Lower ICH Mortality Rate With NOACs Than Warfarin

February 13, 2018

A new, large, real-world study has provided some reassurance about the consequences of suffering an intracerebral hemorrhage (ICH) while receiving one of the new oral anticoagulant (NOAC) drugs.

"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," senior author Gregg Fonarow, MD, from Ronald Reagan University of California, Los Angeles, Medical Center, told Medscape Medical News. "In our study, outcomes were actually better in patients suffering an ICH on NOACs than on warfarin."

Even after adjustment for other baseline differences and comorbidities, there was a 6% absolute reduction in mortality in patients suffering an ICH while receiving a NOAC compared with those receiving warfarin, he said.

"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," he added. "Despite this, there was still a survival benefit in patients suffering an ICH while on a NOAC vs those on warfarin in our real-world study.

"ICH is a devastating adverse effect associated with anticoagulant drugs, with very high mortality rates: one in four of the patients in this study died," Dr Fonarow said. "But our results tell us that if this devastating event does happen, the outcomes are better in those patients taking NOACs than those on warfarin. Our results are an additional reason to potentially favor using a NOAC over warfarin."

The study was published online January 25 in JAMA to coincide with its presentation at International Stroke Conference (ISC) 2018. It has since been published in the February 6 issue of the journal.

Although randomized trials of NOACs showed that patients receiving these drugs are less likely to have an ICH vs those receiving warfarin, because the numbers of patients having an ICH is quite low and patients in clinical trials are often highly selected, there are few "real-world data" on actual clinical outcomes in these individuals, Dr Fonarow explained.

"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]."

The researchers therefore conducted the current retrospective cohort study using data from the American Heart Association/American Stroke Association Get With the Guidelines–Stroke registry, including more than 141,000 patients admitted to hospital with a confirmed ICH.

"This is 100-fold larger than any prior studies on ICH related to use of [OACs]," Dr Fonarow noted. "The patients were also very well characterized, so we were able to make extensive risk adjustments for baseline characteristics and comorbidities, so I think we can say our results are reliable."

Among the 141,311 patients with ICH in the study, 15,036 (10.6%) were taking warfarin and 4918 (3.5%) were taking NOACs preceding the ICH (within 7 days before hospital arrival). Concomitant single- and dual-antiplatelet agents were being taken by 39,585 (28.0%) and 5783 (4.1%) of the patients, respectively.

Results showed that acute ICH stroke severity was not significantly different across the 3 groups.

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 an OAC.

After adjustment for baseline characteristics and comorbidities, compared with patients without prior use of OACs, the risk for in-hospital mortality was higher among patients with prior use of warfarin (absolute risk difference, 9.0%; odds ratio, 1.62) and higher among patients with prior use of NOACs (risk difference, 3.3%; odds ratio, 1.21).

Compared with patients with prior use of warfarin, patients treated previously with NOACs had a lower risk for in-hospital mortality (risk difference, −5.7%; odds ratio, 0.75).

The lower mortality in NOAC-treated patients was still observed with patients receiving warfarin whose international normalized ratio levels were controlled within the therapeutic range.

Antiplatelets Safer With NOACs?

Another interesting observation in the study was that prior use of concomitant antiplatelet therapy was associated with increased odds of in-hospital mortality among patients with preceding warfarin therapy, but such significant differences were not observed among patients with preceding NOAC therapy, although the authors note this could be a result of the smaller sample size of patients with prior NOAC use.

However, they point out that the lower in-hospital mortality among patients with prior NOAC therapy vs prior warfarin therapy was numerically more prominent among patients with prior concomitant antiplatelet therapy.

"While these findings are not conclusive given the relatively small of number of patients with concomitant NOAC and antiplatelet therapy, they may support the hypothesis that NOACs could be a reasonable choice with better safety profiles when combination strategy is required," they write. "The recently published Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran vs Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (RE-DUAL PCI) trial also confirmed this hypothesis."

Dr Fonarow noted that the mechanisms behind this are not really understood, "but it is thought the reason for the lower ICH rate on NOACs may be due to the fact they affect one single blood clotting factor, whereas warfarin affects multiple clotting factors, so may cause more bleeding in general.

"This may also be behind our observations of a lower mortality rate with NOACs if the patient does have an ICH."

Reassuring Findings

Asked to comment, Robert P. Giugliano, MD, Brigham and Women's Hospital, Boston, said these latest findings built on the results from the four landmark trials of the NOACs.

"These showed that NOACs reduce intracranial hemorrhage by approximately 50% and all-cause mortality by 10% compared to warfarin," Dr Giugliano told Medscape Medical News. "Furthermore, from the ENGAGE AF-TIMI 48 we showed 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."

The totality of the evidence is clear, he added. "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." 

Given the "numerous proven advantages" of NOACs, with a few exceptions, such as patients with mechanical heart valves, rheumatic mitral stenosis, and severe hepatic or renal dysfunction, he concluded, "The question should be, why would a clinician recommend warfarin instead of a NOAC?"

Jeff Weitz, MD, McMaster University, Hamilton, Ontario, Canada, pointed out that these findings are important because to date, there are few real world data on the outcome of patients with ICH taking NOACs.  

"The strength of the paper is the large sample size, and the observed correlation between mortality and intensity of anticoagulation with warfarin makes me believe the results are real," Dr Weitz said. "These findings provide yet another reason to use NOACs instead of warfarin."

Umberto Campia, MD, Harvard Medical School, Boston, Massachusetts, agreed.

"Even if this study does not have the same strength of a prospective investigation, it highlights and reinforces the overall improved safety of NOAC use over vitamin K inhibition," Dr Campia said. "It also indicates that the lack of an approved reversal agent for NOACs with anti-Xa activity is not affecting their overall safety and should not be a major concern for their use."

The Get With the Guidelines–Stroke program is provided by the American Heart Association/American Stroke Association. This study was in part supported by the ARAMIS registry, with research funding from Daiichi Sankyo, Genentech, and Janssen. Dr Fonarow reported serving on the Get With the Guidelines steering committee; receiving grant funding from the Patient Centered Outcome Research Institute; being an employee of the University of California, which has a patent on an endovascular therapy device; and serving as a consultant for Janssen.

International Stroke Conference (ISC) 2018. Abstract 131. Presented January 25, 2018.

JAMA. 2018;319:463-473. Article abstract

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