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www.expert-reviews.com ISSN 1477-9072© 2011 Expert Reviews Ltd
THEMED ARTICLE y Surgical Approaches
10.1586/ERC.11.51
In an attempt to prevent cardiopulmonary bypass (CPB)-related morbidity and end-organ dysfunc-tion during surgical myocardial revascularization, off-pump coronary artery bypass (OPCAB) sur-gery, a revascularization technique that does not require CPB, has seen a resurgence in the last decade or so. OPCAB surgery, first introduced in the late 1960s [1], has recently become more pop-ular. Proponents of OPCAB surgery argue that all surgical myocardial revascularizations should be performed without the use of CPB. However, skepticism regarding the technical difficulty of OPCAB surgery and concerns that incomplete-ness of revascularization with this strategy com-promises patient outcomes has prevented OPCAB surgery from being universally adopted [2]. As a result, numerous studies have been performed in an effort to address these issues.
Evidence in the form of randomized con-trolled trials (RCTs) [3–6], meta-analyses [7–12], systematic reviews [13–15] and nonrandomized observational studies [16,17] shows that com-pared with conventional surgical myocardial
revascularization on CPB, OPCAB surgery is associated with similar completeness of revascu-larization, similar early outcomes, shorter length of hospital stay, reduced transfusion require-ments, reduced pulmonary morbidity and fewer postoperative neurologic events.
Despite abundant evidence validating the safety and efficacy of OPCAB surgery, one area of concern, and even greater uncertainty, sur-rounds the issue of the existence of a hyperco-agulable state after OPCAB surgery [18] that can potentially endanger the patency of coronary anastomoses. To discuss the controversial issue of the presence of the hypercoagulable state after OPCAB surgery and its impact on graft pat-ency, we undertook a comprehensive search of published scientific literature to retrieve the best available evidence [19].
Search methodologyThe MEDLINE database was searched from the date of its inception to the first week of December 2010 using Medical Subject Headings (MeSH)
Shahzad G Raja†1 and Shamim Akhtar2
1Department of Cardiac Surgery, Harefield Hospital, Hill End Road, Harefield, London, UB9 6JH, UK 2Department of Haematology, Abbottabad International Medical College, Abbottabad, Pakistan †Author for correspondence:Tel.: +44 189 582 8550 Fax: +44 189 582 8992 [email protected]
During the past decade, there has been a dramatic resurgence in the adoption of off-pump technology in coronary artery bypass surgery. This has inspired remarkable advances in the techniques of localized tissue stabilization and a greater understanding of the physiology of beating-heart mobilization and exposure. An avalanche of reports in the literature has demonstrated the early safety and efficacy of the procedure. However, despite abundant evidence validating the safety and efficacy of off-pump coronary artery bypass surgery, considerable controversy still persists regarding the long-term outcomes of this approach to myocardial revascularization. One area of concern, and even greater uncertainty, surrounds the issue of the existence of a hypercoagulable state after off-pump coronary artery bypass surgery. This article evaluates the current best evidence available from randomized controlled trials to assess the impact of off-pump coronary artery bypass surgery on coagulation, fibrinolysis and platelet activation, discusses the issue of hypercoagulability with emphasis on the mechanisms responsible for this actual or potential hypercoagulability, and explores the implications of this issue for clinical practice.
KEywoRDs: coagulation • fibrinolysis • hemostasis • off-pump coronary artery bypass • platelet activation
Hypercoagulable state after off-pump coronary artery bypass grafting: evidence, mechanisms and implicationsExpert Rev. Cardiovasc. Ther. 9(5), 599–608 (2011)
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Expert Rev. Cardiovasc. Ther. 9(5), (2011)600
Review
search terms ‘off-pump coronary artery bypass’, ‘hemostasis’, ‘coagulation’, ‘fibrinolysis’ and ‘platelet activation’. The search was performed in stages to achieve the search strategy with a high sen-sitivity (meaning that it has the highest likelihood of retrieving all relevant papers). Similar search terms were combined using the Boolean operator ‘OR’ to find all abstracts that contained informa-tion about a particular search term. These individual terms were then combined using the Boolean operator ‘AND’ to find papers that contained information on all the search terms. This is a well-recognized method for performing sensitive searches and has been described in detail in the British Medical Journal [20].
The Excerpta Medica Database (EMBASE), Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Science Citation Index, Current Contents, NHS Economic Evaluation Database, and International Network of Agencies for Health Technology Assessment databases were also searched from the
date of their inception to the first week of December 2010. In addition, tangential electronic exploration of related articles and hand searches of bibliographies, scientific meeting abstracts and related journals were performed.
Inclusion criteriaAll English and non-English articles reporting RCTs specifically comparing the impact of OPCAB surgery and on-pump coro-nary artery bypass grafting (CABG) on hemostasis, coagulation, fibrinolysis and platelet activation were included in this systematic review. The authors of this manuscript chose to include RCTs only as they have been allotted the highest level of evidence [21].
Data extraction & validation of the studiesThe papers found by the search strategy were then appraised. The appraisal of each paper was performed in a structured format, using critical appraisal checklists. These are widely available in several formats and aid in assessing the paper for methodologic and analytical soundness and help to uncover any significant methodologic flaws [101]. The following information was extracted from each study: first author, year of publication, study type, study population characteristics, number of patients and key outcomes. Finally, a conclusion was formulated based on the validity of the studies identified, taking into consid-eration the source and the strength of the evidence by using the grading system proposed by the Centre for Evidence Based Medicine (Tables 1 & 2) [102].
ResultsA total of 1345 citations were screened, and 11 manuscripts met the inclusion criteria [22–32] (Figure 1). All of these were RCTs (Table 3). The majority of the studies [22,24–27,30–32] showed that on-pump CABG caused earlier and more significant generation of thrombin; however, OPCAB surgery caused a late and sustained generation of thrombin. On-pump CABG caused intraopera-tive activation of fibrinolysis and fibrin degradation; however, at 24 h these parameters were equally elevated in both groups. More importantly, an early postoperative decrease in platelet count and increase in platelet activation occurs to a much lesser extent and does not alter bleeding time or ADP-induced platelet aggregation in patients undergoing OPCAB surgery. This lack of significant effects on platelets might in part account for the potential decreased risk in bleeding and for the preserved hemos-tasis observed in patients undergoing OPCAB surgery compared with those undergoing on-pump CABG.
Interestingly, the RCT by Paulitsch et al. [23], contrary to other RCTs, concluded that on-pump CABG was associated with bio-chemical evidence of a prothrombotic state early after surgery but no greater incidence of thrombotic events was observed. They assigned patients prospectively and randomly to either on pump (n = 41) or off pump (n = 51). The concentrations of C-reactive protein, fibrinogen, d-dimer and plasminogen activa-tor inhibitor type-1 in blood were quantified before and after (1 and 24 h) surgery. Clinical events were assessed during initial hospitalization and at the end of 1 year. The results of this RCT
Table 1. Levels of evidence.
Level Therapy/prevention, etiology/harm
1a SR (with homogeneity†) of RCTs
1b Individual RCT (with narrow confidence interval‡)
1c All or none§
2a SR (with homogeneity†) of cohort studies
2b Individual cohort study (including low-quality RCTs; e.g., <80% follow-up)
3a SR (with homogeneity†) of case–control studies
3b Individual case–control study
4 Case series (and poor-quality cohort and case–control studies¶)
5 Expert opinion without explicit critical appraisal, or based on physiology bench research or ‘first principles’
Users can add a minus-sign ‘-’ to denote the level of evidence that fails to provide a conclusive answer because of:• EITHER a single result with a wide confidence interval;• OR a SR with troublesome heterogeneity.
Such evidence is inconclusive, and therefore can only generate grade D recommendations.†Homogeneity means a SR that is free of worrisome variations (heterogeneity) in the directions and degrees of results between individual studies. Not all SRs with statistically significant heterogeneity need be worrisome, and not all worrisome heterogeneity need be statistically significant. As noted above, studies displaying worrisome heterogeneity should be tagged with a ‘-’ at the end of their designated level.‡See note above for advice on how to understand, rate and use trials or other studies with wide confidence intervals.§Met when all patients died before the treatment became available, but some now survive on it; or when some patients died before the treatment became available, but none now die on it.¶Poor-quality cohort study means one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded) objective way in both exposed and nonexposed individuals and/or failed to identify or appropriately control known confounders and/or failed to carry out a sufficiently long and complete follow-up of patients. Poor-quality case–control study means one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded) objective way in both cases and controls and/or failed to identify or appropriately control known confounders. RCT: Randomized controlled trial; SR: Systematic review.Data taken from [102].
Raja & Akhtar
www.expert-reviews.com 601
Review
showed that the concentrations of plas-minogen activator inhibitor type-1 and d-dimer were greater compared with pre-operative values 1 and 24 h after surgery in both groups, but their concentrations increased to a greater extent 24 h after sur-gery in the on-pump group (p < 0.01). The concentration of C-reactive protein did not change appreciably immediately after surgery in either group but increased in a parallel manner 24 h after either on-pump or off-pump surgery (p < 0.01). Bypass surgery in the on-pump group was associated with greater blood loss during surgery and more bleeding after surgery (p < 0.01). The incidence of all other complications was similar in the two groups. According to the authors the prothrombotic state might be a consequence of extracorporeal bypass, compensation in response to more bleeding, or both in patients undergoing on-pump surgery.
It is important to stress that all of the RCTs comparing the impact of OPCAB surgery and on-pump CABG on the acti-vation of the coagulation system have sev-eral limitations. The number of patients is rather small, so these should be considered more as pilot investigations to direct the most appropriate analyses of coagulation variables in a larger cohort. Because the small sample size precludes excluding Type II error, small differences between groups at certain time points could have been missed. In addition, the number of sampling peri-ods is limited, so only data from these pre-defined sampling periods can be supplied; therefore, hemostatic abnormalities at other time points after CABG could have been missed. Second, a number of additional fac-tors associated with the on-pump procedure that could have influenced the results varied between the RCTs. These include:
• Use of dexamethasone (to mitigate the systemic inflammatory response);
• Use of moderate hypothermia;
• Use of cardioplegia to arrest the heart;
• Use of different anticoagulation strate-gies (target activated coagulation time >450 vs 250 s).
Furthermore, several trials used a fixed protamine dosage for heparin reversal. Because activated coagulation time may be influenced by other factors, such as hypothermia and hemodilution, it may not
accurately reflect the extent of anticoagulation by heparin [33]. This could have led to relative protamine overdose and therefore might have influenced the results in the immediate postoperative period [33].
Table 2. Grades of recommendation.
A Consistent level 1 studies
B Consistent level 2 or 3 studies or extrapolations from level 1 studies
C Level 4 studies or extrapolations from level 2 or 3 studies
D Level 5 evidence or troublingly inconsistent or inconclusive studies of any level
Extrapolations are where data are used in a situation that has potentially clinically important differences than the original study situation. Data taken from [102].
1345 abstracts screened
Potentially relevant studies identified and retrieved† (n = 55)
Studies excluded (n = 43)• Comparing more than two techniques, n = 12• Nonrandomized design, n = 22• Reporting nonrelevant outcomes, n = 7• No relevant outcomes reported, n = 1• No extractable data reported, n = 1
Potentially appropriate studiesreporting outcome of interest‡ (n = 12)
Studies excluded (n = 1)• Repeated data, n = 1
Studies comparing specifically impact of OPCAB and on-pump CABG on outcome of interest‡ (n = 11)
Figure 1. Identification of eligible studies.†Randomized controlled trials.‡Coagulation, hemostasis, fibrinolysis or platelet activation.CABG: Coronary artery bypass grafting; OPCAB: Off-pump coronary artery bypass.
Hypercoagulable state after off-pump coronary artery bypass grafting
Expert Rev. Cardiovasc. Ther. 9(5), (2011)602
ReviewTa
ble
3. I
mp
act
of
off
-pu
mp
co
ron
ary
arte
ry b
ypas
s su
rger
y o
n c
oag
ula
tio
n, fi
bri
no
lysi
s an
d p
late
let
acti
vati
on
.
Stu
dy
(yea
r)St
ud
y ty
pe
(lev
el o
f ev
iden
ce)
Pati
ents
(n
)O
utc
om
esK
ey r
esu
ltH
yper
coag
uabl
e st
ate
Ref
.
OPC
AB
CA
BG
OPC
AB
CA
BG
Val
lely
et
al.
(20
09)
RCT
(leve
l 1b)
1010
Tiss
ue f
acto
r pa
thw
ay-f
acto
r V
IIa v
WF
antig
en p
roth
rom
bin
frag
men
ts F
I and
II, d
-dim
er, p
late
let
coun
ts a
nd s
olub
le
P-se
lect
in q
uant
ified
up
to 2
4 h
post
oper
ativ
ely
Late
thr
ombi
n ge
nera
tion,
red
uced
fib
rinol
ysis
and
inta
ct f
unct
ioni
ng p
late
lets
af
ter
OPC
AB
Yes
No
[22]
Paul
itsc
h et
al.
(20
09)
RCT
(leve
l 1b)
5141
CRP
, fibr
inog
en, d
-dim
er a
nd p
lasm
inog
en a
ctiv
ator
inhi
bito
r ty
pe-1
qua
ntifi
ed b
efor
e (1
h) a
nd a
fter
(24
h) s
urge
ry C
linic
al
even
ts a
sses
sed
durin
g in
itial
hos
pita
lizat
ion
and
afte
r 1
year
Sign
ifica
ntly
gre
ater
incr
ease
in p
lasm
inog
en
activ
ator
inhi
bito
r ty
pe-1
and
d-d
imer
co
ncen
trat
ions
aft
er C
ABG
(p <
0.0
1).
No
grea
ter
inci
denc
e of
thr
ombo
tic e
vent
s
No
Yes
[23]
Bedn
ar
et a
l. (2
00
8)
RCT
(leve
l 1b)
40
40
Plat
elet
act
ivit
y as
sess
ed b
y P-
sele
ctin
exp
ress
ion.
Asp
irin
effic
acy
asse
ssed
by
AA
-indu
ced
plat
elet
agg
rega
tion
befo
re o
pera
tion,
imm
edia
tely
aft
er s
urge
ry, a
nd o
n da
ys 1
, 2,
5 a
nd 3
0
Mar
kedl
y in
crea
sed
P-se
lect
in e
xpre
ssio
n in
O
PCA
B gr
oup
on d
ay 2
and
5.
Sim
ilar
P-se
lect
in e
xpre
ssio
n at
day
30.
AA
-indu
ced
plat
elet
agg
rega
tion
incr
ease
d in
OPC
AB
grou
p on
day
2
Yes
No
[24]
Jare
s et
al.
(20
07)
RCT
(leve
l 1b)
1010
roTE
G re
sults
obt
aine
d pr
eope
ratio
n, a
t 15
min
aft
er s
tern
otom
y co
mpl
etio
n of
ana
stom
oses
and
at
the
the
end
of s
urge
ry.
d-d
imer
leve
ls b
efor
e op
erat
ion,
at
end
of s
urge
ry a
nd 2
4 h
late
r
Slig
htly
gre
ater
act
ivat
ion
of fi
brin
olys
is
afte
r C
ABG
Yes
No
[25]
Ballo
tta
et a
l. (2
007
)
RCT
(leve
l 1b)
3030
Plat
elet
cou
nt a
nd f
unct
ion
asse
ssed
2 h
bef
ore
and
afte
r su
rger
ySi
gnifi
cant
dec
reas
e in
pla
tele
t co
unt
and
incr
ease
in p
late
let
activ
atio
n af
ter
CA
BGYe
sN
o[2
6]
Papa
rella
et
al.
(20
06
)
RCT
(leve
l 1b)
1616
Act
ivat
ion
of c
oagu
latio
n an
d fib
rinol
ysis
and
pla
tele
t fu
nctio
n as
sess
ed s
even
tim
es a
day
up
to d
ay 6
po
stop
erat
ivel
y
Nor
mal
ly f
unct
ioni
ng p
late
lets
and
wea
k ac
tivat
ion
of fi
brin
olyt
ic s
ytem
Yes
Yes
[27]
Paro
lari
et a
l. (2
005
)
RCT
(leve
l 1b)
1515
Plas
ma,
mon
ocyt
e-bo
und
and
plat
elet
-bou
nd t
issu
e fa
ctor
ex
pres
sion
. Pla
tele
t an
d so
lubl
e P-
sele
ctin
exp
ress
ion
asse
ssed
be
fore
sur
gery
, aft
er p
rota
min
e ad
min
istr
atio
n, a
nd 4
, 8 a
nd
30 d
ays
afte
r su
rger
y
Sim
ilar
tissu
e fa
ctor
and
P-s
elec
tin
expr
essi
on a
fter
CA
BG a
nd O
PCA
BYe
sYe
s[2
8]
Paro
lari
et a
l. (2
005
)
RCT
(leve
l 1b)
1718
Prot
hrom
bin
frag
men
t F1
.2 t
hrom
bin
–ant
ithro
mbi
n co
mpl
ex
and
d-d
imer
, vW
F an
d V
CA
M1
leve
ls m
easu
red
befo
re
surg
ery
and
1 m
onth
aft
er s
urge
ry
Sim
ilar
rise
in m
arke
rs o
f ac
tivat
ion
of
coag
ulat
ion
fibrin
olys
is a
nd e
ndot
heliu
m
afte
r C
ABG
and
OPC
AB
Yes
Yes
[29]
Ved
in e
t al
. (2
005
)RC
T (le
vel 1
b)17
14Fi
brin
d-d
imer
, pro
thro
mbi
n fr
agm
ent
1.2,
a-2
mac
rogl
obul
in,
prot
ein
C1
este
rase
inhi
bito
r fib
rone
ctin
and
vW
F le
vels
as
sess
ed u
p to
24
h af
ter
surg
ery
Less
act
ivat
ion
of fi
brin
olys
is a
nd
coag
ulat
ion
afte
r O
PCA
B Ye
sN
o[3
0]
Lo e
t al
. (2
00
4)
RCT
(leve
l 1b)
2020
Plat
elet
cou
nt, fi
brin
d-d
imer
, pro
thro
mbi
n fr
agm
ent
1.2,
so
lubl
e fib
rin, P
-sel
ectin
and
vW
F le
vels
mea
sure
d up
to
day
4 af
ter
surg
ery
OPC
AB
grou
p ha
d de
laye
d ac
tivat
ion
of
hem
osta
sis
and
it be
cam
e eq
uiva
lent
to
the
CA
BG g
roup
in t
he la
ter
post
oper
ativ
e pe
riod
(20
–96
h)
Yes
No
[31]
Møl
ler e
t al.
(20
03)
RCT
(leve
l 1b)
1515
Plat
elet
fun
ctio
n as
sess
ed p
reop
erat
ion,
imm
edia
tely
po
stop
erat
ion,
4 h
pos
tope
ratio
n an
d 1
day
post
oper
atio
nSi
gnifi
cant
incr
ease
in P
AF-
indu
ced
plat
elet
ag
greg
atio
n af
ter O
PCA
B co
mpa
red
to C
ABG
Yes
No
[32]
AA
: Ara
chid
onic
aci
d; C
ABG
: On
-pum
p co
rona
ry a
rter
y by
pass
gra
ftin
g; C
RP: C
-rea
ctiv
e pr
otei
n; O
PCA
B: O
ff-p
ump
coro
nary
art
ery
bypa
ss; P
AF:
Pla
tele
t-ac
tiva
ting
fact
or; R
CT:
Ran
dom
ized
con
trol
led
tria
l; ro
TEG
: Rot
atio
n th
rom
boel
asto
grap
hy; v
WF:
Von
Will
ebra
nd f
acto
r.
Raja & Akhtar
www.expert-reviews.com 603
Review
Mechanisms of hypercoagulability after OPCAB surgery Thrombocytopenia has been well documented in patients under-going on-pump surgery and has been attributed to many fac-tors, including hemodilution, mechanical disruption, adhesion to the extracorporeal circuit and sequestration in organs [34]. In addition, platelet dysfunction has also been shown to occur dur-ing on-pump surgery, resulting both in the prolongation of the bleeding time and decrease in ADP-induced platelet aggregation. Similarly, enhanced platelet activation after use of CPB is a rec-ognized phenomenon [35]. Although there is a lack of consensus as to the pathophysiology of platelet activation, many potential explanations have been entertained. Notable among these are exposure to synthetic material of the extracorporeal circuits, gen-eration of thrombin and use of heparin and protamine [36–38]. These decreases in platelet counts and abnormalities of platelet function and activity have been implicated by many in the bleed-ing complications in the postoperative period [39,40]. The fact that these changes are less pronounced in the OPCAB surgery patients compared with on-pump patients could partly explain the rela-tively ‘preserved hemostasis’ in the former group compared with the latter cohort.
Another plausible mechanism by which OPCAB surgery may induce hypercoagulability is via the obligatory periods of regional warm ischemia that accompany the distal anastomoses. Animal models have demonstrated an induction of thrombin production during periods of warm ischemia in as little as 15 min [41,42]. In their pilot study, Kon et al., using transcardiac assays, illustrated that regional coagulation was enhanced after off- compared with on-pump CABG [43].
It is also important to highlight that there are temporal differences in the activation of coagulation as seen after on-pump CABG and OPCAB surgery. In fact, two discrete phases can be distinguished: an early phase, occurring only after on-pump CABG, characterized by a sharp activation of coagulation and fibrinolysis, which may be ascribable to the use of extracorporeal circulation; and a later phase, occurring in patients undergoing either on-pump CABG or OPCAB surgery, probably consequent to an inflammatory reaction induced by general surgical trauma [29].
Expert commentaryTraditional on-pump CABG has established a low incidence of postoperative thrombotic events [44] that is believed to be medi-ated in part by the anticoagulating effect of CPB [45]. By circum-venting CPB, OPCAB surgery is widely believed to be associated with a ‘hypercoagulable state’ akin to that described after gen-eral surgical procedures [46]. Current best available evidence from RCTs confirms that there is a tendency towards decreased activa-tion of both coagulation and fibrinolysis with less pronounced changes in platelet counts and function after OPCAB surgery (level 1, grade A), resulting in a procoagulant state.
It is important to mention that there is no consensus among var-ious researchers regarding a definition for this ‘hyper coagulable state’. Whether activation of the enzymatic component of the coagulation cascade or platelet hyperactivity is synonymous
with the postoperative ‘hypercoagulable state’ remains unclear at present. One could argue that perhaps a more suitable defini-tion for this hypercoagulability could be based on an end point of early failure of the coronary artery bypass graft. However, as graft patency is dependent upon multiple factors, a better defini-tion for ‘hypercoagulability’ could perhaps be achieved by per-forming simple functional tests such as thromboelastography (TEG) or aggregometry, which are cost effective and can be easily performed and interpreted.
Interestingly, despite the preservation of hemostasis and pro-coagulant state after OPCAB surgery, correlation between this procoagulant state and clinical outcome (namely graft patency) is still a matter of debate. Vein graft failure remains a major problem after CABG. Occlusion in the first weeks is secondary to throm-bosis, whereas intimal hyperplasia and eventually atherosclerotic changes with superimposed thrombus formation underlie subse-quent closure [27]. There are several possible explanations for the poorer graft performance in patients operated on by the off-pump technique: the poorer coronary vessel exposure, heart movement and poor coronary visualization provoked by bleeding all render the distal anastomosis more difficult to perform and sometimes less accurate than those made with the heart arrested. The tools used during the anastomoses (intracoronary shunts, coronary occluding stitch and carbon dioxide blower) to improve visualization may all potentially damage the coronary and graft endothelium [47].
To date, none of the RCTs has demonstrated a correlation between the procoagulant state and early graft occlusion. This could be attributed to variable sampling periods in these RCTs with none of the trials powered or designed to detect the impact of the procoagulant state on thrombotic events.
Another important issue that stems from the presence of the procoagulant state after OPCAB surgery and merits further research is the perioperative anticoagulation policy for patients undergoing OPCAB surgery. It is important to highlight that the postoperative anticoagulation treatment may differ quite sig-nificantly between off- and on-pump patients. It is uncertain at present whether the perioperative anticoagulation should be more aggressive for OPCAB surgery patients than that for patients undergoing conventional on-pump CABG. Furthermore, the suitable dose of heparin administered intraoperatively and the need to antagonize the heparin with protamine at the end of the procedure are potential avenues for further research.
There is evidence to suggest that there is a significant increase in platelet resistance to aspirin in off-pump patients with early graft thrombosis [48]. The presence of hypercoagulability after OPCAB surgery along with aspirin resistance in the early postoperative period is extremely risky for early graft failure because of thrombosis. There arises a question whether modification or intensification of the dose regimen of aspirin or different antiplatelet strategies after off-pump and on-pump bypass surgery could lead to a more effective inhibition of platelet aggregation with a minimum influence on postoperative bleeding and thus possibly improved clinical outcomes.
Antiplatelet therapy has been demonstrated to improve vein graft patency [49]. The study by Chesebro et al. [50] demonstrated that the combination of dipyridamol and aspirin was effective.
Hypercoagulable state after off-pump coronary artery bypass grafting
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More aggressive antiplatelet therapy, including clopidogrel, could potentially increase graft patency similar to the effect on intra coronary stents. The American College of Chest Physicians (ACCP) seventh conference on anti-thrombotic and thrombolytic therapy published their guidelines in 2004 [51]. For patients who undergo CABG for non-ST segment elevation acute coronary syndrome, they recommend that clopidogrel should be started in addition to aspirin post-surgery and continued for 9–12 months. This recommendation is based on the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study [52] and the Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) study [53].
The CAPRIE study reported an 8.7% relative risk reduction in the primary composite end point (first occurrence of ischemic stroke, myocardial infarction or vascular death) in favor of clopi-dogrel (75 mg/day) over aspirin (325 mg/day) in a multicenter RCT of 19,185 patients with a history of recent ischemic stroke, recent myocardial infarction or symptomatic peripheral arterial disease [52]. A subana lysis of the CAPRIE database showed that in 1480 patients with a previous history of cardiac surgery, clopidogrel was associated with a relative risk reduction of 39% for vascular death, 38% for myocardial infarction, 25% for all-cause rehospi-talization and 27% for rehospitalization for ischemia or bleeding. A major drawback of this study is the lack of information about the type of cardiac surgery previously performed in these patients.
The CURE randomized patients with acute coronary syn-dromes (n = 12,562) to treatment with clopidogrel (300 mg then 75 mg/day) or placebo in addition to aspirin (75–325 mg/day). The antiplatelet combination resulted in a 20% risk reduc-tion relative to aspirin alone (9.3 vs 11.4%; p < 0.001) in the primary end point of cardiovascular death, myocardial infarc-tion or stroke over a mean 9-month treatment period [53]. The antiplatelet combination produced a 19.0% reduction relative to aspirin alone in the risk of cardiovascular death, myocardial infarction or stroke among those patients who underwent CABG surgery during the initial hospitalization and an 11.0% relative risk reduction among patients who underwent CABG surgery at any time during the treatment period. The clinical benefits of aspirin plus clopidogrel were mainly evident during the preop-erative period with a 18% relative risk reduction in the primary end point observed before CABG surgery compared with a 3% relative risk reduction following CABG surgery relative to aspi-rin alone [54]. The main pitfall of the study is that patients who did not take the drug after surgery were still included in the clopidogrel group and the effect of clopidogrel was not adjusted for other risk factors.
The Clopidogrel for the Reduction of Events During Observation (CREDO) trial evaluated the short-term benefits of combined aspirin and clopidogrel pretreatment and the long-term benefits of sustained therapy in the setting of percutaneous coronary intervention (PCI) in a RCT of 2116 patients. After 1 year of treatment, patients receiving clopidogrel (75 mg/day) plus aspirin (81–325 mg/day) had a significant 26.9% relative risk reduction in the combined end point of death, myocardial infarc-tion or stroke [55]. A subgroup ana lysis of patients who underwent
CABG without PCI had a modest reduction of 1-year events (risk reduction rate: 16.7%) with clopidogrel [56]. But this was a post-hoc ana lysis and the number of patients in this group was small.
With regard to the other high-risk group of patients, namely patients post-PCI having CABG, at present there are no stud-ies that report the outcome of stent patency post-CABG. The ACCP guidelines recommend clopidogrel in addition to aspirin for all patients post-PCI for 9–12 months (grade 1A) [57]. A small study by Kaluza et al. demonstrated that there was an in-stent thrombosis rate of approximately 20% with a similar mortality in patients having surgery of any type shortly following PCI [58]. Therefore, if the stent is not covered by a graft intraoperatively then it would seem reasonable to follow the ACCP guideline with 9–12 months of clopidogrel. However, if the stent is covered by a graft more distally, there is no evidence to support continuation of clopidogrel.
In their study of 197 selected patients undergoing CABG, Gao et al. assigned the patients to two groups according to antiplatelet drug: the clopidogrel group of 102 patients who received clopi-dogrel (75 mg) daily; and the combination group of 95 patients who received clopidogrel (75 mg) plus aspirin (100 mg) daily [59]. Multislice computed tomography angiography was performed to evaluate graft patency at 1 month and 12 months after CABG. At 1 month and 12 months after CABG graft patency rates of clopidogrel group were 99.0 and 96.9%, respectively, for the left internal mammary artery and 98.1 and 93.5% for the saphen-ous vein grafts; the rates of the combination group were 98.9 and 97.8%, respectively, for left internal mammary artery, and 98.2 and 96.3%, respectively, for saphenous vein grafts. There were no significant differences in graft patency between the two groups (p > 0.05). On the other hand, a RCT to evaluate the effect of aspirin plus clopidogrel versus aspirin alone on saphenous vein graft (SVG) occlusion at 3 months after CABG showed that SVG patency was 91.6% (219 out of 239) in the dual antiplate-let therapy group versus 85.7% (198 out of 231) in the aspirin alone group (p = 0.043). In a multivariate ana lysis, combined antiplatelet therapy independently increased venous graft patency (p = 0.045) [60]. Multislice computed tomography angiography was used to evaluate graft patency in this RCT. Similar conclu-sions were reached by Sun et al. in their RCT, which showed a high rate of graft occlusion after CABG surgery [61] and suggested that the addition of clopidogrel to aspirin is feasible and safe.
Interestingly, the Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) trial undertaken to evaluate whether the addition of clopidogrel to aspirin inhibits SVG disease after CABG, as assessed at 1 year by intravascular ultrasound, con-cluded that compared with aspirin monotherapy, the combination of aspirin plus clopidogrel did not significantly reduce the process of SVG intimal hyperplasia 1 year after CABG [62].
The published evidence for the use of dual antiplatelet therapy after OPCAB surgery is extremely scant at present, unlike that for on-pump CABG. Nielsen et al. randomly assigned 29 patients to receive aspirin alone or clopidogrel and aspirin until 30 days after OPCAB surgery [63]. The follow-up time was 2 months including standard blood samples and TEG with a specific platelet inhibition
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assay. In both groups a significant increase in TEG maximum amplitude was found 5 days after surgery. Platelet inhibition showed great variations but was significantly increased in the clopidogrel group (34.1%) compared with the control group (11.0%) after 1 month. This study showed that hypercoagulability was observed 5 days after OPCAB surgery and could not be demonstrated after 1 month. An observational study by Gurbuz et al. showed that clopidogrel therapy with aspirin was independently associated with decreased symptom recurrence and adverse cardiac events following OPCAB surgery [64]. However, extending clopidogrel use beyond 30 days did not have a significant effect on defined end points. A small recently published RCT recruiting 20 patients undergoing OPCAB surgery concluded that early administration of a combined regimen of clopidogrel and aspirin after OPCAB surgery grafting is not associated with increased postoperative bleeding or other major complications [65]. Despite the small number of patients in this study and the small number of examined grafts, the results of this RCT suggest that the addition of clopidogrel may increase graft patency after OPCAB surgery grafting.
Hence, additional studies are needed to address the need for dual antiplatelet therapy after OPCAB surgery, particularly when
it is known that clopidogrel, unlike aspirin, inhibits not only platelet aggregation but also P-selectin expression [24].
Five-year viewIt is expected that in the next 5 years a large multi-institutional RCT will be conducted to determine the impact of the hyper-coagulable state after OPCAB surgery on clinical outcomes of relevance (graft patency and thrombotic events). Any future research in this area will hopefully provide important informa-tion regarding the routine adoption of dual antiplatelet therapy and appropriate perioperative anticoagulation protocols to allay the anxiety attributed to presence of the hypercoagulable state after OPCAB surgery.
Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
• Despite abundant evidence validating the safety and efficacy of off-pump coronary artery bypass (OPCAB), one area of concern, and even greater uncertainty, surrounds the issue of the existence of a hypercoagulable state after OPCAB.
• The current best available evidence from randomized controlled trials confirms that there is a tendency towards decreased activation of both coagulation and fibrinolysis with less pronounced changes in platelet counts and function after OPCAB (level 1, grade A), resulting in a procoagulant state.
• Unresolved issues that require further research include the impact of this procoagulant state on thrombotic events after OPCAB, the prescription of dual antiplatelet therapy and the adoption of appropriate perioperative anticoagulation protocols following OPCAB.
ReferencesPapers of special note have been highlighted as:•ofinterest••ofconsiderableinterest
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