Microsoft word - 11-postoperative bleeding fouda et al.doc
POSTOPERATIVE BLEEDING AFTER MYOCARDIAL REVASCULARIZATION IN PATIENTS ON CLOPIDOGREL
MOHAMMED ABDEL-AAL MD., BAKIR M BAKIR MD., ANJUM JALAL FRCS-CTH,
AHMED AL-SADDIQUE FACS. NASSER H. ALKHAMEES MB. MOHAMMED FOUDA FRCS
Background: Clopidogrel (CL) is a potent inhibitor of platelet aggregation. It has become the standard of care to prevent thrombotic complications following cardiological interventions. Platelet dysfunction is one of the major reasons for postoperative bleeding following coronary artery surgery. The aim of this study was to evaluate the effect of clopidogrel on bleeding and the use of blood and blood products after coronary artery bypass grafting (CABG). Methods: Data were prospectively collected on 286 consecutive patients who underwent isolated conventional CABG (with cardiopulmonary bypass) and two groups were compared: group 1, those who had the drug discontinued more than 7 days prior to surgery or were never on it (n = 201), to group 2, those with clopidogrel exposure up until 72 hours prior to surgery (n = 85). The duration of the study covered the period between April 2004 and March 2006. Preoperative patient characteristics, intraoperative variables, and postoperative outcomes were prospectively collected and recorded in the cardiac surgery database. Results: Chest tube drainage was significantly increased during the first 24 hours following CABG in the group of patients who had clopidogrel treatment (1392 ± 212 vs.785.29 ± 145). These patients also required more transfusion of packed red cells (4.23± 2.3 vs. 2.21± 1.5), platelets (4.1 ± 1.2 vs. 0.2 ± 0.6), and fresh frozen plasma (3 ± 0.9 vs. 1.5± 1.1). Overall, the re-exploration rate due to bleeding was significantly higher in the clopidogrel group (5.88% vs. 1.8%). Conclusion: Patients using clopidogrel 3 days or less prior to CABG surgery have a significantly increased risk of postoperative bleeding, with an increased need for surgical re-exploration as well as risks of transfusion with blood and blood products after coronary artery bypass surgery. Platelets transfused before chest closure had a beneficial effect on preservation of hemostasis. Keywords: Myocardial revascularization, clopidogrel (CL), blood products, bleeding.
CLOPIDOGREL IS AN ACETATE DERIVATIVE OF loading dose) within 4 to 7 days, or more rapidly
with a loading dose of 300 to 600 mg within 4 to 24
aggregation that works by irreversible blockade of
hours. Platelet function recovers completely 7 days
adenosine diphosphate (ADP) mediated platelet after stopping clopidogrel in healthy volunteers.2,3 activation.1 It has several advantages over other
The cause of early postoperative bleeding
antiplatelets, including more rapid onset of action, a
following CABG may be multifactorial: insufficient
more potent antiplatelet effect, and a lower incidence
surgical hemostasis, disorders of the coagulation
system due to hemodilution, and platelet dysfunction
thrombocytopenic purpura(i). The antiplatelet effect as well as the negative effects of increased of clopidogrel is time and dose dependent. Maximal
inhibition of platelet aggregation of 50% to 60% can
procedures, and urgency status, which are the most
be achieved with a dose of 75 mg daily (without a
common causes for impaired hemostasis and postoperative bleeding.2
From the Department of Medicine King Fahad Cardiac Center,
Platelet function is integral to hemostasis in the
College of Medicine, King Saud University, Riyadh, Kingdom Of
early postoperative period. Preoperative antiplatelet
agents have the potential to deliver an additional
Address reprint request and correspondence to Dr. Mohammed
Abdel-Aal Department of Medicine King Fahad Cardiac Center,
insult to already dysfunctional platelets. These agents
King Khalid University Hospital, King Saud University, P O Box
should be discontinued at the appropriate time to
ensure adequate platelet function at the time of
Journal of the Saudi Heart Association, Vol. 19, No. 3, September 2007
necessitate continuation of antiplatelet agents.
whom systemic temperature was kept between 30°C
Although controversial, preoperative aspirin may and 32°C. Myocardial protection was achieved by have a small effect in enhancing postoperative using intermittent anterograde hyperkalemic cold bleeding, but it does not affect transfusion rates. 7
Due to the advantages and superior action of
Patients were transferred to the intensive care
clopidogrel compared to other antiplatelet agents, it
unit (ICU) and managed according to ICU protocols.
is now common practice for cardiologists to give They were extubated following our usual criteria of patients both clopidogrel and aspirin at the time of
hemodynamic stability and no excessive bleeding
coronary angiography for possible coronary stent (less than 3-5 ml/kg/h), normothermia, and full implantation for maximum antiplatelet activity at consciousness. All patients underwent routine the time of stent placement. This results in patients
coagulation screening. Transfusion of red blood cells
with severe coronary artery disease requiring was performed when the hematocrit value was
CABG during the same admission to present for less than 24%. Platelets were transfused when surgery with significant platelets’ function the total count was less than 50,000/µL or there inhibition.8
was excessive post-operative bleeding. The
The aim of this work was to analyze the effect of
decision for re-exploration was taken when bleeding
clopidogrel on postoperative bleeding and blood exceeded 500 ml in the first hour, more than products transfusion requirements in patients who 200 ml/h during next 3 hours, or more than underwent isolated myocardial revascularization.
1 liter over 8 hours despite normalized coagulation
Patients and Methods Statistical Analysis
Data were collected prospectively on 286
consecutive patients who underwent isolated CABG
Statistical analysis was carried out using analysis
with CPB. Exclusion criteria included concomitant
of variance (ANOVA), Fisher’s exact tests and the t
valvular procedures, off-pump CABG, bleeding
test. A P value of 0.05 or less was considered
disorders identified preoperatively, and patients with
impaired renal function. All patients were receiving
aspirin, 81 mg/day. Patients receiving clopidogrel
were on a maintenance dose of 75 mg daily or receiving the loading dose of 300 mg /day just
There were no clinically or statistically
significant differences in age, gender, risk factors, or
Preoperative patient parameters, intraoperative
other main profiles of the patients between both
variables, and postoperative outcomes including groups (Table 1). blood loss in the first 24 hours, and transfusion
requirements in the first 24 hours postoperatively, re-
Table 1: Preoperative Patient Data.
exploration for bleeding, and length of ICU and total
P value
hospital stays, were prospectively collected and Age 59.38 ±
The patients were divided in two groups: group
1: those in whom clopidogrel was discontinued more
than 7 days prior to surgery or were never taking it
(n = 201) and group 2: those with clopidogrel Angina class
exposure up until 72 hours prior to surgery (n = 85
from April 2004 to March 2006. The main Previous
indications for clopidogrel treatment were prior infarction (%)
percutaneous coronary intervention, unstable angina
and patients with critical coronary artery disease NS: non significant. needing surgery within the same hospital admission.
Anesthesia technique, heparin, and protamine management were standardized for all patients in
The intraoperative data are presented in Table 2
Journal of the Saudi Heart Association, Vol. 19, No. 3, September 2007
in which there were no statistically significant differences between the groups. Chest tube drainage
Acquired platelet dysfunction is one of the most
was significantly increased during the first 24 hours
commonly encountered haemostatic defects in
following CABG in the group of patients who had
patients undergoing cardiac surgical procedures. The
clopidogrel treatment (1392 ± 212 vs. 785.29 ± 145)
main factors that may affect bleeding and transfusion
requirements in these patients are the presence of
Those patients who received clopidogrel also risk factors for bleeding, as well as appropriate
required more transfusion of packed red cells, (4.23±
heparin dosing and protamine reversal, but an excess
2.3 vs. 2.21± 1.5), platelets (4.1 ± 1.2 vs. 0.2 ± 0.6)
dose of protamine should be avoided in these
and fresh frozen plasma (3 ± 0.9 vs. 1.5± 1.1; p <
patients due to its adverse effects on coagulation
0.001) (Table 3). Re-exploration for postoperative factors and platelets.9,10 bleeding was significantly higher and was required in
Differentiating between postoperative bleeding
five (5.88%) patients of the CL group, while it was
due to coagulopathy and surgical bleeding that
required in four (1.8%) in the non-CL group. After re-
should be corrected with re-exploration is not always
exploration, no specific sources were identified and straightforward in the early postoperative period. bleeding was thought to be secondary to coagulopathy
The differentiation becomes more difficult in the
in all patients. The median ICU and hospital stay were
face of preoperative clopidogrel administration,
longer in the CL group (Table 4). We had a hospital
mortality of 4 patients (1.3%) from low cardiac cardiologists.11,12 Our study has demonstrated that
exposure to clopidogrel before CABG increased the amount of postoperative blood loss and the number
chest drainge
of blood units transfused, supporting the previous
findings by Yende and Wunderink,7 who reported
their experience with 247 patients, of which 51
received clopidogrel. Hongo and colleagues13
prospectively compared 224 patients, of whom 59
had preoperative clopidogrel exposure within 7 days
before surgery, undergoing non-emergent CABG
and observed the postoperative outcome of those
with and without clopidogrel exposure. They found that chest tube drainage (1485cc) was significantly increased during the first 24 h following CABG in
Figure 1: Postoperative blood loss
the group of patients who had clopidogrel treatment.
output, including patients in both groups.
These patients also required more transfusion of
packed red cells, platelets, and fresh frozen plasma.
Table (3): Transfusion requirements.
Overall, the re-exploration rate due to bleeding was
Blood products P value
significantly higher in the clopidogrel group.
transfused
Similar results were reported by Ray et al.14 The
potent inhibition of platelet function achieved by the
combination of aspirin and clopidogrel has been
reported to prolong bleeding time with an increased risk of major hemorrhage. Moreover, the combined
Table 4: Postoperative outcome.
antiplatelet effect of clopidogrel and aspirin might be
P value
amplified by CPB-related platelet dysfunction. This
finding was also supported by Englberger and associates 8 who reported increased bleeding and platelet and fresh frozen plasma transfusion in
patients receiving clopidogrel within 3 days of
surgery. However, Karabulut et al6 showed no
increase in bleeding and transfusion requirements
Discussion
after preoperative use of clopidogrel and the cause in
Journal of the Saudi Heart Association, Vol. 19, No. 3, September 2007
Our study has also demonstrated a significantly
Karabulut H, Toraman F. Clopidogrel does not increase bleeding and allogenic blood transfusion in coronary artery
increased ICU and postoperative hospital stay in
surgery Eur J Cardiothorac Surg 2004;25:419-423
clopidogrel recipients, similar to a study by Chu and
Yende S, Wunderink RG. Effect of clopidogrel on bleeding
coworkers17 These patients stayed an average of
after coronary artery bypass surgery Crit Care Med
13.7 hours and 1.9 days longer than non-recipients,
Englberger L, Faeh B, Berdat PA, Franz Eberli, Meier B,
respectively. Increased ICU and hospital stay
Carrel T. Impact of clopidogrel in coronary artery bypass
significantly impacts on the cost of CABG and will
grafting Eur J Cardiothorac Surg 2004;26:96-101.
also expose patients to potential hospital stay-related
Nurozler F, Kutlu T, Küçük G and Ökten C. Impact of
clopidogrel on postoperative blood loss after non-elective coronary bypass surgery CardioVasc Thorac Surg
One of the limitations of the present study, which
deserves to be mentioned, is that we did not perform
10. Payne DA, Hayes PD. Combined therapy with clopidogrel
an analysis comparing on-pump to off-pump patients
and aspirin significantly increases the bleeding time through
because of the small numbers of patients enrolled in
a synergistic antiplatelet action J Vasc Surg 2002;35:1204-1209.
11. Harding SA, Boon NA, Flapan AD. Antiplatelet treatment
In conclusion, bleeding after cardiac surgery is a
in unstable anginaaspirin, clopidogrel, glycoprotein IIb/IIIa
multifactorial problem and it can often be difficult to
antagonist, or all three ? Heart 2002;88:11-14.
eliminate all of the confounding factors. However,
12. Patrono C, Bachmann F, Baigent C, et al. Expert consensus
document on the use of antiplatelet agents. The Task Force
our data show that clopidogrel within 3 days of
on the Use of Antiplatelet Agents in Patients with
operation is associated with increased bleeding in the
Atherosclerotic Cardiovascular Disease of the European
first 24 hours and is thus an independent risk factor
Society of Cardiology Eur Heart J 2004;25:166-181.
for increased transfusion requirements and 13. Hongo RH, Ley J, Dick SE, Yee RR. The effect of
clopidogrel in combination with aspirin when given before
prolonged hospital length of stay. One must exercise
coronary artery bypass grafting J Am Coll Cardiol
caution when prescribing clopidogrel to the
preoperative cardiac surgery patient, weighing the 14. Ray JG, Deniz S, Olivieri A, et al. Increased blood product risk of further myocardial ischemia against the risk
use among coronary artery bypass patients prescribed preoperative aspirin and clopidogrel BMC Cardiovasc
of postoperative blood loss and its sequelae.
15. Raimondo Ascione, MD, MCh*, Arup Ghosh, FRCS, Chris
References
A. Rogers, PhD, Alan Cohen, FRCA, Chris Monk, FRCA, Gianni D. Angelini, MD, MCh In-Hospital Patients Exposed to Clopidogrel Before Coronary Artery Bypass
Mueller C, Buttner HJ, Petersen J, Roskamm H. A
Graft Surgery: A Word of Caution Ann Thorac Surg
randomized comparison of clopidogrel and aspirin versus
ticlopidine and aspirin after the placement of coronary-
16. Chen LQ, Bracey AW, Radovancevic R, et al. Clopidogrel
artery stents Circulation 2000;101:590-593.
and bleeding in patients undergoing elective coronary artery
Kam PCA, Nethery CM. The thienopyridire derivatives
bypass grafting J Thorac Cardiovasc Surg 2004;128:425-
(platelet & adenosine diphosphate receptor antagonists),
pharmacology and clinical developments. Anesthesia 17. Chu MWA, Wilson SR, Novick RJ, Stitt LW, Quantz MA.
Does clopidogrel increase blood loss following coronary
Mehta SR, Yusuf S, Peters RJ, et al. Effects of pre-treatment
artery bypass surgery? Ann Thorac Surg 2004;78:1536-
with clopidogrel and aspirin followed by long-term therapy
in patients undergoing percutaneous coronary intervention:
18. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in
the PCI-CURE study Lancet 2001;358:527-533
addition to aspirin in patients with acute coronary
Payne DA, Hayes PD, Jones CL, et al. Combined therapy
syndromes without ST-segment elevation. N Engl J Med.
with clopidogrel and aspirin significantly increases the
bleeding time through a synergistic anti-platelet action J
Levy JH, Smith PK. Platelets inhibitors and cardiac surgery.
Journal of the Saudi Heart Association, Vol. 19, No. 3, September 2007
Foreign trade mark strategies for Australian Take-away tips Some Australian traders omit clearance searching• Develop and implement a foreign trade markbecause of the high cost. While a full trade mark searchstrategy — avoid approaching foreign trade markswith a legal opinion from an attorney in each countrycan be costly, cheaper search options are available. • Clearance searches
REVIEW ARTICLE SEMINARS IN MEDICINE Mitochondria, which probably evolved from inde-pendent organisms that became part of the cell, areable to replicate, transcribe, and translate their DNA BETH ISRAEL HOSPITAL, BOSTON independently of nuclear DNA. However, cellular func-tion and mitochondrial function are interdependent.10Nuclear DNA encodes protein subunits of oxidativephosphorylation