A patient with acute pulmonary embolism (PE) is a challenge
to the clinician because most treatments increase the risk for
bleeding complications. Eighty percent of patients with PE have
identifiable predisposing factors, while idiopathic or unprovoked
PE was about 20% in the International Cooperative Pulmonary
Embolism Registr y (ICOPER) (
1). PE and deep vein
thrombosis (DVT) share the same predisposing factors, where
the strongest setting-related predisposing factor is major surgery
(
2) and therefore, PE is a well-known and feared complication
following surgery with a mortality up to 50% for massive
pulmonary embolism (
3).
Patients suspicious for PE are stratified into high risk,
intermediate risk and low risk according to the guidelines
from the European Society of Cardiology (
4). In general,
circulatory unstable high-risk patients are considered for either
intravenous thrombolysis or embolectomy. Randomized
trials have shown that thrombolytic therapy rapidly resolves
thromboembolic obstruction and exerts beneficial effects on
hemodynamic parameters (
4), where pulmonary embolectomy
is a valuable therapeutic option in patients with high-risk PE
in whom thrombolysis is absolutely contraindicated or has
failed (
4). Unfractionated heparin has been used for certain
patients but is reserved for situations, where thrombolysis is
contraindicated because it is less effective than thrombolysis (
5).
Patients with intermediate risk are treated with anticoagulants,
but thrombolysis may be considered in selected patients after
thorough consideration of conditions increasing the risk of
bleeding (
4,
6), while low-risk patients are treated with lowmolecular
weight heparin (LMWH).
For all stratified groups it is essential that anticoagulant
treatment is initiated without delay, i.e. while diagnostic workup
is still ongoing. For high-risk PE patients the recommended
anticoagulation is unfractionated heparin, while LMWH or
fondaparinux is the recommended initial treatment for most
patients with non-high-risk PE (
4).
At present, a variety of studies are emerging on rapidacting
oral anticoagulants that could replace parenteral agents
for anticoagulant treatment, namely Xa and IIa inhibitors.
Recently, a randomized trial was published in The New England
Journal of Medicine comparing a new factor Xa-inhibitor,
Rivaroxaban, with standard treatment in 4,832 patients
with acute symptomatic PE (
7). The EINSTEIN-PE was a
multicenter study, where a broad spectrum of patients with PE
with or without DVT recruited from 236 sites in 38 countries
were randomized to either Rivaroxaban or standard therapy
(LMWH followed by adjusted-dose vitamin K antagonist). In
summary, Rivaroxaban was found non-inferior to the current
standard therapy in reducing the primary end-point of recurrent
symptomatic venous thromboembolism (symptomatic DVT
and fatal or non-fatal PE) (2.1%
vs. 1.8%, respectively; P=0.003
for non-inferiority). Also, Rivaroxaban demonstrated safety
results comparable with those obtained with standard therapy in
terms of major and non-major clinically relevant bleeding (10.3%
vs. 11.4%, respectively; P=0.23). Of importance, Rivaroxaban
treatment gave a significant reduction in major bleeding events
(1.1%
vs. 2.2%, respectively; P=0.003) compared to the current
standard therapy.
It is a well-designed study, but there are several considerations
to be dealt with: First issue is if the treated patients are
representative for patients with acute PE: Only 36% of the
patients in the trial had predisposing factors, where an expected
ratio of patients with predisposing factors is 80% (1). Another
issue is that the patients were not stratified according to the
guidelines from European Society of Cardiology, so it is unsure
if the patients were treated according to the guidelines or the
indication for anticoagulant therapy was expanded.
As far as safety is concerned Rivaroxaban is comparable to standard therapy when considering all bleeding events, and
superior in regards of major bleeding episodes. However, the
absolute numbers were small (26 vs. 52 patients), and as for
many investigations a larger number of events are needed to
elucidate the safety issue more efficiently. Without doubt,
intracranial haemorrhage is the most feared complication to
anticoagulant treatment, and a reduction would be highly
appreciated, especially if the efficacy is still ascertained. In this
context the lack of a specific antidote could also be vital, but
small studies have indicated that the prothrombin complex
concentrate appears to be an effective antidote; this, however,
needs to be confirmed in larger trials as well.
Third issue is the cost-beneficial circumstances. Many
calculations has been made to describe the cost of these new
anticoagulants: For the time being they are considerably more
expensive than Warfarin treatment, but in the overall calculation
not only efficacy and safety has to be included, but also compliance
and laboratory testing: In the EINSTEIN-PE trial patients did
not get LMWH injections, which is a positive achievement for
the patient as well as for the nursing staff, as it is well-known
that adherence to injection protocols from time to time are
problematic. Also, costs and time-consumption related to blood
sampling and INR measurement is reduced, as monitoring of
these new anticoagulants is unnecessary. However, it is a complex
calculation, and we will probably not know the exact answer before
these drugs are implemented in everyday use.
Finally, monitoring of the treatment may not be necessary
in the uncomplicated patient, but bleeding complications
will occur as well as a need for unplanned surgery, and in
those cases monitoring of the anticoagulant regime will be
necessary. Unfortunately, the existing coagulation parameters are
uncertain for this purpose (aPTT cannot be used, while anti Xameasurement
seems promising), and above all the experience
is sparse. An ongoing effort is put into establishing a laboratory
profile to help in such cases and hopefully, the need can be met
in due time.
Altogether, Rivaroxaban is a new drug with very promising
results and the future will show whether the disadvantage with
no antidote in case of bleeding is balanced by the obvious
advantages of a drug that require no monitoring and is easy to
administer.