Academic Editor: Demosthenes B Panagiotakos
There is limited data about the bleeding complication of antiplatelet therapy
after coronary artery bypass graft (CABG) operations focused on diabetic
patients. Herein, we aimed to evaluate the effects of aspirin and clopidogrel
monotherapies on postoperative bleeding in these patients. A total of 165
diabetic patients who underwent isolated off-pump beating heart coronary artery
bypass (OPCAB) operation were evaluated, 84 patients were included in this
retrospective study. Patients were divided into groups according to the type of
antiplatelet regime. Chest tube drainage amounts and the amount of blood product
transfusions were evaluated. Acetylsalicylic acid (ASA) - group included 42
aspirin monotherapy and Clopidogrel - group included 42 clopidogrel monotherapy
patients after propensity matching. The mean drainage amount in ASA - group was
670.24
Diabetes mellitus and coronary artery disease are both systemic diseases and their concomitance has a worse prognosis than their individual existence [1]. Older age, preoperative lower hemoglobin, preoperative higher creatinine levels, postoperative thrombocytopenia lower left ventricle ejection fraction (LVEF) are significantly related with postoperative bleeding after OPCAB surgery [2, 3]. Diabetes is also accepted as one of the major risk factors for bleeding and major adverse cardiovascular events in the risk scoring systems [4, 5].
Antiplatelet therapy is recommended in both American and European guidelines of CABG surgery in the postoperative period to improve the graft patency after OPCAB surgery [6, 7].
There are many studies conducted on the postoperative results of OPCAB surgery but there are limited data about the early postoperative outcomes in regard to postoperative hemorrhage. Also, these data are not focused on diabetic patients [8, 9, 10, 11, 12].
Herein, we aimed to compare the effects of clopidogrel and aspirin on postoperative bleeding in diabetic patients undergoing OPCAB surgery.
The patients who underwent isolated OPCAB operation between the dates of April
2014–August 2018 in the same health center were evaluated in this retrospective
study. Fasting plasma glucose
Patients were divided into groups according to the type of antiplatelet therapy they had received. In elective operations, clopidogrel and/or aspirin therapies were ceased three to five days before the operation and low molecular weight heparin (LMWH) was administered once a day until the operation day. In emergent situations such as ongoing chest pain and ischemia signs in electrocardiography despite the medical therapy, the patient underwent emergency CABG operation in six hours after the onset of the chest pain. Clopidogrel or aspirin therapies were continued on the first postoperative day. Patients were classified according to the blood loss through the chest tubes as defined in Universal Definition of Perioperative Bleeding in adult cardiac surgery (UDPB) [14] (Table 1). The total blood product transfusions including PRBC and FFP which were done in the postoperative period were evaluated. Local institutional approval for the study execution and data usage was taken.
Bleeding definition | Blood loss within twelve hours (mL) |
Class 0 (insignificant) | |
Class 1 (mild) | 601–800 |
Class 2 (moderate) | 801–1000 |
Class 3 (severe) | 1001–2000 |
Class 4 (massive) |
The general anesthesia induction was done with intravenous injection of fentanyl 10 microgram/kg, midazolam 0.1 mg/kg, and rocuronium 1 mg/kg following the electrocardiography and invasive blood pressure monitoring. The patient was intubated after the establishment of general anesthesia and ventilated with 300–400 mL tidal volume. Also, methylprednisolone 1 mg/kg and intravenous pheniramine were administered to prevent adverse drug reactions after protamine administration.
The activated clotting time was maintained over 300 seconds with the
administration of 300 IU/kg unfractionated heparin before the median sternotomy
and additional doses were administered if necessary throughout the operation.
Left internal mammary artery and saphenous vein grafts were harvested in a
standard fashion. Intravenous infusions of magnesium (1 amp) and lidocaine 1
mg/kg were administered throughout the graft harvesting period as a standard
protocol to prevent arrhythmias. The patient body temperature was kept between
34–36
The statistical analysis of the data was done with the Statistical Package for
the Social Sciences (SPSS 16.0 Inc., Chicago, IL, USA) software. Categorical data
were reported as numbers and percentages. Continuous data were reported as means
A total of 503 patients were identified who underwent isolated OPCAB surgery. Among these patients, 165 diabetic patients were evaluated for the preoperative characteristics. There were significant differences between the groups regarding the variables previous MI, chronic obstructive pulmonary disease, hypertension, and preoperative ejection fraction before the propensity matching. The patient groups were adjusted according to the propensity scores using one-to-one matching ratio and nearest neighbor algorithm. A total of 84 patients were selected. ASA - group included 42 (50%) aspirin monotherapy and Clopidogrel - group included 42 (50%) clopidogrel monotherapy patients after propensity score matching (Fig. 1). The main preoperative characteristics of the patients are presented in Table 2. Two groups were matched for all the preoperative data.
Flow diagram of patient selection. A total of 503 patients were enrolled. Down arrows indicate the flow of the patient selection process and the number of patients included in each step. Side arrows indicate the number of patients excluded in the process. OPCAB, Off-pump coronary artery bypass; ASA, Acetylsalicylic acid.
ASA - group (n = 42) | Clopidogrel - group (n = 42) | p value | ||
Age (Mean |
63.14 |
63.21 |
0.964 | |
Male n (%) | 29 (69.04) | 30 (71.42) | 0.943 | |
BMI (Mean |
31.31 |
30.27 |
0.238 | |
BSA (Mean |
2.09 |
1.98 |
0.159 | |
Preoperative EF (%) (Mean |
54.62 |
52.71 |
0.172 | |
Fasting plasma glucose (mg/dL) (Mean |
170.05 |
174.38 |
0.741 | |
Hemoglobin A1c (%) (Mean |
7.11 |
7.66 |
0.140 | |
Hemobiology and platelet indices (Mean |
||||
Hemoglobin (g/dL) | 12.01 |
11.34 |
0.098 | |
Hematocrit (%) | 36.39 |
34.68 |
0.110 | |
Platelet count (10 |
192.88 |
202.67 |
0.303 | |
PDW (fl) | 14.92 |
14.59 |
0.480 | |
MPV (fl) | 11.44 |
11.21 |
0.302 | |
P-LCR (%) | 35.51 |
34.46 |
0.407 | |
PCT (10 |
0.21 |
0.22 |
0.122 | |
Previous myocardial infarction n (%) | 42 (100) | 42 (100) | 1.000 | |
Emergency surgery n (%) | 5 (11.90) | 4 (9.52) | 1.000 | |
COPD n (%) | 24 (57.14) | 21 (50.00) | 0.512 | |
Hypertension n (%) | 24 (57.14) | 24 (57.14) | 1.000 | |
Hyperlipidemia n (%) | 6 (14.28) | 3 (7.14) | 0.483 | |
Renal dysfunction n (%) | 3 (7.14) | 3 (7.14) | 1.000 | |
ASA, Acetylsalicylic acid; BMI, Body mass index; BSA, Body surface area; EF, Ejection fraction; PDW, Platelet distribution width; MPV, Mean platelet volume; P-LCR, Platelet large cell ratio; PCT, Plateletcrit; COPD, Chronic obstructive pulmonary disease. |
Table 3 presents the postoperative data of the groups. The mean
In the multiple regression analysis body mass index and body surface area were found to be independent predictors for postoperative drainage amount in both groups (Table 4).
ASA - group (n = 42) | Clopidogrel - group (n = 42) | p value | ||
Postoperative drainage (Mean |
670.24 |
921.43 |
||
UDPB n (%) | ||||
Class 0 | 21 (50.00) | 3 (7.14) | ||
Class 1 | 15 (35.71) | 10 (23.81) | 0.232 | |
Class 2 | 6 (14.29) | 23 (54.76) | 0.0001 | |
Class 3 | 0 | 6 (14.29) | 0.011 | |
ABP (mmHg) (Mean |
||||
Systolic | 112.55 |
115.07 |
0.328 | |
Diastolic | 72.62 |
74.45 |
0.414 | |
SVG n (%) | ||||
33 (78.57) | 33 (78.57) | 1 | ||
9 (21.43) | 9 (21.43) | |||
MVS time (hours) (Mean |
5.00 |
5.64 |
0.01 | |
ICU stay time (hours) | 13.29 |
24.29 |
0.047 | |
In-hospital stay time n (%) | ||||
39 (92.86) | 36 (85.71) | 0.29 | ||
3 (7.14) | 6 (14.28) | |||
Inotropic support n (%) | 33 (78.57) | 27 (64.29) | 0.147 | |
IABP n (%) | 3 (7.14) | 3 (7.14) | 1 | |
Postoperative revision n (%) | 6 (14.29) | 9 (21.43) | 0.393 | |
PRBC units transfused (Mean |
0.83 |
2.05 |
||
FFP units transfused (Mean |
1.05 |
1.90 |
||
Mortality n (%) | 2 (4.76) | 4 (9.52) | 0.984 | |
UDPB, Universal definition of perioperative bleeding; ABP, Arterial blood pressure; LIMA, Left internal mammary artery; SVG, Saphenous vein graft; MVS, Mechanical ventilator support; ICU, Intensive care unit; IABP, Intra-aortic balloon pump; PRBC, Packed red blood cell; FFP, Fresh frozen plasma. |
ASA- group | Clopidogrel - group | ||||||||
95.0% Confidence Interval for B | 95.0% Confidence Interval for B | ||||||||
B |
p value | Lower Bound | Upper Bound | B |
p value | Lower Bound | Upper Bound | ||
Age | –5.11 | 0.699 | –32.07 | 21.86 | 3.25 | 0.234 | –2.25 | 8.76 | |
BMI | 11.91 | 0.028 | 1.41 | 22.41 | 20.65 | 10.52 | 30.78 | ||
BSA | 759.84 | 0.020 | 130.25 | 1389.43 | 1095.90 | 624.71 | 1567.10 | ||
FPG | –0.45 | 0.391 | –1.52 | 0.61 | –0.11 | 0.610 | –0.57 | 0.34 | |
Hemoglobin A1c | 17.76 | 0.243 | –12.87 | 48.40 | –13.66 | 0.158 | –33.01 | 5.69 | |
Preoperative EF | –4.90 | 0.299 | –14.41 | 4.62 | –4.98 | 0.151 | –11.89 | 1.94 | |
Preoperative Hemobiology | |||||||||
Hemoglobin | 27.60 | 0.651 | –96.66 | 151.87 | –47.60 | 0.205 | –123.02 | 27.82 | |
Hematocrit | –7.30 | 0.755 | –55.11 | 40.51 | 16.74 | 0.253 | –12.75 | 46.23 | |
Platelet count | –0.45 | 0.416 | –1.58 | 0.67 | –0.21 | 0.504 | –0.86 | 0.43 | |
MPV | 64.59 | 0.219 | –41.11 | 170.28 | –17.98 | 0.129 | –41.55 | 5.59 | |
PDW | –12.96 | 0.479 | –50.12 | 24.21 | –5.32 | 0.369 | –17.30 | 6.67 | |
PLCR | –0.43 | 0.960 | –17.80 | 16.94 | 0.49 | 0.848 | –4.71 | 5.69 | |
PCT | –553.80 | 0.394 | –1869.63 | 762.03 | –812.57 | 0.038 | –1574.78 | –50.37 | |
Systolic ABP | 1.32 | 0.460 | –2.30 | 4.94 | 1.56 | 0.250 | –1.17 | 4.29 | |
Diastolic ABP | 0.21 | 0.921 | –4.16 | 4.58 | –1.65 | 0.278 | –4.73 | 1.42 | |
BSA, Body surface area; FPG, Fasting plasma glucose; EF, Ejection fraction; PDW,
Platelet distribution width; MPV, Mean platelet volume; P-LCR, Platelet large
cell ratio; PCT, Plateletcrit; ABP, Arterial blood pressure; MVS, Mechanic
ventilator support; ICU, Intensive care unit.
|
The results of this study present that the postoperative hemorrhage amount and the need for PRBC transfusion after OPCAB surgery are higher in the diabetic patients receiving clopidogrel monotherapy before surgery than the patients receiving aspirin monotherapy. Also, body mass index and body surface area had significant effects on the postoperative bleeding volumes.
In the practice guidelines for perioperative blood management published in 2015,
it is stated that platelet transfusion is rarely indicated in patients with
platelet count
There are different ideas about postoperative management of the patients
receiving clopidogrel and aspirin before CABG surgery. In some studies, it was
suggested that platelet transfusion would be needed in the postoperative period
in these patients although it had been stated as opposite in the other studies
[15, 16]. The main concept in our clinic is to keep the total blood product
transfusions as low as possible so any blood transfusion is made if it is
mandatory and the hematocrit level
In the European Society of Cardiology (ESC) guidelines published in 2017, the use of risk scoring systems such as DAPT (Dual Antiplatelet Therapy) – score [4] and PRECISE-DAPT (PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy) score [17] was recommended to evaluate the benefits and risks of DAPT therapy (class of recommendation Class IIb, evidence level A) but their value was not clearly identified in improving patient outcomes because none of these risk prediction models were tested in randomized controlled trials [18]. The vein graft patency is possibly improved with DAPT after CABG but the quality of the data is weak [19].
In the 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Guideline for Coronary Artery Bypass Graft Surgery, preoperative aspirin (100 mg to 325 mg daily) administration and clopidogrel cessation for at least five days before the surgery were recommended to CABG patients. In the patients who undergo urgent CABG, clopidogrel was recommended to be discontinued for at least 24 hours before the surgery. The class of these recommendations were class I and the level of evidence was B. Oral aspirin administration was recommended within six hours postoperatively and to be continued indefinitely (class I recommendation and level of evidence A) to improve the graft patency. Clopidogrel was recommended as alternative to aspirin if the patient was allergic or intolerant to aspirin (class IIA, level of evidence A) [6].
In the 2016 ACC/AHA guidelines, in patients being treated with DAPT after
coronary stent implantation or receiving DAPT because of an acute coronary
syndrome (ACS) who undergo CABG surgery, resuming and continuation of the
P2Y
Both of these guidelines recommend aspirin and clopidogrel treatment postoperatively in the CABG patients with careful assessment of the bleeding risks. We think that, the results of this study support these recommendations.
It is possible to confirm the “obesity paradox” for the postoperative bleeding according findings of this study. The “obesity paradox” is first described in 1999 for obese and overweight hemodialysis patients which states that high body mass index (BMI) is associated with lower morbidity and mortality [21]. Moscarella et al. [22] also confirmed the obesity paradox in ACS patients who underwent primary percutaneous coronary intervention (PCI) after ST segment elevated myocardial infarction (STEMI). On the contrary, Calabrò et al. [23] rejected the obesity paradox and found no relation between the BMI and adverse outcomes in ACS patients. In this study, mean BMI levels of the groups were at obesity and overweight levels and it was slightly higher in Clopidogrel – group. Also BMI was found to be one of the independent predictors for postoperative bleeding.
Lower body surface area was reported to be a predictive factor for postoperative blood loss and blood product transfusion [24]. The data of the current study is consistent with the aforementioned study.
Many factors such as postoperative renal dysfunction requiring hemodialysis, poor left ventricle ejection fraction (LVEF), perioperative MI, sepsis, diabetes, age, etc. are related with prolonged internsive care unit (ICU) stay [25, 26, 27, 28]. But Silberman et al. [27] did not find bleeding related with prolonged ICU-stay times. Also Tunç et al. [28] reported that blood product transfusions both intraoperative and in the first 24 hrs postoperatively were not related with prolonged ICU stay. On the other hand, Al-Attar et al. [29] found significantly increased ICU stay times in cardiac surgery patients in case of postoperative bleeding and revision surgery. These studies were conducted on various cardiac surgery patient groups, not on isolated OPCAB patients.
In their study Cislaghi et al. [30] reported that redo surgery, CPB
time longer than 91 mins, more than four units of RBC or FFP intraoperatively and
LVEF
The postoperative bleeding resulted in prolonged MVS and ICU—stay times in this study. This result is valuable because the patient cohort is very specific to diabetic isolated OPCAB patients.
The presence of any hereditary coagulation disorder was an exclusion criterion for the study but it was not identified in some patients because the determination tests were unavailable. Management of postoperative bleeding was carried out by the same surgery team.
Clopidogrel monotherapy has a stronger effect on postoperative bleeding than aspirin monotherapy in diabetic patients after OPCAB surgery. More studies should be conducted to clarify the physiologic and biochemical mechanisms of this effect. Also, body mass index and body surface area are independent predictors of postoperative bleeding in these patients.
ASA, Acetylsalicylic acid; ACS, Acute coronary syndrome; ACT, Activated clotting time; CABG, Coronary artery bypass graft; CAD, Coronary artery disease; CPB, Cardiopulmonary bypass; DAPT, Dual antiplatelet therapy; DM, Diabetes mellitus; FFP, Fresh frozen plasma; LIMA, Left internal mammary artery; MI, Myocardial infarction; OPCAB, Off-pump coronary artery bypass; PCI, Percutaneous coronary intervention; PMVS, Prolonged mechanical ventilator support; PRBC, Packed red blood cell; STEMI, ST-elevation myocardial infarction; SD, Standard deviation; LVEF, Left ventricle ejection fraction.
LA, Designed the study, analyzed the data. EÇ, Collected the data. LA and EÇ, Wrote the manuscript.
No informed consent was obtained because of the retrospective nature of data collection from hospital records in the study. The institutional approval number is 2017/3056.
We thank the reviewers of this manuscript for their excellent comments and criticism.
This research received no external funding.
The authors declare no conflict of interest.