indicating it will correctly predict the risk in about 68% of cases. On this basis, several other scores have been developed, such as the ABC score from the Duke investigators participating in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study [9], and by investigators running The Global Anticoagulant Registry in the FIELD (Garfield) Registry [10], which may have greater predictive ability than CHA2DS2VASc. These new risk scores are web based and incorporate clinical and non-clinical factors in their scoring system, such as biomarkers [16_TD$IF]such as troponin and BNP. This being the case, their applicability may be limited, as some of the risk factors included in them are not routinely measured in patients with NVAF, and have yet to be widely validated in population studies. We cannot see them being widely used in clinical practice in Australia in the near term, even though their predictive capacity may be greater than the CHA2DS2-VASc score. The risk of bleeding must always be taken into account when considering anticoagulation. Physicians often tend to do this intuitively, but the HAS-BLED score [8] has been developed to allow a more systematic and objective assessment of bleeding risk to be made. Using this score, one can stratify patients into low, intermediate or high risk of bleeding, and make appropriate decisions taking this into account. The HAS-BLED score should be used to identify potentially reversible bleeding risks, such as controlling BP or discontinuing aspirin, but a high HASBLED score should not be used as an excuse not to anticoagulate patients with a CHAD2S2VASc score that would justify anticoagulation, as the net clinical benefit is still in favour of anticoagulation [11].
Aspirin For Stroke Prevention in Non-Valvular AF Aspirin has often been used as a default antithrombotic agent in patients with non-valvular AF on the assumption that it will reduce the risk of stroke. Aspirin is commonly used in patients deemed to be unsuitable for anticoagulation due to age, frequent falls or impaired cognitive function but the evidence supporting its usefulness for this indication is weak. Several studies have examined aspirin for stroke prevention in NVAF, and, in general, the point estimates hover around unity, with wide confidence intervals. The only study that was definitively positive for aspirin was in the Stroke Prevention in Atrial Fibrillation (SPAF) II study in which there was a statistically significant reduction of 42% over placebo [12]. In aggregate, at best, there is a 20% reduction in stroke rates with aspirin use in patients with non-valvular AF but the confidence intervals hit one indicating borderline significance [13].
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The effectiveness of aspirin as an antithrombotic agent to reduce stroke in NVAF was examined in the Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) study [14]. Patients who were deemed to be ineligible for anticoagulation with a VKA, for a variety of reasons (such as labile international normalised ratios [INRs], predisposition to falls, patient unwillingness to take anticoagulation, and physician discretion), were randomised to apixaban or aspirin in a randomised, double blind clinical trial. This study was stopped prematurely after 18 months due to a significant benefit from apixaban over aspirin with a 55% reduction in the risk of ischaemic stroke. Unexpectedly, it was also found that the rates of clinically relevant bleeding with aspirin and apixaban in this population were comparable, and although there were numerically more bleeds with apixaban this was not significant. As well, apixaban was better tolerated than aspirin with less patient discontinuations in the apixaban arm. In recognition of this data the European guidelines [8] have recommended that aspirin [17_TD$IF]not be used for stroke prevention in patients with NVAF, and should only be considered in patients who refuse to take any form of oral anticoagulation, with the recognition that if aspirin is given for this indication, the risk of bleeding is similar to that seen with oral anticoagulants (based on the AVERROES study). The British Heart Foundation NICE guidelines have gone even further, and have advised that aspirin never be used for stroke prevention in NVAF [15]. In Australia, aspirin is still frequently used to reduce stroke risk in many patients with high CHA2DS2-VASc scores who would benefit from anticoagulation. This may well make the physician feel better as they perceive that feel they are doing something to reduce stroke risk, but the evidence would suggest this is not the case. Our opinion would be, that if aspirin use is being considered in this population, contemplating using low-dose NOAC therapy should be also considered, particularly with apixaban, given the recent clinical trial results.
Warfarin for Stroke Prevention in Non-Valvular AF Warfarin has been the standard anticoagulant for stroke prevention in NVAF for the last 60 years. Warfarin was identified as an antithrombotic when cows in Wisconsin were found to be bleeding after ingesting clover. The Wisconsin Alumni Research Foundation discovered that the substance in the clover that caused anticoagulation was an ‘‘ARIN”, hence the name warfarin. Warfarin was used as a rodenticide for many years, hence patients often refer to it as ‘‘rat poison”. Warfarin was introduced to clinical practice as an anticoagulant in the 1960s and underwent extensive clinical trials to demonstrate efficacy in reducing strokes in patients with
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NVAF. The seminal trial was the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation (SPINAF) trial, which was a randomised, double blind trial which definitively proved that warfarin reduced stroke rates and death in patients with NVAF [16]. In aggregate, warfarin reduces stroke rates in NVAF by about 70% compared to no treatment and reduces mortality by about 30% [13]. On the basis of this, warfarin became the standard of care for this indication, as there were no other oral agents available. Although warfarin is extremely effective in reducing stroke and mortality in patients with NVAF, it is a difficult drug to use in clinical practice. Warfarin has a slow onset and offset of action and has multiple drug and food interactions. It requires constant monitoring in an attempt to keep the INR within the therapeutic range of 2–3, as if it is <2 there is an increased risk of stroke and >3 an increased risk of bleeding, particularly intracerebral. Intracranial haemorrhage (ICH) is the most feared complication of warfarin and although annual rates are low, this is a devastating and often fatal event. There seems to be an increased risk of bleeding and ICH with warfarin in Asian populations (even in patients whose INR is in the therapeutic range) and in response to this, the target INR in Asian countries is often lower at 1.5–2 rather than the recommended 2–3 in Western populations, although there is little clinical trial data to support this [17– 19]. Even in the best centres, the time in therapeutic range (TTR) is around 70% at best, and more often around 50–60%, as documented in clinical trials and in an Australian context [20,21]. Alternatives to warfarin have, therefore, been long awaited and the new direct acting oral anticoagulants (DOACs) have filled this void.
Novel Direct Acting Oral Anticoagulants in Stroke Prevention Research The development of the novel anticoagulants has revolutionised the management of stroke prevention in patients with NVAF. Until recently, warfarin was the only proven anticoagulant to be effective in this regard, but several large clinical trials have demonstrated that the direct acting anticoagulants have the potential to replace warfarin for this indication [22–25]. The current direct acting anticoagulants available in Australia are the direct thrombin inhibitor dabigatran, and the factor Xa inhibitors rivaroxaban and apixaban. These agents have similarities and differences which are clinically significant. All the agents are active orally and despite having similar half-lives, have been tested in once-daily dosing for rivaroxaban and twice daily dosing for dabigatran and apixaban [23–25]. They have a rapid onset of action so that within one to two hours of dosing full anticoagulation is achieved [26–28]. They also have a rapid offset of action compared with warfarin, so that within 24 hours of taking the last dose the majority of anticoagulant effect has disappeared. Excretion is, however, affected by renal function, with dabigatran being highly dependent on renal excretion, as 85% is excreted
J. Amerena, D. Ridley
unchanged in the urine, whereas apixaban and rivaroxaban are 27% and 33% excreted renally. Thus, in the presence of renal dysfunction, a longer treatment discontinuation is required to allow coagulation status to return to normal, which is important if the patient requires surgery. There are minimal food interactions with the new agents, although it is recommended that rivaroxaban and dabigatran be taken with meals to improve absorption and to reduce the risk of dyspepsia respectively. Although the bioavailability of dabigatran is low (5%) it is affected by P-glycoprotein inhibitors such as verapamil and amiodarone, but there are few other clinically significant drug interactions with this drug. Rivaroxaban and apixaban have potential interactions with agents metabolised by the cytochrome P450 system, but most of these medications are not commonly encountered in the clinical cardiovascular practice. None of the new agents require routine monitoring to evaluate the extent of anticoagulation, and the relationship between standard measures of anticoagulation such as the INR and activated partial thromboplastin time (APTT) and drug levels is nonlinear, and thus not helpful in determining the extent of anticoagulation [29]. These tests can be used to assess compliance with treatment (increased levels) or to assess if an active drug is likely to be in the circulation, as normal levels of these parameters would suggest very little if any active drug is present, making it safe to have surgery. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study [23], was the first study published comparing the direct thrombin inhibitor dabigatran versus warfarin in patients who with NVAF who had >/ = 1 risk factors for stroke. It was an open label study, using a prospective randomised open blinded end-point (PROBE) design, testing the efficacy (stroke prevention and systemic embolism) and safety of 110 mg BD and 150 mg BD against warfarin (target INR 2–3). The higher dose was superior to warfarin in reducing stroke and systemic embolism and, in particular, there was a significant reduction in ischaemic stroke compared with warfarin. At this dose, there was comparable bleeding to warfarin, but post hoc analysis found there was excess gastrointestinal bleeding in patients aged >75 years [30] and thus it has been recommended that the lower dose be used in this age group. The 110 mg BD dose was shown to be non-inferior to warfarin in reducing stroke and embolism in patients with NVAF, but had lower rates of bleeding, although this advantage was attenuated in patients >75 years or those who had moderate degrees of renal impairment [30]. Both doses however significantly reduced the risk of ICH compared with warfarin. The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study [24] examined rivaroxaban versus warfarin in patients with >/ = 2 risk factors for a stroke, and in fact the average CHADS score in this study was 3.5 compared with 2.1 in both the RE-LY and ARISTOTLE studies. In ROCKET–AF, there was a lower time within the therapeutic range (TTR) of 55% than in that the RE-LY or ARISTOTLE
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studies, perhaps because of an increased number of patients with heart failure compared with the other studies, compounded by a different means of calculating the [18_TD$IF]3TTR. The majority of patients received the full dose of 20 mg once daily but there was a dose reduction to 15 mg in patients whose creatinine clearance rate was <50 mL/min. Both doses showed similar efficacy to warfarin in reducing stroke and embolism, and there was similar bleeding, although there was an excess in gastrointestinal haemorrhage compared with warfarin. Both doses showed a significant reduction in ICH. In pre-specified statistical analysis, an on-treatment safety analysis showed superiority to warfarin in terms of stroke/systemic embolism, but this claim was not accepted by regulatory authorities in Australia or the US where the agent has been registered on the basis of non-inferiority. As with dabigatran and apixaban, there was a significant reduction in ICH, and a trend towards a decrease in all-cause mortality. The ARISTOTLE study [25] looked at a similar population of patients with NVAF as the RE-LY study. To be eligible, the patient had to have >/ = 1 risk factor for stroke, and, in fact, the average CHADS score in RE-LY and ARISTOTLE was identical at 2.1. The TTR in ARISTOTLE with similar to that in RE-LY at 62% and 64%, respectively, but ARISTOTLE was a double-dummy double-blind study. Apixaban was given at 5 mg BD to 95% of participants but a dose reduction to 2.5 mg BD was used in a small number of patients who had two criteria out of age >80 yrs, serum creatinine level >133 mg/ dL or body weight <65 kg. The study showed that apixaban was superior to warfarin in stroke reduction and systemic embolism, which was driven primarily by a reduction in haemorrhagic stroke with a similar ischaemic stroke reduction compared with warfarin. Major and clinically relevant non-major bleeding was significantly less with apixaban than with warfarin, and ICH was also significantly reduced. Although there were strong trends with dabigatran and rivaroxaban for reduction in total mortality compared with warfarin, apixaban was (nominally) statistically significant in this regard (p = 0.048). Edoxaban (which is not available in Australia) has also been studied in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation (ENGAGE AF) study [31]. This was a double-dummy double-blind study looking 30 and 60 mg once daily edoxaban versus warfarin, with the same efficacy and safety endpoints as the other studies. The 30 mg dose was disappointing in that it showed more strokes compared with warfarin but less bleeding, whereas the 60 mg dose showed less strokes than warfarin but similar bleeding. Somewhat paradoxically, patients with preserved renal function did worse than those with impaired renal function, suggesting that high levels of renal excretion in patients with normal function could lower effective dose levels within the circulation.
Bleeding When any anti-thrombotic agent is used, there is an increased risk of bleeding, whether it be with aspirin alone, dual
antiplatelet therapy or anticoagulation with warfarin or one of the new agents. Warfarin can be reversed acutely with prothrombin complex concentrate (3 or 4 factor) but this only lasts for hours at a time. Vitamin K is often used to reverse the anticoagulant effects of warfarin, but this relies on production of clotting factors by the liver so it often takes six to eight hours to have an effect. It is difficult to compare the bleeding rates between the different new agents, as, although the primary endpoint for efficacy was the same, there were different definitions for bleeding. Bleeding was extensively evaluated in all the clinical trials with these new therapies, and was comparable to or less than warfarin in all the studies [32]. If bleeding did occur, however, the outcome was generally better if the patient had a bleeding event on the new agent compared with warfarin, despite the lack of a reversal agent being available [33–35]. One of the concerns in clinical practice, with the introduction of the new agents, is that there has been no reversal agent available for any of them. However, in recent times, the specific reversal agent for dabigatran, idarucizumab, has become available. It is a monoclonal antibody specifically targeting dabigatran, and has been tested in the RE-VERSE AD study [36], an update of which was recently published [37]. In this study, idarucizumab was given to patients who were bleeding on dabigatran or in whom urgent surgery was required. Although this was an open label study, patients who were bleeding were easier to manage and patients who required urgent surgery did not bleed excessively in the majority of cases. This agent is given in 2 5 Ml boluses over several minutes, and has been shown to effectively reduce the plasma levels of dabigatran for a prolonged period of time. It is now available in Australia and is TGA approved. Andaxanet Alfa is a potential reversal agent targeting factor Xa inhibitors. That is, it has the potential to block the effects of rivaroxaban, apixaban, edoxaban and low molecular weight heparin, and is currently undergoing phase three clinical trials. Preliminary data was published recently [38], looking at the effect of andenaxet-alfa infusion in patients who were bleeding whilst taking rivaroxaban and apixaban. Andenaxet alfa reduced the levels of these agents within the circulation, but when the infusion stopped, the levels started to rise again. Bleeding was more manageable when Andaxanet alfa was used in this context, but its use in patients who require urgent surgery while taking factor Xa inhibitors has not been evaluated. This agent has been approved for reversal in the US by the FDA, but is unlikely to become available in Australia for several years.
Clinical Use of the Novel Anticoagulants Depending on the agent used, and dose chosen, all the nonVitamin K dependent anticoagulants are superior to, or noninferior to, warfarin in reducing stroke and systemic
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embolism. With respect to bleeding, superiority or non-inferiority compared with warfarin is also seen but it is difficult to compare bleeding rates amongst the studies as the definitions for bleeding were different. All the new agents, at all doses, significantly reduced ICH compared to warfarin. The latest AF guidelines recommend that men who have a CHA2DS2-VASc score of >/ = 2 and women whose score is >/ = 3 should be anticoagulated to reduce stroke risk if they have NVAF, and the ESC has strongly preferred the novel agents to warfarin. In Australia, these agents have been taken up avidly and practice patterns show that new initiations of anticoagulation are increasingly with the new agents. In patients who are on warfarin, those with unstable control are good candidates to swap to a new agent. Patients who do not like having routine blood tests or have difficulty accessing monitoring, such as if they live in remote or regional areas, are also good candidates to swap, as well as those patients who have difficulty adhering to the dietary requirements that are necessary to maintain good control in patients taking a VKA. In patients who are stable on warfarin with good control of their INR, it is not obligatory to swap to a new agent, as many patients feel comfortable with having their routine blood test infrequently to assess their control and reassure them. However, it would be prudent in this stable patient population to discuss that there are new agents available that have advantages over warfarin, particularly with respect to reducing ICH, and that it would be reasonable and justifiable to swap to a new agent should they wish to do so.
J. Amerena, D. Ridley
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Conclusions In summary, the novel anti-coagulants are now available for stroke prevention in patients with NVAF, and have really triggered a paradigm shift in treatment philosophy in this area. We are now encouraging physicians to consider in which patients should anticoagulation not be used when they see patients with NVAF, whereas, in the past, the opposite emphasis was to consider in which patients should we use anticoagulation. All the new agents are more effective than, or similar to, warfarin in terms of stroke reduction and bleeding, depending on the agent chosen and dose used, and our feeling is that, as time goes on, they will replace warfarin for this indication. Warfarin will still need to be used for patients who have valvular AF (metallic prosthetic heart valves and mitral stenosis) and those with NVAF and severe renal dysfunction, but, in the future, the new agents should be the predominant therapy for stroke prevention in patients with NVAF, given the impressive safety and efficacy results found in the clinical trials, and the greater patient acceptability of these new agents compared with warfarin.
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
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[22] Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet 2014;383(9921):955. [23] Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12): 1139. [24] Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. ROCKET AF Investigators Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(10):883. [25] Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. ARISTOTLE Committees and Investigators Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11): 981. [26] Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost 2009;15(Sep–Oct (Suppl 1)). 9S–16S.. [27] Kreutz R. Pharmacokinetics and pharmacodynamics of rivaroxaban–an oral, direct factor Xa inhibitor. Curr Clin Pharmacol 2014;9(Feb (1)):75–83. [28] Frost C, Nepal S, Wang J, Schuster A, Byon W, Boyd RA, et al. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol 2013;76(Nov (5)):776–86. [29] Chan NC, Bhagirath V, Dale BJ, Eikelboom JW. Evaluating coagulation tests in patients with atrial fibrillation using direct oral anticoagulants. Expert Rev Cardiovasc Ther 2015;13(Nov (11)):1213–23. [30] Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulanttherapy (RELY) trial. Circulation 2011;123(May (21)):2363–72. [31] Eisen A, Giugliano RP, Ruff CT, Nordio F, Gogia HS, Awasty VR, et al. Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: An analysis
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from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial. Am Heart J 2016;172(Feb):144–51. Kakkos SK, Kirkilesis GI, Tsolakis IA. Editor’s Choice – efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials. Eur J Vasc Endovasc Surg 2014;48(Nov (5)):565–75. Chai-Adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2015;13(Nov (11)):2012–20. Xu Y, Schulman S, Dowlatshahi D, Holbrook AM, Simpson CS, Shepherd LE, et al. Bleeding Effected by Direct Oral Anticoagulants (BLED-AC) Study Group. Direct oral anticoagulant- or warfarin-related major bleeding: characteristics, reversal strategies and outcomes from a multi-center observational study. Chest )2017;(Feb). pii: S0012-3692(17)30212-X. Majeed A, Hwang HG, Connolly SJ, Eikelboom JW, Ezekowitz MD, Wallentin L, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 2013;128(Nov (21)): 2325–32. Pollack Jr CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med 2015;373 (Aug (6)):511–20. Pollack Jr CV, Bernstein R, Dubiel R, Reilly P, Gruenenfelder F, Huisman MV, et al. Healthcare resource utilization in patients receiving idarucizumab for reversal of dabigatran anticoagulation due to major bleeding, urgent surgery, or procedural interventions: interim results from the REVERSE ADTM study. J Med Econ 2017;(Jan):1–8. Connolly SJ, Milling Jr TJ, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al. ANNEXA-4 Investigators. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med 2016; 375(Sep (12)):1131–41.
Heart, Lung and Circulation (2017) 26, 911–917 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2017.05.131
An Update on Anticoagulation in Atrial Fibrillation John Amerena, MBBS, [5_TD$IF]FRACP, FCSANZ a*, Daryl Ridley, MBBS, FRACP, FCSANZ b[5_TD$IF] Deakin University, Geelong, [6_TD$IF]Vic, Australia University Hospital, Geelong, [6_TD$IF]Vic, Australia
a
b
Online published-ahead-of-print 3 June 2017
Cerebrovascular [9_TD$IF]accidents related to atrial fibrillation (AF) are potentially preventable with anticoagulation. Until recently, warfarin was the only proven anticoagulant to be effective in stroke prevention, however the novel, direct acting oral anticoagulants (DOACs) are now available, triggering a paradigm shift in treatment philosophy. Today, physicians need to consider in which patients anticoagulation should not be used rather than, as in the past, deciding in which patients it should be used. Although warfarin will continue to have a place [10_TD$IF]in managing some patients with AF, in the future, the DOACs should be the predominant therapy for stroke prevention in patients with non-valvular AF. Keywords
Anticoagulation Atrial fibrillation Warfarin Novel anticoagulants
Introduction Atrial fibrillation (AF) is the commonest cardiac arrhythmia and its prevalence is expected to increase globally, and in Australia, over the next 20 years [1]. The incidence of AF increases with age, and is present in around 15% of the population aged above 80 years, so is by far the commonest cause of stroke in this age group. Identification of AF and appropriate institution of anticoagulation is therefore the largest potential way to prevent stroke in this population. Ischaemic stroke is the most common cause of cerebrovascular accident in Australia and 75% of these strokes are directly related to atrial fibrillation [2]. The proportion of stroke from cardioembolic sources rises with age [3], so that 35% or more of stroke in patients over 80 years of age is [1_TD$IF] cardiac in origin, mostly due to AF. Atrial fibrillation causes incomplete and sluggish emptying of the left atrial appendage (LAA) and this is [12_TD$IF]the site where thrombus forms, although thrombus can occasionally be seen in the left atrium itself. These LAA thrombi tend to be large, and when they dislodge and embolise, stroke or peripheral embolisation are the common outcomes. Strokes associated with atrial fibrillation tend to be larger, and are more likely to be fatal or
disabling [4]. Given this mechanism, strokes related to AF are potentially preventable with anticoagulation.
Valvular or Nonvalvular Atrial Fibrillation? Atrial fibrillation is commonly classified as being either valvular or non-valvular in origin, which is an important distinction as it influences the choice of treatment options available for stroke prevention in these patients. The majority of patients with AF have non-valvular AF (NVAF) with the minority having AF associated with valvular heart disease. The definition of valvular/non-valvular AF has been a little confusing over recent years, as American and European definitions are somewhat different. The current AHA/ACC definition of valvular heart disease states that valvular AF is that which is associated with rheumatic mitral stenosis, prosthetic heart valves (metallic or bioprosthetic) and mitral valve repair [5]. This is a fairly broad definition and many clinicians would not agree that mitral valve repair or a bioprosthetic valve is truly valvular heart disease, as, after an initial period of anticoagulation,
*Corresponding author at: [8_TD$IF]4th Floor Kardinia House Bellerine Str Geelong 3220., Email: [email protected] © 2017 Published by Elsevier B.V. on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
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these valvular conditions do not require anticoagulation in their own right. According to these guidelines, anticoagulation with a vitamin K antagonist (VKA), such as warfarin, is recommended for stroke prevention in patients with valvular heart disease, whereas VKA or one of the direct acting oral anticoagulants (DOACs) can be used in patients with NVAF. The latest definition from the European Society of Cardiology (ESC) in 2016 is simpler, and states that valvular heart disease is confined to moderate to severe mitral stenosis or metallic prosthetic heart valves, and that everything else should be considered non-valvular [6]. The ESC recommended that VKAs be used for anticoagulation in patients with valvular heart disease, and that a VKA or DOAC can be used in patients when the valvular heart disease does not require anticoagulation in its own right. This includes patients with a mitral valve repair or bioprosthetic valves after the initial implantation, and also patients with mitral regurgitation, tricuspid regurgitation, aortic incompetence and aortic stenosis which are not haemodynamically significant enough to require intervention. This ESC definition has removed a lot of the confusion about what is valvular and non-valvular AF and we would encourage Australasian clinicians to follow these latest guidelines.
Who to Anticoagulate? All patients with AF associated with valvular heart disease should be considered for anticoagulation with a VKA, as the stroke risk is high without anticoagulation. The decision to anticoagulate patients with NVAF for stroke prevention depends on their risk of stroke, and there are several risk scores that can be used to evaluate stroke risk in these patients. The traditional stroke evaluation tool has been the CHADS2 score which assigns points to various risk factors (see [13_TD$IF]Table 1) and is good at evaluating the risk of stroke in relatively high risk patients but is not good at identifying patients who are at low risk of stroke and thus do not require anticoagulation [7].
Because of this lack of discrimination in low-risk patients, the CHA2DS2-VASc score has been developed [8], and has largely superseded the CHADS2 score. The authors of [14_TD$IF]these guidelines reviewed epidemiological and registry data looking at the risk of stroke related to various risk factors and have incorporated the CHADS2 risk factors in the score and have upgraded age >75 years to the same level of risk as previous stroke, and have also included vascular disease, age >65 years and female gender as significant risk factors for stroke, although the magnitude of gender associated risk has been questioned recently. The score has been validated in large populations and is now the most widely used tool for stroke risk assessment in UK, Europe and Asia Pacific. The real advantage of the CHA2DS2-VASc score is that it is better at identifying truly low-risk patients who would not benefit from anticoagulation and thus not be treated inappropriately. The current US guidelines advise that if the CHADS2 score is >/ = 2 for men or women anticoagulation is recommended but that if the CHADS2 score is 1, anticoagulation or aspirin can be considered depending on the individual patient characteristics and preferences [5]. In a patient with a CHADS2 score of 0, neither anticoagulation nor aspirin is recommended in these [15_TD$IF]American guidelines [5]. The most recent iteration of the European guidelines has recommended that, if men have a CHA2DS2-VASc score of >/ = 2, anticoagulation should be used for stroke prevention, but if the CHA2DS2-VASc score is 1, it should be considered, depending on patient characteristics and preferences [6]. For females, there has been a liberalisation of the recommendations for anticoagulation due to the recognition that female gender is a relatively weak risk factor for stroke. The latest guidelines advise that if a female has a CHA2DS2-VASc score of >/ = 3, anticoagulation is recommended, but if the score is 2, anticoagulation be considered. If the CHA2DS2-VASc score is 0 in men and women or is 1 in a woman, neither anticoagulation nor aspirin is necessary. Although these latest recommendations have been validated, the more liberal risk score for females has yet to be adopted in clinical practice in Australia. These guidelines have also stated that the DOACs are to be preferred over VKA for stroke prevention in NVAF. Australian guidelines for stroke prevention in NVAF are being currently written under the auspices of the CSANZ.
[4_TD$IF]Table 1 Risk score. Risk Score CHADS2
Risk Factors
Risk Score CHA2DS2-VASc
1
Chronic heart failure
1
1
Hypertension
1
1 1
Age ( 75) Diabetes
2 1
2
Stroke/TIA
2
Vascular disease (CAD/MI)
1
Age (65–74)
1
Sex category (female gender)
1
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The CHADS2 and CHA2DS2-VASc scores are good at quantifying the risk of stroke in patients with NVAF, but their ability to do so is far less than ideal. The C statistic for the CHA2DS2-VASc score in stroke prediction is around 0.68, indicating it will correctly predict the risk in about 68% of cases. On this basis, several other scores have been developed, such as the ABC score from the Duke investigators participating in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study [9], and by investigators running The Global Anticoagulant Registry in the FIELD (Garfield) Registry [10], which may have greater predictive ability than CHA2DS2VASc. These new risk scores are web based and incorporate clinical and non-clinical factors in their scoring system, such as biomarkers [16_TD$IF]such as troponin and BNP. This being the case, their applicability may be limited, as some of the risk factors included in them are not routinely measured in patients with NVAF, and have yet to be widely validated in population studies. We cannot see them being widely used in clinical practice in Australia in the near term, even though their predictive capacity may be greater than the CHA2DS2-VASc score. The risk of bleeding must always be taken into account when considering anticoagulation. Physicians often tend to do this intuitively, but the HAS-BLED score [8] has been developed to allow a more systematic and objective assessment of bleeding risk to be made. Using this score, one can stratify patients into low, intermediate or high risk of bleeding, and make appropriate decisions taking this into account. The HAS-BLED score should be used to identify potentially reversible bleeding risks, such as controlling BP or discontinuing aspirin, but a high HASBLED score should not be used as an excuse not to anticoagulate patients with a CHAD2S2VASc score that would justify anticoagulation, as the net clinical benefit is still in favour of anticoagulation [11].
Aspirin For Stroke Prevention in Non-Valvular AF Aspirin has often been used as a default antithrombotic agent in patients with non-valvular AF on the assumption that it will reduce the risk of stroke. Aspirin is commonly used in patients deemed to be unsuitable for anticoagulation due to age, frequent falls or impaired cognitive function but the evidence supporting its usefulness for this indication is weak. Several studies have examined aspirin for stroke prevention in NVAF, and, in general, the point estimates hover around unity, with wide confidence intervals. The only study that was definitively positive for aspirin was in the Stroke Prevention in Atrial Fibrillation (SPAF) II study in which there was a statistically significant reduction of 42% over placebo [12]. In aggregate, at best, there is a 20% reduction in stroke rates with aspirin use in patients with non-valvular AF but the confidence intervals hit one indicating borderline significance [13].
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The effectiveness of aspirin as an antithrombotic agent to reduce stroke in NVAF was examined in the Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) study [14]. Patients who were deemed to be ineligible for anticoagulation with a VKA, for a variety of reasons (such as labile international normalised ratios [INRs], predisposition to falls, patient unwillingness to take anticoagulation, and physician discretion), were randomised to apixaban or aspirin in a randomised, double blind clinical trial. This study was stopped prematurely after 18 months due to a significant benefit from apixaban over aspirin with a 55% reduction in the risk of ischaemic stroke. Unexpectedly, it was also found that the rates of clinically relevant bleeding with aspirin and apixaban in this population were comparable, and although there were numerically more bleeds with apixaban this was not significant. As well, apixaban was better tolerated than aspirin with less patient discontinuations in the apixaban arm. In recognition of this data the European guidelines [8] have recommended that aspirin [17_TD$IF]not be used for stroke prevention in patients with NVAF, and should only be considered in patients who refuse to take any form of oral anticoagulation, with the recognition that if aspirin is given for this indication, the risk of bleeding is similar to that seen with oral anticoagulants (based on the AVERROES study). The British Heart Foundation NICE guidelines have gone even further, and have advised that aspirin never be used for stroke prevention in NVAF [15]. In Australia, aspirin is still frequently used to reduce stroke risk in many patients with high CHA2DS2-VASc scores who would benefit from anticoagulation. This may well make the physician feel better as they perceive that feel they are doing something to reduce stroke risk, but the evidence would suggest this is not the case. Our opinion would be, that if aspirin use is being considered in this population, contemplating using low-dose NOAC therapy should be also considered, particularly with apixaban, given the recent clinical trial results.
Warfarin for Stroke Prevention in Non-Valvular AF Warfarin has been the standard anticoagulant for stroke prevention in NVAF for the last 60 years. Warfarin was identified as an antithrombotic when cows in Wisconsin were found to be bleeding after ingesting clover. The Wisconsin Alumni Research Foundation discovered that the substance in the clover that caused anticoagulation was an ‘‘ARIN”, hence the name warfarin. Warfarin was used as a rodenticide for many years, hence patients often refer to it as ‘‘rat poison”. Warfarin was introduced to clinical practice as an anticoagulant in the 1960s and underwent extensive clinical trials to demonstrate efficacy in reducing strokes in patients with
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NVAF. The seminal trial was the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation (SPINAF) trial, which was a randomised, double blind trial which definitively proved that warfarin reduced stroke rates and death in patients with NVAF [16]. In aggregate, warfarin reduces stroke rates in NVAF by about 70% compared to no treatment and reduces mortality by about 30% [13]. On the basis of this, warfarin became the standard of care for this indication, as there were no other oral agents available. Although warfarin is extremely effective in reducing stroke and mortality in patients with NVAF, it is a difficult drug to use in clinical practice. Warfarin has a slow onset and offset of action and has multiple drug and food interactions. It requires constant monitoring in an attempt to keep the INR within the therapeutic range of 2–3, as if it is <2 there is an increased risk of stroke and >3 an increased risk of bleeding, particularly intracerebral. Intracranial haemorrhage (ICH) is the most feared complication of warfarin and although annual rates are low, this is a devastating and often fatal event. There seems to be an increased risk of bleeding and ICH with warfarin in Asian populations (even in patients whose INR is in the therapeutic range) and in response to this, the target INR in Asian countries is often lower at 1.5–2 rather than the recommended 2–3 in Western populations, although there is little clinical trial data to support this [17– 19]. Even in the best centres, the time in therapeutic range (TTR) is around 70% at best, and more often around 50–60%, as documented in clinical trials and in an Australian context [20,21]. Alternatives to warfarin have, therefore, been long awaited and the new direct acting oral anticoagulants (DOACs) have filled this void.
Novel Direct Acting Oral Anticoagulants in Stroke Prevention Research The development of the novel anticoagulants has revolutionised the management of stroke prevention in patients with NVAF. Until recently, warfarin was the only proven anticoagulant to be effective in this regard, but several large clinical trials have demonstrated that the direct acting anticoagulants have the potential to replace warfarin for this indication [22–25]. The current direct acting anticoagulants available in Australia are the direct thrombin inhibitor dabigatran, and the factor Xa inhibitors rivaroxaban and apixaban. These agents have similarities and differences which are clinically significant. All the agents are active orally and despite having similar half-lives, have been tested in once-daily dosing for rivaroxaban and twice daily dosing for dabigatran and apixaban [23–25]. They have a rapid onset of action so that within one to two hours of dosing full anticoagulation is achieved [26–28]. They also have a rapid offset of action compared with warfarin, so that within 24 hours of taking the last dose the majority of anticoagulant effect has disappeared. Excretion is, however, affected by renal function, with dabigatran being highly dependent on renal excretion, as 85% is excreted
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unchanged in the urine, whereas apixaban and rivaroxaban are 27% and 33% excreted renally. Thus, in the presence of renal dysfunction, a longer treatment discontinuation is required to allow coagulation status to return to normal, which is important if the patient requires surgery. There are minimal food interactions with the new agents, although it is recommended that rivaroxaban and dabigatran be taken with meals to improve absorption and to reduce the risk of dyspepsia respectively. Although the bioavailability of dabigatran is low (5%) it is affected by P-glycoprotein inhibitors such as verapamil and amiodarone, but there are few other clinically significant drug interactions with this drug. Rivaroxaban and apixaban have potential interactions with agents metabolised by the cytochrome P450 system, but most of these medications are not commonly encountered in the clinical cardiovascular practice. None of the new agents require routine monitoring to evaluate the extent of anticoagulation, and the relationship between standard measures of anticoagulation such as the INR and activated partial thromboplastin time (APTT) and drug levels is nonlinear, and thus not helpful in determining the extent of anticoagulation [29]. These tests can be used to assess compliance with treatment (increased levels) or to assess if an active drug is likely to be in the circulation, as normal levels of these parameters would suggest very little if any active drug is present, making it safe to have surgery. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study [23], was the first study published comparing the direct thrombin inhibitor dabigatran versus warfarin in patients who with NVAF who had >/ = 1 risk factors for stroke. It was an open label study, using a prospective randomised open blinded end-point (PROBE) design, testing the efficacy (stroke prevention and systemic embolism) and safety of 110 mg BD and 150 mg BD against warfarin (target INR 2–3). The higher dose was superior to warfarin in reducing stroke and systemic embolism and, in particular, there was a significant reduction in ischaemic stroke compared with warfarin. At this dose, there was comparable bleeding to warfarin, but post hoc analysis found there was excess gastrointestinal bleeding in patients aged >75 years [30] and thus it has been recommended that the lower dose be used in this age group. The 110 mg BD dose was shown to be non-inferior to warfarin in reducing stroke and embolism in patients with NVAF, but had lower rates of bleeding, although this advantage was attenuated in patients >75 years or those who had moderate degrees of renal impairment [30]. Both doses however significantly reduced the risk of ICH compared with warfarin. The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study [24] examined rivaroxaban versus warfarin in patients with >/ = 2 risk factors for a stroke, and in fact the average CHADS score in this study was 3.5 compared with 2.1 in both the RE-LY and ARISTOTLE studies. In ROCKET–AF, there was a lower time within the therapeutic range (TTR) of 55% than in that the RE-LY or ARISTOTLE
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studies, perhaps because of an increased number of patients with heart failure compared with the other studies, compounded by a different means of calculating the [18_TD$IF]3TTR. The majority of patients received the full dose of 20 mg once daily but there was a dose reduction to 15 mg in patients whose creatinine clearance rate was <50 mL/min. Both doses showed similar efficacy to warfarin in reducing stroke and embolism, and there was similar bleeding, although there was an excess in gastrointestinal haemorrhage compared with warfarin. Both doses showed a significant reduction in ICH. In pre-specified statistical analysis, an on-treatment safety analysis showed superiority to warfarin in terms of stroke/systemic embolism, but this claim was not accepted by regulatory authorities in Australia or the US where the agent has been registered on the basis of non-inferiority. As with dabigatran and apixaban, there was a significant reduction in ICH, and a trend towards a decrease in all-cause mortality. The ARISTOTLE study [25] looked at a similar population of patients with NVAF as the RE-LY study. To be eligible, the patient had to have >/ = 1 risk factor for stroke, and, in fact, the average CHADS score in RE-LY and ARISTOTLE was identical at 2.1. The TTR in ARISTOTLE with similar to that in RE-LY at 62% and 64%, respectively, but ARISTOTLE was a double-dummy double-blind study. Apixaban was given at 5 mg BD to 95% of participants but a dose reduction to 2.5 mg BD was used in a small number of patients who had two criteria out of age >80 yrs, serum creatinine level >133 mg/ dL or body weight <65 kg. The study showed that apixaban was superior to warfarin in stroke reduction and systemic embolism, which was driven primarily by a reduction in haemorrhagic stroke with a similar ischaemic stroke reduction compared with warfarin. Major and clinically relevant non-major bleeding was significantly less with apixaban than with warfarin, and ICH was also significantly reduced. Although there were strong trends with dabigatran and rivaroxaban for reduction in total mortality compared with warfarin, apixaban was (nominally) statistically significant in this regard (p = 0.048). Edoxaban (which is not available in Australia) has also been studied in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation (ENGAGE AF) study [31]. This was a double-dummy double-blind study looking 30 and 60 mg once daily edoxaban versus warfarin, with the same efficacy and safety endpoints as the other studies. The 30 mg dose was disappointing in that it showed more strokes compared with warfarin but less bleeding, whereas the 60 mg dose showed less strokes than warfarin but similar bleeding. Somewhat paradoxically, patients with preserved renal function did worse than those with impaired renal function, suggesting that high levels of renal excretion in patients with normal function could lower effective dose levels within the circulation.
Bleeding When any anti-thrombotic agent is used, there is an increased risk of bleeding, whether it be with aspirin alone, dual
antiplatelet therapy or anticoagulation with warfarin or one of the new agents. Warfarin can be reversed acutely with prothrombin complex concentrate (3 or 4 factor) but this only lasts for hours at a time. Vitamin K is often used to reverse the anticoagulant effects of warfarin, but this relies on production of clotting factors by the liver so it often takes six to eight hours to have an effect. It is difficult to compare the bleeding rates between the different new agents, as, although the primary endpoint for efficacy was the same, there were different definitions for bleeding. Bleeding was extensively evaluated in all the clinical trials with these new therapies, and was comparable to or less than warfarin in all the studies [32]. If bleeding did occur, however, the outcome was generally better if the patient had a bleeding event on the new agent compared with warfarin, despite the lack of a reversal agent being available [33–35]. One of the concerns in clinical practice, with the introduction of the new agents, is that there has been no reversal agent available for any of them. However, in recent times, the specific reversal agent for dabigatran, idarucizumab, has become available. It is a monoclonal antibody specifically targeting dabigatran, and has been tested in the RE-VERSE AD study [36], an update of which was recently published [37]. In this study, idarucizumab was given to patients who were bleeding on dabigatran or in whom urgent surgery was required. Although this was an open label study, patients who were bleeding were easier to manage and patients who required urgent surgery did not bleed excessively in the majority of cases. This agent is given in 2 5 Ml boluses over several minutes, and has been shown to effectively reduce the plasma levels of dabigatran for a prolonged period of time. It is now available in Australia and is TGA approved. Andaxanet Alfa is a potential reversal agent targeting factor Xa inhibitors. That is, it has the potential to block the effects of rivaroxaban, apixaban, edoxaban and low molecular weight heparin, and is currently undergoing phase three clinical trials. Preliminary data was published recently [38], looking at the effect of andenaxet-alfa infusion in patients who were bleeding whilst taking rivaroxaban and apixaban. Andenaxet alfa reduced the levels of these agents within the circulation, but when the infusion stopped, the levels started to rise again. Bleeding was more manageable when Andaxanet alfa was used in this context, but its use in patients who require urgent surgery while taking factor Xa inhibitors has not been evaluated. This agent has been approved for reversal in the US by the FDA, but is unlikely to become available in Australia for several years.
Clinical Use of the Novel Anticoagulants Depending on the agent used, and dose chosen, all the nonVitamin K dependent anticoagulants are superior to, or noninferior to, warfarin in reducing stroke and systemic
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embolism. With respect to bleeding, superiority or non-inferiority compared with warfarin is also seen but it is difficult to compare bleeding rates amongst the studies as the definitions for bleeding were different. All the new agents, at all doses, significantly reduced ICH compared to warfarin. The latest AF guidelines recommend that men who have a CHA2DS2-VASc score of >/ = 2 and women whose score is >/ = 3 should be anticoagulated to reduce stroke risk if they have NVAF, and the ESC has strongly preferred the novel agents to warfarin. In Australia, these agents have been taken up avidly and practice patterns show that new initiations of anticoagulation are increasingly with the new agents. In patients who are on warfarin, those with unstable control are good candidates to swap to a new agent. Patients who do not like having routine blood tests or have difficulty accessing monitoring, such as if they live in remote or regional areas, are also good candidates to swap, as well as those patients who have difficulty adhering to the dietary requirements that are necessary to maintain good control in patients taking a VKA. In patients who are stable on warfarin with good control of their INR, it is not obligatory to swap to a new agent, as many patients feel comfortable with having their routine blood test infrequently to assess their control and reassure them. However, it would be prudent in this stable patient population to discuss that there are new agents available that have advantages over warfarin, particularly with respect to reducing ICH, and that it would be reasonable and justifiable to swap to a new agent should they wish to do so.
J. Amerena, D. Ridley
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Conclusions In summary, the novel anti-coagulants are now available for stroke prevention in patients with NVAF, and have really triggered a paradigm shift in treatment philosophy in this area. We are now encouraging physicians to consider in which patients should anticoagulation not be used when they see patients with NVAF, whereas, in the past, the opposite emphasis was to consider in which patients should we use anticoagulation. All the new agents are more effective than, or similar to, warfarin in terms of stroke reduction and bleeding, depending on the agent chosen and dose used, and our feeling is that, as time goes on, they will replace warfarin for this indication. Warfarin will still need to be used for patients who have valvular AF (metallic prosthetic heart valves and mitral stenosis) and those with NVAF and severe renal dysfunction, but, in the future, the new agents should be the predominant therapy for stroke prevention in patients with NVAF, given the impressive safety and efficacy results found in the clinical trials, and the greater patient acceptability of these new agents compared with warfarin.
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
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