Stroke prevention in non-valvular atrial fibrillation: advances in medical therapy
Dr. Karishma Zobair
Tuesday, September 1st, 2015
Introduction: The aim of this article is to review the literature and evaluate the evidence of the different medical treatments for stroke prevention in non-valvular atrial fibrillation. Methods: A literature search using MEDLINE plus OvidSP, PubMed, CINAHL and the New England Journal of Medicine databases was performed with the search terms stroke prevention, atrial fibrillation, anticoagulation, novel anticoagulants, direct thrombin inhibitors and factor Xa inhibitors. Results: Eight studies were identified which assessed the efficacy and adverse effects of the different treatments in stroke prevention in those with non-valvular atrial fibrillation. Conclusion: Evidence suggests that target specific oral anticoagulants have similar or superior efficacy compared to warfarin for stroke prevention in patients with non-valvular atrial fibrillation, however more long term follow-up studies are required.
Atrial fibrillation (AF) is defined as an arrhythmia caused by rapid and irregular depolarisation and contraction of the atrium and is the most common sustained cardiac arrhythmia.  It is classified into three subgroups: paroxysmal, persistent and permanent.  Paroxysmal AF is recurrent AF where the rhythm disturbance terminates spontaneously within seven days, persistent AF is where the rhythm disturbance is sustained for greater than seven days, and permanent AF is where the rhythm disturbance has lasted for longer than one year and not been terminated by medical intervention.  AF affects 1–2% of the general Australian population and importantly this incidence increases with age, with 9% of people over the age of 80 being affected.  Although often considered a benign arrhythmia, AF is a major cause of morbidity and mortality.  The most feared complication is systemic embolism leading to stroke.  AF accounts for 1 in 5 strokes,  with morbidity and mortality determined by the vessel that is occluded and the extent of ischaemia. This is reflected in the stroke prognostic scores (PLAN) which take into account preadmission comorbidities, level of consciousness, age and neurologic deficit, and predict patients who will have a poorer outcome after hospitalisation for acute ischaemic stroke.  Treatment of AF consists of rate and rhythm control as well as antithrombotic therapy to prevent stroke.
There are multiple mechanisms responsible for the increased risk of thromboembolic stroke in individuals with AF. Firstly, altered atrial contraction results in blood stasis in the atria. Secondly, the left atrial appendage acts like a pocket to promote platelet aggregation and thrombus formation. Changes in systemic circulation also increase the risk of clot formation.
Evidence-based guidelines support the use of warfarin and aspirin as the two leading medical therapies for stroke prevention in AF.  Warfarin has been used as the mainstay treatment for the last 60 years, but this has not been without problems. There has been a recent emergence of new therapies, with 20 new novel anticoagulants currently under investigation, many showing promising results in phase III trials.  These drugs have been collectively referred to as new oral anticoagulants (NOACs), and more recently, target specific oral anticoagulants (TSOACs). Recently in Australia the Therapeutic Goods Administration (TGA) has approved a direct thrombin inhibitor, dabigatran, and two factor Xa inhibitors, rivaroxaban and apixaban, for stroke prevention in AF patients. [8,9] The recent attention on emerging treatment options makes us question what the evidence is behind their use in the context of stroke prevention in AF patients as compared to traditional therapies.
The objective of this review was to compare the efficacy and safety profile of TSOACs, in particular the TGA-approved TSOACs, dabigatran, rivaroxaban and apixaban, to standard medical therapy for stroke prevention in AF.
A literature search of MEDLINE plus OvidSP, NCBI PubMed and CINAHL via EBSCOhost and the New England Journal of Medicine databases was conducted. Limits were set to include articles published between the years 1999 to current to reflect modern practice. The search terms used were “stroke prevention” AND “atrial fibrillation” AND “anticoagulation” AND “novel anticoagulants” OR “direct thrombin inhibitors” OR “factor Xa inhibitors”. The reference lists of included studies were also manually reviewed to identify additional relevant literature.
Studies were included if they assessed the efficacy and safety profile of TSOACs as well as standard medical therapy for stroke prevention in those with non-valvular AF. Only studies conducted in humans and published in English were included. There was no restriction on publication type and no limit on study size.
Results and discussion
Database and reference searches yielded 1149 articles of which 89 full text papers were selected and reviewed. 81 articles were excluded, mainly due to lack of focus on the standard medical therapies and TGA- approved TSOACs (dabigatran, rivaroxaban and apixaban) in those with non-valvular AF. Based on the inclusion and exclusion criteria, eight studies were eligible for inclusion in the review. These studies varied in their characteristics with participant groups. Of these studies there were two meta-analyses (level I evidence), one prospective open-label randomised trial, one randomised double-blind controlled trial (level II evidence) and four randomised controlled trials (level II evidence).
Treatment for stroke prevention in patients with AF is guided by risk stratification by the CHADS2 or the CHA2DS2-VASc scores.  In the CHADS2 score, patients are given one point each for age greater than 75, hypertension, diabetes mellitus and heart failure, and two points if they have a history of previous stroke or transient ischaemic attack (TIA). A CHADS2 score of zero confers low risk, one confers moderate risk and a score of equal or greater than two means the patient is at high risk of stroke.  In those with a CHADS2 score of 0, there is a risk of 0.6 events per 100 person-years and this increases to 13.0 events per 100 person-years in those with a CHADS2 score of 6. Compared to the CHADS2 score, the CHA2DS2-VASc score for non-valvular AF has a larger score range (0 to 9) and incorporates a greater number of risk factors (female sex, 65 to 74 years of age, and vascular disease). The CHA2DS2- VASc score has been shown in several studies to better discriminate stroke risk among patients with a baseline CHADS2 score of 0 to 1, as well as in older women. Furthermore there are a range of scores to identify patients at increased bleeding risk. These include the HAS- BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalising ratio (INR), Elderly, Drugs/alcohol concomitantly) and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) scores to name a few. Although helpful clinically, they are not used in the current treatment guidelines. 
In Australia, current therapeutic guidelines recommend that those with a CHADS2 score of 0 should be treated with aspirin or no therapy, with a preference for no therapy. Those with a score of 1 should be treated with oral anticoagulation with warfarin, dabigatran or aspirin with a preference for oral anticoagulation. Those with a score of 2 or more would benefit from oral anticoagulation with warfarin or dabigatran. Warfarin should be maintained at therapeutic levels with INR between 2.0 and 3.0 with a target INR of 2.5.  Although not in the guidelines, the TGA has approved the use of rivaroxaban 20mg once daily and apixaban 5mg twice daily for stroke prevention. [8,9]
The European Society of Cardiology recommends that the CHA2DS2- VASc score should be used to assess stroke risk. Warfarin is the drug of choice in those with mechanical heart valves. In those with a prior stroke, TIA, or CHA2DS2-VASc score greater than 2, oral anticoagulation is recommended with warfarin, dabigatran, rivaroxaban, or apixaban. If therapeutic INR is unable to be maintained then a direct thrombin inhibitor or factor Xa inhibitor is recommended. In those with non- valvular AF and CHA2DS2-VASc score of 0, the guidelines state that it is reasonable to omit antithrombotic therapy. In those with a CHA2DS2- VASc score of 1, no antithrombotic therapy or treatment with an oral anticoagulant or aspirin may be considered. 
The American College of Cardiology / American Heart Association recommend that antithrombotic therapy should be based on the presence of risk factors for stroke and thromboembolism. They recommend that the CHADS2 stroke risk stratification should be used to assess stroke risk. In patients with a CHADS2 score of greater than 2, long term oral anticoagulation therapy, for example with warfarin, is recommended. In patients with a CHADS2 score of 0 to 1, they recommend CHA2DS2-VASc be used to further stratify their risk. They further go on to state that in those with a CHA2DS2-VASc score of 1, aspirin may be considered rather than oral anticoagulation therapy.  The importance of shared decision-making, the patient’s preferences as well as discussion of risks of stroke and bleeding is recommended in all guidelines. [11,12]
Traditional medical therapy
Vitamin K antagonist – warfarin
Historically warfarin has been the cornerstone of pharmacological therapy in stroke prevention in those with AF.  Since approval in 1954 warfarin has been the leading oral anticoagulant choice especially in those at high risk. 
Warfarin interferes with the cyclic interconversion of vitamin K and its 2,3-epoxide. Vitamin K is a cofactor in the pathway of synthesis of vitamin K-dependent coagulation factors (factors II, VII, IX, and X). Warfarin may have a procoagulant effect during initiation of treatment due to earlier clearance of the protein C (half-life 8 h) which is an antithrombotic, compared to prothrombin (50–72 h) which is a prothrombotic.  The dose is titrated with the level of the INR and hence INR needs to be monitored regularly.  Treatment with vitamin K will reverse the anticoagulant effect of warfarin. Plasma products such as fresh frozen plasma and prothrombin complex concentrate may also be used when urgent reversal is required. This is seen as one of the main advantages in choosing this treatment. 
The efficacy of warfarin has been extensively proven. In six trials of warfarin versus placebo warfarin showed a 62% reduction in stroke. Number to treat analysis revealed that one would need to treat 32 patients for one year to prevent one stroke. [2,17]
Although warfarin has been widely proven to be efficacious in stroke prevention, it still remains under-prescribed. The Canadian Stroke Network study found that in high-risk patients with pre-existing AF with no contraindications to anticoagulation, only 40% received warfarin and the majority were not in the therapeutic range. 
Treatment with warfarin is not without limitations. At supra- therapeutic levels warfarin predisposes patients to fatal bleeding. A meta-analysis by Haft et al. found that, compared with placebo, adjusted-dose warfarin was associated with a 130% increase in the relative risk for major extracranial haemorrhage.  The therapeutic range is relatively narrow, resulting in the need for frequent monitoring. [19,20] As one can imagine patient compliance becomes a big factor in the success of treatment.
In addition to this, keeping the INR in therapeutic range is challenging and the dose of warfarin is subject to change as there are many drug– drug, drug–disease and drug–food interactions. Certain medications such as rifampicin, metronidazole and amiodarone can affect INR. Foods that have high vitamin K content such as leafy green vegetables can potentially reverse the anticoagulant effects of warfarin. Medical conditions like diarrhoea, fever, heart failure, liver disease and hyperthyroidism can potentiate warfarin’s anticoagulant effects whereas hypothyroidism can reduce its effects. 
Furthermore what cannot be underestimated is the deep-seated fear in clinical practice of the adverse effect of fatal bleeding leading to reluctance in prescribing. Practitioners tend to overestimate warfarin’s bleeding risk while at the same time underestimate the benefits in stroke prevention. 
Acetylsalicylic acid – aspirin
Acetylsalicylic acid directly and irreversibly inhibits the activity of cyclooxygenase (COX-1 and COX-2) to reduce the formation of thromboxane A2 and inhibit platelet aggregation.  A pooled analysis of the AFASAK I and Stroke Prevention in Atrial Fibrillation (SPAF) I studies on aspirin for stroke prevention found that aspirin reduced the risk of stroke by 36%. 
Like warfarin, the concern with aspirin, especially in the elderly, is the risk of fatal bleeding. The BAFTA trial found that elderly AF patients randomised to warfarin treatment experienced a 52% lower risk of fatal or disabling stroke or intracranial haemorrhage compared to aspirin. This was further confirmed by the WASPO trial which reported higher rates of adverse events and intolerance to aspirin in 80–90–year-old patients. Interestingly the effect of aspirin on stroke attenuates with age and randomised controlled trials found no evidence that aspirin reduces the risk of cardioembolic stroke in those greater than 80 years old. 
Warfarin vs. aspirin
There is significant evidence to suggest superiority of warfarin to aspirin in primary stroke prevention. Five randomised controlled trials showed that adjusted-dose warfarin resulted in a relative risk reduction of 36% when compared with aspirin. Meta-analysis of 13 trials found that warfarin was superior to both aspirin and placebo in reducing the risk of stroke or embolism.  For combination therapy, results from the SPAF III trial found a relative risk reduction of 74% with standard intensity warfarin (INR 2.0–3.0) compared to aspirin plus low intensity warfarin (INR 1.2–1.5). 
Dual antiplatelet therapy (aspirin plus clopidogrel)
Dual antiplatelet therapy has also been studied in two large randomised control trials: ACTIVE-W and ACTIVE-A. [2,22] ACTIVE-W compared aspirin plus clopidogrel with warfarin. The trial was stopped early due to the clear superiority of warfarin with the risk of stroke lower in those treated with warfarin as compared to dual antiplatelet therapy (3.9% vs. 5.6% per year). The risk of major haemorrhage was similar between the two groups but minor bleeding was significantly higher in the dual antiplatelet group. 
New advances in therapy: target-specific oral anticoagulants
Direct thrombin inhibitors – dabigatran
Dabigatran is a direct competitive inhibitor of thrombin, blocking directly at factor IIa, the final step in blood coagulation. The onset of action is two hours and the half-life is 12–17 hours.  Dabigatran is eliminated by renal excretion, making its use difficult in patients with renal insufficiency. 
The Randomised Evaluation of Long Term Anticoagulation Therapy (RE-LY) study was a multicentre, prospective open label randomised controlled trial which included patients with non-valvular AF at moderate to high risk of stroke or systemic embolism as determined by the CHADS2 score. 18113 patients were randomised to receive dabigatran 110 mg twice daily, 150 mg twice daily or warfarin. The mean duration of follow up was two years. The trial found that dabigatran 110 mg twice daily was non-inferior to warfarin in preventing stroke or systemic embolism (1.53% vs. 1.69% per year, p<0.001) and superior to warfarin in regards to major bleeding (2.71% vs. 3.36% per year, p=0.003). The higher dose of 150 mg twice daily was found to be superior to warfarin in preventing stroke and systemic embolism (1.11% vs. 1.69% per year, p<0.001) and non-inferior to warfarin in terms of major bleeding. Although both doses resulted in fewer intracranial haemorrhages compared to warfarin, there was a higher incidence of gastrointestinal bleeding in the higher dose group. [7,23] Importantly discontinuation rate was also higher in the dabigatran group with the most common reason being gastrointestinal symptoms. [6,7,14,20,23–25]
Furthermore the study by Salazar et al. found that direct thrombin inhibitors were as efficacious as vitamin K antagonists for the outcomes of vascular death and ischaemic events. Importantly they found that only the dose of dabigatran 150 mg twice daily was found to be superior to warfarin. Direct thrombin inhibitors were also associated with fewer major haemorrhagic events. Interestingly, adverse events occurred more frequently with direct thrombin inhibitors and led to the discontinuation of treatment. 
Factor Xa inhibitors
These drugs bind directly to the active site of factor Xa, which is located on the convergence of the intrinsic and extrinsic pathways. This inhibits thrombin formation from both pathways and inhibits thrombin formation upstream. 
Rivaroxaban is a potent selective reversible factor Xa inhibitor which inhibits free factor Xa. The time to peak concentration is three hours with a half-life of 9–13 hours.  Rivaroxaban is partially metabolised by the cytochrome P450 (CYP450) system making it subject to drug interactions, and two-thirds is eliminated by the kidneys. [6,7,14]
The Rivaroxaban once daily Oral direct factor Xa inhibition Compared with vitamin K antagonist for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) was a randomised double-blind study enrolling 14264 patients allocated either rivaroxaban 20 mg once daily (or 15 mg once daily if creatinine clearance was 30–49 ml/min), and dose-adjusted warfarin with target INR 2.0–3.0. [7,27] ROCKET-AF was different from other trials due to the medical comorbidities of the study population: 55% of the participants had a history of stroke, 62% had heart failure and 87% had a CHADS2 score of 3 or greater, indicative of a high risk population.  ROCKET-AF found rivaroxaban to be non-inferior to warfarin for stroke and systemic embolism (1.7% vs. 2.2% per year, p<0.001) and the rates of major bleeding were similar between the two groups (14.9% vs. 14.5% per year, p=0.44). Importantly, the rivaroxaban group had significant reductions in intracranial haemorrhage (.5% vs. 0.7%, p=0.02) and fatal bleeding (0.2% vs. 0.5%, p=0.003), suggesting that rivaroxaban may be safer than warfarin. [7,27]
Furthermore in a study by Bruins Slot et al. it was shown that in patients with AF, factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with warfarin.  Factor Xa inhibitors also appeared to reduce the number of major bleeds and intracranial haemorrhages compared with warfarin.  Further head-to-head studies of the different factor Xa inhibitors are required and are currently underway to conclusively determine the most effective and safest factor Xa inhibitor for patients with AF.
Apixaban is an oral factor Xa inhibitor with a half-life of 8–15 hours.  It is eliminated in various pathways, and among the TSOACs has the lowest renal elimination of 25%.  It does not inhibit or induce CYP450 therefore has a low potential for drug interactions. 
There have been two major studies assessing its use in stroke prevention: the Apixaban Verses acetylsalicyclic acid to prevent stroke in AF patients who have failed or are unsuitable for vitamin K antagonist treatment (AVERROES) trial and Apixiban for prevention of stroke in subjects with atrial fibrillation (ARISTOTLE) trial. [29,30]
The AVERROES trial was stopped early due to clear benefits of apixaban compared with aspirin. It included 5599 patients in whom vitamin K antagonist therapy was unsuitable. Patients were randomised to receive apixaban 5 mg twice daily or aspirin 81–325 mg once daily. Patients with apixaban had significantly lower rates of stroke and systemic embolic events (1.6% vs. 3.7%, p<0.001) with no increase in bleeding (1.4% vs. 1.2%, p=0.57). Patients receiving apixaban also had fewer cardiovascular hospitalisations. 
The ARISTOTLE study compared apixaban to warfarin in 18201 AF patients who had at least one other cardiovascular risk factor. This study found that the annual rate of stroke and systemic embolism was 1.27% in the apixaban group compared to 1.60% in the warfarin group (p=0.01). Apixaban was also associated with fewer major haemorrhages (2.13% vs. 3.09% per year, p<0.001) and overall adverse events were similar with a lower discontinuation rate in the apixaban group. Importantly the apixaban group had a lower mortality rate compared to the warfarin group and is the first oral anticoagulant to show a significant mortality benefit over warfarin. 
It is unclear which of these TSOACs is most effective and safe in patients with AF. These trials provide the strongest evidence for apixaban, however there have been no head-to-head trials comparing different TSOACs. The described studies had differing patient demographics and baseline characteristics making it difficult to make comparisons between trials.  Further investigation is needed before one can be said to be superior to another.
Advantages and disadvantages of target specific oral anticoagulants The TSOACs offer many advantages over traditional therapy. They have predictable anticoagulation effects, which allow fixed dosing. [6,14] They also have a wider therapeutic index therefore avoiding the need for routine monitoring.  In general they have lower potential for interactions; dabigatran and apixaban in particular have fewer drug and food interactions as they are not metabolised by CYP450 isoenzymes.  Rivaroxaban however is metabolised to some degree by CYP450 and so there is potential for medication interactions. [7,14,19,24]
Nevertheless they too have their own limitations. Like warfarin, bleeding is the main adverse effect in all the TSOACs. A recent meta- analysis by Chai-Adisaksopha et al. found that, when compared with vitamin K antagonists, TSOACs are associated with less major bleeding, fatal bleeding, intracranial bleeding, clinically relevant non-major bleeding, and total bleeding. Additionally, TSOACs do not increase the risk of gastrointestinal bleeding. 
The main limitation of TSOACs is the lack of specific antidotes to reverse their anticoagulant effects. Although the short half-lives are reassuring in the sense that drug concentrations should decline rapidly when it is discontinued, in situations where reversibility is an emergency, such as trauma, life-threatening bleeding, emergency surgery or in renal insufficiency, it may well be a deadly disadvantage.  Additionally in the absence of monitoring it may be difficult to assess patient compliance. 
While many of the novel agents do not utilise the CYP450 pathway they are still subject to interactions to some degree as all three are p-glycoprotein (P-GP) substrates. P-GP is an intracellular drug transport system that has a role in drug absorption and distribution. Food and drugs can affect its activity. For example rifampicin, a P-GP inducer, results in decreased serum concentration of dabigatran and should be avoided. Likewise antifungals and HIV proteases are contraindicated as they can result in increased serum concentration and may therefore increase the risk of haemorrhage. 
Use of these new agents can only be confidently endorsed once long term follow-up studies are conducted, as anticoagulation therapy is a lifelong treatment. Many of the aforementioned studies had a follow- up period of 2–3 years, however are expected to report long term follow-up results in the coming years.  The long term safety profile of these drugs will need to be considered before widespread transition to TSOACs can be recommended. 
The United States Food and Drug Administration (FDA) has issued boxed warnings on dabigatran, rivaroxaban and apixaban in their use for non-valvular AF. It has been shown in clinical trials that discontinuation of these agents without appropriate cover by another anticoagulant places patients at an increased risk of thrombotic events. Therefore it is recommended to strongly consider replacement with another anticoagulant if these agents are to be discontinued for any reason other than pathological bleeding. [32-34] Additionally the FDA has reported that epidural and spinal hematomas have occurred in
patients treated with dabigatran who receive neuraxial anesthesia or spinal puncture. These may result in long-term or permanent paralysis. 
Exciting new research is underway to identify an antidote for the TSOACs. Phase I trials demonstrate that idarucizumab produces an immediate, complete and sustained reversal of the anticoagulant effect of dabigatran in healthy participants.  Patient enrolment has also started into a randomised, double-blind, placebo-controlled phase III trial. [35,36] This trial will assess the efficacy of andexanetalfa, a factor Xa inhibitor reversal agent, in rapidly reversing rivaroxaban induced anticoagulation. The safety profile will also be evaluated with a follow up period of 43 days.  The synthetic molecule PER977 is also being studied in its ability to reverse the anticoagulant effect of edoxaban. In this study, haemostasis was restored within 10–30 minutes of administration of 100–300 mg of PER977 and was sustained for 24 hours. Additional phase II clinical studies are ongoing.  These ‘FDA- designated breakthrough therapies’ are under an accelerated approval pathway with the hope of bringing the agent into market as soon as possible and potentially overcoming the biggest drawback in the use of TSOACs. 
This review suggests that TSOACs have similar or superior efficacy than warfarin for stroke prevention in patients with non-valvular AF. Importantly, trials consistently demonstrate a favourable side- effect profile for these drugs. Research is currently underway into development of an antidote, overcoming the main argument against their use.  This advancing research will likely see TSOACs replace warfarin as the treatment of choice for stroke prevention in non- valvular AF.
Conflict of interest
K Zobair: firstname.lastname@example.org
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