Corresponding author: Dimitar Kyuchukov ( kiuchukovd@yahoo.com ) Corresponding author: Ivayla Zheleva-Kyuchukova ( iva.jeleva@gmail.com ) Academic editor: Plamen Peikov
© 2020 Dimitar Kyuchukov, Ivayla Zheleva-Kyuchukova, Gencho Nachev.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Kyuchukov D, Zheleva-Kyuchukova I, Nachev G (2020) Antithrombotic regimens in patients after coronary artery bypass grafting and coronary endarterectomy. Pharmacia 67(3): 115-120. https://doi.org/10.3897/pharmacia.67.e52738
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Background: Coronary artery bypass grafting (CABG) remains the gold standard in the treatment of complex chronic forms of coronary heart disease (CHD). Coronary endarterectomy (CEAE) is a useful adjunctive technique to CABG in patients with diffuse coronary artery disease. In order to maintain the patency of the coronary arteries and graft conduits, various antithrombotic protocols have been introduced over the years, combining various antiplatelet and anticoagulant drugs, but still there is no consensus.
Aim: The aim of the study is to compare results between two antithrombotic regimens after CEAE. The first one is a combination of acenocoumarol combined with acetylsalicylic acid (ASA), the second regimen is a dual antiplatelet therapy (DAPT) of clopidogrel combined with ASA.
Material and methods: We retrospectively reviewed 56 consecutive patients (60 ± 8.2 years) undergoing isolated CABG in association with CEAE between January 2018 and December 2019. In the postoperative period, patients were divided into two groups according to the antithrombotic regimens described above. Twenty-four were in the ASA and acenocoumarol group (AA) and 32 were in the ASA and clopidogrel group (AC). Patients were followed up to 30 days after the operation and we access the mortality rate, new ECG changes, levels of myocardial fraction of creatinine phosphokinase (CPK-MB), left ventricular systolic function, pericardial or pleural effusions requiring drainage or revision for bleeding.
Results: Operative mortality was 3,6 %. No differences in the antithrombotic efficacy of the two regimens. A significantly higher level of hemorrhagic complications was observed in the ASA + acenocoumarol treatment group.
Conclusion: Dual antiplatelet therapy (DAPT) after CABG and coronary endarterectomy is an effective pharmacological regimen in regard to 30-day postoperative outcomes and is considerably safety in terms of bleeding complications.
dual antiplatelet therapy (DAPT), coronary endarterectomy (CEAE), coronary artery bypass grafting (CABG)
Complete myocardial revascularization is a major goal in the treatment of coronary heart disease (CHD). Coronary artery bypass grafting (CABG) remains the gold standard in the treatment of complex chronic forms of CHD, despite the widespread entry and improved results of percutaneous coronary intervention (PCI). Coronary endarterectomy (CEAE) is a useful adjunctive technique to CABG in patients with diffuse coronary artery disease. It was introduced by Baeily in 1957 for the treatment of coronary occlusion and during the years his role in cardiac surgery has remained unclear and results remain controversial. Coronary endarterectomy can be performed by either closed or an open technique. The role of antithrombotic therapy to improve long-term graft patency after coronary surgery is well known in literature. It plays a crucial role in preventing postoperative myocardial infraction (MI) in a case of CEAE, though not uniform, has been less aggressive. In order to maintain the patency of the endarterectomized coronary arteries, various antithrombotic protocols have been introduced over the years, combining various antiaggregant and anticoagulant drugs, but still there is no consensus. Antithrombotic treatment with anticoagulants and platelet inhibitors reduces the risk for thromboembolic complications. Strategies to intensify antithrombotic regimens are limited by concomitant increases in clinically significant intraoperative or postoperative bleeding.
Acenocoumarol is a 4-hydroxycoumarin derivative with anticoagulant activity. As a vitamin K antagonist (VKA), acenocoumarol inhibits vitamin K epoxide reductase, thereby inhibiting the reduction of vitamin K and the availability of vitamin KH2 (2-Methyl-3-[(2E)-3,7,11,15-tetramethyl-2-hexadecenyl]-1,4-naphthalenediol). This prevents gamma carboxylation of glutamic acid residues near the N-terminals of the vitamin K-dependent clotting factors, including factor II, VII, IX, and X and anticoagulant proteins C and S. This prevents their activity and thus thrombin formation. Compared to other coumarin derivatives, acenocoumarol has a short half-life.
ASA nonselectively and irreversibly acetylates a serine residue on the cyclooxygenase (COX) enzymes, suppressing the production of prostaglandins and thromboxane A2 (TxA2), a potent platelet activator ASA is one of the cornerstones for the treatment of acute and chronic cardiovascular disease. According to the landmark Antithrombotic Trialists’ Collaboration meta-analysis of 287
studies including 212 000 patients ASA has been shown to reduce mortality, MI and cerebrovascular events in different subsets of patients with occlusive cardiovascular disease especially for secondary prevention. (
Clopidogrel was released onto the market in 1997 in the United States, and in 1998 in Europe, and is a secondgeneration thienopyridine that exerts its anti-aggregating action by irreversibly inhibiting the bond between ADP and the P2Y12 surface purinergic receptors. This binding activates the inhibitory G protein, which results in a reduction of intra-platelet concentration of cyclic adenosine monophosphate (cAMP), which promotes the expression of GPIIb/IIIa aggregation receptors on the platelet surface. Thus, ADP is the P2Y12 receptor agonist, while adenosine triphosphate (ATP) is the receptor antagonist that increases the production of cAMP and therefore reduces platelet aggregation.(
Strategies to intensify antithrombotic regimens should be complemented by approaches that focus on targeting thrombosis while preserving hemostasis. Generally, as routine practice in patients with CABG / CE, it is recommended that vit K antagonist in combination with ASA should be continued until 3 months postoperatively and eventually ASA alone permanently.(
The aim of this study is to compare results between two antithrombotic regimens. The first one is the combination of acenocoumarol (coumarin anticoagulant /VKA) and acetylsalicylic acid (ASA) - irreversible cyclooxygenase-1 inhibitor, which block the formation and release of thromboxane A2, a potent platelet activator. The second regimen is DAPT of clopidogrel - irreversible, competitive, thienopyridine P2Y12 receptor antagonist combined with ASA.
We analyzed 56 consecutive patients undergoing isolated CABG in association with CEAE between January 2018 and December 2019. Patients were not included in the analysis if they had one of the following: concomitant valve or aortic surgery; history of an allergic reaction to any of the medications used in the study; operation in a setting of acute coronary syndrome; prolonged intake of clopidogrel or acenocoumoral in the week before surgery; patients with more or less 3 bypass grafts and more than one vessel with CEAE. All patients had signed an informed consent and underwent standard CABG surgery, under conditions of cardiopulmonary bypass at moderate hypothermia 30–32 °C, aortic clamping, and myocardial protection with intermittent ante- and retrograde infusion of cold blood cardioplegic solution according to the protocol of the clinic. For revascularization of the anterior descending artery, the internal thoracic artery was always used as a “graft in situ” and the rest of the vessels were revascularized with segments of saphenous vein. In all cases, the decision for CEAE was made intraoperatively if the lumen of the coronary artery was completely obstructed and a large extension and a competent anastomosis was impossible. The CEAE itself was performed through a longitudinal arteriotomy measuring 8–20 mm, the so-called “closed method”.
In the postoperative period, patients were divided into two groups according to two antithrombotic regimens. The first one is a combination of acenocoumarol and ASA . The second regimen is DAPT of clopidogrel combined with ASA. 24 pts operated in 2018 were included in the acenocoumarol and ASA group (AA) and 32, operated in 2019, were in the ASA and clopidogrel group (AC). Patients were followed up to 30 days after the operation and we access the mortality rate, new ECG changes (Q-waves and/or ST-T changes), levels of MB fraction of creatinine phosphokinase (CPK-MB), left ventricular systolic function, pericardial or pleural effusions requiring drainage or revision for bleeding. In the AA group in conjunction with intravenous heparin infusion started at the sixth postoperative hour, administration of 80 mg ASA and 6 mg acenocoumarol was initiated 6 hours later. The infusion was stopped when INR (International Normalized Ratio) values reached the range of 2–3. To maintain a stable therapeutic level of acenocoumarol daily INR testing was measured. In the AC group in conjunction with intravenous heparin infusion started at the sixth postoperative hour if there is no bleeding from the drainage on the 12th hour patient received a loading dose of 300 mg clopidogrel plus 80 mg ASA followed by daily therapy of 75 mg clopidogrel and 80 mg ASA.
For all analyzes was used statistical analysis software (Version 18, SPSS). All continuous
values were expressed as mean plus or minus 1 standard deviation of the mean. For categorical
data were used chi-square test, Fisher exact test and t-test. A p-value less than 0.05 was considered significant.
Data from 56 consecutive eligible patients was processed. The average age of patients was 60 ± 8.2 years. Table
АА (N = 24) | АС (N = 32) | P | |
---|---|---|---|
Male (%) | 16(66,7%) | 20 (62,5%) | NS |
Age (years) | 59,86 ± 9,88 | 61,68 ± 10,11 | |
Smoking % | 20 (83,3%) | 28 (87,5%) | |
Arterial hypertension % | 23 (95,8%) | 31 (96,9%) | |
Diabetes % | 13 (54,2%) | 18 (56,3%) | |
Obesitas % | 7 (29,2%) | 10 (31,2%) | |
Previous MI % | 20 (83,3%) | 25 (78,1%) | |
CKD > 2 stage % | 6 (25%) | 9 (28,1%) | |
COPD % | 4 (16,6%) | 4 (12,5%) | |
EuroSCORE | 3,9 ± 1,95 | 3,4 ± 2,21 |
There was no significant difference in the distribution of reported preoperative demographic and risk factors, as well as in the calculated operative risk according to EuroScore system.
The comparison of anatomic and intraoperative data also showed no significance between groups (Table
АА (N = 24) | АС (N = 32) | Р | |
---|---|---|---|
RCA N (%) | 21 (87,5%) | 29 (90,4%) | NS |
LCx N (%) | 1 (4,2%) | 1 (3,2%) | |
LAD N (%) | 2 (8,3%) | 2 (6,4%) | |
Distal anastomosis (average number ± SD) | 2,9 ± 0,43 | 3,03 ± 0,49 | |
CPB (average time, min± SD) | 74,2 ± 10,2 | 77,2 ± 11,3 | |
Ao X clamping (average time, min± SD) | 44,6 ± 3,45 | 46,7 ± 3,29 |
From all CEAE cases only 4 (7,14 %) were in left anterior descending (LAD) coronary artery (equally in both groups) and 50 (89,3%) cases in the right coronary artery (RCA) (including 21 cases in AA group and 29 cases in AC group). The mean ECC time was 74,2 ± 10,2 min in AA group and 77,2 ± 11,3 min in AC group. This difference was not statistically significant. The mean AoXclamping time also showed no difference. (44,6 ± 3,45 for AA group vs 46,7 ± 3,29 for AC group).
Regarding the reported ECG changes, no new onset Q-waves and no significant ST-T changes were found in all patients in the study. Serum MB/CPK levels were checked before surgery and immediately after surgery, in addition to 24 and 48h later. The following Figure
No significant difference was found between groups. Point of interest is the early postoperative increasing of MB/CPK levels, which rapidly dropped off to normal values after 24 hours and persists within these ranges through the whole follow up period.
The ejection fraction (EF) of left ventricle (LV) was recorded by transthoracic echocardiography using the Simpson method, and values were registered before surgery and on the 30-th postoperative day. (Table
АА (N = 24) Mean ± SD | АС (N = 32) Mean ± SD | |
---|---|---|
Preoperative LVEF | 41,61 ± 9,87 | 42,56 ± 7,78 |
Postoperative LVEF | 41,05 ± 10,54 | 44,73 ± 8,61 |
p - value | 0,316 | 0,212 |
The overall mortality rate for all patients was 3.6% and was established in the early postoperative period. For the AA group it is 4.1% and for the AP group 3.1%, the difference is not statistically significant (p = NS) (Fig.
The mortality analysis showed no difference between the two groups within 30-y days. Patients died in the early postoperative period with a picture of low-debit syndrome, resistance to catecholamine and intra-aortic balloon pump therapy.
The percentages of bleeding and pericardial or pleural effusions indicated surgical treatment are presented on Table
Revisions for bleeding % | Pericardial effusions % | Pleural effusions % | |
---|---|---|---|
АА (N = 24) | 3 (12,5%) | 4 (16,6%) | 12 (50%) |
АС (N = 32) | 1 (3,1%) | 1 (3,1%) | 3 (9,3%) |
p-value | 0,004 | 0,004 | 0,0001 |
The differences between the groups are significant in terms of all three indicators and in favor of the group receiving dual antiplatelet therapy.
Coronary endarterectomy was introduced by Baeily in 1957 for the treatment of coronary occlusion and during the years his role in cardiac surgery has remained unclear and results remain debated. The operative mortality ranges from 2.0% to 6.5% and appears higher as compared with CABG without CEAE. (
Our study aims to determine whether dual antiplatelet therapy with clopidogrel and ASA is sufficient to prevent early (up to day 30) thrombosis of endarterectomy coronary arteries and to account for the level of additional risks, formulated as percentages of bleeding and follow-up revisions. Definitive assessment of the patency of the coronary graft requires coronary catheterization, which is not recommended in the absence of other clinical indications. For this reason, we used indirect patency assessment tools, including: postoperative ECG changes (new Q wave and / or ST-T segment changes); increased CPK/MB (excess of more than 5 times standard value); changes in LVEF assessed by ultrasound also considered as an indirect indicator of bypass patency. Most studies regarding patients with CEAE compare their results with those of patients undergoing conventional surgical revascularization, with controversial outcomes. Some authors declare that there are no significant differences in postoperative outcomes between two techniques, and thus substantiate the conclusion that CEAE is a competitive option allowing complete revascularization in patients with severely diffuse atherosclerosis. (
The study has a lot of weak points, most notably the small number of patients, short follow-up, operations performed in one center, chronologically separated groups and lack of opportunity for randomization.
CEAE associated with CABG appears to be an important surgical tool for successful treatment of complex CHD with acceptable 30-day results, although the operative mortality is higher in comparison with CABG alone. In order to reduce the incidence of surgical bleeding, at equal efficiency with respect to graft patency, we recommend the use of DAPT (ASA and Clopidogrel) started early postoperatively.