ACHAIKI IATRIKI | 2023; 42(1):18–27
Christoforos Travlos1, Georgios Leventopoulos2
1Faculty of Medicine, University of Patras, Patras, Greece
2Department of Cardiology, University General Hospital of Patras, Patras, Greece
Received: 01 Apr 2022; Accepted: 03 Aug 2022
Corresponding author: Georgios Leventopoulos, Electrophysiologist, Consultant, Department of Cardiology, University General Hospital of Patras, Patras, Greece. Pineiou 33, 26442, Patras, Tel.: +30 6977 786020, Fax: 2613603281, e-mail: Levent2669@hotmail.com
Key words: Atrial fibrillation, anticoagulation, NOACs
The choice of an OAC (oral anticoagulant) for patients with non-valvular atrial fibrillation (NVAF) is a very complex process. For many years the gold standard in the treatment of these patients was vitamin K antagonists (VKA), primarily warfarin. However, achieving well controlled therapy with warfarin is a very demanding process due to its narrow therapeutic range and its multiple drug and food interactions. Hopefully, over the last decade, new oral anticoagulants (NOACs) have emerged and constitute an alternative to warfarin. Current data suggest that NOACs are at least as effective and safe as warfarin for most NVAF subjects. In this article we try to delineate current knowledge concerning the use of NOACs in the prevention of thromboembolic events in patients with atrial fibrillation (AF).
Atrial fibrillation (AF) is associated with an increased risk of morbidity and mortality, as a result of the high stroke risk in this population [1,2], which is five times higher compared to the general population . Most of these strokes are disabling. Under these circumstances, it is imperative for most AF patients to be on lifelong anticoagulation treatment . Vitamin K antagonists, such as warfarin and acenocoumarol, have been proposed . Warfarin therapy can be very effective in the prevention of stroke in patients with AF reducing by 64% the relative risk compared to control / placebo and by 26% all-cause mortality. The Achilles’ heel of warfarin is the labile international normalized ratio (INR). Keeping stable INR values is not simple for most patients [4,5]. This is attributed mainly to the narrow therapeutic range of warfarin defined as an INR of 2.0–3.0. It has been shown that the beneficial effect of warfarin is highly correlated to the time interval during which the INR lies within the therapeutic range (TTR) that should be >70% . Otherwise, an elevated INR increases bleeding risk, whereas a low INR leads to more stroke events [7,8].
Moreover, warfarin levels depend on food and drug interactions which vary amongst individuals. As a result, it is difficult for patients and healthcare providers to find the right dose that maintains INR within the aforementioned range [4,5]. A failure to achieve TTR can be predicted by the multiple common risk factors that have been defined and prospectively validated . Bleeding risk during warfarin treatment is one of the most important concerns of both physicians and patients, because major bleeding events are associated with increased morbidity and mortality [5,7].
A solution to these issues has been given by the introduction of new oral anticoagulants (NOACs). Routine coagulation monitoring is obsolete as daily dose is fixed. This offers convenience without compromising effectiveness . Moreover, their pharmacokinetic (PK) – pharmacodynamic (PD) profile is consistent . The category of NOACs includes four drugs, of which, dabigatran was the first approved from the FDA in 2010. Dabigatran is a direct thrombin inhibitor. Rivaroxaban, apixaban, and edoxaban fall under the category of direct factor Xa inhibitors that were approved in 2011, 2014, and 2015, respectively.
The aim of this review is to provide an overview of existing clinical trial data on the use of NOACs about the prevention of thromboembolic events in patients with AF and to provide a summary on existing data regarding the treatment of special subpopulations.
The phase III NOAC trials
Four main NOAC trials (the RE-LY (dabigatran 150 mg or 110 mg vs warfarin) , ROCKET AF (rivaroxaban vs warfarin) , ARISTOTLE (apixaban vs warfarin) , and ENGAGE AF–TIMI 48 (edoxaban 60mg or 30 mg vs warfarin)  have been conducted in the context of the management of AF. All these major trials convey the same clinical message. Now more drugs are available in our armory that are at least not inferior to warfarin in terms of safety (bleeding) and efficacy (prevention of stroke and systemic embolism) [10–14]. Although these trials have many similarities, there are some important differences in trial design, study participants and outcome measures that should be considered, and have been analyzed by numerous reviews [15–17].
In these four trials, 42.411 participants received a NOAC and 29.272 participants received warfarin. Results from a meta-analysis  showed that stroke and systemic embolism were significantly reduced in patients receiving NOACs. This result was mainly due to the substantial protection against hemorrhagic stroke, which was reduced by half. Hemorrhagic stroke is the most devastating complication of anticoagulant treatment. Its reduced incidence during NOAC treatment is highlighted as the most important advantage over warfarin. In terms of ischemic stroke prevention, the NOACs were similarly effective to warfarin, which itself is very effective in this regard and reduced ischemic stroke by two-thirds compared with placebo . In general, the NOACs safety profile was favorable compared with warfarin. Results from the same meta-analysis, showed that patients who received a high dose of NOAC (150 mg for dabigatran, 60 mg for edoxaban and the standard dose for apixaban and rivaroxaban) had a 14% non-significant reduction in major bleeding . NOACs were, however, associated with increased gastrointestinal (GI) bleeding except for apixaban that was shown to cause less GI bleeding compared to warfarin in the ARISTOTLE trial. Apixaban was also associated with a marginally statistically significant reduction in all-cause mortality compared with warfarin.
Differences between study populations
In all four trials [10–13] the enrolment of the patients was based on their CHADS2 score. During the enrollment phase, CHADS2 score was not yet replaced by the more updated CHA2DS2VASc score. However, it is worth mentioning that the RE-LY  and ARISTOTLE  trials enrolled patients with AF CHADS2 risk of 1 (i.e., low-risk patients), while the ROCKET-AF  and ENGAGE AF-TIMI 48  trials required patients to have two or more risk factors for stroke (moderate- and high-risk patients) . Thus, there is more experience in higher risk patients with rivaroxaban or edoxaban. On the other hand, patient enrolled in RELY and ARISTOTLE had less comorbidities and hence lower CHADS2.
The risk of stroke was higher in patients enrolled in ROCKET-AF (3.5 mean CHADS2 score) than in patients enrolled in the other three trials (2.1, 2.2, and 2.8 mean CHADS2 score in RE-LY, ARISTOTLE, and ENGAGE AF-TIMI 48 trials, respectively). In the ENGAGE AF-TIMI 48 trial, 52% of patients had a CHADS2 score of < 3. In the ROCKET-AF and ENGAGE AF-TIMI 48 trials no patients with a CHADS2 score of 0 or 1 where included, whereas the RE-LY and ARISTOTLE trials enrolled 32 and 34% of the patients in this low-risk category, respectively. As a consequence, the ROCKET-AF and ENGAGE AF-TIMI 48 trials had higher percentages of patients with hypertension, diabetes, and congestive heart failure. Moreover, in the ROCKET-AF trial 55% of the patients had a history of stroke or transient ischemic attack, whereas this proportion was <30% in each of the other three trials. The percentage of patients with paroxysmal AF was higher in the RE-LY trial (33%) and the ENGAGE AF-TIMI 48 trial (25%) compared to the other trials (Table 1).
NOACs vs NOACs
There are no head-to-head clinical trials comparing the efficacy of NOACs versus other NOACs. However, it has been shown by indirect comparisons and network meta-analyses based on randomized clinical trials (RCTs) that NOACs have generally similar efficacy but varied safety profiles [20,21]. Both the effectiveness and safety of NOACs have been evaluated by emerging observational studies in US clinical practice using single data sources. They provide some evidence of the comparative effectiveness and safety between NOACs but with limited generalizability and a lack of a comprehensive evaluation on outcomes across various subgroups within NVAF patients [22,23].
THE ARISTOPHANES study (Anticoagulants for Reduction in Stroke: Observational Pooled Analysis on Health Outcomes and Experience of Patients) compared the rates of stroke/systemic embolism and major bleeding . Additionally, it evaluated comparative rates across various subgroups among NVAF patients newly prescribed apixaban, dabigatran, rivaroxaban, or warfarin.
According to this study the unadjusted incidence rate of stroke/systemic embolism, including ischemic stroke, hemorrhagic stroke, and systemic embolism, was 1.3 (apixaban), 1.4 (dabigatran), 1.4 (rivaroxaban), and 2.1 (warfarin) per 100 person-years. The unadjusted incidence rate of major bleeding was 3.6 (apixaban), 3.6 (dabigatran), 5.4 (rivaroxaban), and 6.3 (warfarin) per 100 person-years.
Eligibility of NOACs
NOACs are approved for stroke prevention in ‘non-valvular’ AF . The eligibility in most SmPCs (summary of product characteristics) is based on the CHADS2 score given that it was commonly used in the phase III randomized clinical trials. The fact that they have consistent efficacy and safety, has led to the subsequent broadening of their indications on patients qualifying for anticoagulation according to the CHA2DS2-VASc score, with some regional differences (e.g., Canada, Japan).
Selected indications and contraindications, according to the European Society of Cardiology (ESC) guidelines , for NOAC therapy in AF patients are presented in Table 2.
NOACs and CAD
The coexistence of AF and coronary artery disease (CAD) apart from a common clinical scenario necessitates the combination of anticoagulation with antiplatelet treatment. According to the 2020 ESC guidelines , AF patients with co-morbid CAD have at least a CHA2DS2-VASc score of 1 (and most of the times even higher due to the presence of concomitant cardiovascular risk factors) and hence an absolute indication for oral anticoagulant therapy. It is well established that patients without AF need to be on dual antiplatelet treatment (DAPT) (i.e. aspirin and a P2Y12 inhibitor) for the prevention of stent thrombosis or recurrent events after an acute coronary syndrome (ACS) and/or stenting for CAD. DAPT is not sufficient for stroke prevention in case of AF and vice versa. NOAC as stand-alone therapy is not recommended in the immediate phase after ACS or coronary stenting. Therefore, the physician confronts a clinical dilemma about the choice of antithrombotic drug combination: undertreatment and increased risk for a coronary event and/or stroke, or overtreatment and increased risk for a bleeding event.
The combination of NOACs with antiplatelet agents (dual antithrombotic therapy) in patients with AF and ACS or patients who have undergone PCI, in comparison with warfarin combined with a P2Y12 inhibitor and aspirin (triple antithrombotic therapy) exceeds the purpose of this review. However, data from other four trials (RE-DUAL PCI , AUGUSTUS , PIONEER AF-PCI , ENTRUST-AF PCI ) that were mainly designed to compare the safety (bleeding events) and not the efficacy (prevention of thromboembolic events), show the superiority of dual (NOAC + P2Y12 inhibitor) vs triple (warfarin + P2Y12 inhibitor + aspirin) antithrombotic therapy.
In Figure 1 we present the latest ESC guidelines concerning anticoagulation therapy after elective PCI or ACS in patients with AF.
Figure 1. Anticoagulation therapy after elective PCI or ACS in patients with AF. Created with BioRender.com
Abbreviations: ACS: acute coronary syndrome, A: aspirin, C: clopidogrel, Tica: Ticagrelor, NOAC novel oral anticoagulant, PCI percutaneous coronary intervention.
Note: The duration of the triple antithrombotic therapy can be extended if the patient has high thrombotic risk i.e. left main PCI, proximal left anterior descending artery lesion, complex lesion, bifurcation lesion, recurrent myocardial infarction, stent thrombosis.
NOACs PATIENTS’ SUBGROUPS
NOACs in older populations
A significant proportion of older people (>75 years) has been included in all initial major trials and subsequent studies, ranging from 31% to 43%. They comprised over 27.000 elderly patients in whom NOACs were studied. As in the general population, NOAC treatment in older patients similarly reduced stroke rates compared to VKA. More importantly, a higher absolute risk was noted compared to younger patients, resulting in a lower number needed to treat [31–33]. Intracranial bleeding remains lower with all NOACs compared to VKA, but a significant age interaction was observed in older patients on the 150 mg dabigatran dose in terms of extracranial bleeding . However, there was no relation between age and rates of extracranial major bleeding with apixaban, edoxaban or rivaroxaban compared to the overall trial results. Additionally, apixaban and edoxaban appeared to have lower major bleeding complications compared to VKA even in older age groups . The risk of bleeding with age appears largely consistent with trial findings to date as it is indicated by observational registries in older cohorts [23, 34-37].
NOACs in patients with chronic kidney disease
Chronic kidney disease (CKD) and AF strongly interact with each other and are frequent comorbidities. The onset of atrial fibrillation promotes the progression of CKD and vice versa the establishment of renal dysfunction predisposes to AF [38–41]. Clinical management and risk stratification of patients with AF and CKD is very demanding as these patients carry both excessive thromboembolic and bleeding risk . Pharmacokinetic properties differ among all four available NOACs and are mainly determined by kidney elimination: dabigatran has the greatest percentage of renal elimination (80%), compared to 50%, 35%, and 27% of edoxaban, rivaroxaban, and apixaban, respectively.
Oral anticoagulant therapy in patients with severe CKD (CrCl of 15–29 mL/min)
Severe CKD -creatinine clearance (CrCl) of <30 mL/min – was an exclusion criterion in all landmark studies. A very small percentage of patients were studied on apixaban in the ARISTOTLE trial as the cutoff value was 25 ml/min. The small number of patients enrolled with CrCl 25-30ml/min is not sufficient for the generation of robust data. The current status is that patients with CrCl less than 15ml/h or on dialysis should be on warfarin . Existing data on NOAC use is still weak in the aforementioned group. Another “grey” zone is the group of patients with ClCr 15-30ml/min. A reduced dose regimen of rivaroxaban, apixaban, and edoxaban (but not dabigatran) is approved in Europe for patients with severe CKD (stage 4, i.e. a CrCl of 15–29 mL/min). Dabigatran should not be given if ClCr is less than 30 ml/min due to its higher renal elimination compared to the other three NOACs. All three FXa inhibitors appear to have a favorable efficacy and safety profile compared to VKA in patients with severe renal dysfunction, as indicated by observational data that should be interpreted cautiously as there might be substantial confounding factors [44–46]. The 2020 ESC guidelines recommend the “cautious” use of factor Xa inhibitors at reduced doses for patients with CrCl 15–29 mL/min .
Oral anticoagulant therapy in patients with end-stage CKD (CrCl of 15 mL/min and/or dialysis)
In patients with end-stage renal dysfunction and on dialysis, the efficacy and safety of NOACs is unclear and more trials are needed. Till then, a case based individualized approach is followed regarding the dilemma to anticoagulate or not and (if so) which regimen to choose.
NOACs and cardioversion
According to the current ESC guidelines  NOACs are recommended with at least similar efficacy and safety as VKA in patients with NVAF undergoing cardioversion (CV) (Class IA). Prompt administration of NOACs or heparin is strongly recommended before CV (Class IIA). Furthermore, in OAC-naive patients with AF of ≥48 h (or unknown) duration, ESC guidelines  and the European Heart Rhythm Association (EHRA) consensus document  advocate two types of strategy: an “aggressive” early imaging-guided strategy followed by cardioversion or a “defensive” delayed non-imaging-guided strategy after regular and continued NOAC intake for at least 3 weeks before CV . A recent modification is that there is a sub-classification of the first 48 hours to <12 hours and 12-48 hours. It is suggested to consider a more conservative approach in patients with AF presentation 12-48 hours and high CHA2DS2VASc score.
When the early strategy is chosen, a standard initial NOAC dose (rivaroxaban 20/15 mg, edoxaban 60/30 mg, dabigatran 150/110 mg) must be administered >4 h before cardioversion (≥2h after apixaban loading dose) and a TEE or a CT imaging is provisional to exclude left atrial appendage thrombus (LAAT) [48–50]. The EMANATE trial provided data that an initial loading dose of 10mg of apixaban (5 mg if does-adjustment criteria are applied) should be administered. Regarding the other NOACs, a loading dose is not recommended .
If a LAAT is found, cardioversion must be postponed for after a longer period of anticoagulation and after a repeated imaging test to confirm thrombus resolution. The best therapeutic strategy in this setting has not yet been established. But there are the possibilities of 1. converting to heparin to VKA or 2. start or continue with NOACs (best data with rivaroxaban and apixaban) especially in patients on VKA with poor anticoagulation quality (low time in therapeutic range).
On the contrary, limited data are available on safety and efficacy of NOACs for OAC-naïve patients with NVAF of <48 h duration. These patients are usually cardioverted without TEE after a single dose of low molecular weight heparin (LMWH). The last consensus document of EHRA on NOACs in NVAF recommends that these patients follow the local protocol with heparin/VKA as a first choice. As an alternative strategy we could use a single dose of NOACs or a loading dose of apixaban 2-4 h before CV to replace LMWH, according to patient thromboembolic risk and AF duration, with or without TEE .
However, there is no NOAC study on the peri-cardioversion setting including the EMANATE trial (the only study to enroll a certain number of OAC-naive patients with AF of <48 h duration) to demonstrate non-inferiority in terms of safety and efficacy of a single dose of NOACs or a single loading dose of apixaban compared to LMWH in this clinical scenario .
The post-CV duration of anticoagulation with NOACs as for VKA depends on individual patient’s thromboembolic risk assessed with CHA2DS2-VASc score. Long-term OAC therapy regardless of cardioversion success is required for men and women with a CHA2DS2-VASc ≥ 1 and ≥2, respectively. For patients with AF duration >48h and CHA2DS2-VASc score 0 in men and 1 in women, OAC therapy needs to be continued for 4 weeks post-CV. In contrast, the optimal duration of anticoagulation in AF ≤48h (especially when <12h) is unknown. In conclusion, anticoagulation with NOACs appears to be effective and safe in the peri-cardioversion setting .
Management of bleeding under NOAC therapy
NOACs are associated with lower rates of major and fatal bleeding events compared with warfarin as mentioned above. But clinicians may need to achieve rapid reversal of anticoagulation effects of the NOACs in an emergency setting. In Europe, idarucizumab – the direct antidote of dabigatran – is commercially available as opposed to andexanet alfa – the FXa antidote. However, both NOAC reversal agents are currently available in the US .
Peri-operative management of NOACs
The perioperative management of patients depends on the bleeding profile of the operation and the thrombotic risk as it is reflected by the CHA2DS2-VASc score. The advantageous management of NOACs is secondary to their faster onset and offset. NOACs should be pre-operatively paused for operation with a high chance of bleeding risk. The time duration of pause is determined by two factors: the peri-operative bleeding possibility and the renal function of the patient. The pre-operative cessation should be prolonged up to 12h if the patient has been administered medications that increase the half-life of NOACs [54, 55]. NOACs do not require bridging with heparin. Only when the risk of peri-operative bleeding is substantially lower and gastrointestinal passage is back to normal, NOAC therapy can be resumed. For procedures with low bleeding risk, NOAC is reestablished within 6-8 h and the farthest being 24 h post-operation [54–56]. But for operations with a high risk of bleeding, NOACs are restarted within 48-72 h post-operatively .
Administration of antidote is considered in case of an emergency surgery with high bleeding risk. Before the administration of an antidote, the plasma level of the drug should be calculated in order to assess the level of coagulation [57,58]. Idarucizumab is administered intravenously at a 2.5-mg dose initially and then a maintenance dose within 15 min [57,58]. For factor Xa inhibitors, andexanet alpha acts by binding to the agents and eliminating them. In bleeding conditions, an IV bolus and a continuous intravenous infusion of the drug is administered for 120 min.
Under-dosing of NOACs
Patient characteristics, comorbidities, and physician judgment are some of the factors that contribute to current dosing patterns of NOACs. In clinical practice, under- or over-dosing of NOACs in patients with AF is not uncommon. The fact that under-dosing may be associated with reduced effectiveness for stroke prevention compared with the standard dose is shown by an analysis of prospective and retrospective registry and database studies on NOAC use in patients with AF (with at least 250 patients in each treatment arm] .
At this point we should mention that under-dosing regarding dabigatran is debated, because the RE-LY trial was the only one proving that the lower dosage (110mg) was not inferior to warfarin. The United States-based ORBIT-AF II registry found that 12.9% of patients received no recommended NOAC doses according to drug labeling, with 9.4% being under-dosed. Increased rates of hospitalization for cardiovascular reasons were seen in under-dosed patients compared with patients receiving the recommended dose. The highest rates of under-dosing occurred in patients receiving apixaban (12% of the overall population), particularly those on dialysis (29%; according to the U.S. label, patients on dialysis, aged <80 years, and with a body weight >60 kg, can be treated with apixaban 5 mg bid if indicated), and in those with an estimated CrCl of 30–50 mL/min receiving dabigatran (23%) .
The Greece-based PAVE-AF antithrombotic study in older patients with atrial fibrillation showed that 63.2% of patients received NOAC dosing consistent with European label recommendations, 29.7% received a lower dose, while 7.1% were overdosed. The highest rates of under-dosing occurred in this study in patients receiving apixaban (38.5% of the overall population treated with apixaban] .
Dose adjustment for NOACs according to chronic kidney disease severity
We present the recommended dose of NOACs according to chronic kidney disease severity in patients with AF in Table 3. Dosage recommendations are derived from the analysis of data in the subgroups with AF and renal dysfunction from the landmark trials (dabigatran-RE‐LY, rivaroxaban-ROCKET‐AF, apixaban-ARISTOTLE). It is very important to mention that patients with GFR < 30 mL/min (<25 mL/min for apixaban) were excluded from these trials.
The dose of 15 mg for rivaroxaban is recommended if GFR is between 15-49 mL/min and dabigatran 150/110 mg is recommended if GFR is more than 30 mL/min. For apixaban if 2 out of 3 conditions are met (age ≥ 80 years, body weight ≤ 60 kg and creatinine ≥1.5 mg/dL) then the dose is reduced to 2.5 mg BID. This rule was applied in the ARISTOTLE trial where GFR < 25 mL/min was an exclusion criterion. Thus, in practice it applies when GFR is more than 30 mL/min since a very low number of patients were enrolled with GFR of 25-30 mL/min. If someone has GFR < 15-30 mL/min the rule is not valid, and these patients should take the reduced dose 2.5 BID .
NOACs are at least non-inferior to VKAs in the prevention of stroke and systemic embolism in patients with NVAF and they provide the benefits of rapid onset and offset, no pharmacodynamic monitoring or diet restrictions, fewer drug interactions, and predictable pharmacodynamics. Also, NOACs are associated with decreased rates of major bleeding, intracranial and fatal bleeding. New oral anticoagulants offer a reasonable option for patients undergoing cardioversion and facilitate access to surgical procedures. However, the relative safety and efficacy of NOACs in certain patient sub-populations (e.g., older populations and patients with chronic kidney disease) is not well established. Specific antidotes such as andexanet alfa (for Xa inhibitors) and idarucizumab (for dabigatran) can improve outcomes of bleeding or emergency surgery.
Conflict of interest disclosure
Georgios Leventopoulos has received in the past Speaker honoraria from Pfizer and Bayer
Declaration of funding sources
None to declare
CT has searched the relevant literature and has written part of the text; GL has written part of the text and has made the appropriate corrections. Both authors approved the final manuscript as submitted.
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