The New Oral Anticoagulants in Atrial Fibrillation: Once or Twice Daily?
In the clinical setting of atrial fibrillation (AF), clinical trials comparing new anticoagulants (NOACs) with vitamin K antagonists (VKAs) for the prevention of thromboembolism showed that dabigatran etexilate 150 mg twice daily reduced the rates of stroke/systemic embolism without any difference in major bleeding, and dabigatran etexilate 110 mg twice daily had similar efficacy with decreased bleeding;1 rivaroxaban 20 mg once daily was noninferior to warfarin for stroke and systemic embolism without a difference in major bleeding;2 apixaban 5 mg twice daily reduced stroke, systemic embolism and mortality as well as major bleeding;3 edoxaban at both once daily doses of 30 mg and 60 mg was noninferior to warfarin for the prevention of stroke or systemic embolism and was associated with significantly lower rates of bleeding and death from cardiovascular causes.4 All these agents reduced intracranial hemorrhage.5
The different outcomes in these trials is possibly due to the study design, the risk of the patients population, the quality of warfarin management (time-in-therapeutic range), and the duration of the follow-up. It is also however quite possible that the drug regimens selected, including the drug dosage, and also the once daily vs twice daily regimens contribute to explaining the difference between NOACs in the observed results.
The selection of dosing regimens for the new oral anticoagulants in atrial fibrillation
The dosage and daily dosing regimen of drugs for which pharmacological effects depend on their plasma concentrations (reversible agonists or antagonists) are generally first proposed on the basis of pharmacokinetic (PK) properties. In the setting of chronic therapy, after administration and absorption, drug concentration increases and reaches a maximum plasma concentration (Cmax); then, according to clearance kinetics, concentration decreases until a trough (minimum) plasma concentration (Cmin) is achieved before the next dose. The rate of administration, related to drug pharmacokinetics, is usually aimed at maintaining plasma drug concentrations as stable as possible, thus obtaining a limited range of steady-state concentrations at which drug elimination equals the rate of drug intake.6 Besides PK characteristics, pathophysiologic considerations also however play a role in the choice of different doses and dose regimens of drugs such as anticoagulants in different clinical conditions.
The pharmacodynamic and pharmacokinetic characteristics of the NOACs (Table 1) provide the opportunity for either once or twice daily dosing, and the determination of the optimal dosing regimen was based on the assessment of the benefit (reduction in thrombotic events) and risk (increase in bleeding events) in clinical studies.
Only one phase II study compared once vs twice daily regimen of dabigatran: in the BISTRO II study7 for the prevention of venous thromboembolism (VTE) following total hip or knee replacement, 300 mg dabigatran once daily showed almost identical efficacy and bleeding rates, identical overall drug exposure at steady state, but, as expected, a larger peak-trough difference compared with the 150 mg twice daily, showing a stronger correlation between Cmax and both efficacy and safety outcomes (Table 2). This guided the choice of dose regimens in clinical settings at higher risk of thromboembolism, such as AF or VTE treatment (twice daily regimen), compared with VTE prevention (once daily regimen), taking into account efficacy/safety consideration.
A once daily regimen of rivaroxaban was compared with a twice daily regimen in VTE treatment8 (Table 2): here, the dose of 40 mg once daily does not expose patients to a greater risk of bleeding or thrombus growth than 20 mg twice daily, as confirmed by population analyses of phase II clinical data.9 Therefore, the once daily dose of 20 mg was selected for the phase III program in VTE treatment, with an initial three weeks of rivaroxaban 15 mg twice daily – chosen because the higher Cmin levels achievable with twice daily regimens ("intensified" anticoagulant effect) were thought to be beneficial in the acute treatment phase 10-11. This regimen is different from the 10 mg once daily regimen providing the best balance of efficacy and safety in VTE prevention.12 A dose of 20 mg once daily was selected for stroke prevention in AF in the phase III ROCKET-AF trial,2 on the basis of the phase II results in the prevention and treatment of VTE. In an ACS population, rivaroxaban once daily administration – associated, as expected, with higher peaks and lower troughs – resulted in a trend to slightly greater clinically significant bleeding compared with the twice daily administration across most doses, while the secondary efficacy end point was overall similar with the once daily dose administration vs the twice daily administration across doses explored13 (Table 2). Therefore in this case the net clinical benefit appeared to favor the twice daily dose regimen, which was carried forward for the phase III study.14
The phase II clinical trial testing efficacy and safety of apixaban, given either as once or a twice daily dosing compared with enoxaparin or warfarin for the prevention of VTE15 (Table 2), indicated that there was a clear dose effect on total bleeding rates, irrespective of once or twice daily dosing, with lower point estimates (albeit not statistically significant) for the primary outcome with twice vs once daily dosing. Therefore, in the setting of VTE prevention, for which safety was the primary concern, the 2.5 mg twice daily dose was selected for phase III studies,16-17 while in AF, for which increased emphasis was put on efficacy due to the concern for the significant consequences of stroke, the 5 mg twice daily dose was carried forward in the AVERROES18 and the ARISTOTLE3 trial, as this dose appeared to have increased efficacy without substantial incremental increase in major bleeding. In the APPRAISE phase II clinical trial in high-risk patients after an acute coronary syndrome,19 the addition of apixaban to contemporary antiplatelet therapy resulted in a dose-dependent increase bleeding, with 20 mg once daily dose showed a slightly higher rate of major bleeding (albeit not statistically significant) compared with 10 mg twice daily. Therefore, apixaban 5 mg twice daily was chosen for the phase III APPRAISE-2 trial in patients with a recent acute coronary syndrome, which ended up showing a higher number of major bleeding events without a significant reduction in recurrent ischemic events in patient treated with apixaban compared with placebo on top of standard antiplatelet therapy20.
Odd findings from phase II study: can once daily even be safer?
Compared with the relatively scanty differential information on once vs twice daily dosing with the other NOACs, the observed clinical data from the phase II safety study of edoxaban in patients with AF provided potentially new insight on the advantages of a once daily dosing (Table 2). The incidence of bleeding for edoxaban increased as a function of the total daily dose, as expected, but also – and this time unexpectedly – according to the dose regimen: here the once daily edoxaban doses of 30 or 60 mg were associated with a similar incidence of bleeding relative to the warfarin control arm, and the 30 mg twice daily dose was associated with a trend towards increased bleeding than the same 60 mg dose given once daily.21 Total plasma exposure to edoxaban (AUC) being equal, the finding of more bleeding with 30 mg twice daily suggested that either the higher peaks or the lower trough concentrations associated with once daily dosing may be counter-intuitively associated with lesser bleeding: in a correlation analysis of PK parameters with the incidence of bleeding, it was found that Cmin provided the best fit. Therefore, both the 60 once daily (high-exposure) and the 30 mg once daily (low-exposure) regimens were chosen for the phase III ENGAGE AF-TIMI 48 study for stroke prevention in patients with AF;22 30 mg once daily was chosen for VTE prevention23-24 and 60 mg once daily, after an initial five- day heparin treatment period, for VTE treatment.25
In agreement with the above-mentioned results for edoxaban in AF, albeit in a different clinical setting, are the data obtained from a phase II trial in patients with ACS with the FXa inhibitor darexaban: in the RUBY-1 study,26 patients received darexaban at increasing doses (10, 30 or 60 mg daily), with once or twice daily regimens, on top of dual antiplatelet therapy with aspirin and clopidogrel. A clear dose-related two- to four-fold increase in bleeding was observed; in addition to this, and again counterintuitively according to previous expectations, a numerically higher incidence of bleeding resulted for all three twice daily regimens compared with once daily regimens testing the same daily doses, although this trend was not statistically significant.26
Beside pharmacokinetic considerations, the clinical setting of low or high thrombotic risk, and efficacy/safety evaluations, a further important consideration regarding dosing regimens is patient adherence to therapy, which ultimately affects the efficacy of treatment in the real world, independent of the conclusion of clinical trials. Evidence indicates that less frequent dosing regimens results in better compliance,27-29 and this is particularly relevant for patients on anticoagulant therapy, in whom compliance is crucial for the maintenance of a suitable anticoagulation status and the prevention of both thromboembolic episodes and bleeding. Therefore, everything else being equal, a once daily regimen is better tolerated, and thus preferable, to a twice daily regimen.
Mostly pharmacokinetic and pathophysiologic considerations have so far driven the choice among different doses and dose regimens of NOACs in different clinical conditions, with the background awareness that – everything else being equal – a once daily dosing is more convenient and should lead to better patient compliance. For stroke and VTE prevention, once daily dosing, providing less than 24 hours of high-intensity anticoagulation, should be sufficient to prevent thromboembolism, while more constant levels of high-intensity anticoagulation, as achieved with twice daily dosing, might be more appropriate for treatment of patients with existing thrombus. Recent data are however adding new elements for the choice, and may also highlight unsuspected differences among the different NOACs, perhaps even in the same class. Such new data warrant further investigation and evaluation.
- Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
- Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
- Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.
- Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. Available on-line at N Engl J Med 2013, Nov 19. DOI: 10.1056/NEJMoa1310907.
- De Caterina R, Husted S, Wallentin L, et al. New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease position paper. J Am Coll Cardiol 2012;59:1413-25.
- Buxton I. Pharmacokinetics and pharmacodinamics. The dinamic of drug absorption, distribution, action, and elimination. In: Brunton L, ed. Goodman & Gilman's The pharmacological basis of therapeutics 11 ed: McGraw Hill; 2006:1-39.
- Eriksson BI, Dahl OE, Buller HR, et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005;3:103-11.
- Agnelli G, Gallus A, Goldhaber SZ, et al. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation 2007;116:180-7.
- Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011;50:675-86.
- Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-510.
- Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97.
- Turpie AG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011;105:444-53.
- Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009;374:29-38.
- Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9-19.
- Lassen MR, Davidson BL, Gallus A, Pineo G, Ansell J, Deitchman D. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 2007;5:2368-75.
- Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363:2487-98.
- Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010;375:807-15.
- Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17.
- Alexander JH, Becker RC, Bhatt DL, et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009;119:2877-85.
- Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365:699-708.
- Weitz JI, Connolly SJ, Patel I, et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost 2010;104:633-41.
- Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2013; 369(22):2093-104.
- Fuji T, Fujita S, Tachibana S, Kawai Y. A dose-ranging study evaluating the oral factor Xa inhibitor edoxaban for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty. J Thromb Haemost 2010;8:2458-68.
- Fujita S, Fuji T, Tachibana S, Nakamura M, Kawai Y. Safety and efficacy of edoxaban in patients undergoing hip fracture surgery (Abstract). Pathophysiol Haemost Thromb 2010;37:P366.
- Buller HR, Decousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406-15.
- Steg PG, Mehta SR, Jukema JW, et al. RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur Heart J 2011;32:2541-54.
- Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001;23:1296-310.
- Coleman CI, Roberts MS, Sobieraj DM, Lee S, Alam T, Kaur R. Effect of dosing frequency on chronic cardiovascular disease medication adherence. Curr Med Res Opin 2012;28:669-80.
- Laliberte F, Nelson WW, Lefebvre P, Schein JR, Rondeau-Leclaire J, Duh MS. Impact of daily dosing frequency on adherence to chronic medications among nonvalvular atrial fibrillation patients. Adv Ther 2012;29:675-90.
Keywords: Anticoagulants, Atrial Fibrillation, Benzimidazoles, Embolism, Intracranial Hemorrhages, Morpholines, Pyrazoles, Pyridines, Pyridones, Stroke, Thiazoles, Thiophenes, Thromboembolism, Vitamin K, Warfarin
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