CVS

A New Era in Secondary Prevention after Acute CoronarySyndrome

nejm.org january 5, 2012
د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

During the past two decades, the use of antiplatelet therapies has been the focus of new

studies of secondary prevention after acute coronary syndromes, with more than 75% of patients in contemporary practice treated with dual antiplatelet therapy (aspirin plus a thienopyridine) on hospital discharge.

Despite increases in the use of antiplatelet therapies and the development of more potent antiplatelet therapies (prasugrel and ticagrelor), the residual risk of death, myocardial infarction, or stroke up to 1 year after acute coronary syndromes remains high. This represents a therapeutic challenge,since the balance between risk (major bleeding)and benefit (reduction in ischemic events) becomes more delicate with time as the ischemic risk tends to diminish.

The use of an anticoagulant, in addition to

antiplatelet therapy, for secondary prevention has
been explored in the past two decades with limited success. early trials documented that combining antiplatelet and anticoagulant therapies could potentially offer long-term benefit, if the right therapeutic profile could be developed for the outpatient setting,such as good oral bioavailability, reliable anticoagulant effect, and an acceptable safety profile.


A new oral direct thrombin inhibitor (dabigatran)
and oral factor Xa inhibitors (apixaban and
rivaroxaban) appear to fit these criteria, with good
bioavailability and reliable anticoagulant effects
shown for the prevention of deep venous thrombosis
and thromboembolism. However, recently published data have indicated that these agents, when tested in patients after an acute coronary syndrome, have raised safety concerns.

Increasing doses of dabigatran were tested in a randomized trial involving 1861 patients enrolled within 7 days after an acute coronary syndrome, and
bleeding events were more common with higher doses, whereas rates of ischemic events were similar in all dose groups.
Conversely, a single dose of apixaban was tested in a trial involving 7392 patients who were enrolled approximately 6 days after an acute coronary syndrome, but the trial was prematurely terminated because of an increased risk of significant bleeding events (including intracranial hemorrhage) with no observed reduction in ischemic events

In this issue of the Journal, Mega et al.5 report

the results of the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–
Thrombolysis in Myocardial Infarction 51 (ATLAS
ACS 2–TIMI 51) trial (ClinicalTrials.gov number,
NCT00809965), a landmark study that is the culmination of two decades of searching for another
approach for combining antiplatelet and anticoagulant therapies.

A total of 15,526 patients who were hospitalized for an acute coronary syndrome were randomly assigned to receive one of two doses
of rivaroxaban (2.5 mg or 5 mg twice daily) or
placebo.
The rate of the primary end point (a composite of death from cardiovascular causes, myocardial infarction, or stroke) was reduced in both groups receiving rivaroxaban, as compared with placebo, with a rate of 9.1% in the 2.5-mg group


and 8.8% in the 5-mg group versus 10.7%
(P = 0.008) in the placebo group. There were also
reductions in rates of death from both cardiovascular
causes and any cause for the 2.5-mg dose
but not for the 5-mg dose. There was a consistent
treatment benefit across a number of important
subgroups, but the proportions of patients who
were at least 75 years of age (9.0%) or female
(25%) were small, and more than 75% of patients
had normal renal function. Thus, the results
may not be applicable to higher-risk patients
with an acute coronary syndrome who are
commonly treated in routine practice.

The rate of major bleeding (according to TIMI

criteria) that was not related to coronary-artery
bypass grafting was increased by nearly a factor
of 4 in patients receiving rivaroxaban versus those
receiving placebo (2.1% vs. 0.6%, P<0.001), and
the rate of intracranial hemorrhage was increased
by a factor of 3 (0.6% vs. 0.2%, P = 0.009),
Whereas rates of fatal bleeding were similar. In each case, however, bleeding rates were lower in the 2.5-mg group than in the 5.0-mg group.


Many of the major bleeding events occurred after 180 days, with no plateau effect observed, and the risk of bleeding was consistent among all major subgroups, with numerically higher rates of bleeding in lighter-weight and elderly patients, as well as in
those with reduced renal function and those enrolled
in North America.

We believe that the results of this study are an

important development for relatively young and
healthy patients with an acute coronary syndrome.
However, there is much work still to be done,
since a large proportion of patients with an acute
coronary syndrome who are treated in routine
practice are elderly with multiple coexisting illnesses.
1 Given the exquisite balance between
bleeding risks and ischemic benefits of treatment,
we need a better understanding of the role of
rivaroxaban in higher-risk patients.

In particular,the finding that patients with an acute coronary syndrome who are receiving either rivaroxaban or apixaban are at higher risk for intracranial hemorrhage indicates that better predictors of this event are needed. However, it should be recognized that this finding has also been observed in trials with more potent antiplatelet therapies and may be concentrated in patients with a history of cerebrovascular disease.

Thus, a new era of secondary prevention after

an acute coronary syndrome has begun and will
be characterized by the need to balance ischemic
versus bleeding risks when selecting the type,
number, and duration of antithrombotic therapies
for individual patients. Although further studies
are needed to delineate the time dependency of
risks during long-term treatment and how prediction
of these risks will inform treatment selection,
the results of this study indicate that rivaroxaban will play an important role in the future
of optimized secondary prevention.