In the past few years, the use of non-vitamin K antagonist oral anticoagulants (NOACs), instead of warfarin, in atrial fibrillation (AF) patients at high risk of thromboembolic events has remarkably surged.1,2 NOACs appear to have a favorable safety profile, but the annual risk of intracerebral hemorrhage (ICH) remains a concern.3-6 Surprisingly, a large, real-world retrospective study presented at the International Stroke Conference (ISC) 2018 has revealed that suffering an intracranial hemorrhage (ICH) while taking NOACs was associated with lower mortality, when compared to those taking warfarin.7 The study was concurrently published in the Journal of the American Medical Association.7
Real-world evidence on ICH related to use of OACs
Being a crucial independent risk factor for stroke, AF accounts for a 5-fold increase in ischemic stroke risk.8 If patients are deemed at high risk (i.e. CHA2DS2-VASc score ≥2), oral anticoagulants (OACs) are indicated for the prevention of thromboembolic stroke.9 Although both NOACs and warfarin are indicated for such prevention, physicians are often concerned about the increased risk of bleeding and the lack of specific reversal agents for most NOACs, as immediate management is necessary for life-threatening bleeding (such as ICH).10
Although randomized clinical trials have shown that patients receiving NOACs are less likely to suffer from ICH as compared with those receiving warfarin,3-6 the number of patients enrolled in these trials were relatively low, and they may not fully reflect real-world use. “We were interested in real-world outcomes in individuals who had sustained an ICH and how this is affected by whether they were taking an [OAC] and which type of [OAC],” explained Dr. Gregg Fonarow from Ronald Reagan University of California, Los Angeles, US, who is also the senior author of the study.10
In-hospital ICH with prior warfarin showed the greatest mortality risk
To investigate the association between prior use of OACs and in-hospital mortality among patients with ICH in the real world, researchers conducted the retrospective cohort study with the data from the American Heart Association/American Stroke Association: Get With the Guidelines-Stroke (GWTG) registry, which included 141,311 patients admitted to hospital with an ICH.7 Among these patients, 15,036 (10.6%) were taking warfarin and 4,918 (3.5%) were taking NOACs prior to ICH occurrence (defined as within 7 days before arriving at a hospital). Moreover, 39,585 (28.0%) and 5,783 (4.1%) patients were taking concomitant single and dual antiplatelet agents respectively.7
The unadjusted in-hospital mortality rates were 32.6% for patients taking warfarin, 26.5% for those taking NOACs, and 22.5% for those not taking any OACs, but the ICH stroke severity was not significantly different across the three groups.7 Of note, patients with preceding use of warfarin or NOACs were significantly older and had a higher prevalence of AF and prior stroke.7
After adjusting the baseline characteristics and comorbidities, the mortality risk was higher for patients with prior use of warfarin (+9.0%) and those with prior use of NOACs (+3.3%), using patients not taking OACs as baseline. When the warfarin patient group was used as the reference baseline, both patients with prior NOACs or not taking OACs demonstrated a lower risk for in-hospital mortality (Table 1).7 The lower mortality risk in NOAC-treated patients was still observed when it is compared with that in warfarin-treated patients (whose international normalized ratio [INR] levels were within the therapeutic range [2-3]).7
In fact, idarucizumab, a specific reversal agent for dabigatran (a NOAC), was commercially available in the US during the study, but 63% of patients were admitted before its approval.7 Nevertheless, the investigators found that “the preceding use of NOACs was associated with lower odds of mortality and disability compared with prior use of warfarin for which an established reversal strategy could be applied.”7
Interestingly, prior use of concomitant antiplatelet therapy led to a significantly higher in-hospital mortality among patients with preceding warfarin only.7 The investigators noted that such observation could be due to the smaller sample size of patients with preceding NOACs.7
Expert opinions for the study implications
“In contrary to what many physicians think, that suffering an ICH while taking warfarin type [OACs] may be safer than with NOACs because of the availability of specific reversal agents, we actually showed the opposite. In our study, outcomes were actually better in patients suffering an ICH on NOACs than on warfarin,” commented Dr. Fonarow.10
Dr. Robert P. Giugliano from Brigham and Women’s Hospital, Boston, US, applauded the reliable study results, and believed that the totality of the evidence has been well showcased. “NOACs reduce ICH and death, and these two observations are tightly connected since ICH carries such a high mortality rate (ranging from 30% to more than 60%, depending on the population studied). I am hopeful that clinicians will find these findings, along with the prior data, compelling and accelerate the use of NOACs in place of vitamin K antagonists, such as warfarin, for stroke prevention in patients with AF.”10
Dr. Giugliano also mentioned that these results are strongly associated with four landmark trials of the NOACs. “These [results] showed that NOACs reduce intracranial hemorrhage by approximately 50% and all-cause mortality by 10% compared to warfarin. Furthermore, from the ENGAGE AF-TIMI 48, we observed that the reduction in death was mostly attributable due to fewer intracranial bleeds — the most feared complication of anticoagulant therapy. It was reassuring to see that this was confirmed in a more general clinical setting.”10
Several limitations of the study, however, were pinpointed, one of which was the potential confounding factor that might impact the comparison among the three groups of patients. Prof. Magdy H. Selim, the professor of neurology and chief of the division of stroke and cerebrovascular diseases at Beth Israel Deaconess Medical Center in Boston, US, explained that “the problem with GWTG registry is what is excluded from the database, and there are a number of factors that may have affected the results. One of the most important ones is the lack of information on whether or not a patient had a preexisting do-not-resuscitate order that could have limited whether they would have received aggressive care.”11
On the other hand, the investigators likewise acknowledged that timing of the last OAC or antiplatelet agents prior to ICH, as well as the dose of NOAC or antiplatelet agents, were not available in the retrospective analysis. Hence, patients might have received a lower dose of NOACs owing to renal dysfunction or concomitant antiplatelet therapy, leading to a better mortality outcome.7
Therefore, Dr. Selim believed the findings solely reaffirmed the current perception of ICH risks by NOACs and warfarin. “As neurologists, we already know that the mortality of anticoagulation-related ICH is high. The reluctance of some physicians to prescribe NOACs is largely because there hasn’t been a reversal agent, but that is rapidly changing. Previous small studies have indicated that survival is better in patients who have been taking NOACs compared to warfarin. I think the main message here is that we should use NOACs because the risk of ICH is lower, not because they are associated with lower mortality after ICH.”11
Dr. Fonarow elucidated the hesitation of physicians prescribing NOACs due to the lack of specific reversal agents. “We already know that NOACs are associated with less likelihood of developing an ICH vs. warfarin-type agents, but there has been some concern from physicians that if an ICH does happen… outcomes may be worse on NOACs, as patients on warfarin can be given a vitamin K reversal agent to help stop bleeding, but until recently, there hasn’t been any specific reversal agents available for these new drugs.” However, Dr. Fonarow believed that the current findings may substantiate the use of NOACs over warfarin.10
1. Marzec LN, Wang J, Shah ND, et al. Influence of direct oral anticoagulants on rates of oral anticoagulation for atrial fibrillation. J Am Coll Cardiol. 2017;69(20):2475-2484.
2. Gadsbøll K, Staerk L, Fosbøl EL, et al. Increased use of oral anticoagulants in patients with atrial fibrillation: temporal trends from 2005 to 2015 in Denmark. Eur Heart J. 2017;38(12):899-906.
3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151.
4. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.
5. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.
6. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104.
7. Inohara T, Xian Y, Liang L, et al. Association of Intracerebral Hemorrhage Among Patients Taking Non-Vitamin K Antagonist vs Vitamin K Antagonist Oral Anticoagulants With In-Hospital Mortality. JAMA. 2018;319(5):463-473.
8. Wolf PA, Abbott RD, Kannel WB, et al. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991:22(8):983-988.
9. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur J Cardiothorac Surg. 2016;50(5):e1-e88.
10. Lower ICH Mortality Rate With NOACs Than Warfarin. Medscape. 2018 (Accessed February 26, 2018, at https://www.medscape.com/viewarticle/892636).
11. ONLINE FIRST: In the Clinic-Intracerebral Hemorrhage: In-Hospital ICH Mortality Worse with Warfarin than NOACs, Researchers Find. Neurology Today. American Academy of Neurology. 2018 (Accessed February 26, 2018, at https://journals.lww.com/neurotodayonline/blog/breakingnews/Pages/post.aspx?PostID=706).