New
Oral Anticoagulants in the Management of VTE
Stavros
K Kakkos, Ioannis A Tsolakis
Stavros K Kakkos,
Ioannis A Tsolakis, Department of Vascular Surgery, University Hospital of
Patras, Patras, 26504, Greece
Correspondence to: Stavros K Kakkos, MD, MSc, PhD, RVT, Department of
Vascular Surgery, University Hospital of Patras, Patras, 26504, Greece.
Email: kakkos@upatras.gr
Telephone: +30-2613-603406 Fax:
+30-2613-603360
Received: January 2,
2015
Accepted: February 1, 2015
Published online: April 30, 2015
ABSTRACT
The advent of the
new oral anticoagulants (NOAs) for the treatment and long-term (secondary)
prevention of venous thromboembolism has been viewed as a revolution in patient
care. Not only because the NOAs offer a simple solution compared to the
traditional treatment with vitamin K antagonists with similar effectiveness and
no need for dose monitoring, but more importantly because NOAs have first less
bleeding complications, second very few drug and no food interactions, third no
heparin-induced thrombocytopenia has been reported and last but not least two
of them (rivaroxaban and apixaban) can be started as monotherapy. These facts
are outlined by this Editorial.
© 2015 ACT. All
rights reserved.
Key words: Venous thromboembolism; New oral anticoagulants; Vitamin K antagonists
Kakkos SK, Tsolakis IA. New Oral Anticoagulants in the
Management of VTE. International Journal of Hematology Research 2015; 1(1): 4-6
Available from: URL: http://www.ghrnet.org/index.php/ijhr/article/view/1006
EDITORIAL
The new oral anticoagulants (NOAs) dabigatran, rivaroxaban, apixaban
and edoxaban have emerged not only as an effective treatment for venous
thromboembolism (VTE) but also as a safe alternative to traditional management,
i.e. heparin (usually low molecular weight heparin administered subcutaneously)
followed by oral vitamin K antagonists (VKAs). Dabigatran is a factor IIa
(thrombin) inhibitor, while rivaroxaban, apixaban and edoxaban are all factor
Xa inhibitors. Six randomized-controlled trials (RCTs) have compared NOAs with
heparin/VKA[1-6]; four of them were double-blind trials. Four
additional double-blind RCTs had as subject secondary prevention of VTE with
three trials comparing a NOA with placebo and the fourth one comparing directly
warfarin with dabigatran[4,6,7].
The authors
have recently published a systematic review and meta-analysis of all studies on
NOAs in VTE management[8]. Almost 38,000 patients were included and
significant safety advantages were identified with no compromise of
effectiveness. Apart from any difference in these two major outcome measures,
there are several additional aspects that make NOAs different from VKAs.
NOAs, unlike
heparins, fondaparinux and VKAs, are direct inhibitors of factor IIa or Xa,
which could explain their more predictable results. Indeed all VKAs have a
narrow therapeutic window that necessitates frequent INR measurements to
carefully titrate their dose and to prevent recurrent VTE or bleeding in case
of sub-therapeutic of supra-therapeutic INR, respectively. The same applies for
the intravenous administration of heparin during the first days of VTE
management. On the other hand, NOAs do not require any laboratory test to
determine their dose, which is fixed. Therefore there is no cost for INR
measurement in addition to any indirect costs (travelling etc) and patient
inconvenience.
NOAs are
quickly absorbed by the GI tract and their relatively short half-life time
(usually less than 10-15 hours) does not necessitate bridging (with heparin or
low molecular weight heparin) before surgical operations, for switching of
anticoagulant treatments or during initial treatment with rivaroxaban or
apixaban. However, two NOAs (dabigatran and edoxaban) require initial use of a
conventional parenteral anticoagulant to be co-administered with the NOA for
several days. The remaining two NOAs (rivaroxaban and apixaban) are
administered as monotherapy. Unlike VKAs that interact with a very large number
of drugs, the list of drugs that interact with the NOAs is limited. Similarly,
there are no known food interactions for NOAs, while VKA action is altered by
any change in the amount of food that contains vitamin K (e.g. green vegetables
etc). Rivaroxaban in particular should be taken with food to increase its
bioavailability. Heparin-induced thrombocytopenia (HIT) has not been reported
to occur after use of the NOAs.
One point that
requires special attention is renal function, because dose reduction might be
necessary in patients with moderate to severe impairment of renal function and
there is a contraindication in very severe impairment, always based on
glomerular filtration rate (GFR) estimation and the product SPC. Monitoring of
GFR at regular intervals would help dose modification or change to VKAs, as
appropriate in case of deterioration of renal function. An additional area of
active research is the development of a specific antidote[9], to be
used in case of bleeding or the need for urgent surgery, where specific
recommendations have been suggested[10].
In the acute
setting, NOAs are equally effective with VKAs in preventing recurrent
symptomatic DVT (1.1% vs 1.3% with the use of VKA, RR 0.89, 95% CI
0.75-1.05, p=0.16) and also pulmonary embolism (PE), according to a
recent meta-analysis[8]. On subgroup analysis, factor Xa inhibitors
and also NOAs not requiring initial parenteral anticoagulation (rivaroxaban and
apixaban) were associated with a reduced risk of recurrent DVT compared to VKAs
with the difference being statistically significant (RR 0.77, 95% CI 0.60-0.99,
P=0.04 and RR 0.67, 95% CI 0.47-0.94, p=0.02, respectively).
In the same
meta-analysis major bleeding occurred less often with NOAs (1.08% vs
1.73% for VKAs, RR 0.63, 95% CI 0.51-0.77, p<0.00001, Figure 1A) and
so did clinically relevant non-major bleeding (8.5% vs 6.6% for NOAs, RR
0.74, 95% CI 0.59-0.93, p=0.01)[8]. Additionally, fatal
bleeding occurred less often with NOAs (0.09% vs 0.18% for VKAs, RR
0.51, 95% CI 0.26-1.01, p=0.05, Figure 1B). This improved safety profile
of NOAs is evident also in trials on atrial fibrillation, where NOAs are
associated with a reduced rate of intracranial bleeding, which has a high
fatality rate[11].
The single RCT
(RE-MEDY) that compared dabigatran with warfarin concluded that dabigatran was
not inferior to warfarin (recurrent VTE 1.8% vs 1.3% for warfarin, p=0.01
for noninferiority), however major or clinically relevant bleeding occurred
less frequently with dabigatran (RR 0.54, 95% CI 0.41 to 0.71)[7].
In three
secondary prevention trials, comparing the NOAs with placebo[4,6,7],
as expected the former reduced significantly pooled VTE recurrence rates at the
expense of an increased clinically-relevant non-major bleeding, but not major
bleeding[8]. Surprisingly, pooled all-cause mortality rate was
reduced to 0.41% with NOAs vs 0.86% with placebo (RR 0.38, 95% CI
0.18-0.79, p=0.009)[8].
Nevertheless
NOAs and particularly rivaroxaban are considered as a cost-effective
alternative to warfarin, given the equal effectiveness and reduced bleeding
rates[12].
In conclusion,
compared to VKAs, NOAs are not only effective but also safer regarding bleeding
rates, which makes them suitable for long-term secondary prevention of VTE, as
also shown by the corresponding trials. Because of their favorable
characteristics and the above facts, NOAs are expected to simplify the
management of VTE.
CONFLICT OF INTERESTS
The Author has no conflicts of interest to declare.
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Peer reviewer: Yuri V. Bobryshev, PhD,
School of Medical Sciences, Faculty of Medicine, University of New South Wales,
NSW 2506 Kensington, Sydney, Australia.
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