A Single-Center Bleeding Comparison of Warfarin Plus Aspirin or Clopidogrel Following Coronary Artery Bypass Grafting and Surgical Valve Replacement

Abstract

The optimal antithrombotic therapy following combined coronary artery bypass graft (CABG) and surgical valve replacement (SVR) surgery remains unclear. The aim of this single-center, retrospective cohort study was to assess the safety and effectiveness of a vitamin K antagonist (VKA) plus either aspirin or clopidogrel in patients following combined CABG and SVR. The primary endpoint was the occurrence of bleeding within six months. The secondary endpoint was the occurrence of CV death, stroke, acute coronary syndrome (ACS), or valve dysfunction. Outcomes were identified by pre-specified ICD codes. A total of 629 patients were included in the analysis, with 583 patients receiving aspirin and 46 patients receiving clopidogrel. Bleeding occurred in 1.7% of patients receiving aspirin and in 0% of patients receiving clopidogrel (p = 0.99). CV death, stroke, ACS, or valve dysfunction occurred in 3.1% of patients receiving aspirin and 4.3% of patients receiving clopidogrel (p = 0.65). In this study, there were no differences in the safety or effectiveness of a VKA plus either aspirin or clopidogrel following combined CABG and SVR.

Keywords

valve replacement surgery coronary artery bypass graft surgery CABG antithrombotic warfarin antiplatelet aspirin clopidogrel bleeding

Introduction

Patients with concomitant coronary artery disease (CAD) and valvular heart disease (VHD) are candidates for combined coronary artery bypass grafting (CABG) plus surgical valve replacement (SVR) and account for approximately 7% of all major cardiac surgery procedures.¹ While the morbidity and mortality of CABG plus SVR remain low, the combined procedure is associated with a higher morbidity and mortality than either operation alone.¹ Thrombotic complications related to CABG include graft occlusion and stroke, while thrombotic complications related to SVR include stroke, valve thrombosis, or valve dysfunction. Bleeding is common after either procedure alone^2–9. To prevent thrombotic complications, dual antiplatelet therapy (DAPT) is utilized following isolated CABG, while anticoagulation with a vitamin K antagonist (VKA) for at least 3–6 months is indicated following isolated SVR. The optimal antithrombotic therapy following combined CABG and SVR remains unknown.^2,3,10 Evidence from patients with atrial fibrillation and acute coronary syndrome (ACS) undergoing percutaneous intervention suggests that the combination of an oral anticoagulant (OAC) in addition to DAPT in patients poses a greater risk of bleeding without a difference in major adverse cardiovascular events when compared to patients that received OAC with only a single antiplatelet agent.^11–15 Extrapolation of this data would suggest that anticoagulation plus a single antiplatelet agent may best balance the risk of bleeding and thrombotic protection following combined CABG and SVR, but which antiplatelet agent to utilize remains unclear. The objective of this study was to compare the safety and effectiveness of an antithrombotic regimen consisting of a VKA plus either aspirin or clopidogrel in patients following combined CABG and SVR.

Methods

This study was a single-center, retrospective cohort study of patients that underwent combined CABG and SVR between January 1, 2012 and September 30, 2019 at St. Mary's Hospital in Rochester, MN. Patients were identified through the institution's prospectively managed Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database. Patients 18 years or older who underwent combined CABG and SVR that were discharge on a VKA plus either aspirin or clopidogrel were included in the analysis. Patients were excluded if they underwent additional procedures, required valve replacement outside of the mitral or aortic position, had congenital heart disease, were pregnant or incarcerated, or declined authorization for medical research conducted in Minnesota. This study was exempt from institutional board review as it used pre-existing de-identified data.

Current practice at our institution during the study period was to use a VKA for six months and antiplatelet therapy lifelong following bioprosthetic valve replacement. Patients receiving a mechanical valve replacement were prescribed a VKA lifelong plus a single antiplatelet agent. The standard INR goal was 2–3 for patients receiving any bioprosthetic valve or mechanical aortic valve and was 2.5–3.5 for patients receiving a mechanical mitral valve. During the study period, the preferred antiplatelet therapy following CABG was lifelong aspirin prior to 2016 and transitioned to DAPT in 2016.¹⁶ The antiplatelet agent paired with a VKA following combined CABG and SVR was based upon the surgeon's preference.

Outcomes

The primary endpoint was the occurrence of bleeding within six months following the procedure. Re-operation for bleeding during the index admission was not included in the composite bleeding endpoint but was recorded. The secondary endpoint was the composite of cardiovascular (CV) death, stroke, acute coronary syndrome (ACS), or valve dysfunction in the six months following the procedure. CV mortality was identified by the STS database while other endpoints were identified by International Classification of Diseases (ICD)-9 and ICD-10 codes for bleeding, stroke, acute coronary syndrome, and valve dysfunction (supplemental table 1). All events were validated by the study team.

Statistical Analysis

Data was summarized using frequencies and percentages for categorical data, and medians and interquartile ranges for continuous data. Baseline characteristics were compared between patients discharged on a VKA plus either aspirin or plus clopidogrel using a Chi-square or Fisher's exact test for categorical data, and a Wilcoxon rank sum test for continuous data. The outcomes of interest were compared between groups using Fisher's exact tests. Due to a limited number of events, no multivariable modeling was performed. All tests were two-sided, and p-values ≤ 0.05 were considered statistically significant. All analyses were performed using SAS version 9.4 software (SAS Institute Inc.; Cary, NC).

Our assumption that 65% of patients would have received VKA plus aspirin and 35% had received a VKA plus P2Y12 inhibitor, and that 5% of those who receive VKA plus aspirin will have a bleeding event within 6 months, with a level of significance of 0.05, we would need 673 VKA plus aspirin patients and 363 VKA plus P2Y12 inhibitor patients in order to have 80% power to detect and increase in bleeding events of 5% or more in those receiving VKA plus P2Y12 inhibitor compared to VKA plus aspirin.

Results

Study Population

From January 1, 2012 to September 30, 2019, a total of 1273 patients underwent combined CABG plus SVR. A total of 629 patients met inclusion and exclusion criteria with a total of 583 patients discharged on aspirin and 46 patients discharged clopidogrel. Common reasons for exclusion were lack of a VKA prescribed on discharge (n = 340), additional surgery outside of SVR plus CABG (n = 264), and concomitant congenital heart disease (n = 40) (Figure 1).

Figure 1.

Application of inclusions and exclusion criteria. CABG, coronary artery bypass graft; SVR, surgical valve replacement; VKA, vitamin K antagonist.

Baseline characteristics of patients analyzed are outlined in Table 1. The median age was 74 and 71 years old in the aspirin and clopidogrel groups, respectively, and most patients were male in both groups. Comorbidities were common in each group, although patients receiving clopidogrel were more likely to have a history of diabetes, cerebral vascular disease, or previous PCI when compared to those receiving aspirin. Most patients underwent CABG plus aortic valve replacement while fewer underwent CABG plus mitral valve replacement. Mechanical valves were used more common than bioprosthetic valves. Cardiopulmonary bypass was utilized in all patients.

Table 1.

Baseline Characteristics.

Characteristic	Aspirin (n = 583)	Clopidogrel (n = 46)	p-value
Demographics
Age – years (Median, IQR)	74 (66, 79)	71 (64, 75)	0.14
Male – n (%)	448 (76.8%)	41 (89.1%)	0.054
Height (centimeters) (Median, IQR)	173 (165, 178)	177 (171, 181)	0.010
Weight (kilograms) (Median, IQR)	89 (76.2, 103)	85.6 (80.2, 101)	0.87
BMI (Median, IQR)	30.1 (26.8, 34.3)	30.2 (25.7, 32.2)	0.29
Race/Ethnicity – n (%)			0.67
White	556 (95.4%)	43 (93.5%)
Black/African American	(0.7%)	1 (2.2%)
Asian	3 (0.5%)	0 (0.0%)
Race – Other or Unknown	20 (3.4%)	2 (4.3%)
Medical History - n (%)
Diabetes	206 (35.3%)	23 (50.0%)	0.047
Dyslipidemia	523 (89.7%)	42 (91.3%)	0.73
Hypertension	503 (86.3%)	41 (89.1%)	0.59
Congestive Heart Failure	11 (1.9%)	0 (0.0%)	0.35
Cerebral Vascular Disease	111 (19.0%)	15 (33.3%)	0.021
Prior Myocardial Infarction	139 (23.8%)	16 (34.8%)	0.097
Prior Percutaneous Coronary Intervention	135 (23.2%)	20 (43.5%)	0.002
Peripheral Vascular Disease	109 (18.7%)	9 (19.6%)	0.88
Atrial Fibrillation or Atrial Flutter	108 (18.5%)	5 (10.9%)	0.19
Renal Fail-Dialysis	12 (2.1%)	1 (2.2%)	0.96
Tobacco Use	275 (61.1%)*	30 (65.2%)	0.59
Chronic Lung Disease	89 (15.3%)	7 (15.2%)	0.99
Previous Sternotomy	60 (10.3%)	6 (13.0%)	0.56
Surgical Variables
Surgery Status – n (%)			0.75
Elective	476 (81.6%)	39 (84.9%)
Urgent	102 (17.5%)	7 (15.2%)
Emergent	5 (0.9%)	0 (0.0%)
Cross Clamp Time (minutes) (Median, IQR)	102 (80, 126)	111 (92, 127)	0.12
Arterial Graft Used – n (%)			0.15
Missing	146	26
Number of Arterial Grafts	437	20
1	288 (65.9%)	9 (45%)
2	6 (1.4%)	0
3	12 (2.7%)	0
4	131 (30.0%)	11 (55%)
Venous Graft Used – n (%)			0.084
Missing	44	11
Number of Venous Grafts	520	35
1	102 (19.6%)	2 (5.7%)
2	273 (52.5%)	25 (71.4%)
3	137 (26.3%)	7 (20.0%)
4	7 (1.3%)	1 (2.9%)
5	1 (0.2%)	0
Aortic Valve Replacement – n (%) ^a			0.76
Number of Aortic Valve Replacements	502	41
Tissue	123 (24.5%)	12 (29.3%)
Mechanical	379 (75.5%)	29 (70.7%)
Mitral Valve Replacement – n (%)			0.45
Number of Mitral Valve Replacements	98	5
Tissue	38 (38.8%)	1 (20%)
Mechanical	60 (61.2%)	4 (80%)

Missing in 133. IQR interquartile range.

Outcomes

Bleeding occurred in 1.7% of patients in the aspirin group and in 0% of patients in clopidogrel group within six months following the procedure (p = 0.99) (Table 2). The most common site of bleeding in the aspirin group was gastrointestinal bleeding with seven events. In the ten patients that experienced a bleeding event, the median time from the surgical date to bleeding was 59 days with an interquartile range of 33 to 136 days. The median INR at the time of the bleeding event was 3.05 with an interquartile range of 2.7 to 3.4.

Table 2.

Results.

	Aspirin (n = 583)	Clopidogrel (n = 46)	p-value
Primary			0.99
Bleeding, n (%)	10 (1.7%)	0
Gastrointestinal	7 (1.2%)	0
Hemothorax	1 (0.2%)	0
Intracranial	2 (0.3%)	0
Secondary:			0.65
CV death, stroke, ACS, valve dysfunction, n (%)	18 (3.1%)	2 (4.3%)
CV death	6 (1%)	0
Stroke	9 (1.5%)	1 (2.1%)
ACS	1 (0.2%)	1 (2.1%)
Valve dysfunction	2 (0.3%)	0

The composite of CV death, stroke, ACS, or valve dysfunction occurred in 3.1% of patients in the aspirin group and in 4.3% of patients in the clopidogrel group (p = 0.65). CV death occurred in six (1%) patients in the aspirin group and in zero patients in the clopidogrel group. Stroke occurred in nine patients (1.5%) in the aspirin group and in one patient (2.1%) in the clopidogrel group. ACS occurred in one patient in each group (0.2% vs 2.1%), while valve dysfunction occurred in two patients (0.3%) of patients in the aspirin group and zero patients (0%) in the clopidogrel group.

Discussion

Oral anticoagulation plus antiplatelet therapy is the mainstay of antithrombotic therapy following combined CABG and SVR. The findings of this study suggest that there is no difference in rates of bleeding or the combined risk of CV death, stroke, ACS, or valve dysfunction among anticoagulated patients discharged on either aspirin or clopidogrel following combined CABG and SVR.

Current VHD guidelines recommend anticoagulation with a VKA for at least six months and indefinite aspirin in patients following bioprosthetic aortic and/or mitral valve replacement. Indefinite anticoagulation with a VKA is recommended for patients following mechanical aortic and/or mitral valve replacement.³ Previous CABG guidelines have recognized indefinite aspirin monotherapy as standard of care in patients following CABG to reduce the risk of graft occlusion.² More recently, data has emerged to suggest that the use of DAPT may be associated with a further reduction in the risk of graft occlusion and has resulted in formal recommendations to utilize DAPT following CABG in patients with ACS.^16–20 As such, patients that undergo combined CABG and SVR are candidates to receive triple antithrombotic therapy in the form of a VKA plus DAPT.

Numerous studies in patients with CAD undergoing percutaneous coronary intervention (PCI) have suggested an increased risk of bleeding with the use of OAC plus DAPT when compared OAC plus a single antiplatelet agent.^11–15 Considering the more invasive nature of cardiovascular surgical procedures when compared to PCI, avoidance of triple antithrombotic therapy in the surgical population is prudent.

While use of OAC plus either aspirin or a P2Y12 inhibitor have been separately evaluated in patients following transcatheter aortic valve replacement (TAVR), it is difficult to make substantial conclusions regarding their head-to-head safety and effectiveness.^21,22 Different OAC agents utilized, inherent differences in baseline characteristics between studies, and known differences in the risk of bleeding between TAVR and SVR limit the ability to extrapolate those results to patients that require antithrombotic therapy following SVR.^23–25 Furthermore, only approximately 40% of patients in those trials had documented CAD at baseline, limiting the generalizability of their findings to patients with combined VHD and significant CAD requiring surgical revascularization.

When comparing aspirin monotherapy to P2Y12 inhibitor monotherapy in patients with known cardiovascular disease, including patients with recent ACS, a P2Y12 inhibitor reduced the composite outcome of CV death, stroke, or ACS when compared to aspirin, without an observed difference in bleeding in one study.²⁶ Another study comparing aspirin and clopidogrel monotherapy suggested clopidogrel use was associated with lower rates of both ischemic and bleeding events than aspirin.²⁷ In both studies, clopidogrel was associated with less gastrointestinal bleeding. This is consistent with the findings from our study in which numerically less gastrointestinal bleeding was observed in patients receiving clopidogrel. The consistent reduction in thrombotic events observed in these trials suggests that clopidogrel may be preferred over aspirin in patients with risk factors or comorbidities that predispose patients for high risk of future thrombotic events. Notably, patients requiring long-term anticoagulation and those with scheduled major surgery were excluded from both trials, limiting their generalizability of these findings to patients requiring anticoagulation following CABG and SVR.

Both groups in our study experienced rates of stroke similar to historical controls undergoing CABG plus aortic valve placement (AVR) and CABG plus mitral valve replacement (MVR). In 2019, stroke occurred in 2% of patients undergoing CABG plus AVR and in 3.1% of patients undergoing CABG plus MVR. No data were available for estimates of CV death, ACS, or valve dysfunction in historical controls. The findings describing the safety and effectiveness in our study are especially important given the consistently high cases of CABG plus SVR reported to the international STS Adult Cardiac Surgery Database, with over 14,000 patients having underwent CABG plus AVR and over 3400 patients having underwent CABG plus MVR in 2018 alone.²⁸

To the author's knowledge, this is the only study to date evaluating the safety and effectiveness of aspirin versus clopidogrel in patients also anticoagulated with a VKA following CABG and SVR. There are, however, several limitations to this study. Despite the large sample size, low event rates may have limited the ability to detect a difference between groups. The time in therapeutic range was not collected for patients on warfarin nor was the exact duration of antithrombotic therapy. While anticoagulation was recommended for six months in patients following bioprosthetic valve replacement and lifelong for patients following mechanical valve replacement, outpatient compliance was unable to be accessed. Finally, the retrospective, observational nature of the study limits the ability to draw major conclusions regarding causality.

Conclusion

In this study, no difference in bleeding or risk of CV death, stroke, ACS, or valve dysfunction was observed among patients receiving VKA plus either aspirin or clopidogrel following CABG and SVR. In patients undergoing combined CABG and SVR, the choice in antiplatelet agent utilized should be based on patient-specific factors in the setting of no clear safety or effectiveness signals. Larger and randomized studies are warranted to confirm these findings.

Supplemental Material

sj-docx-1-cat-10.1177_10760296231156175 - Supplemental material for A Single-Center Bleeding Comparison of Warfarin Plus Aspirin or Clopidogrel Following Coronary Artery Bypass Grafting and Surgical Valve Replacement

Supplemental material, sj-docx-1-cat-10.1177_10760296231156175 for A Single-Center Bleeding Comparison of Warfarin Plus Aspirin or Clopidogrel Following Coronary Artery Bypass Grafting and Surgical Valve Replacement by Joseph J. Zieminski, Kristin C. Mara and Kyle S. Wamsley, John M. Stulak, Scott D. Nei in Clinical and Applied Thrombosis/Hemostasis

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Joseph J. Zieminski

Scott D. Nei

Supplemental Material

Supplemental material for this article is available online.

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