Higher Incidence of Ischemic Stroke in Patients Taking Novel Oral Anticoagulants

Max Shpak, PhD; Anurekha Ramakrishnan, MS; Zoltan Nadasdy, PhD; Matthew Cowperthwaite, PhD; Christopher Fanale, MD


Stroke. 2018;49(12):2851-2856. 

In This Article

Abstract and Introduction


Background and Purpose: The increased use of novel oral anticoagulants (NOACs) to control atrial fibrillation is largely driven by the assumption that they are equally effective as warfarin at preventing ischemic stroke while putting patients at lower risk of hemorrhages. To test this hypothesis, a retrospective study of the relative incidence of strokes among patients taking NOACs versus those taking warfarin is performed.

Methods: Relative stroke incidence in the 2 groups of patients was compared using odds ratios and Fisher exact tests for significance using a data set of 71 365 on NOACs and 59 546 patients on warfarin. In addition, the 7033 patients with a record of both warfarin and NOAC use were analyzed as a separate cohort.

Results: There is a significantly higher (odds ratio=1.29, <0.001) frequency of ischemic strokes among patients prescribed NOACs compared with those on warfarin. The relative frequency of ischemic strokes was also higher for every individual NOAC compared with warfarin (these higher frequencies are statistically significant for dabigatran and apixaban, though not for edoxaban and rivaroxaban). There is a lower incidence of intracranial hemorrhages and nontraumatic hemorrhages in general among patients taking NOACs, consistent with the published literature. Comparisons of the demographic and clinical profiles of the patients taking NOACs to those on warfarin do not show significantly higher background stroke risk in NOAC patients; in fact, patients on NOACs tend to be at lower background risk overall for ischemic strokes.

Conclusions: Because NOAC use is associated with higher ischemic stroke risk together with a lower risk of hemorrhages than warfarin use, it can be concluded that patients on warfarin are more strongly anticoagulated. The observed effect could be a secondary consequence of dosage control or alternatively a result of different anticoagulant effects among the different medications.


Atrial fibrillation (AFib) is an important risk factor for acute ischemic stroke because AFib is associated with the formation of thrombi, which can ultimately lead to embolisms.[1] Consequently, one of the primary reasons AFib patients is prescribed anticoagulants as long-term medication is to reduce the risk of suffering an acute ischemic stroke. For decades, the standard of care for AFib was to prescribe the vitamin K antagonist warfarin (also known as Coumadin and numerous other trade names) as a prophylactic. Warfarin primary disadvantages as a medication to treat the consequences of AFib is the difficulty of dosage control because of its long (>40 hours) half-life,[2,3] and the long time interval required to acclimate patients to a given dose as a result of delayed effect onset.[4]

Partly because of these substantial drawbacks, new nonvitamin K antagonist anticoagulants have been developed which are increasingly being used as an alternative to warfarin. Among these novel oral anticoagulants (NOACs) are the thrombin inhibitor dabigatran (Pradaxa) and the Xa factor inhibitors, such as rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa/Lixiana). In the more recent literature, these anticoagulants are often referred to as direct-acting oral anticoagulants because of their comparatively rapid onset of action. This rapid onset of anticoagulant effect, as well as the comparatively short half-lives (14–17 hours for dabigatran, typically <10 hours for the Xa inhibitors), provide an advantage of simpler dosage control than warfarin.[5] In addition, NOACs are associated with a lower incidence of side effects such as intracranial hemorrhages.[6,7]

Nevertheless, there are disadvantages associated with NOACs. Among these are their relatively high price, as well as the general absence of simple and reliable tests to assess their efficacy. For example, the standard prothrombin time (PT) test used for warfarin is not a reliable indicator of dabigatran efficacy and is of marginal value for assessing the efficacy of the Xa inhibitors.[8] Furthermore, until recently the absence of Food and Drug Administration approved medications to reverse the actions of NOACs other than dabigatran[9] was another drawback to their use (as of 2018, the Food and Drug Administration approved Andexxa as a reversal agent for rivaroxaban and apixaban[10]).

In spite of these concerns, the use of NOACs to treat AFib and thromboses has increased significantly because of their initial introduction several years ago. One recent survey[11] documents NOAC global use increasing from <3% of prescribed anticoagulants in 2013 to >15% in 2015. In recent years, NOAC use had surpassed that of warfarin in the United States. Because of their ubiquitous use, it is of vital interest to accurately evaluate the side effects and relative efficacies of these medications in comparison to warfarin. A number of clinical trials and meta-analyses of prospective studies have compared stroke incidence in AFib patients on warfarin to those on NOACs and have generally found either no significant differences.[12,13]

However, because of highly controlled patient selection, dosing and compliance, analyses of clinical trial data may provide imprecise predictors of real-world patient outcomes. The goal of this study is to perform a retrospective analysis of the relative frequencies of acute ischemic stroke in AFib patients taking warfarin as a home medication in comparison to those patients who are taking NOACS (these will be referred to as warfarin patients and NOAC patients, respectively, throughout the article). These analyses will provide insight into the question of whether NOACs are indeed as effective at stroke prevention in the AFib patient population. The relative frequencies of intracranial hemorrhages in particular and nontraumatic bleeds in general between NOAC and warfarin patients will also be considered for comparison.