Clinical Significance of Non-Vitamin K Antagonist Oral Anticoagulants in the Management of Atrial Fibrillation

Abstract

Atrial fibrillation (AF) is the most commonly observed rhythm disorder in clinical practice. It is associated with a high risk of thromboembolic stroke and increased cardiovascular mortality. Vitamin K antagonists (VKAs), the only oral anticoagulants used for thromboembolic prophylaxis in AF patients over the past 60 years, have been effective in reducing thromboembolic stroke, compared with placebo and aspirin, in this group of patients. However, VKAs have a very narrow therapeutic window, so regular monitoring of the therapeutic effect is obligatory for their use. The need for regular assessment of blood anticoagulation often causes dissatisfaction and reduces patients’ quality of life. Non-VKA oral anticoagulants (NOACs), such as dabigatran, a direct thrombin inhibitor, and 3 factor Xa inhibitors, namely rivaroxaban, apixaban, and edoxaban, have been developed in recent years and have increased the armamentarium available to the physician for thromboprophylaxis in non-valvular AF (NVAF) patients. This review describes the characteristics of NOACs, analyzing aspects related to their use in the thromboprophylaxis of NVAF patients. It also discusses how to optimize NOAC therapy in specific clinical conditions, such as renal or liver impairment, and concomitant assumption of drugs potentially interfering with NOACs action. Finally, it focuses on NOAC-related bleeding management in the setting of non-cardiac surgery or radiofrequency catheter ablation of NVAF. (Circ J 2015; 79: 914–923)

Despite recent improvements in pharmacologic and electrical therapies, atrial fibrillation (AF) still remains the most common supraventricular tachyarrhythmia encountered in daily clinical practice. It affects 1–2% of the general population and its incidence increases in older patients.¹ The disease is frequently asymptomatic, but associated with a 2-fold increase in mortality, a 3-fold increase in congestive heart failure and a 5-fold increase in the risk of thromboembolic events, leading to frequent hospitalizations and worsened quality of life.² Although the use of antiarrhythmic medications leads to a significant improvement in symptoms,³ assessment of thromboembolic risk and the use of adequate anticoagulation is mandatory in the proper therapeutic management of AF.^4,5

Physiopathology of Thromboembolism and Anticoagulants in AF

The association between AF and thromboembolic risk is widely recognized and the genesis of thrombus formation in AF is multifactorial. All the anatomical and physiopathological features of the triad of events necessary for thrombus formation, described 150 years ago by Rudolph Virchow,⁶ are present in AF. In fact, AF is often characterized by endocardial damage, from dilatation of the atria,⁷ blood slowdown and stasis,⁸ related to the anatomy of the atria, and abnormal changes in blood constituents, including platelet activation,⁹ as well as inflammation¹⁰ and changes in growth factor.¹¹ For these reasons, AF can favor a prothrombotic and hypercoagulable state. Warfarin, a VKA, is the most commonly used agent among the OACs used for thromboembolic prophylaxis in AF patients. Its effectiveness is proven by 64% relative risk reduction of stroke compared with placebo,¹² and it also shows superior results to aspirin¹³ and to aspirin plus clopidogrel.¹⁴ However, VKAs have some faults: (a) it takes time (days) to achieve a satisfactory therapeutic effect; (b) intricate superimposition with parenteral anticoagulants; (c) narrow therapeutic window; (d) significant interaction with several drugs and food, making regular monitoring of the therapeutic effect obligatory. For these reasons, a review found that up to 65% of patients at risk were not taking OACs, and the international normalized ratio (INR) was out of range in a further 19% of patients.¹⁵ Thus, the impetus for the development of the non-vitamin K antagonist oral anticoagulants (NOACs), such as dabigatran a direct thrombin inhibitor, and 3 factor Xa inhibitors, namely rivaroxaban, apixaban, and edoxaban. Their therapeutic use for prevention of cardio-embolic complications was validated in recent large phase III trials, demonstrating their non-inferiority, and superiority in some cases, to warfarin.^16–19 Use of NOACs is currently recommended by guidelines for stroke prevention in patients with non-valvular AF (NVAF).^4,5 They have a predictable anticoagulant effect, and do not require routine blood monitoring, which makes them an attractive alternative to VKAs.

Thromboembolic Risk Stratification and Recommendation for Anticoagulant Therapy

In the clinical evaluation of patients with NVAF, the estimation of thromboembolic risk is very important, because not all patients with NVAF need to receive anticoagulation therapy. There are some conditions in which the risks may outweigh the potential benefits, in light of the fact that the average annual frequency of major bleeding during warfarin therapy ranges from 1.3% to 7.2%.²⁰ The most commonly risk scores used to stage the thromboembolic risk in AF patients are the CHADS₂ and CHA₂DS₂-VASc scores (Table 1). The 2012 focused update of the guidelines of the European Society of Cardiology⁴ recommends oral anticoagulation therapy (NOACs or VKAs) in all NVAF patients >65 years or showing a moderate or high thromboembolic risk, quantified by a CHA₂DS₂-VASc ≥1. In very low risk patients with a CHA₂DS₂-VASc=0 (ie, aged <65 years, including females and lone AF), no antithrombotic therapy is recommended (Table 2). Antiplatelet therapy with aspirin plus clopidogrel or, less effectively, aspirin, should be considered only in patients who refuse or cannot tolerate any OACs.

Table 1. Thromboembolic Risk Scores

Risk factors	CHADS2	CHA2DS2-VASc
Congestive heart failure/LV dysfunction	1	1
Hypertension	1	1
Age ≥75 years	1	2
Diabetes mellitus	1	1
Stroke/TIA/thromboembolism	2	2
Vascular disease	–	1
Age 65–74 years	–	1
Sex category (ie, female)	–	1
Maximum score	6	9

CHADS₂ score includes history of congestive heart failure, arterial hypertension, age ≥75 years, diabetes mellitus and history of stroke (2 points). The acronym CHA₂DS₂-VASc score considers history of congestive heart failure, arterial hypertension, age >65 years (age ≥75 years=2 points), diabetes mellitus, history of stroke (2 points), vascular disease and sex category. LV, left ventricular; TIA, transient ischemic attack.

Table 2. 2012 Focused Update of the European Society of Cardiology Guideline Recommendations for Anticoagulation Therapy in AF

Risk category	CHA2DS2-VASc score	Recommended antithrombotic therapy
One “major” risk factor or ≥2 “clinically relevant” non-major risk factors	≥2	OAC
One “clinically relevant non-major” risk factor	1	OAC (unless 1 point score is for female sex, in which case no antithrombotic therapy is recommended)
No risk factors (ie, aged <65 years and lone AF)	0	No antithrombotic therapy

AF patients with CHA₂DS₂-VASc score ≥1 are recommended to begin OAC, whereas no antithrombotic therapy is recommended for AF patients with CHA₂DS₂-VASc score=0. AF, atrial fibrillation; OAC, oral anticoagulation therapy.

Pharmacokinetic Profile of Warfarin Compared With NOACs

Thrombin plays a crucial role in the coagulation cascade, converting fibrinogen to fibrin monomer, with the ensuing fibrin polymer forming the actual clot and promoting thrombus formation (Figure 1). Warfarin, by inhibiting vitamin K-dependent γ-carboxylation, blocks the synthesis of multiple factors (II, VII, IX, X) of the coagulation cascade, preventing thrombus formation. NOACs act in a completely different way to warfarin. In fact, they selectively inhibit a single coagulation factor. Currently, 4 NOACs have been approved for anticoagulation in NVAF by the US Food and Drug Administration (FDA): dabigatran, rivaroxaban, apixaban and edoxaban. The first 3 anti-clotting drugs were also licensed by the European Medicine Agency (EMA) in Europe. Dabigatran is the only direct inhibitor of thrombin, as opposed to the other 3 drugs that directly inhibit factor Xa (Figure 1). Their pharmacokinetic profiles, recommended doses, and drug interactions are shown in Table 3.

Figure 1.

Sites of action of anticoagulants within the coagulation cascade. Warfarin inhibits production of factors II, VII, IX and X, whereas non-vitamin K antagonist oral anticoagulants (NOACs) inhibit thrombin (dabigatran) or factor Xa (apixaban, edoxaban, and rivaroxaban).

Table 3. Characteristics of Vitamin K and Non-Vitamin K Inhibitor Oral Anticoagulants

	Warfarin/Phenprocoumon/Acenocoumarol	Dabigatran		Rivaroxaban		Apixaban		Edoxaban
Target	Vitamin K epoxide reductase	Thrombin		Factor Xa		Factor Xa		Factor Xa
Oral bioavailability	>90%/>90%/60%	6.5%		80–100%		50%		62%
Time for peak effect	48–72 h/72–96 h/36–48 h	2–3 h		2–4 h		3–4 h		1–2 h
Plasm half-life	36–42 h/120–200 h/8–14 h	14–17 h		5–13 h		12 h		10–14 h
Metabolism/elimination	Via CYP450, Renal 90%/mainly hepatic/renal 60%, fecal 30%	Via P-gp transporter/80% renal excretion		Via CYP450, Via P-gp transporter/35% renal excretion		Via CYP450, Via P-gp transporter/27% renal excretion		Via CYP450, Via P Gp transporter/50% renal excretion
Drug interaction	400 known interactions	Strong P-gp inhibitors: ↑↑↑ NOAC exposure		Strong CYP3A4 and P-gp inhibitors: ↑↑↑ NOAC exposure		Strong CYP3A4 and P-gp inhibitors: ↑↑↑ NOAC exposure
		- ketoconazole - itraconazole - cyclosporine - tacrolimus - dronedarone	Controindicated association	*Azole-antimycotics - ketoconazole - itraconazole - voriconazole - posaconazole *HIV protease inhibitors *Dronedarone	Controindicated association	Azole-antimycotics - ketoconazole - itraconazole - voriconazole - posaconazole HIV protease inhibitors	Controindicated association
		Mild-moderate P-gp inhibitors: ↑ NOAC exposure
		- ketoconazole - amiodarone - quinidine - verapamil - clarithromycin	Use association with caution
		P-gp inducers: ↓ NOAC exposure		CYP3A4 inducers: ↓ NOAC exposure		CYP3A4 inducers: ↓ NOAC exposure		CYP3A4 inducers: ↓ NOAC exposure
		- rifampicin - phenytoin - carbamazepine - Hypericum perforatum	Controindicated association	- rifampicin - phenytoin - carbamazepine - phenobarbital - Hypericum perforatum	Use association with caution	- rifampicin - phenytoin - carbamazepine - phenobarbital - Hypericum perforatum	Use association with caution	- rifampicin	Use association with caution
Dosage in NVAF	According to INR (INR 2–3)	150 mg twice daily		20 mg daily		5 mg twice daily		60 mg daily
Dose monitoring	INR values	If required with thrombin time		–		–		–

CYP450, cytochrome P 450; CYP3A4, cytochrome P 450 3A4; INR, international normalized ratio; NOAC, non-vitamin K antagonist oral anticoagulant; P-gp, P-glycoprotein.

Efficacy and Safety Studies Comparing NOACs With Warfarin for Thromboprophylaxis in NVAF

Dabigatran was the first NOAC to receive both FDA and EMA approval, on the basis of the results of the RE-LY trial,¹⁶ in which 18,113 patients with NVAF and at least 1 additional risk factor for stroke were equally randomized into 3 different groups: group 1 received an open-label adjusted-dose of warfarin (INR 2.0–3.0), while group 2 and group 3 received 2 blinded doses of dabigatran (150 mg BID (D150) and 110 mg BID (D110)). The results of the RE-LY trial showed non-inferiority of both doses of dabigatran compared with warfarin in terms of the primary endpoints (stroke and systemic embolism), as well as for the rate of safety endpoints (severe bleeding complications). The results of the trial also documented the superiority of D150 compared with VKA in reducing the primary efficacy endpoints, without increasing the rate of major hemorrhagic events. As compared with warfarin, D110 was associated with reduced major bleeding. Performing a subanalysis of the side effects reported in the 3 groups, dabigatran, in both dosage regimens, was associated with a significantly lower risk of intracranial bleeding compared with VKA, and D150 showed a higher rate of gastrointestinal bleeding compared with either D110 or the VKA. A recent study, comparing the safety of dabigatran vs. warfarin in NVAF, in general practice settings, confirmed the results of RE-LY,¹⁶ showing that dabigatran has a favorable risk/benefit profile in a large general population of NVAF patients.²¹ The largest trial to evaluate the efficacy and safety of rivaroxaban, compared with warfarin, in NVAF patients was ROCKET-AF.¹⁷ In this double-blind trial, 14,264 patients with NVAF and high risk for stroke were randomly assigned to receive either once-daily dose of rivaroxaban 20 mg or dose-adjusted warfarin (INR 2.0–3.0). Patients with impaired renal function (creatinine clearance, CrCl, of 30–49 ml/min) were treated with a reduced 15 mg rivaroxaban daily dose. The results of the trial showed that rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolism (primary efficacy endpoints) and that there were no significant differences in the rate of major bleeding between the 2 different anticoagulation therapies, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. Afterwards, in a large pharmacovigilance observational study evaluating major bleeding in NVAF patients treated with rivaroxaban in a “real-world” clinical setting, the rates and patterns of major bleeding were consistent with the results observed in the ROCKET-AF trial and fatal bleeds were rare.²² Apixaban was investigated in the AVERROES trial,²³ in which it was compared with aspirin for stroke prophylaxis in patients who were intolerant to warfarin. This trial showed a statistically significant lower incidence of stroke or systemic embolism, with no significant difference in rates of major bleeding in the apixaban group compared with the aspirin one. The ultimate confirmation of the efficacy of apixaban in preventing stroke in AF patients was obtained with the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.¹⁸ In this randomized, double-blind trial, apixaban (at a dose of 5 mg twice daily) was compared with dose-adjusted warfarin (INR 2.0–3.0) in 18,201 NVAF patients who had 1 additional risk factor for stroke. Patients with increased risk of bleeding and the presence of 2 risk markers (age ≥80 years, body weight ≤60 kg, creatinine ≥1.5 mg/dl) were treated with the lower dose of apixaban 2.5 mg twice daily. The results of this trial documented that apixaban was superior to warfarin in preventing stroke or systemic embolism; in addition, it caused less bleeding than warfarin and resulted in lower mortality. Edoxaban has recently been examined by a randomized multicenter trial named ENGAGE-TIMI 48,¹⁹ in which 21,105 NVAF patients with moderate-high risk were randomized to receive 60 mg once-daily dose of edoxaban, 30 mg once-daily dose of edoxaban or dose-adjusted warfarin (INR 2.0–3.0). The trial showed that both regimens of edoxaban were non-inferior to warfarin with respect to the prevention of stroke or systemic embolism during 2.8 years of follow-up and that they were associated with significantly lower rates of bleeding and death from cardiovascular causes. Table 4 summarizes the results of all NOAC randomized trials. A recent meta-analysis,²⁴ including data from all 4 NOAC randomized trials,^16–19 showed the superiority of NOACs compared with warfarin in reducing stroke, intracranial hemorrhage and mortality while causing an increase in gastrointestinal bleeding (Figure 2). Head-to-head studies do not exist and direct comparisons between the NOACs may not be made.

Table 4. Efficacy and Safety Randomized Trials Comparing NOACs and Warfarin in Patients With NVAF

	RE-LY (dabigatran)	ROCKET-AF (rivaroxaban)	ARISTOTLE (apixaban)	ENGAGE AF-TIMI 48 (edoxaban)
No. of patients	18,113	14,264	18,201	21,105
Study population	Patients with NVAF CHADS2 score ≥1 (mean 2.1) Mean age: 72 years	Patients with NVAF CHADS2 score ≥2 (mean 3.5) Mean age: 73 years	Patients with NVAF CHADS2 score ≥1 (mean 2.1) Mean age: 70 years	Patients with NVAF CHADS2 score ≥2 (mean 2.8) Mean age: 72 years
Study design	Double-blind randomized, non-inferiority trial	Double-blind randomized, non-inferiority trial	Double-blind randomized, non-inferiority trial	Double-blind randomized, non-inferiority trial
Dosage	150 mg (110 mg) twice daily	20 mg (15 mg) once daily	5 mg (2.5 mg) twice daily	60 mg (30 mg) once daily
Control drug	Warfarin (INR 2–3) TTR 64%	Warfarin (INR 2–3) TTR 55%	Warfarin (INR 2–3) TTR 62%	Warfarin (INR 2–3) TTR 68.4%
Primary efficacy outcome	Stroke (ischemic or hemorrhagic) or systemic embolism	Stroke (ischemic or hemorrhagic) or systemic embolism	Stroke (ischemic or hemorrhagic) or systemic embolism	Stroke (ischemic or hemorrhagic) or systemic embolism
Principal safety endpoint	Major bleeding	Composite of major and non-major bleeding	Major bleeding	Major bleeding
Results	Efficacy of dabigatran 110 mg vs. warfarin (0.91; 95% CI, 0.74–1.11; P<0.001 for non-inferiority) Efficacy of dabigatran 150 mg vs. warfarin (0.66; 95% CI, 0.53–0.82; P<0.001 for superiority) Safety of dabigatran 110 mg vs. warfarin (0.80; 95% CI, 0.69–0.93; P=0.003) Safety of dabigatran 150 mg vs. warfarin (0.93; 95% CI, 0.81–1.07; P=0.31)	Efficacy of rivaroxaban 20 mg vs. warfarin (0.88; 95% CI, 0.74–1.03; P<0.001 for non-inferiority; P=0.12 for superiority) Safety of rivaroxaban 20 mg vs. warfarin (1.03; 95% CI, 0.96–1.11; P=0.44)	Efficacy of apixaban 5 mg vs. warfarin (0.79; 95% CI, 0.66–0.95; P<0.001 for non-inferiority; P=0.01 for superiority) Safety of apixaban 20 mg vs. warfarin (0.69; 95% CI, 0.60–0.80; P<0.001)	Efficacy of edoxaban 60 mg vs. warfarin (0.87; 97.5% CI, 0.73–1.04; P=0.08 for superiority Efficacy of edoxaban 30 mg vs. warfarin (1.13; 97.5% CI, 0.96–1.34; P=0.10 for superiority Safety of edoxaban 60 mg vs. warfarin (0.80; 95% CI, 0.71–0.91; P<0.001) Safety of edoxaban 30 mg vs. warfarin (0.47; 95% CI, 0.41–0.55; P<0.001)

ARISTOTLE, Apixaban for reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; CI, confidence interval; ENGAGE AF-TIMI 48, Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48; NVAF, mon-valvular atrial fibrillation; RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy trial; ROCKET-AF, Rivaroxaban Once-daily, oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation; TTR, mean percent of time in the therapeutic range. Other abbreviations as in Table 3.

Figure 2.

Meta-analysis of data from 4 randomized trials comparing NOACs and warfarin in NVAF patients. (A) Stroke or systemic embolic events. (B) Secondary efficacy and safety outcomes. CI, confidence interval; NOACs, non-vitamin K antagonist oral anticoagulants; NVAF, non-valvular atrial fibrillation; RR, risk ratio. (Modified with permission from Ruff CT, et al.²⁴)

Efficacy and Safety Studies Comparing NOACs With Warfarin for Thromboprophylaxis in NVAF Following Cardioversion or Radiofrequency Catheter Ablation (RFCA)

Based on recent trials, the European Society of Cardiology⁴ and the American Society of Cardiology⁵ suggest the use of NOACs as an effective alternative to warfarin in patients with NVAF, especially those patients unable to tolerate warfarin and in all circumstances those failing to reach the INR target value. Despite the reassuring results provided by the abovementioned trials, clinicians still face uncertainties about the efficacy and safety of NOACs in patients undergoing cardioversion or RFCA of AF. This clinical indecision is due to the lack of evidence, because none of the discussed studies addressed AF patients undergoing cardioversion or RFCA. In a post-hoc analysis of the RE-LY trial,²⁵ the frequencies of stroke and major bleeding within 30 days of cardioversion on dabigatran were low and comparable with those with treatment by warfarin, suggesting that dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion. A further post-hoc analysis of the ROCKET-AF trial²⁶ reported similar outcomes between patients undergoing cardioversion or RFCA, and such results were independent by treatment with rivaroxaban or warfarin. The X-VeRT trial²⁷ was the first prospective randomized trial that tested rivaroxaban in AF patients undergoing elective cardioversion. In this study, 1,504 patients were enrolled and assigned to rivaroxaban (20 mg once daily, 15 mg once daily if CrCl 30–49 ml/min) or to VKA in a 2:1 ratio. Investigators selected either an early (1–5 days after randomization) or delayed (3–8 weeks) cardioversion strategy. The results of the study showed no difference in either efficacy (stroke, transient ischemic attack, peripheral embolism, myocardial infarction and cardiovascular death) or safety (major bleeding) outcomes between rivaroxaban and VKA; intriguingly, rivaroxaban was associated with a significantly shorter time to cardioversion compared with VKA. Also in the ARISTOTLE trial, post-hoc analysis testing the efficacy and safety of apixaban vs. warfarin in AF patients undergoing cardioversion demonstrated that clinical events, occurring after cardioversion of AF, were comparable between warfarin and apixaban.²⁸ There are several reports suggesting that RFCA may be performed with fewer complications when oral anticoagulation therapy with warfarin is continued (INR 2.0–3.0). Di Biase et al²⁹ in fact demonstrated that the combination of an open irrigation ablation catheter and periprocedural anticoagulation with warfarin (INR 2.0–3.0) may reduce the risk of periprocedural stroke, without increasing the risk of pericardial effusion or other bleeding complications. The same outcomes were obtained in another study in which the authors compared the rate of ablation-induced cardiac tamponade between patients with and without continuous anticoagulation during the procedure.³⁰ The results of that study showed that cardiac tamponade is not more severe or difficult to manage in the presence of therapeutic anticoagulation with warfarin in patients undergoing RFCA of AF. Continuation of warfarin is also recommended in the recent HRS/EHRA/APHRS consensus statement as an alternative to a bridging approach with heparin for patient on VKAs prior to RFCA.³¹ Experience with NOACs is limited. Several centers have reported their experience with using NOACs during the periprocedural phase of RFCA.^32–34 The most used NOAC was the dabigatran, typically held for 1 or 2 doses prior RFCA and compared with continued warfarin. These reports suggest that the use of dabigatran is associated with a similar risk of bleeding and thromboembolic events, compared with uninterrupted warfarin. Dillier et al recently tested the safety and efficacy of continuous periprocedural rivaroxaban intake, compared with uninterrupted VKA, in patients undergoing RFCA, showing that continuing periprocedural rivaroxaban is safe as uninterrupted VKA administration.³⁵ Despite the promising results of these trials, the lack of randomized studies does not allow us to know the exact relative risk of uninterrupted anticoagulation with NOACs during the periprocedural phase of RFCA.

Antidotes and Laboratory Monitoring

Currently, there are no specific antidotes for any of the available NOACs. Therefore, it is possible to antagonize the anticoagulant effect of VKAs, by orally or intravenously administered vitamin K, but there is no way of directly neutralizing the anticoagulant effect of NOACs. Because the procoagulative effect exerted by vitamin K takes approximately 24 h, administration of fresh frozen plasma or coagulation factors can quickly reverse the anticoagulant effect of VKAs. Such a therapeutic approach cannot be considered effective in antagonizing NOACs, because the newly administered coagulation factors also may be blocked by the plasma abundance of the drug itself. If INR measurement constitutes a limitation of the VKAs, on the other hand it offers the advantage of being able to establish the anticoagulant effect. Moreover, also if NOACs show the convenience of not requiring repeated blood checks, there are circumstances in which laboratory monitoring may be necessary (ie, life-threatening bleeding; surgical intervention in a patient with assumed NOAC administration in the previous 24 h; identification of sub- or supratherapeutic anticoagulant levels in patients consuming other drugs that can affect NOACs pharmacokinetics, or who have concomitant renal impairment). Traditional laboratory tests can be performed for a qualitative assessment of the NOACs anticoagulant effect: dabigatran may prolong the activated partial thromboplastin time (aPTT).³⁶ Prothrombin time (PT), INR and the thrombin time (TT) also may be prolonged by dabigatran.³⁷ The TT is particularly prolonged at low dabigatran plasma concentration and blood becomes unclottable as plasma levels increase.³⁷ A normal TT excludes a clinically significant plasma concentration of dabigatran.³⁷ Rivaroxaban and apixaban do not affect the TT.³⁷ PT and INR may be increased by rivaroxaban, but are not significantly altered by apixaban.³⁷ Very poor data are currently available for edoxaban: aPTT prolongation seems to be the more reliable indication of high drug plasma levels.³⁸ Anti-factor Xa “chromogenic assays” assessing the plasma concentrations of the factor Xa inhibitors are commercially available, but do not measure the intensity of the drug’s anticoagulant activity.

Management of NOACs in Specific Clinical Conditions

The different pharmacodynamic and pharmacokinetic properties of NOACs impose a different therapeutic management compared with warfarin in specific clinical conditions.

Acute Coronary Syndromes (ACSs) and Percutaneous Coronary Interventions (PCIs)

ESC guidelines for the management of AF published in 2010³⁹ and the 2012 focused update of the ESC guidelines for patients with AF⁴ suggest that a period of triple therapy is needed (OAC+aspirin+clopidogrel) in patients with AF undergoing PCI with stenting, followed by the combination OAC plus a single antiplatelet drug and, after 1 year, management can be with an OAC alone (VKA or NOAC) in stable patients. Data sources for understanding the role of NOACs as part of a triple therapy include trials conducted in patients with NVAF and trials conducted in patients undergoing ACS/PCI. In NVAF trials, the use of a single antithrombotic therapy (aspirin or clopidogrel) on top of an OAC represented one-third of the study populations (with clopidogrel use in 0–5% of patients).^16–19 The only trial in which dual antiplatelet therapy (DAPT), with aspirin plus clopidogrel, was used in addition to a NOAC, but only in a very small percentage of the patient population, was RE-LY;¹⁶ in an ACS trial of low-dose rivaroxaban (2.5 mg BID or 5 mg BID), a triple therapy (ie, low-dose rivaroxaban+DAPT) was found to reduce the combined ischemic endpoint at the cost of increased bleeding (hazard ratio 3.96, 95% confidence interval: 2.46–6.38, P<0.001).⁴⁰ The 2014 ESC/EACTS guidelines on myocardial revascularization recommend (Class IIa, level of evidence C) DAPT plus OAC (VKA or NOAC) for the management of AF patients with ACS and/or undergoing PCI/stenting; the duration of triple therapy is dependent on stroke risk, bleeding risk and type of stent.⁴¹ The benefits of NOACs in the scenario of NVAF patients undergoing PCI will be elucidated by ongoing studies, including PIONEER AF-PCI for rivaroxaban (NCT01830543) and RE-DUAL PCI for dabigatran (NCT02164864), as well as the recently announced AAA for apixaban.

Chronic Kidney Disease

Chronic renal failure is an independent predictor of stroke and systemic embolism⁴² and acts as an additional risk factor for thromboembolic and hemorrhagic events in patients with NVAF.⁴³ For this reason, the management of anticoagulation therapy in this category of AF patients is particularly intricate. VKAs are effective in reducing thromboembolic events in patients with chronic renal impairment, yet there is an increased bleeding risk.^43,44 NOACs currently available show a not negligible renal elimination; therefore, evaluation of the patient’s renal function, by the Cockcroft-Gault formula, is crucial before prescribing this new class of drugs. Dabigatran has 80% renal elimination and EHRA guidelines⁴⁵ do not recommend dabigatran in patients with severe renal failure (CrCl 15–30 ml/min). Half-dose (75 mg twice daily) was approved by the FDA and it is currently recommended by AHA/ASA guidelines⁴⁶ for patients with low CrCl (15–30 ml/min). Approximately 35% and 27% of rivaroxaban and apixaban, respectively, are renally eliminated as active drug; for these reasons the EHRA and AHA/ASA guidelines do not recommend their use in patients with severe renal failure (CrCl <15 ml/min) and moreover, the EHRA guidelines suggest using rivaroxaban at the lower dose of 15 mg once daily in patients with CrCl between 15 and 49 ml/min, and apixaban at the lower dose of 2.5 mg twice daily in patients with CrCl between 15 and 29 ml/min or serum creatinine ≥1.5 mg in combination with age ≥80 years or weight ≤60 kg. Conversely, the 2012 focused update of the ESC guidelines for patients with AF⁴ do not recommend dabigatran, rivaroxaban or apixaban in patients with severe renal impairment (CrCl <30 ml/min). Edoxaban renal clearance is 50% and currently the FDA has only approved edoxaban at the half dose of 30 mg once daily for patients with moderate to severe renal impairment (CrCl between 15 and 50 ml/min). Not one of the NOAC trials enrolled patients on dialysis, so their use is actually contraindicated in this setting.

Chronic Liver Disease

Impaired liver function and chronic liver disease can determine thrombocytopenia and coagulation abnormalities; in fact, they represent an independent bleeding risk factor (1 point in the HAS-BLED score; Table 5). Patients with active liver disease were excluded from all safety and efficacy NOAC trials, so this clinical condition represents a contraindication to their use.

Table 5. Bleeding Risk Score

Risk factor	HAS-BLED
Hypertension	1
Abnormal renal and liver function	1 or 2
Stroke	1
Bleeding	1
Labile INR	1
Elderly (age >65 years)	1
Drugs or alcohol	1 or 2
Maximum score	9

HAS-BLED score includes arterial hypertension, abnormal renal liver function, history of stroke, bleeding, labile INR, advanced age (>65 years) and history of drugs (antiplatelet or non-steroidal anti-inflammatory agents) or alcohol abuse. INR, international normalized ratio.

Advanced Age and Low Body Weight

Advanced age is often associated with renal impairment, so it is very important to quantify renal function in elderly patients before starting NOAC therapy. Because RE-LY documented an increased plasma concentration of dabigatran in elderly patients, lower doses of dabigatran (110 mg BID) are recommended in octogenarians. In the absence of other bleeding risk factors, no age- and weight-related dose adjustment is recommended for the other NOACs.

Patients Undergoing Surgical Interventions

The NOACs, as do the VKAs, increase the peri- and post-procedural bleeding complications of surgical interventions. Therefore, according to the EHRA guidelines,⁴⁵ their adminstration should be provisionally interrupted in view of surgical intervention. The effective half-life of warfarin ranges from 20 to 60 h,⁴⁷ so its discontinuation and bridging with unfractionated heparin (UFH) in AF patients with higher thromboembolic risk has been proposed.³⁹ That approach is not mandatory in NOAC-treated patients, because their half-lives are much shorter compared with the VKAs and complete restoration of coagulation function is possible in 12–24 h. Therefore, a suitably timed temporary interruption and later restoration of NOAC therapy can be planned, before and after surgery.⁴⁸ The main features to consider before discontinuing NOAC therapy are surgical bleeding risk, age, weight and renal function. Bleeding risk related to surgery can be low when the surgical intervention is minimally invasive or when adequate local hemostasis can be achieved (eg, eye anterior chamber surgery, dental procedures and superficial plastic surgery), or high, as when surgery is major (thoracic, abdominal, cardiovascular, orthopedic, urological and neurological). On the basis of pharmacokinetic data, the EHRA guidelines⁴⁵ recommend discontinuation of NOAC therapy 24 and 48 h before minor and major elective bleeding risk interventions, respectively, in patients with normal kidney function. ESC experts suggest that interventions not foreseeing a significant bleeding risk can be concurrently planned at the lower plasma drug concentration (ie, 12 or 24 h after the last intake, depending on BID or QD dosing), but they should be avoided at drug peak concentration. For patients with renal impairment, it is advisable to suspend the factor Xa inhibitors 24–48 h before surgery according to bleeding risk, and dabigatran should be discontinued at least 36 h to a maximum 72 h before low and high bleeding risk interventions, respectively, if the CrCl ranges from 50 to 80 ml/min. An interruption to dabigatran administration until 96 h is recommended in patients with CrCl ranging from 30 to 50 ml/min and undergoing a high bleeding risk surgical intervention.⁴⁵ In patients undergoing an urgent surgical intervention, NOACs should be immediately stopped and surgery, if possible, should be postponed at least 12 h and preferably 24 h after the last administration. If surgical intervention is not deferrable, common coagulation tests (aPTT, PT, TT) can be performed to assess the partial vanishing of the anticoagulant effect. NOACs can be resumed 6–8 h after surgery, if a complete homeostasis has been achieved.⁴⁵

Switching Between Different Anticoagulant Regimens

The replacement of VKAs with NOACs can be carried out as soon as the INR is ≤2. In the event of an INR between 2 and 2.5, the NOAC can be started the next day. If the INR is >2.5, it is preferable to start the NOAC when the INR is ≤2.⁴⁵ However, the product infomation leaflet⁴⁹ recommends starting rivaroxaban when the INR is ≤3. When UFH is used, the NOAC can be started as soon as the infusion has been interrupted, in the absence of impaired renal function (in which case elimination of UFH can take longer). In the case of a NOAC needing to be replaced by a VKA, the latter can be immediately started without interrupting NOAC administration and it is advisable to administer both drugs together until the target INR has been obtained, and then stop the NOAC while continuing with the VKA. As NOAC can affect the INR measurement, during the overlap phase it is always advisable to measure it immediately before the next dose of NOAC and 24 h after the last dose. Replacement of a NOAC with parenteral anticoagulants can be made by starting the latter 12 h (dabigatran or apixaban) or 24 h (rivaroxaban or edoxaban) after the last NOAC intake. Similarly, a NOAC is to be replaced with another NOAC, start the new anticoagulant when the next dose is due (with a longer interval in patients with impaired renal function).

Bleeding Complications Management

The annual incidence of major bleeding complications in AF patients treated with OACs ranges from 1.3 to 7.2 depending on the patients’ bleeding risk.²⁰ The ESC guidelines³⁹ recommend using the HAS-BLED score (Table 5) to evaluate the bleeding risk of patients before starting anticoagulation therapy and suggest also using caution and frequent clinical follow-up for patients with HAS-BLED ≥3. Despite the long plasma half-life, the anticoagulant effect of VKAs can be reversed by administration of vitamin K associated with administration of fresh frozen plasma and coagulation factors. The lack of a specific antidote and rapid laboratory tests to establish their anticoagulant effects makes more urgent and quite challenging the management of a major bleed in patients taking NOACs. In fact, the high plasma concentration reached in the first hours after administration can nullify the effect of coagulation factors newly administered, making poorly effective their usage. Relying on the relatively short half-life of NOACs, the EHRA guidelines⁴⁵ recommend supportive measures such as mechanical compression, surgical hemostasis and fluid replacement in the case of non-life-threatening bleeding, whereas for life-threatening bleeding they suggest that activated prothrombin complex concentrates or activated factor VIIa (FEIBA) be considered in addition to the previously described measures. Although dabigatran can be eliminated by dialysis, the clinical experience in this setting is very limited. In contrast to dabigatran, dialysis is not efficacious in reducing factor Xa inhibitors plasma levels.

Conclusions

The NOACs have been approved for the prevention of ischemic stroke in high thromboembolic risk NVAF and they currently represent a valid and effective alternative to warfarin. The advantages of using them are definitely represented by the fixed dose and by the absence of the need for continuous blood monitoring. Efficacy and safety trials have documented their non-inferiority and in some cases also their superiority in preventing stroke or systemic embolism and reducing intracranial bleeding in NVAF, compared with warfarin. Nevertheless, it should be pointed out that the costs of NOACs are high and there is a lack, in specific subsets of patients, of a large clinical experience with this new class of drugs. Before prescribing a NOAC, the clinical features of the patient should always be taken into account, particularly his/her thromboembolic and bleeding risk profiles, as well as age, weight, and liver/kidney function. Finally, the concomitant administration of additional therapies that potentially interfere with the pharmacokinetics of NOACs should always be investigated. The lack of head-to-head studies comparing different NOACs has precluded the establishing of the superiority of one agent over another in clinical practice.

In conclusion, NOACs appear to have many advantages over warfarin in AF patients, which has been documented by randomized trials as well as “real life” registries. However, VKAs remain the only pharmacologic agents for thromboembolic prophylaxis of patients with valvular AF and for patient with mechanical heart valve prostheses.⁵⁰

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