**5.2. Vitamin-K antagonist**

Vitamin-K antagonist, for example, warfarin, was first used as an anticoagulant in the 1960s when it was validated through multiple randomized, controlled clinical trials comparing it versus placebo or no therapy, that it had superior efficacy in reducing strokes in patients with NVAF [31, 32]. Warfarin's effectiveness was confirmed in the pivotal 1992 Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation (SPINAF) trial [33]. This trial definitively proved that warfarin reduced stroke rates in patients with NVAF by approximately 70% and mortality by approximately 30% [33]. Furthermore, when investigated with regard to intention to treat, it was found that there was a 68% risk reduction in stroke for patients taking warfarin when compared to the control groups who were not anticoagulated [34, 35].

Although warfarin is extremely effective in reducing stroke and mortality, it is an incredibly difficult drug to use in clinical practice. Warfarin has a slow onset and offset of action and has multiple drug and food interactions. Warfarin requires constant monitoring to ensure the INR remains within the therapeutic range of 2–3. Studies have shown that an INR <2 carries an increased risk of stroke, whereas an INR of >3 confers an increased risk of bleeding [31, 32, 36, 37]. From an Australian perspective, the difficulties of warfarin's clinical usage were seen in multicenter trials showing the time in therapeutic range (TTR) is near 70% at best, but more often found to be around 50–60% [38]. Interestingly there seems to be an increased risk of bleeding and intracranial hemorrhage (ICH) with warfarin in Asian populations, even in patients with an INR within the therapeutic range. This has seen some major centers in Asia adopt a lower therapeutic range of 1.5–2 [31, 32].

Formal anticoagulation using Warfarin has been shown to significantly reduce the incidence of stroke in CKD patients with AF. The Stroke Prevention in Atrial Fibrillation [SPAF-III] Study analyzed 516 AF participants with CKD and showed that warfarin was able to reduce ischemic stroke or systemic embolism by 76% (95% CI 42–90, *P* < 0.001) [39]. In a populationbased retrospective cohort study conducted by Mitesh et al., it was found that CKD patients requiring dialysis with AF, warfarin use, in comparison with no-warfarin use, did not reduce the risk for stroke however it was associated with a 44% higher risk for having a bleeding event, whereas warfarin use in nondialysis patients with AF was associated with a 13% lower risk for stroke with a 19% higher risk for bleeding event [32, 40]. Bleeding in this study was grouped and defined as intracerebral bleeding, gastrointestinal bleeding, intraocular bleeding, hematuria, and unspecified location of bleeding. This data should not be surprising though as it is well known that HD patients have both platelet and coagulation abnormalities and also have associated comorbidities such as uncontrolled hypertension and diabetes mellitus, all of which contribute to an increase in the risk for stroke and bleeding [32, 41]. Furthermore, HD patients usually also receive heparin during dialysis, which also adds to their increased risk for bleeding. Warfarin use in HD patients, through the inhibition of matrix Gla protein and Gas-6, thus causing calciphylaxis, can accelerate vascular calcification, which may also increase the risk for ischemic stroke [32, 42, 43]. This is further supported by a 134,410 patient retrospective study cohort by Chen et al. who compared ESRD patients requiring renal replacement therapy with AF receiving either monotherapy with antiplatelets or Warfarin with a control group who were not using either of the medications [44]. They showed that the incidence of ischemic stroke or TIAs was no different between the intervention group and the control group [44]. Furthermore, the results stayed unchanged after propensity match and also showed no beneficial effect of antiplatelet or warfarin therapy in any subgroups, such as age and gender [44].
