NOACs Seem to Perform Just Fine in

Patients With A-fib and Most Types of

Valvular Disease
Patients with moderate-to-severe mitral stenosis or
mechanical heart valves shouldn’t receive NOACs,
but others are fair game, experts say.

By Todd Neale

March 14, 2017

The efficacy and safety of the non-vitamin K antagonist oral
anticoagulants (NOACs) relative to warfarin do not substantially differ
based on the presence of valvular heart disease, data from pivotal
trials of the newer agents indicate.

Those trials consistently excluded patients with moderate-to-severe

mitral stenosis or mechanical heart valves but allowed most patients
with other types of valvular disease to participate. Although the
presence of valve disease was associated with higher risks of death
and major bleeding overall, it did not modify treatment effects on a
variety of outcomes, according to a meta-analysis by Giulia Renda,
MD, PhD (G. d’Annunzio University, Chieti, Italy), and colleagues.

Compared with warfarin-treated patients, those receiving NOACs had a

similar risk of major bleeding and significantly lower risks of stroke or
systemic embolism and intracranial hemorrhage.

The meta-analysis included previously published data from the RE-LY,

ARISTOTLE, and ROCKET AF trials, as well as from a new analysis of
the ENGAGE AF-TIMI 48 trial led by Raffaele De Caterina, MD, PhD (G.
d’Annunzio University, Chieti, Italy). Both that latter study and the
meta-analysis are being published in the March 21, 2017, issue of
the Journal of the American College of Cardiology.

“There was no signal of loss of efficacy or worse safety with the NOACs
compared with warfarin, which is consistent with what we’ve been
thinking all along, that it’s just the mechanical heart valve patients
and the mitral stenosis patients that one needs more data on and for
the moment ought to avoid the NOACs,” Robert Giugliano, MD
(Brigham and Women’s Hospital, Boston), a coauthor on both papers,
told TCTMD.

This is an area that has created confusion among clinicians stemming

from use of the term “nonvalvular A-fib” to describe patients included
in the clinical trials of the NOACs, Giugliano said, pointing out that
some prescribing physicians have assumed that any degree of
valvular disease precludes NOAC therapy.

That’s not the case, as 19% of patients pooled for the meta-analysis
had some type of valvular disorder, most commonly moderate-to-
severe mitral regurgitation.

Giugliano said he supports doing away with the term “nonvalvular A-

fib” and instead using MARM-AF (mechanical and rheumatic mitral
valvular AF)—which was coined by De Caterina and John Camm, MD
(St. George’s University of London, England)—to distinguish patients
who should receive warfarin or another vitamin K antagonist over a
NOAC, at least until further research is conducted in those groups.

The most recent European A-fib guidelines stopped using the term

nonvalvular A-fib, and Giugliano would like to see a similar change
made when the US guidelines are updated. “I think that it ought to be
eliminated because even if you were to redefine it, it would be
confusing,” he said, adding that he thinks the US Food and Drug
Administration should revise prescribing information for oral
anticoagulants, as well.

Evidence Gap Starting to Fill

Prior analyses of the RE-LY, ROCKET AF, and ARISTOTLE trials

supported the idea that the performance of dabigatran (Pradaxa;
Boehringer Ingelheim), rivaroxaban (Xarelto; Janssen
Pharmaceuticals), apixaban (Eliquis; Bristol-Myers Squibb),
respectively, compared with that of warfarin was generally the same
in patients with and without valve conditions. The new analysis of the
ENGAGE AF-TIMI 48 trial of edoxaban (Savaysa; Daiichi Sankyo)
yielded similar results.

There were some differences across trials in terms of design and

inclusion/exclusion criteria, so Renda et al performed a meta-analysis
to further explore the potential impact of valvular disease. The trials
included a total of 71,683 patients, of whom 13,585 had valvular
disease. Moderate-to-severe mitral regurgitation accounted for 73.3%
to 87.7% of valve disease, but some patients had aortic regurgitation
or stenosis, tricuspid regurgitation, mild mitral stenosis, or a history of
valve surgery.

The main analysis evaluated the effects of the higher NOAC doses
when multiple doses were used for a particular drug, although a
secondary analysis that incorporated all doses produced similar
findings.

The presence of valvular disease did not modify treatment effects (P >
0.05 for all interactions) for stroke or systemic embolism, major
bleeding, or intracranial hemorrhage. There was an interaction
regarding all-cause death (P = 0.03), which was reduced with NOACs
versus warfarin in patients without valve disease but not in those with
valve disease.

That finding “may be spurious, or alternatively related to a different

sensitivity of some components of death to the effect of NOACs versus
warfarin in [valvular heart disease] patients. However, the small
number of death events may also have caused a type I error,” the
authors say. They add that there was no indication of harm with NOAC
therapy.

The findings “[suggest] that NOACs can be safely used in patients

without moderate-to-severe mitral stenosis or mechanical valves,” the
authors say. “Future trials should specifically address patients with
bioprosthetic heart valves and valve repair surgery who were
relatively underrepresented in trials performed to date.”

Commenting for TCTMD, Dan Atar, MD (Oslo University Hospital,

Norway), a coauthor of the 2016 European A-fib guidelines, said there
is a gap in evidence regarding the utility of NOACs in patients with
valvular heart disease that is starting to be filled with analyses like
those by Renda et al and De Caterina et al.

It is becoming clearer that clinicians should not be discouraged from

using NOACs in patients with certain types of valvular disease, he said.
“There is no reason to suspect that the favorable results of NOACs
versus warfarin in the A-fib trials would not be reflected in an A-fib
patient who also has a certain valvular component in his heart
disease,” said Atar, a former vice president of the European Society of
Cardiology. He added, however, “We must nevertheless be aware that
we do not have good data and good evidence in this field.”

Next Steps

Atar said more trials should be done to explore the efficacy and safety
of NOACs in patients with various types of valvular disease. “We would
like to have solid evidence to show that if you have severe aortic
stenosis or severe mitral insufficiency, for example, NOACs are still
good to use,” he said.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572042/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5692140/

https://thaythuocvietnam.vn/thuvien/cham-soc-benh-nhan-dung-khang-dong-duong-uong-moi-trong-
tinh-huong-cap-tinh/?fbclid=IwAR1jbNpAevflnhJfz5N1rmhR0RYIp8RZy4Ey07u5G0_-uO72x7nGywaGjsA

Giugliano agreed that further study in patients with aortic stenosis

would be useful, particularly because interventions in that area—
including TAVR and implantation of a new mechanical heart valve
called On-X (CryoLife)—are evolving so rapidly.

Another group of patients that would be a prime target for future

studies would be those with a recent valve surgery. In that situation,
Giugliano said, many cardiac surgeons like to use short-term
anticoagulation therapy.
It would also be worth exploring the utility of NOACs in patients with
moderate-to-severe mitral stenosis, he said, but conducting such trials
is challenging because the disease is becoming rarer in North America
and Europe.

While awaiting additional trials, clinicians “should continue to choose

warfarin or another vitamin K antagonist . . . in patients with
mechanical heart valves or moderate-to-severe mitral stenosis,”
Giugliano said, adding that current data “provide support to use the
NOACs instead of warfarin in all the other types of valvular disease,
excepting those who are within 3 months of surgery.”