It has almost been a century since the outbreak of sweet clover disease in North America which led to the discovery of warfarin and its derivatives. It was not known that a farmers’ problem would turn out to be a useful treatment for many patientsCitation1. Today, oral anticoagulant (OAC) therapy is the cornerstone for stroke prevention in patients with atrial fibrillation (AF). The only available OACs have been the vitamin K antagonists (VKA) for more than 50 years but they have some well-known problems such as drug-drug, drug-food interactions and low therapeutic index. The development of direct oral anticoagulants (DOAC) changed the management of non-valvular atrial fibrillation (NVAF) patients dramatically in the last decadeCitation2. They have some advantages compared with VKAs, like fixed dose and predictable effects (i.e. no need for monitoring)Citation3.
One of the major problems with OACs is adherence. Anticoagulation should be a lifetime process in patients with NVAF; poor adherence will place these patients at a higher risk of stroke. Drugs work only if patients take themCitation4. Patients on DOACs tend to have a better profile in terms of adherence compared with patients on VKAs which might partly explain the favourable effects of these drugsCitation5. Among DOACs, apixaban treated patients were less likely to discontinue or switch to another OACCitation6 which might also be an advantage for the drug.
The introduction of DOACs into clinical practice has resulted in another problem that has not been the case before, i.e. the option to switch from one OAC to another. While treatment changes from VKA to other OACs could be related to lower time in therapeutic range (TTR) values, changes from DOAC to another OAC could be related with a major clinical event. A Danish study has shown the most common reason leading up to a switch from DOAC to VKA was cardioversionCitation7. Another study has also shown that switching among OACs was associated with increased rate of clinical eventsCitation4. Patients who switch from one OAC to another might be at higher risk for clinical events which might explain the higher event rate. However, some studies have shown that switching from VKA to DOAC does not alter the risk of haemorrhagic complications in patients with NVAFCitation8. Real-world outcome studies have shown that the annualized medical and total costs were lower with DOACs compared with VKAs although pharmacy costs were higher with DOACsCitation9. Hence, it is not logical to switch from a DOAC to VKA because of higher pharmacy cost.
Elderly patients have an increased risk for stroke, however, OACs were generally less prescribed to these patients because of comorbiditiesCitation10. Frailty, chronic renal disease and polypharmacy are the main contributors of elevated embolic and bleeding risk in these patients that have to be taken into consideration when making a decision on OAC therapyCitation11. We showed that physicians tend to prescribe more OAC for elderly NVAF patients if they had elevated risk score for stroke and lower risk score for bleedingCitation10. However, currently available risk scores are far from perfect. Hence the benefits and risks of OACs should be carefully evaluated and the management of NVAF should be individualizedCitation12. If a decision is made to anticoagulate an elderly patient, it should be known that the net benefit of DOACs seems consistent in pivotal DOAC trials and an even greater benefit of these drugs has been shown by real-world dataCitation13. Therefore, most of the elderly NVAF patients should be on an OAC and preferentially on a DOAC.
A recent study from the Journal reported that patients who switch from apixaban to another OAC had a twice higher risk for major bleeding related hospitalization rates compared with patients who continue apixaban treatmentCitation14. Interestingly most of the switchers had switched from apixaban to warfarin which might be a confirmation of the safety of DOACs and especially apixaban. However, they could not demonstrate any association between stroke/systemic embolization risk and switching among drugs. Major bleeding related medical costs, stroke/systemic embolism related medical costs and total all cause medical costs were higher for switchers. The results might not be unexpected as the costs went up if a patient had a clinical event. However, total all-cause healthcare costs were similar between switchers and continuers. This might be related to the pharmacy costs of apixaban as mentioned by the authors. One might expect that the drug costs would decrease but medical costs would increase with time. Hence, it is reasonable to avoid switching from apixaban to another OAC and probably from DOACs to VKAs.
Switching to different OAC might sometimes be an obligation because of worsening renal/hepatic function or starting an interacting drug. In this case, it is important to test the INR and to start the OAC in an appropriate timeCitation2. When switching from DOAC to VKA the INR should be checked and DOAC should not be stopped before INR > 2 which usually takes 3–4 days. Patients are vulnerable in this period and early discontinuation of DOAC may lead to excess in thromboembolic event rates. The opposite is also true as early initiation of DOAC may lead to increased bleeding events. It is utmost important to follow the well-established guidelines when performing a necessary switch among OACsCitation15.
Transparency
Declaration of funding
This editorial was written independently; no company or institution supported the authors financially or by providing a professional writer.
Declaration of financial/other relationships
The authors and peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Acknowledgments
None reported.
References
- Wardrop D, Keeling D. The story of the discovery of heparin and warfarin. [cited 2019 Jul 6]; Available at https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2141.2008.07119.x.
- Pastori D, Menichelli D, Gingis R, et al. Tailored practical management of patients with atrial fibrillation: a risk factor-based approach. Front Cardiovasc Med. 2019;6:17.
- Eikelboom JW, Quinlan DJ, Hirsh J, et al. Laboratory monitoring of non–vitamin k antagonist oral anticoagulant use in patients with atrial fibrillation. JAMA Cardiol. 2017;2(5):566.
- Sørensen R, Jamie Nielsen B, Langtved Pallisgaard J, et al. Adherence with oral anticoagulation in non-valvular atrial fibrillation: a comparison of vitamin K antagonists and non-vitamin K antagonists. Eur Hear J Cardiovasc Pharmacother. 2017;3(3):151–156.
- Cataldo N, Pegoraro V, Ripellino C, et al. Non-persistence risk and health care resource utilization of Italian patients with non-valvular atrial fibrillation. Recenti Prog Med. 2018;109:113–121.
- Baker CL, Dhamane AD, Mardekian J, et al. Comparison of drug switching and discontinuation rates in patients with nonvalvular atrial fibrillation treated with direct oral anticoagulants in the United States. Adv Ther. 2019;36(1):162–174.
- Hellfritzsch M, Grove EL, Husted SE, et al. Clinical events preceding switching and discontinuation of oral anticoagulant treatment in patients with atrial fibrillation. Europace. 2016;19:euw241.
- Bouillon K, Bertrand M, Maura G, et al. Risk of bleeding and arterial thromboembolism in patients with non-valvular atrial fibrillation either maintained on a vitamin K antagonist or switched to a non-vitamin K-antagonist oral anticoagulant: a retrospective, matched-cohort study. Lancet Haematol. 2015;2(4):e150–e159.
- Datar M, Crivera C, Rozjabek H, et al. Comparison of real-world outcomes in patients with nonvalvular atrial fibrillation treated with direct oral anticoagulant agents or warfarin. Am J Heal Pharm. 2019;76(5):275–285.
- Biteker M, Başaran Ö, Doğan V, et al. Real-world clinical characteristics and treatment patterns of individuals aged 80 and older with nonvalvular atrial fibrillation: results from the ReAl-life Multicenter Survey Evaluating Stroke Study. J Am Geriatr Soc. 2017;65(8):1684–1690.
- Cavallari I, Patti G. Efficacy and safety of oral anticoagulation in elderly patients with atrial fibrillation. Anatol J Cardiol. 2018;19:67–71.
- Sabbag A, Yao X, Siontis KC, et al. Anticoagulation for Stroke Prevention in Older Adults with Atrial Fibrillation and Comorbidity: Current Evidence and Treatment Challenges. Korean Circ J. 2018;48(10):873–889.
- Patti G, Pecen L, Lucerna M, et al. Net clinical benefit of non-vitamin K antagonist vs vitamin K antagonist anticoagulants in elderly patients with atrial fibrillation. Am J Med. 2019;132(6):749–757.e5.
- Dhamane AD, Baker CL, Rajpura J, et al. Continuation with apixaban treatment is associated with lower risk for hospitalization and medical costs among elderly patients. Curr Med Res Opin. [cited 2019 Jun 5]; [8 p.]. DOI:10.1080/03007995.2019.1623187
- Steffel J, Verhamme P, Potpara TS, et al. The European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39:1330–1393.