A comparison between vitamin K antagonists and new oral anticoagulants

Although the cohort study by Gieling and colleagues showed that, overall, the hazard ratio (HR) of major bleeding was 2.07 for the new oral anticoagulants (NOACs) compared with vitamin K antagonists (VKAs) 1, a more nuanced pattern emerged in two reviews of phase III clinical studies comparing dabigatran, rivaroxaban, apixaban and edoxaban with warfarin in patients with nonvalvular atrial fibrillation (NVAF) 2, 3. In one of these reviews, data were presented on 6076 subjects taking dabigatran 150 mg b.i.d., and 6015 subjects taking dabigatran 110 mg b.i.d., vs. 6022 subjects taking warfarin. The relative risk of intracranial haemorrhage (ICH) for dabigatran vs. warfarin was 0.40 (95% confidence interval 0.27, 0.60) for the 150 mg b.i.d. dose (P < 0.001) and 0.31 (95% CI 0.20, 0.47) for the 110 mg b.i.d. dose (P < 0.001), in both cases to the detriment of warfarin. In the comparison between dabigatran vs. warfarin, major gastrointestinal haemorrhage was associated with a relative risk of 1.50 (95% CI 1.19, 1.89), to the detriment of dabigatran 150 mg b.i.d. (P < 0.001), but no significant difference between dabigatran 110 mg b.i.d. and warfarin. Data on 7111 NVAF subjects taking rivaroxaban were compared with those on 7125 subjects taking warfarin. The HR for ICH was 0.67 (95% CI 0.47, 0.93; P = 0.02), to the detriment of warfarin, but the HR for major gastrointestinal haemorrhage was 1.61 (95% CI 1.30, 1.99), to the detriment of rivaroxaban (P < 0.001). Data on 9088 subjects taking apixaban were compared with those on 9052 subjects taking warfarin. The HR for ICH was 0.42 (95% CI 0.30, 0.58; P < 0.001), to the detriment of warfarin, but patients taking apixaban were just as likely to experience major gastrointestinal haemorrhage as their counterparts on warfarin. Finally, 7012 patients taking edoxaban 60 mg day–1, and 7002 others taking edoxaban 30 mg day–1 were compared with 7012 of their counterparts taking warfarin. At the higher dose of edoxaban, the HR for ICH was 0.47 (95% CI 0.34, 0.63; P < 0.001), to the detriment of warfarin. At the lower dose, the HR was 0.30 (95% CI 0.21, 0.43; P < 0.001), to the detriment of warfarin. For major gastrointestinal haemorrhage, the HR was 1.23 (95% CI 1.02, 1.50; P = 0.03), to the detriment of the higher dose of edoxaban. For the lower dose of edoxaban, the HR was 0.67 (95% CI 0.53, 0.83; P < 0.001), to the detriment of warfarin 2. Similar outcomes were reported in the second review 3, although the data were presented as P-values rather than confidence intervals 3. These data show that the only generalisation that one can make about these four NOACs is that they are less likely than warfarin to cause ICH. Major gastrointestinal bleeding, however, is just as likely with warfarin as it is with either dabigatran 110 mg b.i.d. or apixaban. Edoxaban is in the unique position of generating a significantly lower risk of both ICH and major gastrointestinal haemorrhage compared with warfarin 2, 3. Also requiring closer scrutiny is the observation that VKAs are superior to aspirin in their efficacy in mitigating the risk of cardioembolic stroke 1. This efficacy is suboptimal 4, partly as a result of the fact that some of the strokes which occur in NVAF patients are attributable not to cardioembolism, but to embolism from a stenosed carotid artery 5, 6. The latter subtype of embolism is not amenable to amelioration by VKAs. Embolic cerebral infarcts are also prone to haemorrhagic transformation, especially in patients who are on anticoagulant therapy 7. What remains to be seen is whether or not the reduction in the risk of ICH documented in the comparison between NOACs and VKAs 2, 3 translates into a reduction in the risk of haemorrhagic transformation of embolic cerebral infarcts from whatever source, when embolic infracts occur during the course of anticoagulant therapy. Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 8, and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16. There are no competing interests to declare.