The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l

An Important Step for Thrombocardiology

Eugene Braunwald, M.D.

It has been known for more than a century that
coronary-artery thrombosis is the most common
precipitant of acute myocardial infarction and
that atherosclerotic plaques in the coronary ar-
teries are often responsible for angina pectoris.
When anticoagulants and antiplatelet agents be-
came available, clinical investigators rushed to
study their efficacy and safety in patients with
coronary artery disease. Attention was focused
on two large populations — patients with acute
coronary syndromes and those with stable isch-
emic disease, many of whom had previously had
an acute event. Hundreds of trials, registries, and
systematic analyses on the benefits and risks of
individual and various combinations of antithrom-
botic drugs have been conducted. There is now
general agreement on several points regarding
such therapy in patients with stable ischemic heart
disease.
First, monotherapy with low-dose aspirin is
clearly superior in efficacy to placebo or no anti-
platelet therapy, and it is associated with a very
low incidence of serious bleeding.1 Second, the
addition of a second antiplatelet agent, such as a
P2Y12 inhibitor or a thrombin-receptor antagonist,
to aspirin (i.e., dual antiplatelet therapy) enhances
efficacy, albeit at the cost of additional bleeding.2-4
Third, warfarin, when added to aspirin, reduces
reinfarction but also increases serious bleeding
substantially5; with respect to long-term second-
ary prevention, the need for frequent monitoring
and dose adjustment leads to poor adherence.6
Fourth, the further addition of the usual dose of
an anticoagulant to dual antiplatelet therapy (i.e.,
triple antithrombotic therapy) is responsible for a
high risk of serious bleeding and is therefore
considered unacceptable over the long term.
We took these “givens” into consideration in
the Anti-Xa Therapy to Lower Cardiovascular
Events in Addition to Standard Therapy in Sub-
jects with Acute Coronary Syndrome 2–Throm-
bolysis in Myocardial Infarction 51 (ATLAS ACS
2–TIMI 51) trial7 by adding low doses of the
factor Xa inhibitor rivaroxaban to either single
or dual antiplatelet therapy. We studied doses of
5 mg twice daily and 2.5 mg twice daily — one
half and one fourth, respectively, of the rivaroxa-
ban dose approved for stroke prevention in patients
with atrial fibrillation. The rate of the composite
primary end point (cardiovascular death, myocar-
dial infarction, or stroke) was significantly lower
with either dose of rivaroxaban than with placebo,
although the risk of major bleeding (but not fatal
bleeding) was higher with rivaroxaban. The lower
dose of rivaroxaban resulted in significantly lower
cardiovascular mortality and total mortality than
with placebo.
The Cardiovascular Outcomes for People Using
Anticoagulation Strategies (COMPASS) trial, now
reported in the Journal,8 built on these and other
observations by comparing three antithrombotic
regimens in patients with stable ischemic coronary
or peripheral arterial disease: low-dose (100 mg
once daily) aspirin monotherapy, considered to be
the control regimen; low-dose (5 mg twice daily)
rivaroxaban monotherapy; and the combination
of low-dose aspirin (as above) and very-low-dose
rivaroxaban (2.5 mg twice daily). This combina-
tion was the clear winner. The rate of the com-
posite primary end point of cardiovascular death,
myocardial infarction, or stroke was significantly
lower with combination therapy than with aspirin
monotherapy, as were total mortality, coronary
heart disease mortality, and cardiovascular mor-
tality, and the net clinical benefit was enhanced.
Interestingly, although the rate of stroke was lower

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 The n e w e ng l a n d j o u r na l of m e dic i n e

with rivaroxaban plus aspirin than with aspirin But for now, sincere congratulations to the
alone, there was not a significant effect on the rate COMPASS investigators for their important con-
of myocardial infarction. The rates of major bleed- tribution to thrombocardiology.
ing events were significantly higher in the rivar- Disclosure forms provided by the author are available with the
oxaban groups than in the aspirin-alone group, but full text of this editorial at NEJM.org.
the rates of fatal or intracranial bleeding were not
From the Thrombolysis in Myocardial Infarction (TIMI) Study
significantly higher. The COMPASS trial was Group, Cardiovascular Division, Brigham and Women’s Hospi-
stopped for overwhelming efficacy when only one tal, Harvard Medical School, Boston.
half of the primary end-point events had occurred.
This editorial was published on August 27, 2017, at NEJM.org.
This trial represents an important step forward
in thrombocardiology, and it is likely to change 1. Antithrombotic Trialists’ Collaboration. Collaborative meta-
practice guidelines. But is it the end of clinical in- analysis of randomised trials of antiplatelet therapy for preven-
tion of death, myocardial infarction, and stroke in high risk
vestigation in this area? Probably not. There are patients. BMJ 2002;​324:​71-86.
several possibilities. First, a meta-analysis of dual 2. The Clopidogrel in Unstable Angina to Prevent Recurrent
antiplatelet therapy as compared with aspirin Events Trial Investigators. Effects of clopidogrel in addition to
aspirin in patients with acute coronary syndromes without
monotherapy for secondary prevention of cardio- ST-segment elevation. N Engl J Med 2001;​345:​494-502.
vascular events in patients with previous myocar- 3. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ti-
dial infarction also showed a significant between- cagrelor in patients with prior myocardial infarction. N Engl J
Med 2015;​372:​1791-800.
group difference (in favor of dual therapy) in the 4. Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the
same primary end point used in the COMPASS secondary prevention of atherothrombotic events. N Engl J Med
trial as well as in cardiovascular death, myocar- 2012;​366:​1404-13.
5. Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR. War-
dial infarction, and stroke individually. It is dif- farin plus aspirin after myocardial infarction or the acute coro-
ficult to compare results of trials studying dif- nary syndrome: meta-analysis with estimates of risk and bene-
ferent drugs in different populations.9 Therefore, fit. Ann Intern Med 2005;​143:​241-50.
6. Dlott JS, George RA, Huang X, et al. National assessment of
a head-to-head comparison between the addition warfarin anticoagulation therapy for stroke prevention in atrial
to aspirin of a second antiplatelet drug versus a fibrillation. Circulation 2014;​129:​1407-14.
very low dose of a factor Xa inhibitor could be of 7. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in pa-
tients with a recent acute coronary syndrome. N Engl J Med
great interest. 2012;​366:​9-19.
Second, perhaps substituting a P2Y12 inhibitor 8. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with
or thrombin-receptor antagonist for aspirin, to- or without aspirin in stable cardiovascular disease. N Engl J
Med. DOI:​10.1056/NEJMoa1709118.
gether with a very low dose of a factor Xa inhibi- 9. Udell JA, Bonaca MP, Collet J-P, et al. Long-term dual anti-
tor, might lead to even greater efficacy by reducing platelet therapy for secondary prevention of cardiovascular
myocardial infarction.10 Third, it is possible that events in the subgroup of patients with previous myocardial in-
farction: a collaborative meta-analysis of randomized trials. Eur
different subgroups of patients with stable isch- Heart J 2016;​37:​390-9.
emic heart disease, such as those with a history of 10. Ohman EM, Roe MT, Steg PG, et al. Clinically significant
an acute coronary syndrome or those with heart bleeding with low-dose rivaroxaban versus aspirin, in addition to
P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1):
failure, will have different responses to these a double-blind, multicentre, randomised trial. Lancet 2017;​389:​
various drug combinations, and this could lead to 1799-808.
a more personalized approach to patients with DOI: 10.1056/NEJMe1710241
stable ischemic heart disease. Copyright © 2017 Massachusetts Medical Society.

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