Journal of Thrombosis and Thrombolysis
https://doi.org/10.1007/s11239-019-01896-9
LETTER TO THE EDITOR
The fading role of triple therapy in patients with atrial fibrillation
and acute coronary syndrome: a Bayesian network meta‑analysis
Mohammed Osman1 · Babikir Kheiri2 · Muhammad Bilal Munir1 · Jason A. Moreland1 · Sudarshan Balla1 ·
Samir Kapadia3
© Springer Science+Business Media, LLC, part of Springer Nature 2019
The management of patients with concomitant atrial fibril-
lation (AF) and acute coronary syndrome (ACS) or percu-
taneous coronary intervention (PCI) represents a medical
dilemma. Recent US guidelines recommend dual therapy
(DT) with non-vitamin K antagonist oral anticoagulants
(NOACs) and P2Y12 inhibitor instead of triple therapy (TT)
which includes aspirin [1]. To date there is no head-to-head
comparison among NOACs with respect to bleeding and
ischemic events when utilized in AF patients with ACS and/
or PCI. We used the advanced meta-analytic properties of
Bayesian analysis to compare different dual therapy regi-
men including apixaban, rivaroxaban, dabigatran, warfarin
among each other and to TT with warfarin. We used study
level data and pooled the primary safety outcome of bleed-
ing (as defined by the included trial) and the primary efficacy
outcome of major adverse cardiovascular events (composite
of cardiac death, stent thrombosis, stroke and myocardial
infarction) from available published randomized controlled
trials (RCTs). Analysis was performed using NetMetaXL
version 1.6.1 and WinBUGS version 1.4.3.
Four RCTs comparing different NOACs DT regimen
to warfarin TT were included [2–5]. A significant reduc-
tion in bleeding was seen in apixaban, rivaroxaban, dabi-
gatran and warfarin dual therapies compared to warfarin
TT (OR 0.49, 95% Cr.I 0.31–0.78, ­I2 = 13%), (OR 0.59,
95% Cr.I 0.38–0.95), (OR 0.44, 95% Cr.I 0.26–0.74) and
(OR 0.46, 95% Cr.I 0.32–0.63), respectively. There was no
* Mohammed Osman
mohammed.osman@hsc.wcu.edu
1
Division of Cardiology, West Virginia University School
of Medicine, 1 Medical Center Drive, Morgantown,
WV 26506, USA
2
Hurley Medical Center, Michigan State University, Flint, MI,
USA
3
Department of Cardiovascular Medicine, Heart and Vascular
Institute, Cleveland Clinic, Cleveland, OH, USA
statistically significant difference in the rate of bleeding
among DT groups (Fig. 1a). Moreover, there was no statis-
tically significance difference in the rate of major adverse
cardiovascular events (MACE) in apixaban, rivaroxaban,
dabigatran and warfarin dual therapies compared to warfa-
rin TT (OR 0.83, 95% Cr.I 0.03–38.02), (OR 0.84, 95% Cr.I
0.07–11.94),(OR 1.02, 95% Cr.I 0.07–14.82) and (OR 0.47,
95% Cr.I 0.03–6.48), respectively. There was no statistically
significant difference in the rate of MACE outcome among
DT groups (Fig. 1b).
The main findings from our current investigation are:
[1] DT is superior in terms of bleeding when compared to
TT and within DT group no agent is superior over another
[2]. No difference is noted with respect to MACE outcome
among different agents utilized in DT group compared to
warfarin TT group.
The management of AF patients with associated ACS
and/or PCI is fraught with uncertainty. While there is a
contemporary trend of utilizing TT in AF patients at least
initially after ACS or PCI, this practice is often associated
with significant bleeding complications resulting in signifi-
cant patient morbidity. There is no real-life data on head-
to-head comparison of various NOACs agents with respect
to bleeding and MACE in patients who have indications for
anti-platelet and anti-thrombotic therapy. Our analysis has
shown that as a class effect, NOACs (as utilized in DT) are
significantly better than warfarin TT in minimizing bleeding
complications but within themselves, no significant differ-
ence was noted. Additionally, warfarin DT was also safer
with respect to bleeding when compared to warfarin TT.
While TT is losing ground slowly, all the current avail-
able RCTs on NOACs DT excluded patients with mechanical
heart valves, severe renal insufficiently and patients with a
diagnosis of hypercoagulable status, in these cases the effi-
cacy of dual therapy with one of the NOACs is yet to be
established and warfarin DT or TT is still considered a valid
option. The recently published AUGUSTUS trial utilized
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 M. Osman et al.

Fig. 1  Forest plot comparing:

a bleeding events between dif-
ferent regimens of dual therapy
and triple therapy. b Major
adverse cardiovascular events
(MACE) between different
regimens of dual therapy and
triple therapy

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The fading role of triple therapy in patients with atrial fibrillation and acute coronary…
2 × 2 factorial randomization and comparisons were done
among patients taking either apixaban or warfarin and aspi-
rin or P2Y12 therapy. This unique design which is different
than the other trials allowed the comparison of DT versus
TT and on top of that the comparison of aspirin vs placebo.
At 6 months follow up, about 10.5% of patients receiving
apixaban therapy witnessed major bleeding event when com-
pared to 14.7% of patients on warfarin (HR 0.69, 95% CI
0.58–0.81) [5]. Our analysis, however, showed that apixaban
dual therapy is similar in terms of bleeding complications
when compared to warfarin dual therapy (OR 0.94, 95% CI
0.50–1.58, see Fig. 1) [5]. In our current study, we have also
pooled data from WOEST trial that compared warfarin TT
group to warfarin DT group and found less prevalence of
bleeding in DT group when compared to TT group (19.4%
vs 44.4%, HR 0.36, 95% CI 0.26–0.50) [3]. Since WOEST
trial showed significantly improved bleeding outcomes in
patients on warfarin DT group when compared to TT group,
it seems likely that the effect of improved bleeding outcomes
in apixaban group as shown in AUGUSTUS trial was diluted
in our meta-analysis due to pooling of this data. It is impor-
tant to note that in the AUGUSTUS trial the addition of
aspirin to DT (Coumadin or DAOC based) increased the risk
of bleeding without any benefits in reduction of ischemic
events. In line with all these accumulated evidence the recent
focused update of atrial fibrillation guidelines in US recom-
mended DT in patients with atrial fibrillation who received
coronary artery stenting (COR IIa, B-R) [1]. In contrast the
European guidelines continue to endorse TT for a minimum
duration of 4 weeks post stent placement in all patients with
atrial fibrillation after that period the regimen could be
downgraded to DT [6]. Given the current available evidence
we believe that an approach of DT with one of the NOACs
and P2Y12 inhibitor should be the default strategy in the
majority of patients with atrial fibrillation with ACS and/or
PCI. However, in high-risk patients with stent thrombosis
or complex percutaneous intervention who are deemed to
be high risk for thrombosis and low bleeding risk a regimen
of TT for no longer than 4 weeks followed by dropping the
aspirin after that is a reasonable alternative [1, 6]. There is
still a need for more large RCTs comparing various NOACs
among each other and to warfarin DT in AF patients with
ACS and/or PCI who are taking anti-platelet agents.
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