Direct Oral Anticoagulants in the Management of Non-Valvular Oral Atrial Fibrillation: From Efficacy to Effectiveness
Mariano A Giorgi1,2,3*, Claudio Daniel Gonzalez1 and Guillermo Di Girolamo4,5
1Department of Pharmacology, School of Medicine. CEMIC University Institute, Autonomous City of Buenos Aires Argentina, South America
2Cardiology Section, Department of Medicine, Norberto Quirno Medical Education and Clinical Research Center “CEMIC”, Autonomous City of Buenos Aires, Argentina, South America
3Health Economic and Outcome Research Unit. CEMIC University Institute, Autonomous City of Buenos Aires Argentina, South America
4Department of Toxicology and Pharmacology, Faculty of Medicine University of Buenos Aires, Autonomous City of Buenos Aires Argentina, South America
5Alberto C. Taquini Institute of Research in Translational Medicine, Faculty of Medicine University of Buenos Aires - CONICET, Autonomous City of Buenos Aires Argentina, South America
Submission: January 17, 2023; Published: February 08, 2023
*Corresponding author:Mariano A Giorgi, Instituto Universitario - CEMIC Health Economics and Technology Assessment Unit. Buenos Aires, Argentina, South America
How to cite this article:Mariano A Giorgi, Claudio Daniel Gonzalez and Guillermo Di Girolamo. Direct Oral Anticoagulants in the Management of Non- Valvular Oral Atrial Fibrillation: From Efficacy to Effectiveness. J of Pharmacol & Clin Res. 2023; 9(1): 555755. DOI: 10.19080/JPCR.2023.09.555755
Keywords: Direct Oral Anticoagulants; Thromboembolism; Anticoagulation; Rivaroxaban; Haemorrhagic Stroke; Gastrointestinal Bleeding; Vitamin–K Antagonists
Abbreviations: DOACs: Direct Oral Anticoagulants; NVAF: Non-Valvular Atrial Fibrillation; VKA: Vitamin – K Antagonists; RCTs: Randomised Controlled Trials
Opinion
Since its introduction in the market more than a decade ago, Direct Oral Anticoagulants (DOACs) have become a standard of care worldwide for the prevention of thromboembolism in non-valvular atrial fibrillation (NVAF) [1-3] as an alternative to vitamin–K antagonists (VKA) (warfarin and other dicoumarins). Despite have been a mainstay anticoagulant since the 1950´s [4] with evidence from randomised controlled trials (RCTs) supporting a ~ 50% relative reduction in stroke risk compared with aspirin [5], warfarin has several limitations. One is the slow onset of the anticoagulatory effect due to its mechanism of action through the reduction of vitamin-K dependent coagulation factors [6]. Other is the variability achieving effective and safe levels of anticoagulation expressed as an International Normalized Ratio 2 to 3 [6] to avoid thrombotic and bleeding events, respectively, due to drug-drug pharmacokinetic interactions and polymorphisms in the VKOR and CYP 2C9 genes [7]. Aiming to overcome such limitations, the advent of DOACs (dabigatran, rivaroxaban, apixaban and edoxaban) offered different pharmacodynamic and pharmacokinetic properties, compared with warfarin, and changed the paradigm in the use of oral anticoagulation in NVAF [8]. Direct oral anticoagulants exert their effect through direct inhibition on thrombin (dabigatran [9]) or by inhibiting activated factor X –anti Xa – (apixaban [10], rivaroxaban [11], edoxaban [12]). Both direct mechanisms lead to an early onset of the anticoagulatory effect, no overlapping with parenteral anticoagulants is required and, they could be restarted 1 or 2 days after a surgical procedure [13]. Besides, in the need to suspend the anticoagulation (i.e., in the case of a scheduled surgical procedure) the effect is reversed more faster than with VKAs, there´s no need for bridging with parenteral anticoagulants and, no antidote is usually needed in such cases. Four large phase III clinical trials including dabigatran [14], rivaroxaban [15], apixaban [16] and edoxaban [17] proved the safety and efficacy of DOACs in the management of NVAF showing non-inferiority to warfarin in the prevention of thromboembolic events (i.e., stroke / pulmonary embolism). Data from a meta-analysis of these RCTs revealed a 10% reduction in all-cause mortality, a 19% risk reduction in stroke or systemic embolism and a 51% reduction in haemorrhagic stroke compared with warfarin [18].
Despite the overall evidence from RCTs that supports the use of these drugs, there are some pending questions to be answered or solved. First, there´s limited availability to antidotes. In case of an urgent surgical procedure or a life-threatening bleeding there are two FDA-licensed antidotes, idarucizumab for dabigatran [19] and andexanet alfa for apixaban and rivaroxaban [20] and there´s no approved antidote for edoxaban. Besides, trialbased evidence to guide their use is very limited. Second, phase III trials have validated fixed dose schemes for almost all patients (including those with impaired renal function and the elderly). However, in certain groups of patients, such as those with extremely obesity [21], pregnant and lactating people [22] there´s scarce data regarding their safety and efficacy that supported the “one-size-fits-all” dose regimes. In the case of frail elderly and very elderly patients (which represents a considerable amount of anticoagulated NVAF patients) dose adjustments were based in subgroups analysis of RCTs for apixaban, dabigatran and rivaroxaban [23] and only edoxaban has a trial specifically designed to treat patients ≥ 75 years old [24]. Finally, although there´s usually no need to monitor their anticoagulant levels, in some cases (as in unexplained bleeding o in high-bleeding risk procedures) it could be useful to know it and define the need to administer an antidote. In such cases, there´s still debate regarding the availability of such tests, prompt results and reference levels of anti-Xa or cloting time essays for DOACs [25].
Years after their marketing authorisation, many observational, real-world studies (RWE) brought new data about the effectiveness of DOACs, assessing them in populations not previously included in phase III trials, reflecting the results in real clinical practice, and providing indirect head-to head comparison between DOACs. Since this type of research is subjected to some controversies regarding inclusion bias not all RWE studies provide high quality evidence [26]. We will mention two relevant examples of such type of research. Chan et al. [27] published a systematic review and meta-analysis of 18 observational studies with bias control methods (9 used propensity score matching, 2 propensity score weighting, and 6 multivariable logistic regression) showed that DOACS, compared with warfarin were associated with reduction in the risk of gastrointestinal bleeding (HR=0.66 [95%CI 0.46-0.95]; I2 60), all-cause mortality (HR=0.62 [95%CI 0.56-0.69]; I2 0) intracranial haemorrhage (HR=0.50 [95%CI 0.40-0.62]; I223) and in thromboembolic events (HR= 0.70 [9%CI5 0.63-0.78]; I2 66) [27] There were no differences between DOACs and warfarin regarding the risk of stroke and no significant differences were reported between DOACs. Another interesting example is the retrospective cohort study with propensity-score matching of patients at high gastrointestinal bleeding risk who were treated with oral anticoagulants for NVAF [28]. A significant lower risk of stroke and/or systemic embolism were observed with DOACs compared with warfarin. Regarding major bleeding, there were differences between DOACs with lower risk associated with apixaban and dabigatran compared with warfarin (for apixaban HR=0.59 [95%CI 0.56- 0.63] and for dabigatran HR=0.78 [95%CI 0.70-0.86]) [28]. Considering the amount and quality of data collected in the previous decade current evidence invigorates the findings from phase III trials and widens the spectrum of data to support a broader use of DOACs. Many questions remain unanswered by RCTs and good quality real-world evidence studies could provide evidence to fill those gaps.
References
- Lip GYH, Banerjee A, Boriani G, Chiang CE, Fargo R, et al. (2018) Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest 154(5): 1121-1201.
- January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, et al. (2019) 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration with the Society of T horacic Surgeons. Circulation 140(2): e125-e151.
- Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, et al. (2021) 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 42(5): 373-498.
- Wardrop D, Keeling D (2008) The story of the discovery of heparin and warfarin. Br J Haematol 141(6): 757-763.
- Van Walraven C, Hart RG, Singer DE, Laupacis A, Connolly S, et al. (2002) Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. JAMA 288(19): 2441-2448.
- Hogg K, Weitz JI (2018) Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs. In: Brunton LL, Hilal-Dandan R, Knollmann BC, editors. Goodman & Gilman´s The Pharmacological Basis of Therapeutics 13e. New York (NY): McGraw-Hill Education pp: 585-603.
- Redman AR (2001) Implications of cytochrome P450 2C9 polymorphism on warfarin metabolism and dosing. Pharmacotherapy 21(2): 235-242.
- Giorgi MA, Cohen Arazi H, Gonzalez CD, Di Girolamo G (2011) Changing anticoagulant paradigms for atrial fibrillation: dabigatran, apixaban and rivaroxaban. Expert Opin Pharmacother 12(4): 567- 577.
- Stangier J, Rathgen K, Stähle H, Gansser D, Roth W (2007) The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 64(3): 292-303.
- Pinto DJ, Orwat MJ, Koch S, Rossi KA, Alexander RS, et al. (2007) Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-opiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro 1H-pyrazolo3,4-c] pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J Med Chem 50(22): 5339-5356.
- Perzborn E, Strassburger J, Wilmen A, Pohlmann J, Roehrig S, et al. (2005) In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939 -- an oral, direct factor Xa inhibitor. J Thromb Haemost 3(3): 514-521.
- Ogata K, Mendell-Harary J, Tachibana M, Masumoto H, Oguma T, et al. (2010) Kojima M, Kunitada S. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 50(7): 743-753.
- Mujer MTP, Rai MP, Atti V, Dimaandal IL, Chan AS, et al. (2020) An update on the reversal of nonvitamin K antagonist oral anticoagulants. Adv Hemato.
- Camm AJ (2009) The RE-LY study: Randomized Evaluation of Long-term anticoagulant therapY: dabigatran vs. warfarin. Eur Heart J 30(21): 2554-2555.
- Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, et al. (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365(10): 883-891.
- Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, et al. (2011) Apixaban versus warfarin in patients with atrial
fibrillation. N Engl J Med 365(11): 981-992.
fibrillation. N Engl J Med 369(22): 2093-2104
- Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, et al. (2014) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383(9921): 955–962.
- (2015) PRAXBIND (idarucizumab).
- (2022) ANDEXXA (andexanet alfa).
- Moll S, Crona DJ, Martin K (2018) Direct oral anticoagulants in extremely obese patients: OK to use? Res Pract Thromb Haemost 3(2): 152-155.
- Paul C, Baby M, Anthraper AR, Krishnakumar K (2020) NOACs: an emerging class of oral anticoagulants-a review article. Futur J Pharm Sci 6: 95.
- Giuliano P (2022) Non-vitamin K antagonist oral anticoagulants in older and frail patients with atrial fibrillation. Eur Heart J Suppl 24 (Suppl A): A1–A10
- Okumura K, Akao M, Yoshida T, Kawata M, Okazaki O, et al. (2020) Low-dose edoxaban in very elderly patients with atrial fibrillation. N Engl J Med 383:1735–1745.
- Van der Linden L, Hias J, Vanassche T (2022) The value and limitations of new oral anticoagulant plasma level assessments. Eur Heart J Suppl 24(Suppl A): A32-A41.
- Bortman L, Mitchell F, Perez Morales J, Naveiro S, Gonzalez CD, et al. (2022) Direct Oral Anticoagulants. An Updated Systematic Review of its Clinical Pharmacology and Clinical Effectiveness and Safety in patients with Nonvalvular Atrial Fibrillation. J Clin Pharmacol.
- Chan YH, Lee HF, Chao TF, Wu CT, Chang SH, et al. (2019) Real-world Comparisons of Direct Oral Anticoagulants for Stroke Prevention in Asian Patients with Non-valvular Atrial Fibrillation: A Systematic Review and Metaanalysis. Cardiovasc Drugs Ther 33(6): 701-710.
- Lip GYH, Keshishian AV, Zhang Y, Kang A, Dhamane AD, et al. (2021) Oral Anticoagulants for Nonvalvular Atrial Fibrillation in Patients With High Risk of Gastrointestinal Bleeding. JAMA Netw Open 4(8): e2120064.