CVS

Oral Rivaroxaban for the Treatmentof Symptomatic Pulmonary Embolism original article

NEJM March 29, 2012.
د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

Background

A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to
be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis,
without the need for laboratory monitoring. This approach may also simplify
the treatment of pulmonary embolism.

Methods

In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis,
we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major
or clinically relevant nonmajor bleeding.


Results
Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P = 0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group
(2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurredin 10.3% of patients in the rivaroxaban group and 11.4% of those in the standardtherapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P = 0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the
standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P = 0.003). Rates of other adverse events were similar in the two groups.

Conclusions

A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy
for the initial and long-term treatment of pulmonary embolism and had a potentially
improved benefit–risk profile.

In this study involving patients with symptomatic

pulmonary embolism, oral rivaroxaban alone provided
protection from recurrent venous thromboembolism
that was similar to the protection provided
by standard therapy, with similar bleeding
rates. During a mean study duration of approximately
9 months, there was a recurrence in 2.1%
of patients in the rivaroxaban group and 1.8% of
those in the standard-therapy group.
Discussion


The primary safety outcome of major or clinically relevant nonmajor bleeding was observed in 10.3% of patients in the rivaroxaban group and 11.4% of those
in the standard-therapy group, and major bleeding
was observed in 1.1% and 2.2% of patients, respectively.

Our observations are consistent with those of other trials in which rates of recurrence of thromboembolism in the standard-therapy group were 1.6 to 2.7% and the corresponding rates of major bleeding were 1.4 to 2.4%.
In previous studies involving patients with pulmonary embolism before the advent of new compounds (idrabiotaparinux or dabigatran etexilate),
low-molecular-weight heparin was used as initial therapy. In our study, we tested the concept of a single-drug approach with an oral compound in a large population of patients with pulmonary embolism.

Several aspects of this study deserve comment.

We believe that our population is representative of
the spectrum of patients who present with symptomatic pulmonary embolism, with the exception of those for whom fibrinolytic therapy is planned.
A total of 1173 patients (nearly 25%) in our study
met our definition of extensive disease, and 608
(13%) had limited pulmonary embolism.

Furthermore, nearly 25% had concomitant symptomatic deep-vein thrombosis. The baseline characteristics of the patients, including the presence of risk factors, were similar to those in previous studies of pulmonary embolism. In keeping with current practice, the duration of treatment was 3, 6, or 12 months, with most patients receiving 6 months
or more of therapy.

We analyzed factors that may have influenced

outcomes. Specifically, the quality of standard
therapy was well within clinical acceptability,
with the INR in the therapeutic range 62.7% of
the time and exceeding 3.0 only 15.5% of the
time. These results compare favorably with the
findings in other contemporary studies of venous
thromboembolism.8,15,17 Adherence to the rivaroxaban regimen was high in 94% of patients.The number of patients who were lost to followup was negligible.


The suggestion that rivaroxaban can be administered
at the same dose in all patients without laboratory monitoring has raised concern. Therefore,
we performed multiple subgroup analyses
for both efficacy and safety. Rates of recurrent
venous thromboembolism and bleeding were similar
in the two study groups regardless of age,
sex, presence or absence of obesity, level of renal
function, or extent of pulmonary embolism.

We decided to start therapy with an intensive

rivaroxaban regimen (15 mg twice daily) for the
first 3 weeks for two reasons. In previous studies,
failure to provide adequate initial therapy led
to unacceptable recurrence rates.4,9,18,19 In addition,
in phase 2 studies, the use of twice-daily
rivaroxaban led to an earlier steady state, higher
trough levels, and better thrombus regression at
3 weeks than did once-daily administration.20,21

In our study, the Kaplan–Meier curves for recurrence

with this regimen and with standard therapy
were identical. One concern about the intensified
initial dose of rivaroxaban was that it could
potentially increase the risk of hemorrhage. However,
during the initial period, the bleeding rates were similar in the two study groups, with fewer major bleeding events in the rivaroxaban group.
Furthermore, during the entire course of treatment,
there were fewer episodes of intracranial bleeding or bleeding in critical areas in the rivaroxaban group than in the standard-therapy group.The explanation for this finding requires further study.


Before randomization, almost all patients received low-molecular-weight heparin, which is unavoidable in clinical trials of venous thromboembolism, since such treatment is consistent with current practice pending confirmation of the diagnosis.

In nearly 60% of patients in our study, this therapy was limited to 1 day, and less than 2% of patients received more than 2 days of treatment before enrollment. It seems unlikely that this brief exposure would have significant effects on the study outcomes.
Since the study had an open design, there is a
potential for a diagnostic-suspicion bias. Indeed,
the absolute number of patients with suspected recurrence was higher in the rivaroxaban group,
and the proportions of patients with confirmed events were similar in the two groups (10.2% in the rivaroxaban group and 9.7% in the tandardtherapy group).

This finding suggests that the open design may have caused a slight bias against rivaroxaban. Careful follow-up revealed similarly low rates of both acute coronary events and changes in liver-function tests in the two study groups.
Our findings in this study involving patients
with pulmonary embolism, along with those of
our previous evaluation involving patients with
deep-vein thrombosis,15 support the use of rivaroxaban as a single oral agent for patients with venous thromboembolism.