Badimón, Juan J.

Cabrales, Jaime R.

del Portillo, Hernando

Echeverri, Darío

Revista Colombiana de Cardiología

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The role of the new oral anticoagulants in the treatment of coronary disease 

Hernando del Portillo

Juan J. Badimón

Jaime R. Cabrales

Darío Echeverri

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The role of the new oral anticoagulants in the treatment of coronary disease

Rev Colomb Cardiol. 2016;23(6):e13--e15
www.elsevier.es/revcolcar
Revista Colombiana de
Cardiología
EDITORIAL
The  role of the  new  oral  anticoagulants  in the
treatment of  coronary  disease
Papel  de  los  nuevos  anticoagulantes  orales  en  el  tratamiento  de  la
enfermedad  coronaria
Hernando del Portilloa, Juan J. Badimónb, Jaime R. Cabralesa, Darío Echeverri a,∗
a Department  of  Hemodynamics  and  Cardiovascular  Interventionism,  Fundación  CardioInfantil  --  Instituto  de  Cardiología  --
Department of  Medicine,  Universidad  del  Rosario,  Bogotá,  Colombia
b Atherothrombosis  Research  Unit,  The  Zena  and  Michael  A.  Wiener  Cardiovascular  Institute,  Icahn  School  of  Medicine  at  Mount
Sinai, New  York,  United  States
Received  30  September  2016;  accepted  6  October  2016n
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cAvailable  online  17  November  2016
The  new  oral  anticoagulants  are  here  to  stay  in  the  preven-
tion  of  ischemic  cerebrovascular  accidents  in  patients  with
nonvalvular  atrial  ﬁbrillation.  Several  clinical  studies  have
established  their  efﬁcacy  and  safety1--3.  However,  the  role
these  new  oral  anticoagulants  might  have  in  other  patholo-
gies,  such  as  coronary  disease,  has  not  been  well  studied
and  there  are  still  several  important  questions  which  have
not  been  answered.  One  of  these  questions  is  the  role  the
new  oral  anticoagulants  could  have  in  the  secondary  pre-
vention  of  coronary  disease,  given  that  in  spite  of  optimal
medical  treatment  and  dual  anti-platelet  therapy,  the  risk
of  reinfarction  has  only  decreased  30%.  This  phenomenon
may  possibly  be  explained  by  other  related  factors,  such
as  lipid  metabolism,  the  inﬂammatory  state,  and  the  pro-
thrombotic  state,  in  which  the  activated  X  factor  (Xa),  plays
a  fundamental  role  by  triggering  the  conversion  of  inactive
prothrombin  into  thrombin,  which  is  the  strongest  agonist
for  platelet  aggregation4,5.  The  second  question  is  related  to
those  patients  with  nonvalvular  atrial  ﬁbrillation  and  coro-
nary  disease  who  require  stent  implantation,  in  whom  theDOI of original article:
http://dx.doi.org/10.1016/j.rccar.2016.10.032
∗ Corresponding author.
E-mail address: decheverri@cardioinfantil.org (D. Echeverri).
e
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b
d
http://dx.doi.org/10.1016/j.rccar.2016.10.033
0120-5633/© 2016 Published by Elsevier Espan˜a, S.L.U. on behalf of Socie
open access article under the CC BY-NC-ND license (http://creativecommew  oral  anticoagulants  could  be  an  alternative  in  combina-
ion  with  antiplatelet  medications.
Currently  in  Colombia,  there  are  two  types  of  new
ral  anticoagulants  available:  direct  inhibitors  of  activated
actor  X  (rivaroxaban  and  apixaban)  and  direct  thrombin
nhibitors  (dabigatran),  which  may  be  new  therapeutic  tools
o  answer  these  questions.  Factor  Xa  inhibitors  indirectly
uppress  the  synthesis  of  thrombin  by  inhibiting  this  factor,
hile  the  direct  antithrombin  agents  inhibit  the  activity  of
hrombin.
irst scenario: secondary prevention in
oronary disease
oronary  thrombosis  depends  on  platelet  activity  and  its
ntegration  with  the  coagulation  pathways,  where  the  vita-
in  K-dependent  factors  (II,VII,  IX,  and  X)  play  a  very
mportant  role6;  this  is  why  vitamin  K  antagonists  (VKA)
ere  studied  a  few  years  ago  for  secondary  prevention
f  cardiovascular  events,  signiﬁcantly  reducing  episodes  of
erebrovascular  accidents  and  myocardial  infarction.  The
normous  beneﬁts  of  this  class  of  agents  had  an  enor-
ous  disadvantage,  which  was  the  signiﬁcant  increase  in
leeding7.  This  increase  is  probably  associated  with  the
ifﬁculty  in  achieving  and  maintaining  INR  levels  within
dad Colombiana de Cardiolog´ıa y Cirug´ıa Cardiovascular. This is an
ons.org/licenses/by-nc-nd/4.0/).
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R14  
herapeutic  range,  due  to  multiple  interactions  with  other
edications  and  even  with  foods,  as  well  as  a  slow  onset  of
ction.  All  these  conditioning  factors  are  part  of  the  reason
hy  VKA  are  not  currently  considered  ﬁrst  choice  medica-
ions  for  the  prevention  and  treatment  of  cardiovascular
vents.
Recent  studies  have  evaluated  the  therapeutic  potential
f  the  new  oral  anticoagulants  for  secondary  prevention  in
atients  with  coronary  disease.  The  most  important  studies
re  APPRAISE-2  with  apixaban8,  and  the  ATLAS-ACS  2  TIMI  51
ith  rivaroxaban9,  whose  primary  objective  was  to  decrease
ardiovascular  death,  myocardial  infarction,  and  CVA  in
atients  with  known  coronary  disease.  Unfortunately,  the
esults  were  not  very  encouraging.  APPRAISE-2  was  prema-
urely  terminated  due  to  excessive  bleeding.  The  ATLAS-ACS
 TIMI  51  study  was  positive,  but  the  results  are  hard  to
xplain  from  a  pharmacological  point  of  view,  since  the  low
oses  of  rivaroxaban  at  2.5  mg  every  12  hours  decreased  car-
iovascular  mortality,  but  not  myocardial  infarction  (which
s  the  principal  cause  of  cardiovascular  death);  while  the
 mg  dose  every  12  hours  reduced  the  rate  of  myocardial
nfarction  but  not  cardiovascular  mortality.  In  addition,
oth  doses  showed  increased  bleeding  compared  with  the
eference  control  group.
However,  the  idea  that  stands  out  to  us,  and  which  we
onsider  important  to  highlight,  is  in  the  ﬁeld  of  secondary
revention,  since  the  beneﬁt  was  mainly  conferred  by
he  results  attained  after  the  ﬁrst  year  of  treatment,  the
oint  at  which  most  patients  discontinue  dual  antiplatelet
herapy.  This  is  why  we  ask  ourselves,  ¨Will  rivaroxaban
e  the  next  medication  of  choice  for  secondary  prevention
n  coronary  disease?  In  an  effort  to  answer  this  question,
he  GEMINI-ACS-1  phase  II  study10 is  currently  underway,
hich  will  use  rivaroxaban  doses  of  2.5  mg  every  12  hours
n  place  of  acetylsalicylic  acid  combined  with  clopidogrel
nd  ticagrelor,  seeking  a  double  mechanism  of  action,  and
hose  principle  objective  will  be  to  evaluate  safety  in
erms  of  bleeding,  measured  using  the  TIMI  scale.
econd scenario: Triple therapy with new oral
nticoagulants
ith  the  changes  in  the  population  pyramid  which  entail  an
ncreased  patient  age,  as  well  as  the  increased  incidence  of
trial  ﬁbrillation  and  clear  beneﬁt  of  anticoagulation  with
ew  oral  anticoagulants  in  patients  with  atrial  ﬁbrillation,
t  is  increasingly  more  common  for  patients  to  require  dual
ntiplatelet  therapy  and  anticoagulation.  With  regard  to
riple  therapy  in  patients  with  atrial  ﬁbrillation  and  coro-
ary  disease  plus  percutaneous  coronary  intervention  (PCI),
here  are  currently  several  ongoing  studies  using  different
ypes  and  doses  of  new  oral  anticoagulants,  such  as  RE-
UAL  PCI  with  dabigatran,  PIONEER-atrial  ﬁbrillation  with
ivaroxaban,  and  AUGUSTUS  with  apixaban11,  which  will
valuate  the  combination  of  these  new  oral  anticoagulants
ith  the  various  P2Y12 receptor  inhibitors.  These  studies  are
uite  logical  if  three  aspects  are  considered:  1)  the  greatest
eneﬁt  of  new  oral  anticoagulants  versus  VKA  is  a  lower  risk
f  bleeding;  2)  some  new  oral  anticoagulants  have  already
een  studied  for  secondary  prevention;  and  3)  the  new  oralH.  del  Portillo  et  al.
nticoagulants  already  have  antidotes,  some  in  phase  III  of
esearch.
ew and possible scenarios of new oral
nticoagulants in coronary disease
n  cases  of  ischemic  heart  failure  and  a  reduced  ejec-
ion  fraction,  a  phase  three  study,  COMMANDER-HF12,  is
n  progress,  which  is  based  on  the  theory  of  thrombin  as
he  critical  element  for  worsening  heart  failure.  Conse-
uently,  rivaroxaban  2.5  mg  every  12  hours  plus  dual  or  single
ntiplatelet  therapy  will  evaluate  the  outcome  consisting
f  mortality  due  to  any  cause,  myocardial  infarction  and
erebrovascular  accident.  In  this  same  context,  but  in  the
resence  of  left  ventricular  thrombi,  cases  have  already
een  reported  using  new  oral  anticoagulants  with  complete
esolution  of  the  thrombus  during  echocardiographic  follow-
p13.
Finally,  in  coronary  ectasia,  slow  coronary  ﬂow,  endothe-
ial  lesions  and  a  pro-inﬂammatory  state  have  been  shown,
hich  create  a  hypercoagulability  environment14.  Thus,  as
hey  fulﬁll  the  still  accepted  characteristics  of  Virchows´
riad,  these  patients  would  have  a  high  predisposition
or  thrombus  formation  and  the  recurrence  of  myocardial
schemic  events.  In  this  coronary  ectasia  with  slow  ﬂow  and
oronary  thrombosis,  different  treatment  strategies  have
een  used,  such  as  manual  thrombectomy  plus  anticoagula-
ion,  intracoronary  thrombolytics,  acetylsalicylic  acid  plus
arfarin,  glycoprotein  IIb/IIIa inhibitors,  and  drug  eluting
tents,  yielding  controversial  results15.  In  light  of  this,  a  dose
f  rivaroxaban  of  2.5  mg  every  12  hours  could  be  an  inter-
sting  and  viable  pharmacological  option  for  this  group  of
atients,  since  there  is  as  yet  no  known  speciﬁc  treatment
or  the  management  of  this  pathology.  The  use  of  new  oral
nticoagulants  in  this  context  could  be  a  new  ﬁeld  to  explore
n  clinical  research.
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The role of the new oral anticoagulants in the treatment of coronary disease

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