Use of preoperative aspirin in combined coronary and valve operations

Cardiac Presented at the Academic Surgical Congress 2016

Use of preoperative aspirin in combined coronary and valve operations Rustin Kashani, BS, Cayley Bowles, MS, Sohail Sareh, MD, William Toppen, MD, Ryan Ou, BS, Richard Shemin, MD, and Peyman Benharash, MD, Los Angeles, CA

Background. The aim of this study was to determine the relationship between preoperative aspirin use and postoperative outcomes in patients undergoing combined coronary artery bypass grafting and valve operations. Methods. All combined coronary artery bypass grafting and valve procedures from 2008 to 2015 at our institution were identified. After exclusions, patients were stratified according to those that received preoperative aspirin and those who did not. Propensity score methodology was used to match the 2 groups using baseline and operative characteristics. Logistic regression models were then developed to assess differences in postoperative outcomes between groups. Results. Of the 563 patients identified, 534 met inclusion criteria: preoperative aspirin = 327 (61.2%), no preoperative aspirin = 207 (38.8%). After propensity matching, 194 patient pairs were analyzed, with no significant differences in preoperative characteristics. No significant differences were observed between the preoperative aspirin and no preoperative aspirin groups in rates of 30-day mortality (3.6% vs 4.1%, P = 1.00), major adverse cardiovascular events (23.2% vs 24.2%, P = .91), or 30-day readmission (12.4% vs 11.9%, P = 1.00), among others. Conclusion. Preoperative aspirin use in patients undergoing combined coronary artery bypass grafting and valve operations was not associated with significant differences in major postoperative outcomes. Large-scale, randomized trials are needed to better establish the role of preoperative aspirin in this population. (Surgery 2016;160:1612-8.) From the Division of Cardiac Surgery, Department of Surgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA

ASPIRIN is a widely used therapeutic due to both its anti-inflammatory and antiplatelet properties.1 While its efficacy in preventing thrombotic events is recognized, prior studies have also shown an

Presented at the 11th Annual Academic Surgical Congress in Jacksonville, FL, February 2–4, 2016, in the Cardiothoracic Oral Session. Accepted for publication July 23, 2016. Reprint requests: Peyman Benharash, MD, Division of Cardiac Surgery, Department of Surgery, David Geffen School of Medicine, 10833 Le Conte Avenue, UCLA Center for Health Sciences, Room 62-249, Los Angeles, CA 90095. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2016.07.034

1612 SURGERY

increased risk of both spontaneous and postoperative bleeding with aspirin administration.2,3 Thus, current guidelines recommend aspirin use in patients for whom the benefit of reduced risk of myocardial infarction or ischemic stroke outweighs the increased risk of gastrointestinal bleeding.4 In cardiac, operatively treated patients, aspirin use is considered standard of care for up to 1 year after coronary revascularization (CABG) procedures due to its improvement of early graft patency and protection against cardiovascular events.5-7 Many studies have even demonstrated improved survival in CABG patients receiving aspirin postoperatively.8-10 However, the role of preoperative aspirin in cardiac operations remains unclear. While numerous studies have examined the effect of aspirin prior to CABG operations, results

Kashani et al 1613

Surgery Volume 160, Number 6

Table I. Baseline characteristics Preoperative use of aspirin within 5 days before operation Before propensity score matching Patient characteristics Preoperative clinical characteristics Age (mean ± SD) Male Caucasian BMI, kg/m2 (mean ± SD) Smoker Cerebrovascular disease Chronic lung disease Vascular disease Dyslipidemia Dialysis Elevated creatinine* Anemiay Diabetes Hypertension Congestive heart failure Prior cardiovascular intervention Preoperative medications Beta-blocker Nonwarfarin anticoagulant Warfarin ADP receptor inhibitor ACE-inhibitor Statin Operative characteristics Urgent Elective Mitral valve operation Aortic valve operation Tricuspid valve operation Pulmonic valve operation Multiple valve operation Multivessel CABG Number of grafts (mean ± SD)

After propensity score matching

N-ASA (n = 207)

ASA (n = 327)

P value

N-ASA (n = 194)

ASA (n = 194)

P value

70.2 ± 11 140 141 27.4 ± 6 51 38 149 84 132 12 44 103 78 148 124 78

71.9 ± 11 232 224 27.5 ± 6 84 62 260 174 250 29 79 191 130 267 197 126

.08 .44 .92 .91 .84 .91 .04 <.01 <.01 .24 .46 .06 .65 <.01 1.00 .86

69.9 ± 11 129 137 27.4 ± 6 50 37 145 78 128 12 35 101 76 144 117 73

71.1 ± 12 133 144 27.5 ± 6 48 38 145 75 132 12 41 103 71 146 115 67

.30 .75 .50 .90 .91 1.00 1.00 .84 .75 1.00 .52 .92 .68 .91 .92 .60

131 44 27 13 76 96

239 44 30 39 175 219

.02 .02 .20 .04 <.01 <.01

126 43 26 12 75 90

129 38 23 12 75 98

.83 .62 .76 1.00 1.00 .48

75 129 87 149 26 21 64 109 1.9 ± 1

127 197 128 234 28 25 79 188 2.1 ± 1

.58 .65 .53 1.00 .14 .34 .09 .28 .05

72 119 81 141 25 19 60 101 1.9 ± 1

71 122 71 146 18 18 51 106 2.0 ± 1

1.00 .83 .35 .64 .33 1.00 .37 .68 .14

*Defined as serum creatinine >1.5 mg/dL if a man, >1.4 mg/dL if a woman. yDefined as hematocrit <39 if a man, <36 if a woman. BMI, Body mass index; ADP, adenosine diphosphate; ACE, angiotensin converting enzyme.

have been inconsistent.11-19 A review of patients undergoing first-time CABG found that preoperative aspirin reduced the risk of perioperative myocardial infarction (MI) but increased risk of bleeding, need for blood transfusion, and operative re-exploration.4 However, others have not reliably duplicated these findings, and considerable variation exists with respect to guidelines and clinical practice.20 Similarly, limited data exist on the benefits of preoperative aspirin for patients undergoing combined off-pump CABG and valvular procedures.17,21-23 It has been previously reported that

patients on aspirin who undergo combined CABG and valve operations experience higher postoperative complication rates than patients undergoing either procedure alone.24,25 Given that aspirin improves graft patency but may lead to additional blood loss, defining the role of preoperative aspirin for patients undergoing combined coronary/valve operations is of particular interest.7 The present study was performed to determine the effect of preoperative aspirin administration on clinical outcomes in patients undergoing combined coronary revascularization and valve

1614 Kashani et al

Surgery December 2016

Fig 1. Study sample selection. Eligible patients undergoing coronary artery bypass grafting (CABG) with valve operations were identified from our institutional database. Propensity matching was used after application of exclusionary criteria to yield the analyzed study groups.

operations. We hypothesized that administration of preoperative aspirin would not significantly alter postoperative outcomes. METHODS Our institutional Society of Thoracic Surgeons database was used to identify all adult patients who underwent combined CABG and valve operations from January 2008 to December 2015. Patients undergoing emergency, redo, and transplant operations were excluded to reduce variability and the influence of outliers. The remaining patients were divided into 2 groups: those who received aspirin within 5 days prior to an operation (ASA group) and those who did not (N-ASA group). To control for significant intergroup differences and eliminate possible selection bias, propensity score–matching methodology was utilized, accounting for 29 baseline patient characteristics associated with aspirin use (Table I). A multivariate logistic regression model was used to determine an individual propensity score (dependent variable) for each patient, defined as the probability that a patient would receive preoperative aspirin. Next, based on the propensity score, each patient in the ASA group was matched to a subject in the N-ASA group using a 1:1 greedy matching algorithm. Patients without a suitable match were excluded from further analysis. The primary outcome of the study was all-cause mortality at 30 days after an operation. Secondary

outcomes included hospital duration of stay; 30day readmission; complications of anticoagulation, such as heparin-induced thrombocytopenia; reoperation for bleeding requiring a perioperative transfusion, both intraoperatively or postoperatively; acute renal failure; and a composite of major adverse cardiovascular events (MACE), defined as: atrial fibrillation, cardiac arrest, stroke, transient ischemic attack, MI, or recurrent angina. Logistic regression models were used to compute odds ratios (OR), P values, and confidence intervals (CI) for each outcome variable. Of note, a “preoperative anticoagulation” variable was developed based on the administration of unfractionated heparin, low molecular weight heparin, or direct thrombin inhibitors within 48 hours of an operation. All other preoperative and outcome variables were defined as specified by the Adult Cardiac Database Specifications (version 2.81; Society of Thoracic Surgeons, Chicago, IL).26 STATA (version 13.0; StataCorp LP, College Station, TX) software was used for all statistical analysis. This study was approved by the institutional review board at the University of California, Los Angeles, and waiver of consent was obtained. RESULTS Patient and operative characteristics. Of the 4,744 patients who underwent cardiac operations at our facility during the study period, 563 were

Kashani et al 1615

Surgery Volume 160, Number 6

Table II. Associations between preoperative aspirin use and outcome variables in propensity score– matched patients No preoperative aspirin (n = 194)

Preoperative aspirin (n = 194)

Outcome

N

%

N

%

OR

95% CI

P value

30-day mortality Perioperative transfusion Intraoperative transfusion Postoperative transfusion Reoperation for bleeding 30-day readmission Anticoagulant complications Renal failure MACE*

8 167 152 85 4 23 2 4 47

4.1 86.1 78.4 43.8 2.1 11.9 1.0 2.1 24.2

7 176 160 93 5 24 1 7 45

3.6 90.1 82.5 47.9 2.6 12.4 0.5 3.6 23.2

0.57 1.46 1.03 1.10 1.29 0.99 0.28 2.91 0.94

0.17–1.93 0.52–4.12 0.47–2.26 0.70–1.73 0.32–5.17 0.53–1.84 0.02–3.94 0.61–13.86 0.58–1.53

1.00 .20 .37 .47 1.00 1.00 1.00 .54 .91

*Defined as atrial fibrillation, cardiac arrest, stroke, transient ischemic attack, MI, or recurrent angina.

identified as having a combined CABG and valve procedure. After application of exclusion criteria, 534 (ASA group = 327, 61.2%) patients were included in the study (Fig 1). Patients in the ASA group were significantly more likely to have chronic lung disease, vascular disease, dyslipidemia, and hypertension (Table I). Additionally, patients in the ASA group had higher rates of beta-blockade, statin, angiotensin-converting enzyme inhibitor, and adenosine diphosphate receptor inhibitor use prior to an operation. Patients in the ASA group were also less likely to be taking nonwarfarin anticoagulants. Propensity score matching. Propensity matching using the greedy matching algorithm yielded 194 patient pairs (Table II). The standardized percent difference in covariates before and after matching can be found in Fig 2. No significant differences in baseline characteristics were found after propensity score matching (Table I). Postoperative outcomes. As shown in Table II, no significant difference in all-cause, 30-day mortality was noted between groups (ASA = 3.6% vs N-ASA = 4.1%, P = 1.00). Moreover, both cohorts had similar rates of secondary outcomes; ORs were calculated for complications, such as reoperation for bleeding, renal failure, MACE, and complications of anticoagulation, and none yielded a significant difference with the use of aspirin (Table II). Subgroup analyses were performed to further investigate effects of preoperative aspirin in patients undergoing aortic valve replacement with single vessel disease. These patients are often thought to have lesser systemic atherosclerotic burden. Those taking preoperative aspirin were found to have lower rates of 30-day readmission

Fig 2. Standardized percent difference in covariates before and after matching. Baseline characteristics were compared between patients before and after propensity score matching. ACE, Angiotensin-converting enzyme; ADP, adenosine diphosphate.

when compared to patients who did not take preoperative aspirin (Table III, P = .05). Origin of conduit (arterial versus venous) did not significantly differ relative to preoperative aspirin in these patients (ASA = 50.5% venous vs NASA = 55.1% venous, P = .73). All patients included in our analysis underwent on-pump CABG and aortic valve replacement. Among patients undergoing multivessel CABG with aortic valve replacement, preoperative aspirin use did not have a significant effect on rates of clinical outcomes (Table IV). Number of conduits used can be found in Table V. A similar analysis was repeated in patients undergoing mitral, tricuspid, pulmonic, and combined valve operations, yielding no significant findings.

1616 Kashani et al

Surgery December 2016

Table III. Effects of preoperative aspirin in patients undergoing single-vessel CABG with aortic valve replacement No preoperative aspirin (n = 69)

Preoperative aspirin (n = 75)

Outcome

N

%

N

%

P value

30-day mortality Perioperative transfusion Intraoperative transfusion Postoperative transfusion Reoperation for bleeding 30-day readmission Anticoagulant complications Renal failure MACE*

0 61 57 29 0 11 1 0 14

0.0 88.4 82.6 42.0 0.0 15.9 1.5 0.0 20.3

2 68 60 33 1 4 1 3 20

2.7 90.7 80.0 44.0 1.3 5.3 1.3 4.0 26.7

.50 .79 .83 .87 1.00 .05 1.00 .25 .43

*Defined as atrial fibrillation, cardiac arrest, stroke, transient ischemic attack, MI, or recurrent angina.

Table IV. Effect of preoperative aspirin in patients undergoing multivessel CABG with aortic valve replacement No preoperative aspirin (n = 72)

Preoperative aspirin (n = 71)

Outcome

N

%

N

%

P value

30-day mortality Perioperative transfusion Intraoperative transfusion Postoperative transfusion Reoperation for bleeding 30-day readmission Anticoagulant complications Renal failure MACE*

5 64 58 33 3 7 1 2 25

6.9 88.9 80.6 45.8 4.2 9.7 1.4 2.8 34.7

3 64 60 35 3 10 0 4 16

4.2 90.1 84.5 49.3 4.2 14.1 0.0 5.6 23.0

.72 1.00 .66 .74 1.00 .45 1.00 .44 .14

*Defined as atrial fibrillation, cardiac arrest, stroke, transient ischemic attack, MI, or recurrent angina.

Table V. Number of conduits in multivessel CABG with aortic valve replacement

Number of conduits 2 3 4 5

No preoperative aspirin (n = 72)

Preoperative aspirin (n = 71)

All patients (n = 143)

N

%

N

%

N

%

43 27 2 0

59.7 37.5 2.8 0.0

34 28 7 2

47.9 39.4 9.9 2.8

77 55 9 2

53.8 38.5 6.3 1.4

DISCUSSION In this propensity-matched study of adult patients undergoing combined CABG and valve operations, preoperative use of aspirin was not associated with statistically significant differences

in mortality, bleeding, or other acute adverse outcomes. To date, only one other study by Jacob et al24 has examined the effects of aspirin in patients undergoing combined CABG and valve operations. We did not share their finding of higher postoperative transfusions with the use of preoperative aspirin. Subgroup analysis among patients undergoing single-vessel CABG with aortic valve replacement revealed a trend toward decreased rate of readmission among those receiving preoperative aspirin. This association was not seen in the subsequent analysis of patients having multivessel CABG with aortic valve replacement. Larger-scale studies are needed to further explore this potential deleterious effect. The considerable variability in reported effects of preoperative aspirin in cardiac operation patients may be due to a number of factors. Firstly, most previous studies of preoperative aspirin have compared heterogeneous populations. Patients

Kashani et al 1617

Surgery Volume 160, Number 6

already on aspirin before a cardiac operation may reasonably be expected to have risk factors for systemic atherosclerosis and have a higher risk profile. Significant differences in baseline characteristics, as was the case in the present study, limit the utility of nonmatched studies that may be confounded by large, intergroup disparities. Few randomized trials evaluating the use of aspirin in cardiac operations have been reported11,18; however, a recent randomized study showed no differences in bleeding, mortality, or thrombotic complications with preoperative aspirin in CABG patients.27 The risk of bleeding after aspirin use is likely related to the antiplatelet effects of the drug. Specifically, it inhibits platelet cyclooxygenase-1 and prevents the production of thromboxane-A2, a thromboxane that promotes platelet aggregation and vasoconstriction.28 However, aspirin also prevents the production of prostacyclin in the vascular endothelium and inhibits platelet aggregation.29 Aspirin has also been recognized as a major antiinflammatory agent, and as such, reduces oxidative stress and the overall inflammatory response. Since inflammation plays a large role in postoperative bleeding and fibrinolysis, the effects of aspirin on hemorrhage may be mixed and difficult to discern clinically.30 Our study has several limitations, which include those inherent to its retrospective nature. This was a single-center study, and the findings may not be generalizable. We attempted to reduce bias by minimizing exclusion criteria, using propensity matching, utilizing a large sample size and accounting for many possible risk factors. The database did not include data on chest tube drainage, and we were unable to evaluate postoperative blood loss. Transfusion requirements in the postoperative period were used to assess this parameter. Also, the dosage of aspirin was not available, as its usage was marked as a binary question in the data set. Finally, some postoperative complications occurred with very low frequency, increasing the likelihood of type II error when interpreting the results of our study. In conclusion, preoperative administration of aspirin in patients undergoing combined coronary/valve operations was not associated with significant differences in major outcomes including mortality and bleeding. Given our findings and the available previously published data, insufficient evidence exists regarding the routine use or discontinuation of aspirin in these patients. This question deserves further evaluation in large-scale, randomized trials.

REFERENCES 1. Ittaman SV, VanWormer JJ, Rezkalla SH. The role of aspirin in the prevention of cardiovascular disease. Clin Med Res 2014;12:147-54. 2. Huang ES, Strate LL, Ho WW, Lee SS, Chan AT. Long-term use of aspirin and the risk of gastrointestinal bleeding. Am J Med 2011;124:426-33. 3. Scott IA, Shohag HA, Kam PCA, Jelinek MV, Khadem GM. Preoperative cardiac evaluation and management of patients undergoing elective non-cardiac surgery. Med J Aust 2013;199:667-73. 4. Hastings S, Myles P, McIlroy D. Aspirin and coronary artery surgery: a systematic review and meta-analysis. Br J Anaesth 2015;115:376-85. 5. Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, et al. Saphenous vein graft patency 1 year after coronary artery bypass surgery and effects of antiplatelet therapy. Results of a Veterans Administration Cooperative Study. Circulation 1989;80:1190-7. 6. Stein P, Schunemann H, Dalen J, Gutterman D. Antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:600S-8S. 7. Gukop P, Gutman N, Bilkhu R, Karapanagiotidis GT. Who might benefit from early aspirin after coronary artery surgery? Interact Cardiovasc Thorac Surg 2014;19: 505-11. 8. Eagle KA, Guyton RA, Davidoff R, Edwards FH, Ewy GA, Gardner TJ, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery). Circulation 2004;110:116876. 9. Ferraris VA, Ferraris SP, Moliterno DJ, Camp P, Walenga JM, Messmore HL, et al. The Society of Thoracic Surgeons practice guideline series: aspirin and other antiplatelet agents during operative coronary revascularization (executive summary). Ann Thorac Surg 2005;79:1454-61. 10. Kempfert J, Anger K, Rastan A, Krabbes S, Lehmann S, Garbade J, et al. Postoperative development of aspirin resistance following coronary artery bypass. Eur J Clin Invest 2009;39:769-74. 11. Ma X, Ma C, Yun Y, Zhang Q, Zheng X. Safety and efficacy outcomes of preoperative aspirin in patients undergoing coronary artery bypass grafting: a systematic review and meta-analysis. J Cardiovasc Pharmacol Ther 2014;19:97-113. 12. Alghamdi AA, Moussa F, Fremes SE. Does the use of preoperative aspirin increase the risk of bleeding in patients undergoing coronary artery bypass grafting surgery? Systematic review and meta-analysis. J Card Surg 2007;22: 247-56. 13. Oscarsson A, Gupta A, Fredrikson M, Jarhult J, Nystrom M, Pettersson E, et al. To continue or discontinue aspirin in the perioperative period: a randomized, controlled clinical trial. Br J Anaesth 2010;104:305-12. 14. Bybee KA, Powell BD, Valeti U, Rosales AG, Kopecky SL, Mullany C, et al. Preoperative aspirin therapy is associated with improved postoperative outcomes in patients undergoing coronary artery bypass grafting. Circulation 2005;112(9 Suppl):I286-92. 15. Dacey LJ, Munoz JJ, Johnson ER, Leavitt BJ, Maloney CT, Morton JR, et al. Effect of preoperative aspirin use on

1618 Kashani et al

16.

17.

18.

19.

20.

21.

22.

mortality in coronary artery bypass grafting patients. Ann Thorac Surg 2000;70:1986-90. Yao L, Young N, Liu H, Li Z, Sun W, Goldhammer J, et al. Evidence for preoperative aspirin improving major outcomes in patients with chronic kidney disease undergoing cardiac surgery: a cohort study. Ann Surg 2015; 261:207-12. Srinivasan AK, Grayson AD, Pullan DM, Fabri BM, Dihmis WC. Effect of preoperative aspirin use in off-pump coronary artery bypass operations. Ann Thorac Surg 2003;76:41-5. Deja MA, Kargul T, Domaradzki W, Stacel T, Mazur W, Wojakowski W, et al. Effects of preoperative aspirin in coronary artery bypass grafting: a double-blind, placebocontrolled, randomized trial. J Thorac Cardiovasc Surg 2012;144:204-9. Cao L, Young N, Liu H, Silvestry S, Sun W, Zhao N, et al. Preoperative aspirin use and outcomes in cardiac surgery patients. Ann Surg 2012;255:399-404. Dunning J, Versteegh M, Fabbri A, Pavie A, Kolh P, Lockowandt U, et al. Guideline on antiplatelet and anticoagulation management in cardiac surgery. Eur J Cardiothorac Surg 2008;34:73-92. Mazzeffi M, Kassa W, Gammie J, Tanaka K, Roman P, Zhan M, et al. Preoperative aspirin use and lung injury after aortic valve replacement surgery: a retrospective cohort study. Anesth Analg 2015;121:271-7. Huang J, Donneyong M, Trivedi J, Barnard A, Chaney J, Dotson A, et al. Preoperative aspirin use and its effect on adverse events in patients undergoing cardiac operations. Ann Thorac Surg 2015;99:1975-81.

Surgery December 2016

23. Xiao F, Wu H, Sun H, Pan S, Xu J, Song Y. Effect of preoperatively continued aspirin use on early and mid-term outcomes in off-pump coronary bypass surgery: a propensity scorematched study of 1418 patients. PLoS One 2015;10:e0116311. 24. Jacob M, Smedira N, Blackstone E, Williams S, Cho L. Effect of timing of chronic preoperative aspirin discontinuation on morbidity and mortality in patients having combined coronary artery bypass grafting and valve surgery. Am J Cardiol 2012;109:824-30. 25. Li Z, Anderson I, Amsterdam EA, Young JN, Parker J, Armstrong EJ. Effect of coronary artery disease extent on contemporary outcomes of combined aortic valve replacement and coronary artery bypass graft surgery. Ann Thorac Surg 2013;96:2075-82. 26. STS adult cardiac database data specifications version 2.81. Chicago (IL): Society of Thoracic Surgeons; 2014. 27. Myles PS, Smith JA, Forbes A, Silbert B, Jayarajah M, Painter T, et al. Stopping vs continuing aspirin before coronary artery surgery. N Engl J Med 2016;374:728-37. 28. Reilly IA, Fitzgerald GA. Aspirin in cardiovascular disease. Drugs 1988;35:154-76. 29. Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 1976;263:663-5. 30. Nenna A, Spadaccio C, Prestipino F, Lusini M, Sutherland FW, Beattie GW, et al. Effect of preoperative aspirin replacement with enoxaparin in patients undergoing primary isolated on-pump coronary artery bypass grafting. Am J Cardiol 2016;117:563-70.