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Alina M. Pirlog1, Cristian D. Pirlog2, Cristian Pop3, Marius A. Maghiar4

1 Department of General Medicine, Faculty of Medicine and Pharmacy, Oradea University, Romania
2 Department of Dentistry, Faculty of Medicine and Pharmacy, Oradea University, Romania
3 Department of Mechatronics, Faculty of Mechanical Engineering, Politehnica University, Timisoara, Romania
4 Department of General Surgery, Faculty of Medicine and Pharmacy, Oradea University, Romania

Abstract: Objectives – Direct oral anticoagulants (DOACs) have been analysed in clinical trials and real world data stu-dies as their use in clinical practice has increased over the recent years. This study aimed to compare DOACs and warfarin in patients with non valvular atrial fibrillation (NVAF) focusing particularly on stroke prevention efficacy and side effects. Methods – We reviewed 150 patients’ notes from a single Scottish medical practice between October 2015- October 2017. The statistical methods were cox regression analysis and Chi square test. Results – The mean CHA₂DS₂-VASc score was 1.89 for DOACs group and 2.05 for warfarin group. Ischaemic stroke while on anticoagulants occurred in one patient in DOACs group compared to five patients in the warfarin group (p=0.291). Side effects such as minor bleeding occurred in 11 patients in the DOACs group contrasting 29 cases in the warfarin group (p=0.024). Major bleeding was reported in three patients in each anticoagulant group (p=0.711). Conclusion – Minor bleeding events were significantly lower in DOACs group compared to warfarin group. In this real-world sample of NVAF patients, effectiveness and risks of DOACs versus warfarin were similar in regard to ischaemic stroke and major bleeding.
Keywords: bleeding, direct oral anticoagulants, non valvular atrial fibrillation, stroke prevention, warfarin.

INTRODUCTION
Atrial fibrillation (AF) remains one of the most pre-valent sustained heart rhythm disorder, affecting an estimated 2% of the world population and poses a significant risk factor for stroke, heart failure, sudden death and cardiovascular morbidity worldwide1,2. Oral anticoagulation was underused in patients with atrial fibrillation but this was improved by educational in-tervention and clinical guidelines3. Understandably, major work has been done by medical professionals worldwide to improve stroke prevention therapy with an ultimate goal to save many lives. Therefore, therapy with oral anticoagulants was developed and numerous studies have demonstrated that these can prevent the majority of ischaemic strokes in AF patients therefore prolong life4-6. For NVAF patients taking oral anticoa-gulants, the net clinical benefit is significantly positive with the exception of those at very low stroke risk which was shown in meta-analysis and observational studies4,6. Side effects such as minor or major blee-ding and monitoring vitamin K antagonists therapy are among the most common reasons for withholding or interrupting completely oral anticoagulants7,8.
Although Warfarin has been the dominant anticoa-gulant treatment for AF for many years, DOACs are being increasingly used for this common medical con-dition. The four DOACs have proven their safety and effectiveness in double-blind, randomized clinical trials (RCTs) of patients with NVAF at increased risk for stroke but also in real world data studies published in recent years9-12. The emergence of several DOACs has offered potential advantages over warfarin, such as predictable and stable pharmacokinetic profile and less interactions with food or other drugs14. Large ran-domised trials have demonstrated the relative safety and efficacy of these agents versus Warfarin, but in selected patients with NVAF9-12 and subsequent ob-servational data have provided conflicting results.
Conclusion of RCTs are that DOACs are an effecti-ve treatment in stroke prevention but their use is also associated with a higher risk of bleeding either minor or major14. When medical professionals prescribe an-ticoagulants they should select the most appropriate one, taking into consideration patient’s risk factors, patient’s preference, cost, tolerability, drug interactions and time in the INR time in the therapeutic range (TTR) if the patient is on warfarin.
The aim of this study was to compare DOACs with warfarin in patients with NVAF considering mainly their efficacy and side effects in a real-world setting.

MATERIAL AND METHODS
Based on data availability from a Scottish medical prac-tice we retrieved 150 anonymized patients’ notes with a diagnosis of NVAF. This study represented a single centre retrospective observational cohort study per-formed between october 2015 – october 2017. Inclu-sion criteria was represented by all patients diagnosed with NVAF taking an oral anticoagulant. We have ex-cluded patients who have been diagnosed with valvu-lar AF, had absolute contraindications to oral antico-agulants and patients treated with antiplatelet therapy (aspirin or clopidogrel). The following information was collected for the observation period: comorbidities, possible contraindications to anticoagulation, previo-us stroke, type of medication, side effects of medi-cation, CHADS, CHA₂DS₂-VASC score, HAS-BLED score and demographic characteristics (age and sex). To reduce the selection bias, we matched the demo-graphic data for patients from the two anticoagulant groups (DOACs vs warfarin). Ethical approval was obtained from the institution review board, all data being anonymised before the review of medical notes.

Statistical analysis
The baseline characteristics of the cohort were com-pared using Chi-squared test for categorical data. Sta-tistically significant was defined as p-value <0.05. For comparison and outcome, cross tabulation table was used with number of cases and percentages. Hazard ratio were estimated using Cox proportional hazard regression analysis models. Statistical analysis was carried out using IBM SPSS software version 22 and Numbers for iOS 2016.

RESULTS
Baseline characteristics
The DOACs group was comprised of 65 patients (43%) whereas warfarin group had 85 patients (57%). Demographically, DOACs group consisted of 71% males and 29% females and warfarin group was re-presented by 69% males and 31% females. Age mean was 74.78 (SD, 8.45) in the DOACs group and 74.06 (SD, 8.21) in the warfarin group. DOACs users had CHA2DS2-VASC score mean of 1.89 compared to 2.05 in the warfarin group (Figure 1). The mean HAS-BLED score was approximately 2.5 in both DOACs and warfarin users. The patients in the warfarin group had overall suffered from a higher number of comorbidities (Table 1, Figure 2).

Figure 1. CHA2DS2-VASc score in both anticoagulant groups

Ischaemic stroke
A total of six patients suffered an ischaemic stroke while on anticoagulants. Hence, one patient was on DOAC therapy and five patients were on warfarin. Patients were admitted to hospital, so INR was not documented at the time of stroke. In the Cox propor-tional hazard regression analysis for ischaemic stroke events, the hazard ratio (HR) was 3.183 (CI), 0.372-27.263 with p value of 0.291 (Table 2).

Side effects
Three cases in the DOACs group and three cases in the warfarin group suffered from a major gastroin-testinal hemorrhage (p 0.711) (Table 3). Throughout the study period there were no hemorrhagic strokes reported. Minor bleeding occurred in 11 patients in the DOACs group contrasting with 29 cases in the warfarin group (Cramer’s value=0.185, p value 0.024) (Table 4). Based on the type of minor bleeding pre-sented in these groups, there were fi ve patients with epistaxis, fi ve patients with lower gastrointestinal ble-eding and one patient with haematuria in the DOACs group. In the warfarin group there were 29 patients with minor bleeding. Consequently, 12 patients had epistaxis, 9 patients had lower gastrointestinal blee-ding, 4 patients had vaginal bleeding, 3 patients had haematuria and one patient had haemoptisis.

DISCUSSION
Taking into account the general characteristics of the study’s population and comparing the number of pati-ents in both groups, the warfarin group had more patients than the DOACs group. Demographically (sex, age), DOACs and warfarin groups were almost iden-tical in characteristics with an average age of 74 years and less females compared to males. This result was similar to the large RCTs that compared each DOAC with warfarin^9-12. CHA ₂DS₂-VASC score was slightly lower in the DOACs group compared to warfarin group (Figure 1). The mean HAS-BLED score was similar in both groups. The patients in the warfarin group had suffered from a higher number of comorbi-dities except epilepsy, malignancy and psychosis.

Figure 2. Comorbidities in the two anticoagulant groups: DOACs and Warfarin (n=150).

Ischaemic stroke
A total of six patients suffered an ischaemic stroke: one patient was on a DOAC and five patients were on Warfarin. The HR was 3.183 which showed that the risk of having an ischaemic stroke while taking warfarin was three times higher compared to taking DOACs. However, p=0.291 result was not statisti-cally significant. The above results showed similarities with many real world data studies and clinical trials in regard to stroke prevention meaning that warfarin and DOACs have similar efficacy in preventing stroke15,16. A similar conclusion was reported in Hart et al study4 where DOACs had a non-inferior efficacy to warfarin and a reduced ischaemic stroke by two-thirds com-pared with placebo. This study showed no difference between DOACs compared with warfarin in terms of the risk of having an ischemic stroke or systemic em-bolism.
In contrast, XANTUS study17 described the use of DOACs for stroke prevention in a broad NVAF pa-tient population which showed better outcomes for DOACs compared to warfarin.

Side effects
In this study, major gastrointestinal bleeding requiring admission to hospital was equally distributed in both groups, three patients were admitted to hospital from each group. The p value of 0.711 for major bleeding events accepted the null hypothesis that there was no statistically significant differences between the two groups of patients on warfarin vs DOACs anticoagu-lants.
In contrast to the above findings, Sterne et al.18 demonstrated advantages for taking DOACs because these were associated with lower risk of major ble-eding, and mortality compared with warfarin in the largest real-world practice in patients with non valvu-lar atrial fi brillation. Other studies such as Sjogren et al.15 showed that DOACs are as effective for stroke prevention as well-managed warfarin but cause fewer major bleedings.
In this study there was a higher prevalence of mi-nor bleeding events reported in the warfarin group (Cramer’s value=0.185, p value 0.024). These results suggest that there was a small correlation between the type of anticoagulant and minor bleeding. Minor bleeding events in this study illustrated that patients taking warfarin had an increased risk for minor blee-ding compared with patients taking DOACs. Likewise, Yap et al19 shows that dabigatran had fewer reported minor bleeding compared to warfarin.
This study’s findings were similar compared with studies such as Patel et al and Granger et al10,11 which found decreased bleeding in apixaban and rivaroxaban (DOACs) compared with warfarin.
Sjogren et al15 found that the risks for all-cause stroke or systemic embolism were similar in both groups of oral anticoagulants (DOACs vs warfarin), but DOACs were associated with significantly lower risks of all-cause mortality, major bleeding and intra-cranial haemorrhage but higher risk of gastrointestinal bleeding15.
DOACs have advantages over warfarin in patients with AF, but Sterne et al found no strong evidence that DOACs should replace warfarin or low mole-cular weight heparin (LMWH) in primary prevention, treatment or secondary prevention of venous throm-boembolism (VTE)18.
All DOACs seem to be safe and effective alternati-ves to warfarin in a routine care setting20. Pandya et al. demonstrated that the risks of death, any bleeding, or major bleeding were significantly lower for apixaban and dabigatran etexilate compared with warfarin20. The above conclusions were similar with most lar-ge observational real world data studies around the world concluding that DOACs were showing similar efficacy compared with warfarin for stroke preventi-on but may possibly have better outcomes in reduced risk of bleeding21-24.
Hanley et al21 goes beyond and states that it can be difficult to understand why a prescriber would start warfarin in a new patient without a contraindication to a DOAC25. In addition, Hanley et al21 stated that switching to a newer agent may not be necessary for the patient in whom the INR has been well controlled with warfarin and concluded that the decision to use a DOAC versus warfarin must be an individual one21. Similarly to Hanley et al21, we recommend the use of up-to-date guidelines for oral anticoagulants and that warfarin is a very effective treatment and should be continued in patients who have good TTR but patients should be aware that they can have slightly increased risk of bleeding compared to DOACs. Finally, DOACs have showed to be effective in stroke prevention for patients with NVAF and have fewer bleeding events compared to warfarin17.

CONCLUSION
Overall minor bleeding events were significantly lower in the DOACs group compared to warfarin group. In this real-world sample of NVAF patients, effectiveness and risks of DOACs versus warfarin were similar in regard to ischaemic stroke and major bleeding. Future studies should ideally focus on different subgroups of patients and have a larger number of patients such as a national database.

LIMITATIONS
As with all retrospective observational single centre studies, the accuracy of data depend on the quality of notes taking by medical professionals. Some minor side effects may not be reported by patients or docu-mented by the clinician as they were deemed not life threatening.

Abbreviations
aF= Atrial Fibrillation; CAD=coronary artery disease; CHA₂DS₂-VASc=congestive heart failure/left ventricu-lar dysfunction, hypertension, age ≥75 years (doubled), diabetes, previous stroke/TIA/thromboembolism (doubled), vascular disease, age 65–74 years, female sex; CHF=congestive heart failure; CI=confidence in-tervals; DOACs=direct oral anticoagulants; GI= gas-trointestinal; HAS-BLED=Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INR, Elderly, Drugs or alcohol; INR=International Nor-malised Ratio; NVAF=non valvular Atrial Fibrillation; HR=hazard ratio; RCTs=randomised clinical trials; TTR=Time in Therapeutic Range
Conflict of interest: None declared.

References
1. Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Herpen G, Stricker BH, Stijnen T, Lip GY, Witteman JC. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 2006;27:949-953
2. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D’Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ. Life-time risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004;110:1042–1046
3. Vinereanu D, Lopes R, Bahit C, Xavier D, Jiang J, Al Khalidi H, He W, Xian Y, Ciobanu A, Kamath D, Fox KA, Rao MP, Pokorney SD, Ber-wanger O, Tajer C. A multifaceted intervention to improve treat-ment with oral anticoagulants in atrial fibrillation (IMPACT-AF): an international cluster-randomised trial. Lancet 2017;390:1737-1746
4. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic ther-apy to prevent stroke in patients who have non valvular atrial fibril-lation. Ann Intern Med 2007;146(12):857-67
5. Potpara TS, Dan GA, Trendafilova E, Goda A, Kusliugic Z, Manola S, Music L, Musetescu R, Badila E, Mitic G, Paparisto V, Dimitrova ES. Stroke prevention in atrial fibrillation and ‘real world’ adherence to guidelines in the Balkan Region: The BALKAN-AF Survey. Sci. Rep. 6, 20432; doi: 10.1038/srep20432(2016)
6. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkahomenko A, Ya-mashita T, Antman EM. Comparison of the effi cacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955-962
7. Frankel DS, Parker SE, Rosenfeld LE, Gorelick PB. HRS/NSA2014 Survey of Atrial Fibrillation and Stroke: Gaps in Knowledge and Per-spective, Opportunities for Improvement. Heart Rhythm 2015;12: e105-113
8. Le Heuzey JY, Ammentorp B, Darius H, De Caterina R, Schilling RJ, Schmitt J, Zamorano JL, Kirchhof P. Differences among west-ern European countries in anticoagulation management of atrial fibrillation. Data from the PREFER IN AF registry. Thromb Haemost 2014;111:833-841
9. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M. Dabi-gatran versus Warfarin in Patients with Atrial Fibrillation, N Engl J Med 2009; 361:1139-1151
10. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, M.D., Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel
CC. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med 2011;365:883-891
11. Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit C, Diaz R. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2011;365:981-992
12. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Hal-perin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M. Edoxaban versus Warfarin in Patients with Atrial Fibrilla-tion. N Engl J Med 2013;369:2093-2104
13. Hanley CM, Kowey PR. Are the novel anticoagulants better than warfarin for patients with atrial fibrillation? J Thorac Disease 2015; 7(2):165-171
14. Lip GY, Mitchell SA, Liu X, Liu LZ, Phatak H, Kachroo S, Batson
S. Relative efficacy and safety of non-Vitamin K oral anticoagulants for non-valvular atrial fibrillation: Network meta-analysis comparing apixaban, dabigatran, rivaroxaban and edoxaban in three patient sub-groups. Int J Cardiol 2016;204:88-94
15. Sjogren V, Bystrom B, Renlund H, Svensson PJ, Oldgren J, Norrv-ing B, Sjalander A. Non-vitamin K oral anticoagulants are non-in-ferior for stroke prevention but cause fewer major bleedings than well-managed warfarin: A retrospective register study. PLoS One 2017;12(7):e0181000. https://doi.org/10.1371/journal.pone.0181000
16. Nielsen PB, Skjoth F, Kjaldgaard JN, Lip GYH, Larsen TB. Effective-ness and Safety of Standard-Dose Non vitamin K Antagonist Oral Anticoagulants and Warfarin Among Patients With Atrial Fibrillation With a Single Stroke Risk Factor: A Nationwide Cohort Study. BMJ 2017;356:J510
17. Camm J, Amarenco P, Haas S, Hess S, Kirchhof P, Kuhls S, van Eick-els M, Turpie AGG. Atrial fi brillation- XANTUS: a real-world, pro
spective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation Eur Heart J 2016;37:1145-1153
18. Sterne JA, Bodalia PN, Bryden PA, Davies PA, Lopez-Lopez JA, Okoli GN, Thom HHZ, Hingorani AD. Oral anticoagulants for primary prevention, treatment and secondary prevention of venous throm-boembolic disease, and for prevention of stroke in atrial fibrilla-tion: systematic review, network meta-analysis and cost-effective-ness analysis. Health Technol Assess. 2017;21(9):1-386. doi:10.3310/ hta21090
19. Yap SH, Ng YP, Roslan A, Kolanthaivelu J, Koh KW, P’ng HS, Liang BY, Hoo FK, Yap LB. A comparison of dabigatran and warfarin for stroke prevention in elderly Asian population with non valvular atrial fibrillation: An audit of current practice in Malaysia. Med J Malaysia 2017;72(6):360-364
20. Pandya EY, Anderson E, Chow C, Wang Y, Bajorek B. Contempo-rary utilization of antithrombotic therapy for stroke prevention in patients with atrial fibrillation: an audit in an Australian hospital set-ting. Ther Adv Drug Saf 2018;9(2):97-111
21. Hanley CM, Kowey R. Are the novel anticoagulants better than war-farin for patients with atrial fi brillation? J Thorac Dis 2015;7(2):165-171
22. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrilla-tion. Am J Cardiol 2012;110:453-460
23. Chan YH, See LC, Tu HT, Yeh YH, Chan SH, Wu LS, Lee HF, Wang CL, Kuo CF. Efficacy and Safety of Apixaban, Dabigatran, Rivarox-aban, and Warfarin in Asians With Nonvalvular Atrial Fibrillation. J Am Heart Assoc 2018;7(8).pii:e008150. https://doi.org/10.1161/ JAHA.117.008150
24. Friberg L, Oldgren J. Effi cacy and safety of non-vitamin K antago-nist oral anticoagulants compared with warfarin in patients with atri-al fibrillation. Open Heart. 2017;4(2):e000682. doi: 10.1136/open heart-2017-000682