Note: Descriptions are shown in the official language in which they were submitted.
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COMBINATION OF RIVAROXABAN AND ACETYLSALICYLIC ACID
FOR REDUCING THE RISK OF CARDIOVASCULAR EVENTS
FIELD OF THE INVENTION
The present invention concerns medical therapy to treat or prevent
cardiovascular events
in patients with atherosclerotic vascular disease, coronary artery disease
and/or peripheral arterial
disease.
BACKGROUND OF THE INVENTION
Rivaroxaban is a medication used for the treatment and prevention of
thromboembolic
disorders. Rivaroxaban has the chemical name 5-chloro-N-({(5S)-2-oxo-314-(3-
oxo-4-
morpholinyl)pheny1]-1,3-oxazolidin-5-yllmethyl)-2-thiophenecarboxamide, and
has the chemical
structure of the formula (I):
Ci
0\\
O.
0 0
Rivaroxaban acts as a selective inhibitor of coagulation factor Xa (FXa) and
as an anticoagulant
(WO 01/47919). Combinations of FXa inhibitors with platelet aggregation
inhibitors,
anticoagulants, fibrinolytics, lipid-lowering agents, coronary therapeutic
agents and/or
vasodilators are described in WO 03/000256. Combinations of the compound of
formula (I) with
acetylsalicylic acid and clopidogrel are disclosed in US Pat. App. Pub.
2010/0120718 Al.
Coronary artery disease ("CAD"), also called coronary heart disease, is the
most common
type of heart disease. It occurs when plaque builds up in the heart's
arteries, a condition called
atherosclerosis. As plaque builds up, the arteries narrow, making it more
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difficult for blood to flow to the heart. If blood flow becomes reduced or
blocked, angina
(chest pain) or a heart attack may occur. Over time, coronary artery disease
can also lead to
heart failure and arrhythmias. Peripheral artery disease ("PAD") occurs when
narrow arteries
reduce blood flow to the limbs and the head, such as narrowed arteries to the
legs, feet and/or
head. Symptoms can include pain in the legs or buttocks when exercising that
goes away
when the activity is stopped, or abrupt closure of the vessels in the neck
leading to brain
damage (stroke). PAD is a progressive vascular disease that may lead to
atherothrombosis,
acute or chronic limb ischemia, amputation, and stroke. Both PAD and CAD are
caused by
atherosclerosis that narrows and blocks arteries in various critical regions
of the body.
Patients with PAD or CAD are at high risk for major adverse cardiovascular
events of
myocardial infarction, stroke, and cardiovascular death. Anticoagulant
therapies until the
present invention have not been shown to the satisfaction of governmental
health authorities
to be superior to antiplatelet therapy in PAD and have been rejected as having
unacceptably
high rates of major bleeding (Warfarin Antiplatelet Vascular Evaluation Trial
Investigators,
Anand S et al., N Eng J Med 2007; 357:217-27). Specifically, high and moderate
intensity
warfarin used with AspirinTM does not reduce major adverse cardiovascular
events but does
increase the risk of life-threatening bleeding, including intracranial
hemorrhage (The Dutch
Bypass Oral Anticoagulants or Aspirin Study Group, Lancet 2000; 355: 346-51).
The
mainstay of treatment for patients with PAD includes use of a single
antiplatelet agent daily to
prevent major adverse cardiovascular events. Other antithrombotic regimens
have been tested
in PAD patients including vitamin K antagonists and newer antiplatelet agents
such as P2Y12
antagonists used alone or in combination with Aspirin, but none have been
shown to be
superior to antiplatelet therapy alone (Anand S. et al., Lancet 2017; 391: 219-
229).
Antiplatelet therapy is frequently used in patients with CAD. For example,
Aspirin
alone, or Aspirin in combination with an antiplatelet agent from the class
known as P2Y12
inhibitors such as clopidogrel are used in CAD patients. Despite the
availability of these
therapies, there is still a need for new approaches to improve health outcomes
in CAD and
PAD patients.
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Various antithrombotic regimens have been tested as alternatives to Aspirin
for long-
term cardiovascular prevention. Trials of vitamin K antagonists involving
patients with stable
cardiovascular disease showed a reduction in the risk of subsequent
cardiovascular events
(Anand, "Oral anticoagulants in patients with coronary artery disease," J Am
Coll Cardiol
2003:41:Suppl S:62S-69S). However, there was no benefit in patients with
peripheral arterial
disease (The Warfarin Antiplatelet Vascular Evaluation Trial Investigators,
"Oral anti-
coagulant and antiplatelet therapy and peripheral arterial disease," N Engl J
Med
2007;357:217-27), and there was a significant increase in bleeding, including
intracranial
bleeding (Anand, J Am Coll Cardiol and The Warfarin Antiplatelet Vascular
Evaluation Trial
Investigators, supra). Among patients with stable cardiovascular disease,
those who received
clopidogrel had a lower risk of major adverse cardiovascular events than those
who received
Aspirin, but there was no significant difference in the risk of cardiovascular
death or death
from any cause (CAPRIE Steering Committee, "A randomized, blinded, trial of
clopidogrel
versus Aspirin in patients at risk of ischaemic events (CAPRIE), Lancet
1996;348:1329-39).
Among patients with symptomatic stable cardiovascular disease or multiple risk
factors, the
combination of clopidogrel and Aspirin did not result in a significantly lower
rate of major
adverse cardiovascular events or death from any cause than Aspirin alone
(Bhatt,
"Clopidogrel and Aspirin versus Aspirin alone for the prevention of
atherothrombotic events,"
N Engl J Med 2006;354:1706-17). Among patients who had had myocardial
infarction 1 to 3
years previously, the combination of ticagrelor and Aspirin resulted in a
lower rate of major
adverse cardiovascular events and a higher rate of major bleeding than Aspirin
alone, and
there was no significant between-group difference in mortality (Bonaca, "Long-
term use of
ticagrelor in patients with prior myocardial infarction," N Engl J Med
2015;372:1791-800).
Among patients with stable peripheral arterial disease, ticagrelor did not
result in a
significantly lower rate of major adverse cardiovascular events than
clopidogrel (Hiatt,
"Ticagrelor versus clopidogrel in symptomatic peripheral artery disease," N
Engl J Med
2017;376:32-40). Among patients with stable cardiovascular disease who were
receiving
single or dual antiplatelet therapy, vorapaxar, a PAR-1 receptor antagonist,
resulted in a lower
rate of major adverse cardiovascular events and a higher rate of moderate or
severe bleeding
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than placebo, with no significant between-group difference in mortality
(Morrow, "Vorapaxar
in the secondary prevention of atherothrombotic events," N Engl J Med
2012;366:1404-13).
The potential benefit of rivaroxaban in patients with cardiovascular disease
was
evaluated in the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to
Standard
Therapy in Subjects with Acute Coronary Syndrome 2¨ Thrombolysis in Myocardial
Infarction 51 (ATLAS ACS 2¨TIMI 51) trial and the dose-finding trial
associated with it,
ATLAS ACS-TIMI 46. The ATLAS ACS 2-TIMI 51 trial tested rivaroxaban on a
background of single or dual antiplatelet therapy in patients with a recent
acute coronary
syndrome. Rivaroxaban at a dose of 2.5 mg twice daily or 5 mg twice daily
resulted in a lower
rate of major adverse cardiovascular events than placebo, and the dose of 2.5
mg twice daily
resulted in lower mortality (Mega, "Rivaroxaban in patients with a recent
acute coronary
syndrome," N Engl J Med 2012;366:9-19).
The findings presented herein were obtained from the phase III COMPASS trial
evaluating the efficacy and safety of rivaroxaban (Xarelto0) for the
prevention of major
adverse cardiac events including cardiovascular death, myocardial infarction
and stroke in
patients with CAD or PAD, and are reported in Eikelboom et al., "Rivaroxaban
with or
without Aspirin in stable cardiovascular disease," N Engl J Med 2017;377;1319-
30. The
mean duration of rivaroxaban treatment in the ATLAS ACS 2¨TIMI 51 trial was
13.3 months,
whereas persons enrolled in the COMPASS trial who had a history of myocardial
infarction
were enrolled a mean of 7.1 years after the acute event and continued to
receive treatment for
a mean of 23 months.
W02017180683 A2 to Adams Pharmaceuticals discloses methods of preventing
atherosclerosis by administering an inhibitor of factor Xa, such as
rivaroxaban, apixaban,
betrixaban, edoxaban, and otamixaban.
SUMMARY
The invention concerns the discovery that combination therapy of rivaroxaban
and
Aspirin administered to patients with stable atherosclerotic vascular disease,
including
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coronary artery disease and/or peripheral artery disease, shows efficacy in
reducing the risk of
myocardial infarction, stroke, and/or cardiovascular death. Furthelinore, this
combination
therapy does not result in unacceptable bleeding, such as an unacceptably high
risk of fatal
bleeding or bleeding in critical organs.
In one embodiment, the invention is a use rivaroxaban in combination with
acetylsalicylic acid for the prevention of stroke, myocardial infarction or
cardiovascular death,
or for the prevention of acute limb ischemia and mortality, in patients with
stable coronary
artery disease (CAD) or peripheral artery disease (PAD), comprising use of
rivaroxaban in an
amount of 2.5 mg twice daily and acetylsalicylic acid in an amount of 75-100
mg daily.
In another embodiment, the invention is a method of reducing the risk of
myocardial
infarction, stroke or cardiovascular death in a human patient with coronary
artery disease
and/or peripheral artery disease, comprising administering to the human
patient rivaroxaban
and Aspirin in amounts that are clinically proven effective in reducing the
risk of myocardial
infarction, stroke or cardiovascular death in a human patient with coronary
artery disease
and/or peripheral arterial disease, wherein rivaroxaban is administered in an
amount of 2.5 mg
twice daily and Aspirin is administered in an amount of 75-100 mg daily, or in
an amount of
75 mg, 81 mg or 100 mg daily.
In another embodiment, the invention is a use of rivaroxaban in combination
with
acetylsalicylic acid for reducing the risk of myocardial infarction, stroke or
cardiovascular
death in a human patient with stable coronary artery disease (CAD) and/or
peripheral artery
disease (PAD), comprising the use of rivaroxaban in an amount of 2.5 mg twice
daily and
acetylsalicylic acid in an amount of 75-100 mg daily.
In another embodiment, the invention is a method of reducing the risk of
myocardial
infarction, stroke or cardiovascular death in a human patient with coronary
artery disease
and/or peripheral artery disease, the method comprising administering to the
human patient a
product comprising rivaroxaban and Aspirin in amounts that are clinically
proven effective in
reducing the risk of myocardial infarction, stroke or cardiovascular death in
a human patient
with coronary artery disease and/or peripheral arterial disease, wherein
rivaroxaban is
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administered in an amount of 2.5 mg twice daily and Aspirin is administered in
an amount of
75-100 mg daily.
The invention also concerns an effective pharmaceutical product for reducing
the risk
of myocardial infarction, stroke or cardiovascular death in a human patient
with stable
coronary artery disease and/or peripheral artery disease, wherein the
pharmaceutical product
comprises 2.5 mg rivaroxaban and 75-100 mg, 75 mg, 81 mg or 100 mg
acetylsalicylic acid.
In another embodiment, the invention also concerns an effective pharmaceutical
product for
reducing the risk of myocardial infarction, stroke or cardiovascular death in
a human patient
with stable coronary artery disease and/or peripheral artery disease, wherein
the
pharmaceutical product comprises 2.5 mg rivaroxaban and 35-38 mg, 39-41 mg, or
49-51 mg
acetylsalicylic acid.
In another embodiment, the invention is a method of reducing the risk of major
adverse limb events (MALE), including without limitation acute limb ischemia,
in a human
patient with peripheral artery disease, comprising administering to the human
patient
rivaroxaban and Aspirin in amounts that are clinically proven effective in
reducing the risk of
risk of major adverse limb events such as acute limb ischemia in a human
patient with
peripheral arterial disease, wherein rivaroxaban is administered in an amount
of 2.5 mg twice
daily and Aspirin is administered in an amount of 75-100 mg daily, or in an
amount of 75 mg,
81 mg or 100 mg daily.
In another embodiment, the invention is a use of rivaroxaban in combination
with
acetylsalicylic acid for reducing the risk of major adverse limb events (MALE)
in a human
patient with peripheral artery disease, comprising use of rivaroxaban in an
amount of 2.5 mg
twice daily and acetylsalicylic acid in an amount of 75-100 mg daily.
Another embodiment of the invention is a use of rivaroxaban in combination
with
acetylsalicylic acid in patients with stable coronary artery disease (CAD) or
peripheral artery
disease (PAD) to provide a lower composite net-clinical-benefit outcome of
cardiovascular
death, stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding
into a critical
organ than treatment with acetylsalicylic acid alone, comprising use of
rivaroxaban in an
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amount of 2.5 mg twice daily and acetylsalicylic acid in an amount of 75-100
mg daily. In
some embodiments, the use is in a patient with stable CAD or PAD, for the
prevention of
stroke, myocardial infarction or cardiovascular death, or for the prevention
of acute limb
ischemia and mortality.
In another embodiment, the invention is a method of reducing the risk of major
adverse limb events, such as without limitation acute limb ischemia, in a
human patient with
peripheral artery disease, the method comprising administering to the human
patient a product
comprising rivaroxaban and Aspirin in amounts that are clinically proven
effective in
reducing the risk of major adverse limb events, such as without limitation
acute limb
ischemia, in a human patient with peripheral arterial disease, wherein
rivaroxaban is
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administered in an amount of 2.5 mg twice daily and Aspirin is administered in
an amount of
75-100 mg daily. The invention also concerns an effective pharmaceutical
product for
reducing the risk of major adverse limb events, such as without limitation
acute limb
ischemia, in a human patient with peripheral artery disease, wherein the
pharmaceutical
product comprises 2.5 mg rivaroxaban and 75-100 mg, 75 mg, 81 mg or 100 mg
Aspirin. In
another embodiment, the invention also concerns an effective pharmaceutical
product for
reducing the risk of major adverse limb events, such as without limitation
acute limb
ischemia, in a human patient with peripheral artery disease, wherein the
pharmaceutical
product comprises 2.5 mg rivaroxaban and 35-38 mg, 39-41 mg, or 49-51 mg
Aspirin.
Another embodiment of the invention is a method of reducing the risk of
myocardial
infarction, stroke or cardiovascular death in a population of human patients
with coronary
artery disease and/or peripheral artery disease, comprising administering to
each human
patient in the population rivaroxaban and Aspirin in amounts that are
clinically proven
effective in reducing the risk of myocardial infarction, stroke or
cardiovascular death in a
human patient with coronary artery disease and/or peripheral arterial disease,
wherein
rivaroxaban is administered in an amount of 2.5 mg twice daily and Aspirin is
administered in
an amount of 75-100 mg daily, and wherein the hazard ratio for myocardial
infarction, stroke,
or cardiovascular death with the administration of rivaroxaban and Aspirin
compared to
Aspirin alone is 0.70-0.80 with a 95% confidence interval of at least 0.56 to
0.96, preferably
0.76, and, in certain embodiments, the method additionally has a hazard ratio
for major
bleeding events with the administration of rivaroxaban and Aspirin compared to
Aspirin alone
is 1.60-1.90, preferably 1.84, with a 95% confidence interval of at least 1.35
to 2.15,
preferably 1.50 to 2.26, wherein major bleeding events are defined herein
using a modified
ISTH standard.
In another embodiment, the invention is a use of rivaroxaban in combination
with
acetylsalicylic acid for reducing the risk of myocardial infarction, stroke or
cardiovascular
death in a population of human patients with coronary artery disease and/or
peripheral artery
disease, comprising use of rivaroxaban in an amount of 2.5 mg twice daily and
acetylsalicylic
acid in an amount of 75-100 mg daily, and wherein the hazard ratio for
myocardial infarction,
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stroke, or cardiovascular death with the use of rivaroxaban and
acetylsalicylic acid compared
to acetylsalicylic acid alone is 0.70-0.80 with a confidence interval of at
least 0.56 to 0.96.
Another embodiment of the invention is a method of reducing the risk of
stroke,
myocardial infarction, or cardiovascular death, in a population of human
patients with
peripheral artery disease, comprising administering to each human patient in
the population
rivaroxaban and Aspirin in amounts that are clinically proven effective in
reducing the risk of
stroke, myocardial infarction, or cardiovascular death, in a human patient
with peripheral
arterial disease, wherein rivaroxaban is administered in an amount of 2.5 mg
twice daily and
Aspirin is administered in an amount of 75-100 mg daily, and wherein the
hazard ratio for
stroke, myocardial infarction, or cardiovascular death with the administration
of rivaroxaban
and Aspirin compared to Aspirin alone is 0.50-0.60, preferably 0.72, with a
95% confidence
interval of at least 0.30-1.10, preferably 0.57-0.90.
In another embodiment, the invention is a use of rivaroxaban in combination
with
acetylsalicylic acid for reducing the risk of stroke, myocardial infarction,
or cardiovascular
death, in a population of human patients with peripheral artery disease,
comprising use of
rivaroxaban in an amount of 2.5 mg twice daily and acetylsalicylic acid in an
amount of 75-
100 mg daily, and wherein the hazard ratio for stroke, myocardial infarction,
or cardiovascular
death is 0.50-0.60, with a 95% confidence interval of at least 0.30-1.10.
Another embodiment of the invention is a method of reducing the risk of acute
limb
ischemia in a human patient with peripheral artery disease, comprising
administering to the
human patient rivaroxaban and Aspirin in amounts that are clinically proven
effective in
reducing the risk of acute limb ischemia in patients with peripheral artery
disease, wherein
rivaroxaban is administered in an amount of 2.5 mg twice daily and Aspirin is
administered in
an amount of 75-100 mg daily, and wherein the hazard ratio for acute limb
ischemia with the
administration of rivaroxaban and Aspirin compared to Aspirin alone is 0.45-
0.65, preferably
0.56, with a 95% confidence interval of at least 0.25-1.10, preferably 0.32-
0.99.
Another embodiment of the invention is a method of reducing the risk of
myocardial
infarction, stroke or cardiovascular death in a population of human patients
with coronary
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artery disease and/or peripheral artery disease, comprising administering to
each human
patient in the population rivaroxaban and Aspirin in amounts that are
clinically proven
effective in reducing the risk of myocardial infarction, stroke or
cardiovascular death in a
human patient with coronary artery disease and/or peripheral arterial disease,
wherein
rivaroxaban is administered in an amount of 2.5 mg twice daily and Aspirin is
administered in
an amount of 75-100 mg daily, and wherein the composite outcome of net
clinical benefit
with the administration of rivaroxaban and Aspirin compared to Aspirin alone
has a hazard
ratio of 0.70-0.90 with a 95% confidence interval of at least 0.56 to 0.96,
preferably a hazard
ratio of 0.80 with a confidence interval of 0.70 to 0.91, wherein the
composite outcome of net
clinical benefit consists of cardiovascular death, myocardial infarction,
stroke, and fatal or
symptomatic critical-organ bleeding events.
Another embodiment of the invention is a method of reducing the risk of
stroke,
myocardial infarction, or cardiovascular death, in a population of human
patients with
peripheral artery disease, comprising administering to each human patient in
the population
rivaroxaban and Aspirin in amounts that are clinically proven effective in
reducing the risk of
stroke, myocardial infarction, or cardiovascular death, in a human patient
with peripheral
arterial disease, wherein rivaroxaban is administered in an amount of 2.5 mg
twice daily and
Aspirin is administered in an amount of 75-100 mg daily, and wherein the
composite outcome
of net clinical benefit with the administration of rivaroxaban and Aspirin
compared to Aspirin
alone has a hazard ratio of 0.60-0.80 with a 95% confidence interval of at
least 0.50 to 0.99,
preferably a hazard ratio of 0.75 with a confidence interval of 0.60 to 0.94,
wherein the
composite outcome of net clinical benefit consists of cardiovascular death,
myocardial
infarction, stroke, and fatal or symptomatic critical-organ bleeding.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
FIG. lA and FIG. 1B together are Table 1, which shows the baseline
characteristics of
the COMPASS clinical study participants. The legend for FIGs. 1A and 1B is as
follows:
*Plus-minus values are means Sll. There were no significant differences among
the
three randomized groups. Participants in the rivaroxaban-plus-Aspirin group
received 2.5mg
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of rivaroxaban twice daily and 100mg of Aspirin once daily. Participants in
the rivaroxaban-
alone group received 5mg of rivaroxaban twice daily and an Aspirin-matched
placebo once
daily. Participants in the Aspirin-alone group received 100mg of Aspirin once
daily and a
rivaroxaban-matched placebo twice daily. To convert cholesterol values to
milligrams per
deciliter, divide by 0.02586. ACE denotes angiotensin-converting enzyme, ARB
angiotensin-
receptor blocker, GFR glomerular filtration rate, NSAID nonsteroidal anti-
inflammatory drug,
and PPI proton-pump inhibitor.
-F The body-mass index is the weight in kilograms divided by the square of the
height
in meters.
+ Shown are patients with a history of coronary artery disease irrespective of
whether
it met the inclusion criteria for the trial.
6 Shown are patients with a history of peripheral arterial disease
irrespective of
whether it met the inclusion criteria for the trial.
IT The GFR was calculated by means of the Chronic Kidney Disease Epidemiology
Collaboration formula. Data on GFR were missing for four patients in the
rivaroxaban-plus-
Aspirin group and four in the rivaroxaban-alone group.
// Race was reported by the patient
FIG. 2A and FIG. 2B together are Table 2, which shows the efficacy outcomes
for the
COMPASS clinical trial. The legend for FIGs. 2A and 2B is as follows:
*ALI denotes acute limb ischemia, CIID coronary heart disease, CI confidence
interval, and CV cardiovascular.
-F Only P values for the primary outcome are confirmatory.
6 There was no adjustment for the testing of these outcomes.
If One participant in the rivaroxaban-alone group had more than one type of
stroke.
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A total of 26 of the 392 participants who were reported to have atrial
fibrillation had a
stroke: 7 participants in the rivaroxaban-plus-Aspirin group, 8 participants
in the rivaroxaban-
alone group, and 11 participants in the Aspirin-alone group.
FIG. 3 is a graph showing the cumulative incidence of the primary efficacy
outcome of
cumulative risk of cardiovascular death, stroke, or myocardial infarction
between
administration of rivaroxaban plus Aspirin, rivaroxaban alone, or Aspirin
alone in the
COMPASS clinical trial.
Participants in the rivaroxaban-plus-Aspirin group received 2.5mg of
rivaroxaban
twice daily and 100mg of Aspirin once daily. Participants in the rivaroxaban-
alone group
received 5mg of rivaroxaban twice daily and an Aspirin-matched placebo once
daily.
Participants in the Aspirin-alone group received 100mg of Aspirin once daily
and a
rivaroxaban- matched placebo twice daily. The inset shows the same data on an
expanded y
axis.
FIG. 4 is a graph showing the efficacy outcome of the COMPASS clinical trial.
"HR"
is hazard ratio. Data above the bars show FIR and 95% confidence interval
versus Aspirin.
"BID" means twice daily; "CV" means cardiovascular; and "MI" means myocardial
infarction.
FIG. 5A and FIG. 5B together are Table 3, which shows the incidence of
bleeding
events and the net clinical benefit in the COMPASS clinical trial. The legend
for the figure is
as follows:
*ICH denotes intracranial hemorrhage, and ISTH International Society on
Thrombosis
and Haemostasis.
+ If a participant had more than one event of major bleeding, only the most
serious
bleeding event was counted in these analyses.
FIG. 6 is a graph showing safety data from the COMPASS clinical trial in terms
of
major bleeding and sites of major bleeding. Data above the bars show HR and
95%
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confidence interval versus Aspirin. Abbreviations are as with other figures.
"OD" means
once daily.
FIG. 7A and FIG. 7B show data and a graphic representation of the hazard ratio
for
cardiovascular death, stroke, or myocardial infarction by subgroup of
participants for
rivaroxaban plus Aspirin and Aspirin alone in the COMPASS clinical trial.
The size of each box is proportional to the number of events. Arrows indicate
that the
limits of the confidence interval are not shown. The subgroup labeled "Western
Europe" also
includes participants in Israel, Australia, and South Africa. GFR denotes
glomerular filtration
rate.
FIG. 8 is a graph showing cumulative incidence of MACE or MALE including major
amputation in the PAD cohort of the COMPASS clinical trial. Abbreviations are
as discussed
for other figures.
FIG. 9 is a graph showing individual limb-specific outcomes in the PAD cohort
of the
COMPASS clinical trial.
DETAILED DESCRIPTION OF THE INVENTION
A 2.5 mg dose twice daily of rivaroxaban administered in combination with
Aspirin
has been shown to be more effective than Aspirin alone in reducing major
adverse
cardiovascular events including myocardial infarction, stroke and
cardiovascular death in
patients with stable atherosclerotic vascular disease, including patients with
CAD and/or
PAD, with an acceptable safety profile. In patients with PAD, a 2.5 mg dose
twice daily of
rivaroxaban administered in combination with Aspirin reduced the number of
major adverse
limb events such as acute limb ischemia or amputation.
Major adverse limb events ("MALE") as used herein is defined as the
development of
acute limb ischemia or chronic limb ischemia including major amputations not
included in
acute limb ischemia or chromic limb ischemia. Major adverse cardiovascular
events are
abbreviated as MACE.
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Rivaroxaban may be prepared as described in WO 01/47919, and is commercially
available. Aspirin is also known as acetylsalicylic acid or
Dosages to be used in embodiments of the present invention include rivaroxaban
at
0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9,
2.0, 2.1, 2.2, 2.3, 2.4, 2.5,
2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.5, or 3.5 mg administered twice
daily in combination
with Aspirin. In another embodiment rivaroxaban is administered at a dosage of
1.8-3.0, 1.9-
2.9, 2.0-2.8, 2.1-2.7, 2.2-2.6, 2.3-2.5, 2.4-2.8, 2.4-2.9, 2.4-2.7, 2.4-3.0,
2.3-2.6, 2.4-2.6, about
2.5, or 2.5 mg twice daily in combination with Aspirin. Aspirin may be
administered at 30,
35, 40, 45, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65,
66, 67, 68, 69, 70, 71,
72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,
91, 92, 93, 94, 95, 96,
97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 115, 120,
125, 130, 135,
140, 145, or 150 mg once daily in combination with twice daily rivaroxaban.
Aspirin may
also be administered in the combination therapy at 30-200, 30-190, 30-180, 30-
170, 30-160,
30-150, 40-140, 50-130, 60-120, 70-150, 70-140, 70-130, 70-120, 70-110, 70-
100, 70-90, 70-
80, 75-150, 75-140, 75-130, 75-120, 75-110, 75-100, 75-90, 75-85, about 75,
75, 80-150, 80-
120, 80-100, 90-150, 90-140, 90-130, 90-120, 90-110,90-100, 100-200, 100-190,
100-180,
100-170, 100-160, 100-150, 100-140, 100-130, 100-120, 100-110, about 100, or
100 mg once
daily. In another embodiment, the twice daily rivaroxaban dosage is in
combination with
Aspirin administered twice daily, with each of the twice daily Aspirin dosages
being 20, 25,
30, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53,
54, 55, 60, 65, 70,
or 75 mg Aspirin. In one embodiment, rivaroxaban is administered at 2.5 mg
twice daily and
Aspirin is administered at 75-100 mg once daily. In certain embodiments
rivaroxaban is
administered at 2.5 mg twice daily and Aspirin is administered at 75, 81 or
100 mg once daily.
It is believed that chronic administration of Aspirin at doses between 75 mg
to 100 mg are
comparable based on the pharmacokinetic profiles, pharmacodynamic effects and
results of
clinical studies and meta-analyses of Aspirin at these dosages.
In a further embodiment rivaroxaban is administered at 0.5, 0.6, 0.7, 0.8,
0.9, 1.0, 1.1,
1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,
2.7, 2.8, 2.9, 3.0, 3.1, 3.2,
3.3, 3.5, or 3.5 mg in combination with Aspirin. In another embodiment
rivaroxaban is
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administered at a dosage of 1.8-3.0, 1.9-2.9, 2.0-2.8, 2.1-2.7, 2.2-2.6, 2.3-
2.5, 2.4-2.8, 2.4-2.9,
2.4-2.7, 2.4-3.0, 2.3-2.6, 2.4-2.6, about 2.5, or 2.5 mg in combination with
Aspirin. Aspirin
may be administered at 30, 35, 40, 45, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,
60, 61, 62, 63, 64,
65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,
84, 85, 86, 87, 88, 89,
90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106,
107, 108, 109, 110,
115, 120, 125, 130, 135, 140, 145, or 150 mg in combination with rivaroxaban.
Aspirin may
also be administered in the combination therapy at 30-200, 30-190, 30-180, 30-
170, 30-160,
30-150, 40-140, 50-130, 60-120, 70-150, 70-140, 70-130, 70-120, 70-110, 70-
100, 70-90, 70-
80, 75-150, 75-140, 75-130, 75-120, 75-110, 75-100, 75-90, 75-85, about 75,
75, 80-150, 80-
120, 80-100, 90-150, 90-140, 90-130, 90-120, 90-110, 90-100, 100-200, 100-190,
100-180,
100-170, 100-160, 100-150,100-140, 100-130, 100-120, 100-110, about 100, or
100 mg. In
one embodiment, rivaroxaban is administered at 2.5 mg and Aspirin is
administered at 75-
100 mg. In certain embodiments rivaroxaban is administered at 2.5 mg and
Aspirin is
administered at 75, 81 or 100 mg.
The combination therapy may be administered using separate dosage forms for
rivaroxaban and Aspirin, or using a combination dosage form containing both
rivaroxaban and
Aspirin. A combination dosage form further comprises a pharmaceutically
acceptable
excipient. If a combination dosage form is used, the invention includes using
a combination
dosage form for one of the daily administrations and using a dosage form
containing
rivaroxaban without Aspirin as the second dosage form in the daily regimen.
The invention
also includes using a combination dosage form containing Aspirin and
rivaroxaban for both of
the twice daily administrations. "Combinations" mean for the purposes of the
invention not
only dosage forms which comprise all the components (so-called fixed dose
combinations),
and combination packs or kits which comprise the components separate from one
another in a
package together, optionally with instructions for use according to one of the
methods of
treatment or methods of reducing the risk of a disorder or injury disclosed
herein, but also
components administered simultaneously or sequentially as long as they are
employed for the
prophylaxis and/or treatment of the same disease. The combinations of the
invention may
also be used in the manufacture of a medicament.
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The individual active ingredients of the combinations are disclosed in the
literature
and are commercially available. They can be employed in doses that, if used
alone without the
other elements of the claimed combination, are subtherapeutically effective
doses.
Formulations of rivaroxaban are known in the art and include the formulations
disclosed in US Patent 7,157,456 to Straub et al., issued January 2, 2007 and
in US Patent
9,402,851 to Benke, issued August 2, 2016. Combination dosage forms comprising
both
rivaroxaban and Aspirin can be made by following these examples for
formulations of
rivaroxaban, well-known formulations of Aspirin, and the understanding of the
person of
ordinary skill in pharmaceutical formulation.
The methods and combinations disclosed herein may be used in combination with
a
further cardiovascular medication or medications. For example, the methods and
combinations involving rivaroxaban and Aspirin disclosed herein may be used
with one or
more of the following further cardiovascular medications: (1) angiotensin-
converting enzyme
(ACE) inhibitors, such as benazepril (Lotensint), captopril (Capotet),
enalapril (Vasotec0),
fosinopril (Monoprile), lisinopril (Prinivilt, Zestri10), moexipril
(Univasct), perindopril
(Aceont), quinapril (Accupri10), ramipril (Altacce), and trandolapril
(Mavike); (2)
angiotensin II (All) receptor antagonists, such as embusartan, losartan
(Cozaar ), valsartan
(Diovan0), irbesartan (Avapro0), candesartan (Atacande), eprosartan (Teveten0)
and
telmisartan (Micardis0); (3) statins, such as atorvastatin (Lipitor0),
rosuvastatin (Crestore),
and simvastatin (Zocor and FloLipid0); (4) nicotinic acids, such as
lovastatin (Advicort),
(5) cholesterol absorption inhibitors such as ezetimibe/simvastatin
(Vytorine); and (6) beta-
adrenergic blocking agents such as acebutolol (Sectrale), atenolol
(Tenormint), betaxolol
(Kerlone0), bisoprolol/hydrochlorothiazide (Ziace), bisoprolol (Zebeta0),
metoprolol
(Lopressor0, Toprol0 XL), nadolol (Corgarde), propranolol (Inderal0), and
sotalol
(Retapacee).
All usual administration forms are suitable for administering the combinations
of the
invention. Administration preferably takes place orally, lingually,
sublingually, buccally,
rectally, topically or parenterally (i.e. avoiding the intestinal tract, i.e.
intravenous,
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intracardiac, intracutaneous, subcutaneous, transdermal, intraperitoneal or
intramuscular),
preferably orally for both rivaroxaban and Aspirin.
The present invention includes pharmaceutical preparations which, besides non-
toxic,
inert pharmaceutically suitable excipients and/or carriers, comprise
rivaroxaban, Aspirin, or
both rivaroxaban and Aspirin and processes for producing these preparations.
The abovementioned pharmaceutical preparations may, besides the combinations
of
the invention, also comprise further active pharmaceutical ingredients such as
the
cardiovascular medications discussed herein for use with the combinations and
methods of
use of the present invention.
The methods and products of the invention concern dosages that are clinically
proven
safe and effective. Adverse events that impact whether the inventive
combinations and
combination therapy are safe are adverse bleeding events that include, for
example, major
bleeding, minor bleeding, intracranial bleeding, and symptomatic bleeding into
a critical
organ. "Major bleeding" as used herein is a modification of the International
Society on
Thrombosis and Haemostasis (ISTH) criteria for major bleeding and includes
fatal bleeding,
symptomatic bleeding into a critical organ, bleeding into a surgical site
requiring reoperation,
and bleeding that led to hospitalization (including presentation to an acute
care facility
without an overnight stay). Unlike the ISTH criteria, all bleeding that led to
presentation to an
acute care facility or hospitalization is considered as major. In one
embodiment, the term
"safe" refers to a dosage determined by the US Food and Drug Administration
("US FDA") as
acceptable for administration to reduce the risk of major cardiovascular
events (cardiovascular
death, myocardial infarction, or stroke), such as a dosage shown in trials of
over 9,000 CAD
and/or PAD patients taking rivaroxaban and Aspirin as being safe that had
serious adverse
bleeding events in less than about 8.0 % or in about 7.9% or in 7.9% of
patients, as compared
to serious adverse bleeding events in about 7.0-7.5% or in 7.3% of patients
taking Aspirin
alone. In an embodiment directed to reducing the risk of acute limb ischemia
and/or MALE
in patients with PAD, the term "safe" refers to a dosage determined by the US
FDA as
acceptable for administration to reduce the risk of acute limb ischemia and/or
MALE, such as
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a dosage shown in trials of over 6,000 patients taking rivaroxaban and Aspirin
as being safe
that had serious adverse bleeding events in less than about 3.0 % or in about
3.0 % or in 3.0%
of PAD patients, as compared to serious adverse bleeding events in about 2.0-
2.5% or in 2.0%
of patients taking Aspirin alone.
"Safe" for the methods disclosed herein may also be measured by the net
clinical
benefit of the inventive method or product compared to administration of
Aspirin alone. The
net clinical benefit outcome consists of cardiovascular death, myocardial
infarction, stroke,
and fatal or critical organ bleeding.
According to the invention, the terms "effective" or "efficacy," as they
relate to terms
such as dose, dosage regimen, or treatment with an anticoagulant that is
rivaroxaban and
Aspirin refer to reducing the risk of myocardial infarction, stroke, or
cardiovascular death in
patients with CAD and/or PAD or other atherosclerotic vascular disease, such
as by reducing
the risk when compared to therapy with Aspirin alone. Preferably, the terms
"effective" and
"efficacy" refer to a dosage determined by the US FDA as acceptable for
administration to
reduce the risk of major cardiovascular events (cardiovascular death,
myocardial infarction, or
stroke) in CAD and/or PAD patients, or to reduce the risk of acute limb
ischemia or MALE
generally in PAD patients.
One measure of efficacy is the hazard ratio of the occurrence of stroke,
myocardial
infarction or cardiovascular death between the inventive method and
administration of Aspirin
alone. For example, the terms "effective" or "efficacy" for patients with CAD
and/or PAD
refers to a therapy wherein the hazard ratio in patients having CAD and/or PAD
for
myocardial infarction, stroke, or cardiovascular death with the administration
of rivaroxaban
and Aspirin compared to Aspirin alone is 0.70-0.80, 0.60-0.80, 0.50-0.90, or
0.76, with a 95%
confidence interval of at least 0.56 to 0.96 or at least 0.45 to 1.10.
Optionally the hazard ratio
for major bleeding events with the administration of rivaroxaban and Aspirin
compared to
Aspirin alone is 1.60-1.90 with a 95% confidence interval of at least 1.35 to
2.15. These
hazard ratios may be obtained from studies in a population of at least 9,000
CAD and/or PAD
patients In other embodiments, the clinical trials and the populations being
treated have more
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than 10,000, more than 15,000, or more than 20,000 patients enrolled suffering
from CAD
and/or PAD that form a population from which the hazard ratios may be
determined and that
have a sufficiently large enrollment to establish to the satisfaction of the
US FDA the safety
and efficacy of the administration of rivaroxaban in combination with Aspirin.
In another example, the terms "effective" or "efficacy" for patients with PAD
refer to
a therapy wherein the hazard ratio for patients having PAD for myocardial
infarction, stroke,
or cardiovascular death with the administration of rivaroxaban and Aspirin
compared to
Aspirin alone is 0.70-0.80, 0.60-0.80, 0.50-0.90, or 0.72 with a 95%
confidence interval of at
least 0.57 to 0.90 or at least 0.45 to 1Ø
In another embodiment concerning patients with PAD according to the invention,
an
"effective" dose, dosage regimen, or treatment with an anticoagulant that is
rivaroxaban and
Aspirin refer to reducing the risk of acute limb ischemia, such as by reducing
the risk when
compared to therapy with Aspirin alone. In this embodiment, effective therapy
refers to a
therapy wherein the hazard ratio for acute limb ischemia with the
administration of
rivaroxaban and Aspirin compared to Aspirin alone is 0.50-0.60, or 0.56 with a
95%
confidence interval of at least 0.30 to 1.00, or 0.32 to 0.99.
In certain embodiments, the hazard ratio for major bleeding events in patients
with
CAD and/or PAD with the administration of rivaroxaban and Aspirin compared to
Aspirin
alone is 1.60-1.90 with a 95% confidence interval of at least 1.35 to 2.15, or
is 1.84 with a
95% confidence interval of 1.50 to 2.26.
These hazard ratios may be obtained from studies in patient populations over a
sufficient duration that enough events (e.g., cardiovascular outcomes such as
myocardial
infarction, cardiovascular death, etc.) occur to allow for statistically
meaningful measurement
such as would be acceptable by the US FDA. Useful studies for the hazard
ratios described
herein to be measured involve a population of at least 9,000 CAD and/or PAD
patients over
more than two years. In other embodiments, the clinical trials and the
populations being
treated have more than 10,000, more than 15,000, or more than 20,000 patients
enrolled
suffering from CAD and/or PAD that form a population from which the hazard
ratios may be
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determined. For methods of treatment and reduction of risk in PAD, the study
size may be
more than 2,000, more than 3,000, more than 4,000, more than 2,400; or 2492
PAD patients
over at least two years.
In one embodiment, a treatment according to the present invention is
efficacious when
in a study of at least 9,000 patients with stable atherosclerotic disease it
is determined that the
primary endpoint of cardiovascular death, stroke, or myocardial infarction
occurs in 4.1% of
patients or less assigned to a combination therapy of rivaroxaban twice daily
and Aspirin once
daily when Aspirin alone resulted in 5.4% of the patients having a primary
endpoint. In other
embodiments, a study of at least 10,000, 15,000, or 20,000 patients is used to
show the
achievement of primary endpoints within these numerical measurements. In an
embodiment
directed to patients with PAD, a treatment according to the present invention
is efficacious
when in a study of at least 2,400 patients with PAD it is determined that the
primary endpoint
of cardiovascular death, stroke, or myocardial infarction occurs in 2.8% of
patients or less
assigned to a combination therapy of rivaroxaban twice daily and Aspirin once
daily when
Aspirin alone resulted in 3.92% of the patients having a primary endpoint. In
other
embodiments, a study of at least 2,492; 5.000; or 8,000 patients is used to
show the
achievement of primary endpoints within these numerical measurements for PAD.
In an
embodiment directed to patients with PAD, a treatment according to the present
invention is
efficacious when in a study of at least 2,400 patients with PAD it is
determined that the
endpoint of acute limb ischemia occurs in 0.42% of patients or less assigned
to a combination
therapy of rivaroxaban twice daily and Aspirin once daily when Aspirin alone
resulted in
0.75% of the patients having acute limb ischemia.
Alternatively, effective therapy is found according to the present invention
by
reducing the crude cumulative incidence of cardiovascular death, myocardial
infarction and
stroke by at least 1.3% when compared to therapy with Aspirin alone over the
same duration
of time.
Because the products and methods of the present invention involve medications
that
cause the desired reduction in the risk of myocardial infarction, stroke, or
cardiovascular death
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yet also cause undesired bleeding, the "net clinical benefit" of the therapy
is important to
consider. The "net clinical benefit" composite is a positive benefit risk
ratio that was derived
using severe bleeding events (intracranial bleeding, fatal bleeding, and
critical organ bleeding)
as a component of the composite. In clinical studies, the risk of the
composite net clinical
benefit outcome of cardiovascular death, stroke, myocardial infarction, fatal
bleeding or
symptomatic bleeding into a critical organ was lower with twice-daily 2.5 mg
rivaroxaban
combined with once daily 100 mg Aspirin (4.7%) than with Aspirin alone (100 mg
once
daily) (5.9%), hazard ratio 0.80.
In one embodiment, the invention concerns a safe and effective pharmaceutical
product for reducing the risk of myocardial infarction, stroke or
cardiovascular death in a
human patient with coronary artery disease and/or peripheral artery disease,
wherein the
pharmaceutical product comprises 2.5 mg rivaroxaban and 75, 81, or 100 mg
Aspirin. In a
further embodiment, the invention concerns a safe and effective pharmaceutical
product for
reducing the risk of myocardial infarction, stroke or cardiovascular death in
a human patient
with coronary artery disease and/or peripheral artery disease, wherein the
pharmaceutical
product comprises 2.5 mg rivaroxaban and 75-100 mg Aspirin. The pharmaceutical
product
may also contain pharmaceutically suitable excipients, such as fillers,
disintegrants, etc.
In one embodiment, the invention is directed to a method of prevention of
stroke,
myocardial infarction and cardiovascular death, and for the prevention of
acute limb ischemia
and mortality in patients with coronary artery disease (CAD) or peripheral
artery disease
(PAD) comprising administering 2.5 mg of rivaroxaban in combination with 75 mg
¨ 100 mg
of Aspirin. Rivaroxaban may be administered once or twice daily in a dose of
2.5 mg. In
another embodiment, the invention is a method for the prevention of
atherothrombotic events
in adult patients with severe coronary artery disease comprising administering
a
therapeutically effective amount of rivaroxaban and Aspirin. In another
embodiment, the
invention is to a method for reducing the risk in patients with stable
peripheral or carotid
artery disease.
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In another embodiment, the invention concerns a method of reducing the risk of
death,
myocardial infarction or stroke in patients with heart failure and also having
significant
coronary artery disease following an episode of decompensated heart failure by
administering
2.5 mg rivaroxaban in combination with other medications that are the standard
of care for
heart failure. In one embodiment of this invention, the method comprises
administering to a
patient suffering from heart failure and/or coronary artery disease 2.5 mg
rivaroxaban twice
daily, optionally also administering standard medications known to those of
ordinary skill in
the art as approved for use in heart failure and coronary artery disease, such
as without
limitation beta blockers, ACE inhibitors, angiotensin-receptor blockers
(ARBs), diuretics, etc.
In one embodiment the patients suffering from heart failure and also having
significant
coronary artery disease also have PAD.
There is also provided a method of reducing the risk of all-cause mortality
(ACM),
myocardial infarction and/or stroke in a patient with heart failure and/or
significant coronary
artery disease comprising administering 2.5 mg of rivaroxaban, and wherein
optionally the
patient is also receiving other medications that are known within the standard
of care.
Standard care may include a diuretic, renin angiotensin system (RAS)
inhibitor/vasodilator
therapy (angiotensin-converting enzyme inhibitors, angiotensin receptor
blockers or
hydralazine/nitrates), beta blocker therapy, aldosterone antagonist if
indicated, and Aspirin (or
other antiplatelet agent as appropriate). The dose of Aspirin should be 100 mg
or less per day,
unless not clinically appropriate. Dual antiplatelet therapy is allowed where
indicated.
EXAMPLES
Trial Conduct
The COMPASS trial, conducted at 602 centers in 33 countries, is a double-
blind,
double-dummy, randomized trial using a 3-by-2 partial factorial design and
involving patients
with a history of stable atherosclerotic vascular disease. In one randomized
comparison (now
completed and reported here and in Eikelboom, supra and in Anand, "Rivaroxaban
with or
without Aspirin in patients with stable peripheral or carotid artery disease:
an international,
randomized, double-blind, placebo-controlled trial," Lancet; published online
at S0140-
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6736(17)32409-1 on November 10, 2017)), rivaroxaban with or without Aspirin
was
compared with Aspirin alone.
The trial protocol was approved by the relevant health authorities (including
the US
FDA) and institutional review boards.
Eligibility
Patients were eligible if they provided written informed consent and met the
criteria
for coronary artery disease, peripheral arterial disease, or both. Patients
with coronary artery
disease who were younger than 65 years of age were also required to have
documentation of
atherosclerosis involving at least two vascular beds or to have at least two
additional risk
factors (current smoking, diabetes mellitus, an estimated glomerular
filtration rate ("GFR")
<60 ml per minute, heart failure, or nonlacunar ischemic stroke >1 month
earlier). Exclusion
criteria were a high bleeding risk; a recent stroke or previous hemorrhagic or
lacunar stroke;
severe heart failure; advanced stable kidney disease (estimated GFR <15 ml per
minute); the
use of dual antiplatelet therapy, anticoagulation, or other antithrombotic
therapy; and
noncardiovascular conditions deemed by the investigator to be associated with
a poor
prognosis.
Randomization and Follow-up
Eligible participants (except those who underwent randomization 4 to 14 days
after
coronary-artery bypass graft ("CABG") surgery) entered a run-in phase during
which they
received a rivaroxaban-matched placebo twice daily and Aspirin at a dose of
100 mg once
daily. The purpose of the run-in phase was to identify participants who were
unwilling or
unable to adhere to the trial regimen, who had adverse events, or who were
otherwise not
suitable for randomization. Patients who underwent randomization 4 to 14 days
after CABG
surgery were not required to participate in the run-in phase because
thrombotic graft occlusion
is most common during the first few weeks after surgery and we sought to
enroll such patients
promptly.
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Participants who adhered to the assigned regimen and who did not have adverse
events, as well as those enrolled 4 to 14 days after CABG surgery, were
randomly assigned in
a 1:1:1 ratio to receive rivaroxaban (2.5 mg twice daily) plus Aspirin (100 mg
once daily),
rivaroxaban (5 mg twice daily) with an Aspirin-matched placebo once daily, or
Aspirin
(100 mg once daily) with a rivaroxaban-matched placebo twice daily, stratified
according to
center and the use of proton-pump inhibitor therapy at the time of
randomization. Study
Aspirin was enteric-coated. After randomization, participants were seen at 1
and 6 months and
then at 6-month intervals.
Outcomes
The primary efficacy outcome for the randomized comparison of rivaroxaban with
or
without Aspirin versus Aspirin alone was the composite of cardiovascular
death, stroke, or
myocardial infarction. The main safety outcome was a modification of the ISTH
criteria for
major bleeding and included fatal bleeding, symptomatic bleeding into a
critical organ,
bleeding into a surgical site requiring reoperation, and bleeding that led to
hospitalization
(including presentation to an acute care facility without an overnight stay).
Unlike the ISTH
criteria, all bleeding that led to presentation to an acute care facility or
hospitalization was
considered as major.
Three secondary efficacy outcomes were specified: the composite of ischemic
stroke,
myocardial infarction, acute limb ischemia, or death from coronary heart
disease; the
composite of ischemic stroke, myocardial infarction, acute limb ischemia, or
cardiovascular
death; and death from any cause. Tertiary efficacy outcomes included
individual components
of the primary and secondary outcomes, as well as hospitalization for
cardiovascular causes,
revascularization, limb amputation, stent thrombosis, angina, heart failure,
venous
thromboembolism, resuscitated cardiac arrest, and a new diagnosis of cancer.
The net-clinical-
benefit outcome was the composite of cardiovascular death, stroke, myocardial
infarction,
fatal bleeding, or symptomatic bleeding into a critical organ.
Statistical Analysis
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The clinical study organizers projecting enrolling about 21,000 patients, but
due to
lower than expected event rates, the projected enrollment was increased to
27,400
participants. As an event-driven trial, with an expected control-group event
rate of 3.3 per 100
person-years, it was designed to continue until at least 2200 participants had
a confirmed
primary efficacy outcome, thereby providing 90% power to detect a 20% lower
risk in each of
the two comparisons of rivaroxaban versus Aspirin.
An independent data and safety monitoring board monitored the study, with
formal
stopping guidelines for efficacy and nonformal guidelines for safety. Two
formal interim
analyses of efficacy were planned, when 50% and 75% of primary efficacy events
had
occurred. A modified Haybittle¨Peto rule was used, which required a difference
of 4 standard
deviation ("SD") at the first interim analysis that was consistent over a
period of 3 months,
and a consistent difference of 3 SD at the second interim analysis.
All the outcome events in all randomly assigned patients that occurred between
randomization and the date of stopping the trial were included in the
analysis, according to the
intention-to-treat principle. An early stop of both antithrombotic treatment
groups for efficacy
had not been anticipated, and therefore a strategy for formal testing of
secondary outcomes at
the interim analysis was not prespecified.
Kaplan¨Meier estimates of the cumulative risk were used to evaluate the timing
of
event occurrences in the three antithrombotic treatment groups. Hazard ratios
and
corresponding 95% confidence intervals were obtained from stratified Cox
proportional-
hazards models. The assumptions of the Cox models were verified with plots of
log of
negative log of the survival function against the log of time. All reported P
values are two-
sided.
RESULTS
Participants
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From March 2013 through May 2016, a total of 27,395 persons who successfully
completed the run-in phase or who were enrolled 4 to 14 days after CABG
surgery were
randomly assigned to rivaroxaban plus Aspirin, rivaroxaban, or Aspirin.
Baseline characteristics are presented in Figure 1, Table 1. The mean age of
participants was 68.2 years, and 22.0% were women. Lipid-lowering agents were
used by
89.8%, and angiotensin-converting¨ enzyme inhibitors or angiotensin-receptor
blockers by
71.2%. The mean systolic blood pressure was 136 mm Hg, the mean diastolic
blood pressure
78 mm Hg, and the mean total cholesterol level 4.2 mmol per liter (162 mg per
deciliter). A
total of 90.6% of the participants had a history of coronary artery disease,
and 27.3% had a
history of peripheral arterial disease.
Early Termination, Follow-up, and Adherence
At the first formal interim analysis for efficacy (50% of planned events), the
independent data and safety monitoring board recommended early termination of
the
randomized comparison of rivaroxaban with or without Aspirin versus Aspirin
alone on
February 6, 2017, having observed a consistent difference in the primary
efficacy outcome in
favor of rivaroxaban plus Aspirin (z = ¨4.592).
The z statistic for the comparison of rivaroxaban plus Aspirin versus Aspirin
alone
was larger than the prespecified 4 SD, but the z statistic for the comparison
of rivaroxaban
alone versus Aspirin alone had not met this criterion (z= ¨2.44). Because
there was a
statistically significant effect for both comparisons, the data and safety
monitoring board
recommended stopping the rivaroxaban and Aspirin groups of the trial.
Vital status was available for 27,331 participants (99.8%) to February 6,
2017, and the
mean duration of follow-up of these participants was 23 months (maximum
duration, 47
months). At the final visit for this component of the trial, the percentage of
participants who
had permanently discontinued study treatment was 16.5% in the rivaroxaban-plus-
Aspirin
group, 17.0% in the rivaroxaban-alone group, and 15.7% in the Aspirin-alone
group.
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Primary Efficacy Outcome
A primary outcome event of cardiovascular death, stroke, or myocardial
infarction
occurred in 379 patients (4.1%) who were assigned to rivaroxaban plus Aspirin,
448 (4.9%)
who were assigned to rivaroxaban alone, and 496 (5.4%) who were assigned to
Aspirin alone
(Fig. 2, showing Table 2 and Fig. 3). For the comparison of rivaroxaban (2.5
mg twice daily)
plus Aspirin with Aspirin alone, the hazard ratio for the primary outcome was
0.76 (95%
confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126). For the comparison
of rivaroxaban
(5 mg twice daily) alone with Aspirin alone, the hazard ratio was 0.90 (95%
CI, 0.79 to 1.03;
P=0.12; z=-1.575).
Dual pathway inhibition with rivaroxaban 2.5 mg bid plus Aspirin significantly
reduced the composite of cardiovascular death, stroke, and myocardial
infarction by 24%
(p<0.001) (Fig. 3). Rivaroxaban 2.5 mg bid plus Aspirin was associated with an
18%
reduction in all-cause mortality compared with Aspirin alone (P=0.01)(Fig. 4).
Fig. 4 also
shows the efficacy outcome for each of the primary endpoints of cardiovascular
death, stroke,
or myocardial infarction. Rivaroxaban 5 mg bid was not associated with a
significant
reduction in the rate of the primary outcome compared with Aspirin alone.
Secondary Efficacy Outcomes
The secondary composite outcome of ischemic stroke, myocardial infarction,
acute
limb ischemia, or death from coronary heart disease occurred in fewer patients
in the
rivaroxaban-plus-Aspirin group than in the Aspirin-alone group (329 patients
[3.6%] vs. 450
patients [4.9%]; hazard ratio, 0.72; 95% CI, 0.63 to 0.83; P<0.001) (Fig. 2,
Table 2). The
secondary outcome of ischemic stroke, myocardial infarction, acute limb
ischemia, or
cardiovascular death also occurred in fewer patients in the rivaroxaban-plus-
Aspirin group
than in the Aspirin-alone group (389 patients [4.3%] vs. 516 patients [5.7%];
hazard ratio,
0.74; 95% Cl, 0.65 to 0.85; P<0.001). There were 313 deaths (3.4%) in the
rivaroxaban-plus-
Aspirin group as compared with 378 (4.1%) in the Aspirin-alone group (hazard
ratio, 0.82;
95% CI, 0.71 to 0.96; P = 0.01). The threshold P value using the Hochberg
procedure for each
of the above comparisons was 0.0025. For the regimen of rivaroxaban alone as
compared with
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Aspirin alone, because no significant effect was seen for the primary
composite outcome,
foinial testing of the secondary outcomes was not performed.
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Bleeding and Other Adverse Events
Major bleeding events occurred in more patients in the rivaroxaban-plus-
Aspirin group
than in the Aspirin-alone group (288 patients [3.1%] vs. 170 patients [1.9%1;
hazard ratio,
1.70; 95% CI, 1.40 to 2.05; P<0.001) (Fig. 5, Table 3), mainly owing to a
difference in
bleeding that led to presentation to an acute care facility or
hospitalization. Most of the excess
major bleeding was into the gastrointestinal tract, with no significant
between-group
difference in the rate of fatal bleeding, intracranial bleeding, or
symptomatic bleeding into a
critical organ. Fig.6 is a graph showing for each patient group the safety
outcomes in major
bleeding and sites of major bleeding. The rate of major bleeding as defined by
the ISTH
criteria (the composite of fatal bleeding, bleeding into a critical organ,
bleeding requiring 2:2
units of transfusion within 48 hours, and bleeding associated with a decrease
in the
hemoglobin level of >2 g per deciliter) was significantly greater with
rivaroxaban plus Aspirin
than with Aspirin alone.
Major bleeding events occurred in more patients in the rivaroxaban-alone group
than
.. in the Aspirin-alone group (255 patients [2.8%] vs. 170 patients [1.9%];
hazard ratio, 1.51;
95% CI, 1.25 to 1.84; P<0.001) (Figure 5, Table 3). The excess major bleeding
included
symptomatic bleeding into a critical organ and bleeding that led to
hospitalization.
Serious adverse events were reported in 721 patients (7.9%) assigned to
rivaroxaban
plus Aspirin, 702 (7.7%) assigned to rivaroxaban alone, and 662 (7.3%)
assigned to Aspirin
alone.
Net Clinical Benefit
The risk of the composite net-clinical-benefit outcome of cardiovascular
death, stroke,
myocardial infarction, fatal bleeding, or symptomatic bleeding into a critical
organ was lower
with rivaroxaban plus Aspirin than with Aspirin alone (431 patients [4.7%] vs.
534 patients
[5.9%]; hazard ratio, 0.80; 95% CI, 0.70 to 0.91; P<0.001) (Fig. 5, Table 3).
The risk of the
net-clinical-benefit outcome was not significantly lower with rivaroxaban
alone than with
Aspirin alone.
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Subgroup Analyses
The effects of rivaroxaban plus Aspirin as compared with Aspirin alone on the
primary
outcome (Fig. 7) and on major bleeding were consistent among subgroups that
were defined
according to age, sex, geographic region, race or ethnic group, body weight,
renal function,
and history of cardiovascular risk factors (tobacco use, hypertension,
diabetes, or
dyslipidemia). Results in participants who met the eligibility criteria for
coronary artery
disease and in those who met the eligibility criteria for peripheral arterial
disease were also
consistent.
PAD Patients
In the PAD cohort of the COMPASS trial, compared with Aspirin alone, dual
pathway
inhibition with rivaroxaban 2.5 mg bid plus Aspirin significantly reduced the
risk of
cardiovascular death, myocardial infarction, or stroke by 28% (hazard ratio
=0.54; 95%
confidence interval 0.35-0.84; p=0.0054). MALE, including major amputations
not included
in acute limb ischemia and chromic limb ischemia, was reduced by 46% (hazard
ratio =0.54;
95% confidence interval 0.35-0.82; p=0.0037). MACE, MALE or major amputation
was
reduced by 31% (Fig. 8). In this PAD cohort, other limb-specific outcomes,
including a
reduction in the risk of major amputation was reduced by 70% (Fig. 9).
DISCUSSION
Among patients with stable atherosclerotic vascular disease, a high proportion
of
.. whom were receiving proven secondary prevention therapies, the rate of the
primary outcome
(a composite of cardiovascular death, stroke, or myocardial infarction) was
lower by 24%
with rivaroxaban (2.5 mg twice daily) plus Aspirin than with Aspirin alone
(4.1% vs. 5.4%),
but the rate of major bleeding was higher by 70% (3.1% vs. 1.9%). The rate of
the net-
clinical-benefit outcome was lower by 20% with rivaroxaban plus Aspirin than
with Aspirin
alone (4.7% vs. 5.9%). The comparison of rivaroxaban (5 mg twice daily) alone
with Aspirin
alone did not show a significant difference in the primary outcome or the net-
clinical-benefit
outcome, but the rate of major bleeding was higher with rivaroxaban alone.
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The definition of major bleeding in the COMPASS trial was based on the ISTH
definition, which includes fatal bleeding, symptomatic bleeding into a
critical area or organ,
bleeding causing a decrease in the hemoglobin level of 2 g or more per
deciliter, or bleeding
that led to transfusion of 2 or more units of whole blood or red cells.
However, the definition
.. used in the COMPASS trial, which had been adopted in response to a request
from regulators,
differed from the ISTH definition in that it did not take into account whether
bleeding was
associated with a decrease in the hemoglobin level or with blood transfusion,
and it included
any bleeding that led to hospitalization with or without an overnight stay,
thus including
events that would not be considered major bleeding in other trials. Although
there was also a
significant increase in the rate of major bleeding with rivaroxaban with the
use of the ISTH
scale, there were approximately one third fewer major bleeding events with
this definition
than with the use of the modified ISTH definition. Our definition of net
clinical benefit
balanced the lower risk of cardiovascular death, stroke, or myocardial
infarction against the
most serious bleeding events and showed a significant benefit of combination
therapy.
There are a few limitations of the trial that should be considered. First, we
did not
specifically study patients with a previous stroke. However, of those
enrolled, 1032 also had a
history of stroke, and the benefits of the combination of rivaroxaban and
Aspirin in preventing
cardiovascular death, stroke, or myocardial infarction were consistent in
these patients.
Furthermore, the combination of rivaroxaban and Aspirin resulted in a lower
rate of ischemic
.. stroke than Aspirin alone. Second, although the majority of patients were
receiving proven
secondary prevention therapies, and the blood pressure and total cholesterol
levels were
serially recorded during the study, we did not specifically record statin use
or low-density
lipoprotein cholesterol levels at baseline, and the trial protocol did not
specifically emphasize
aggressive use of secondary prevention therapies to lower blood pressure and
cholesterol
.. levels. However, the results were consistent in patients with baseline
blood pressure below or
above the mean and in those with baseline cholesterol levels below or above
the median,
supporting the conclusion that the benefits of combination therapy are
additive to those of
other proven secondary preventive therapies. Third, trials that are stopped
early for efficacy
may overestimate the treatment effect. However, before the time of stopping,
the data and
safety monitoring board had observed a progressive increase in benefit of the
combination of
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rivaroxaban and Aspirin for more than I year. Furthermore, the data reported
here include
additional events that occurred before the cutoff but were not reported at the
time of stopping
the study and exclude some events that were refuted during adjudication. It is
noteworthy that
the results based on events reported by the sites and after adjudication are
nearly identical.
In conclusion, in patients with stable atherosclerotic vascular disease, we
compared
three antiplatelet regimens: rivaroxaban (2.5 mg twice daily) plus Aspirin
(100 mg once
daily), rivaroxaban (5 mg twice daily), and Aspirin (100 mg once daily). The
risk of major
adverse cardiovascular events was significantly lower with the combination of
rivaroxaban
plus Aspirin than with Aspirin alone, and the risk of major bleeding was
significantly higher.
Rivaroxaban alone did not result in a significantly lower risk of major
adverse cardiovascular
events than Aspirin alone and resulted in a significantly higher risk of major
bleeding.
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