Postoperative stroke remains a relatively common and often debilitating complication after cardiac surgery, affecting approximately 2% of patients, and carrying a 5-fold higher risk for postoperative mortality.1 Despite important advances in patient care, surgical strategies, and cardiopulmonary bypass (CPB) equipment, this incidence of stroke has not changed significantly over the past 2 decades.2 Thus, as increasing numbers of older patients with more comorbidities are undergoing cardiac surgery, and as more patients are surviving surgery, the prediction, management, and prevention of stroke after coronary artery bypass grafting (CABG) surgery are health care priorities of increasing concern.
The etiology of stroke after on-pump CABG surgery is complex and multifactorial,3,4 with important differences between early (0–1 days) and delayed (≥2 days) strokes. Most early strokes purportedly arise from particulate and gaseous embolism during surgery,5 and/or are precipitated by intraoperative hemodynamic perturbations.6 In contrast, a crucial factor in the development of delayed strokes is likely the prothrombotic postoperative state,7 promoted by significant and protracted humoral and cellular inflammatory responses,8 and platelet activation9,10 during and after cardiac surgery.
The role of platelets has come under significant scrutiny in various disease processes as they are increasingly recognized as important and ubiquitously present regulators of tissue inflammation.11 We recently reported that, similar to observations in critically ill patients,12 postoperative thrombocytopenia, defined as the lowest in-hospital values, is associated with acute kidney injury and increased risk for mortality after CABG surgery.13 The cause of the postoperative decline in platelet counts and, importantly, the connection between thrombocytopenia and the development of adverse outcomes remain unknown. Because platelet counts frequently drop to a nadir after cardiac surgery,13 the observed thrombocytopenia is likely the result of platelet activation and consumption in a setting of systemic hypercoagulability. We therefore hypothesized that thrombocytopenia after on-pump CABG surgery is associated with postoperative stroke.
After approval by the Institutional Review Board for Clinical Investigations at Duke University Medical Center (Durham, NC), we conducted this retrospective observational study on patients older than 18 years who underwent isolated urgent or elective CABG surgery with CPB at the Duke University Medical Center from January 1, 2001, to July 18, 2015. For patients who had more than one cardiac surgery during that period, only data from the first surgery were evaluated. Of the original 6921 patients, 6131 had complete data for preoperative and postoperative platelet counts and met criteria for inclusion in the present study. Of the 6131 patients analyzed and reported in this study, 4217 have been analyzed as part of a separate publication.13
A standard set of perioperative data were collected from Duke University Medical Center databases including the Duke Perioperative Electronic Database (Innovian Anesthesia; Draeger Medical, Inc, Telford, PA), Cardiac Surgery Quality Assurance Database, Duke Databank for Cardiovascular Diseases, and from Duke MAESTRO CARE (Medical Application Environments Supporting Transformation of Research and Operations, http://www.dukehealth.org/maestrocare), Duke Medicine’s platform-based electronic health record (Epic Systems Corporation, Verona, WI; http://www.epic.com).
Clinical Risk Factors
The clinical risk factors for postoperative stroke included patient characteristics, preoperative and intraoperative cardiovascular medication use including prothrombin complex and recombinant factor VII, components of the European System for Cardiac Operative Risk Evaluation score,14 CPB and aortic cross-clamp times, insertion of intra-aortic balloon pump (IABP), intraoperative and postoperative blood transfusions, and hemoglobin and platelet counts. According to institutional practice, preoperative antiplatelet therapy with aspirin was maintained until the day before surgery, clopidogrel was discontinued 7 days or longer before surgery, and warfarin was discontinued 4 days before surgery and “bridged” with intravenous heparin infusion.13
Per institutional protocol, platelet counts were also measured preoperatively in the Duke Clinical Pathology Laboratory and for the first 10 days postoperatively or until discharge, whichever came first, as described previously.13 We analyzed the association of both daily minimum postoperative platelet values and lowest minimum (nadir) platelet counts with our stroke outcome. For the analysis of association of nadir platelet values, we conditionally defined nadir platelets relative to stroke outcomes. When stroke preceded the postoperative nadir platelet counts, we used lowest prestroke platelet value as a predictor of postoperative stroke. These values were subsequently used as a continuous predictor of postoperative stroke. Further, based on laboratory definitions of thrombocytopenia, postoperative platelet values were used as a categorical predictor (mild thrombocytopenia [100–150 × 109/L] and moderate to severe thrombocytopenia [<100 × 109/L]) and as a threshold for clinical characterization of patients with different grades of postoperative thrombocytopenia.
Similarly, serum hemoglobin concentrations were measured per institutional protocol, preoperatively and for the first 10 days postoperatively or until discharge, whichever came first. Daily and minimum serum hemoglobin concentrations were defined as the lowest in-hospital values measured during the first 10 postoperative days (PODs) or to day of hospital discharge and were considered as adjustment variables in our analyses of postoperative stroke.
Classification of Outcome
Postoperative stroke was chosen as the outcome and was ascertained and categorized in a manner similar to the study by Hogue et al.4 In brief, postoperative stroke was defined as any new permanent global or focal neurologic deficit that could not be attributed to preexisting neurologic and/or nonneurologic pathophysiologic abnormalities. Reversible cerebral ischemic events, such as a transient ischemic attack, were not included in the current study because the residual effect of perioperative medications could hinder their detection. Per Duke institutional protocol, all patients undergoing cardiac surgery were screened daily during the postoperative period to identify patients with postoperative stroke. When a new postoperative neurologic deficit was detected, a stroke code was initiated. A subsequent diagnosis of stroke was established by the attending neurologist, and was substantiated in most patients by neuroimaging, eg, computed tomography (CT) or magnetic resonance imaging (MRI) head scan. In the current study, the patients’ electronic health records were screened for International Classification of Disease-9th Revision (http://www.cdc.gov/nchs/icd/icd9cm.htm) codes for cerebrovascular accident, eg, ischemic (434.91), embolic (434.11), hemorrhagic (430, 431, 432.0–432.9), thrombotic (434.01), and postoperative cerebrovascular accident (997.02). In parallel, electronic imaging records, as part of the electronic health records of all patients, we screened for the current procedural terminology billing codes for a CT scan of the head (70450 [CT scan of the head without contrast], 70460 [CT scan of the head with contrast], and 70470 [CT scan without contrast followed by a CT procedure with contrast]) and for an MRI scan of the brain (70551 [MRI brain without contrast], 70552 [MRI brain with contrast], and 70553 [MRI brain without contrast followed by an MRI procedure with contrast]). CT and MRI scans with a date stamp within 30 days of CABG surgery were selected and reviewed for a diagnosis of acute postoperative stroke. All stroke diagnoses and imaging reports were then reviewed by 3 investigators (A.E.M., J.A.K., M.D.K.), and the diagnoses and timing of strokes were ascertained in relation to the date of surgery. New neurologic deficits identified before the end of POD 1 were classified as early strokes, and neurologic deficits that occurred between POD 2 and 30 inclusively were classified as delayed strokes.
Summary statistics are presented as median (interquartile range) for continuous variables, or as group frequencies and percentages for categorical variables by categories of postoperative thrombocytopenia that were defined using the lowest in-hospital value or the lowest platelet value before stroke. Kruskal-Wallis or χ2 tests were used for descriptive group comparisons as appropriate.
Univariable and multivariable Cox proportional hazard regression models were applied to evaluate the unadjusted and adjusted prognostic importance of postoperative platelet counts and risk for postoperative stroke. Given the day-to-day variations in postoperative platelet counts and serum hemoglobin concentrations in our study, we used extended Cox regression analysis with time-varying covariates and hazard ratios (HRs) to model the effects of day-to-day variations in postoperative platelet counts and serum hemoglobin concentrations on the risk for postoperative stroke.15–17 We defined the time-varying platelet counts variable (both categorical and continuous) in our proportional hazards models based on the most recent daily minimum platelet counts relative to the time being evaluated. For all time points after discharge or POD 10, whichever came first, time-varying platelet counts model term was based on the last recorded daily minimum value. The resulting HR estimates for effect of postoperative platelet counts in these models should be interpreted as comparisons of the hazard for 2 patients with different postoperative platelet counts on the same day after surgery. Univariable associations with P < .10 were evaluated using a forward stepwise technique to derive the final multivariable Cox proportional hazard regression model containing variables with P < .05. Continuous variables (ie, age, serum creatinine, hemoglobin and platelet counts, and duration of CPB time) were evaluated for nonlinearity, and transformations were performed if warranted. Of note, including time-dependent covariates for postoperative platelet counts and serum hemoglobin concentrations precluded us from the evaluation of the discriminatory ability and calibration of the final multivariable Cox regression models.
In a subsequent analysis, we investigated the association between daily postoperative platelet counts and timing of stroke using the Fine-Gray method of proportional hazard models for the subdistribution of early and delayed strokes.18 Under the Fine-Gray method, the subdistribution hazard for a given subevent is defined as the hazard for a patient who either suffers the subevent or not and expands the risk set at a given time to include both those who have experienced a different subevent and those who are currently event free. This analysis method allows us to estimate the effect of daily postoperative platelet counts on the absolute risk of early and delayed stroke and to estimate the cumulative impact of daily postoperative platelet counts on patient stroke prognosis.19 We built multivariable models separately for each subevent using forward stepwise technique to derive final multivariable proportional hazards models containing variables with P < .05 for early and delayed stroke events. As in the main analysis, we used a time-varying effect for day-to-day variations in postoperative platelet counts (both categorical and continuous).
A sensitivity analysis was also performed to determine whether exclusion of patients with heparin-induced thrombocytopenia (HIT) affected the observed association between thrombocytopenia and stroke. The presence of HIT was ascertained by reviewing the patients’ electronic health records for the diagnosis of HIT and by searching laboratory records for enzyme-linked immunosorbent assays that were positive for human platelet factor 4/heparin complex antibodies. HRs and odds ratios with corresponding 95% confidence limits are reported. SAS Version 9.4 (SAS Institute, Inc, Cary, NC) was used for all statistical analyses.
The overall median (interquartile range) for postoperative nadir platelet counts was 123.0 (98.0–155.0) × 109/L. The 6130 patients studied were separated into 3 groups according to postoperative nadir platelet counts: (1) no thrombocytopenia (>150 × 109/L; 27%, n = 1750); (2) mild thrombocytopenia (100–150 × 109/L; 44.4%, n = 2726); and (3) moderate to severe thrombocytopenia (<100 × 109/L; 28.6%, n = 1654). Demographic and clinical characteristics of the 3 groups according to postoperative nadir platelet counts are compared in Table 1. Several significant differences between the groups were found including age, race, female sex, medical history, comorbidities, preoperative and intraoperative medication use, and intraoperative characteristics. Of note, none of the patients who developed stroke had received prothrombin complex or recombinant factor VII.
The overall incidence of postoperative stroke was 1.8% (n = 110) within 30 days after surgery. In 101 patients (91%), the diagnosis of postoperative stroke was substantiated by neuroimaging such as a CT or MRI head scan; in 9 patients (9%), the stroke diagnosis was established by the attending neurologist. Most of these strokes were ischemic (90%). Of the remainder, 4.5% were hemorrhagic and 5.5% were embolic strokes. In cohorts with no thrombocytopenia, mild thrombocytopenia, and moderate to severe thrombocytopenia, the incidence of stroke was 1.09% (n = 19), 1.50% (n = 41), and 3.02% (n = 50), respectively.
Univariable predictors of postoperative stroke are shown in Table 2. Several preoperative and intraoperative variables were significantly associated with an increased risk for postoperative stroke (Table 2). Daily postoperative platelet counts as a time-varying covariate, defined as mild thrombocytopenia 100 to 150 × 109/L (unadjusted HR, 1.51; 95% confidence interval [CI], 0.95–2.40, P = .0850) was not significantly associated with postoperative stroke, but moderate to severe thrombocytopenia <100 × 109/L (unadjusted HR, 2.54; 95% CI, 1.53–4.22; P = .0003), or as a continuous variable for every 30 × 109/L daily decrease (univariable HR, 1.19; 95% CI, 1.07–1.32; P = .001), were significantly associated with postoperative stroke. According to our multivariable analysis, age, history of peripheral vascular disease (PVD), intraoperative insertion of IABP, and packed red blood cell transfusion were independent risk factors for postoperative stroke, whereas preoperative statin use was associated with a reduced risk for postoperative stroke (Table 2). After adjusting for differences in baseline and clinical characteristics, categorical postoperative thrombocytopenia showed a strong association with postoperative stroke (Table 2). Multivariable analysis that incorporated postoperative platelet count as a time-varying continuous variable showed that, on a given POD for every 30 × 109/L decrease in platelet counts, the risk for postoperative stroke increased by 12% (adjusted HR, 1.12; 95% CI, 1.01–1.24; P = .0255).
Early and Delayed Stroke
To study the impact of nadir platelet counts on timing of stroke after CABG surgery, patients were divided into 2 groups: early stroke (POD 0–1; n = 35) and delayed stroke (POD 2–30; n = 75). We then performed a stepwise multivariable competing risks proportional hazards model analysis following the Fine-Gray method to test for an association between severity of postoperative thrombocytopenia defined as a time-varying effect and timing of stroke. The results indicated that when postoperative platelet counts are defined as a time-varying covariate, moderate to severe thrombocytopenia was significantly associated with delayed but not early postoperative stroke (Table 3). Similarly, when postoperative platelet counts were defined as a time-varying continuous predictor, for every 30 × 109/L decrease in platelet counts the risk for delayed postoperative stroke was significantly elevated (subdistribution adjusted HR, 1.18; 95% CI, 1.04–1.35; P = .0109).
Of the 6130 subjects studied, 0.38% (n = 23) developed and received treatment for postoperative HIT. To determine whether the association between postoperative thrombocytopenia and postoperative stroke persisted, we repeated the analysis excluding patients with HIT. Both associations between daily moderate to severe postoperative thrombocytopenia (adjusted HR, 1.92; 95% CI, 1.15–3.22; P = .01) and daily platelet counts as a continuous variable (adjusted HR for every 30 × 109/L decrease in platelet counts, 1.13; 95% CI, 1.02–1.25; P = .02) remained statistically significant. The association of delayed stroke with time-varying moderate to severe postoperative thrombocytopenia (adjusted subdistribution HR, 2.90; 95% CI, 1.51–5.57; P = .001) and time-varying postoperative platelet counts as a continuous variable (adjusted subdistribution HR, 1.19; 95% CI, 1.05–1.36; P = .009) also remained statistically significant.
In this single-center study of 6130 patients undergoing on-pump CABG surgery, we identified that moderate to severe postoperative thrombocytopenia was an independent risk factor for the development of postoperative stroke. Importantly, analysis of the subdistribution hazards for early stroke (0–1 days after surgery) and delayed stroke (≥2 days after surgery) demonstrated relation of thrombocytopenia with delayed but not with early stroke. Perioperative stroke signifies a dramatic setback for patients undergoing CABG surgery, not only for its neurologic implications. Indeed, similar to previous reports,1 patients who developed postoperative stroke in our study were at a significantly higher rate of 30-day mortality compared to patients without postoperative stroke (16.4% vs 1.2%, P < .0001). These numbers bear striking witness on the importance to identify modifiable predictors influencing postoperative stroke after CABG surgery.
Currently, the main clinical focus regarding platelets in cardiac surgery is centered on bleeding complications secondary to both quantitative and qualitative platelet defects. However, complications associated with increased platelet thrombogenicity have gained additional attention.20–23 Most prominently, Mangano20 found that early initiation of aspirin therapy after CABG surgery is associated with a reduction in stroke, myocardial infarction, renal failure, bowel infarction, and overall mortality. Aspirin appears safe in terms of bleeding risk,24 but its efficacy to improve outcomes as a single agent may be limited by its relatively weak antiplatelet effect, as well as acquired perioperative aspirin resistance.22 In addition, the timing of aspirin initiation immediately after CABG surgery varies considerably within the same institution and among institutions, which may explain inconsistent results with aspirin use as a single preventive therapy.24 Platelet inhibition with clopidogrel has also been shown to reduce ischemic complications in patients undergoing CABG surgery, but concerns of higher risk for perioperative bleeding complications has led to the common practice of preoperative discontinuation of clopidogrel therapy.25 Hence, the best strategy for perioperative antiplatelet therapy remains uncertain. Antiplatelet medications, such as the novel P2Y12 and protease-activated receptor 1 inhibitors, may offer a better bleeding risk profile while protecting against postoperative cardiovascular complications including stroke.26,27 For instance, addition of ticagrelor, a novel P2Y12 inhibitor, as compared to aspirin alone has recently been shown to reduce the risk for graft occlusion after CABG surgery.27 A recent observational study demonstrated that vorapaxar, a novel protease-activated receptor 1 inhibitor, was associated with a reduced risk for composite outcomes of death, myocardial infarction, stroke, rehospitalization due to recurrent ischemia, and urgent revascularization, as compared to placebo after CABG surgery.26 Neither ticagrelor nor vorapaxar administration was associated with an increased risk for major bleeding complications.
Thrombocytopenia and Platelet Activation
We have recently demonstrated that low postoperative platelet counts are associated with an increased risk for acute kidney injury and death after CABG surgery,13 which is similar to observations in critically ill patients12 and in patients after transaortic valve replacement.28 The mechanism for developing thrombocytopenia in these patients remains unclear, but the association of postoperative platelet counts with stroke after CABG surgery suggests that the reduction in platelet numbers likely occurs in a context of increased platelet reactivity. This notion is supported by the fact that in a noncardiac surgical context, low platelet counts are predictive of deep vein thrombosis,29,30 and that a drop in platelet numbers is a risk factor for recurrence of pulmonary embolism,31 reinfarction after ST segment elevation myocardial infarction,32 and severity of stroke.33 In addition, a study in patients with acute coronary syndrome demonstrated that low platelet counts are associated with an increased risk for recurrent infarction, stroke, and death in drug-associated (ie, heparin, glycoprotein inhibitors) as well as drug-independent thrombocytopenia.34
Early and Delayed Stroke
We observed nadir platelet counts on POD 2, which coincides with the increased spontaneous and stimulant-evoked platelet reactivity reported for the first week after CABG surgery.35 Interestingly, our data on day-to-day variations of postoperative platelet counts also tightly correlated with the timing of stroke in our study, and in the study by Tarakji et al36 who found that stroke risk peaked approximately 40 hours after CABG surgery, stayed significantly elevated until day 5 after surgery, and then on POD 6, stabilized at the steady background state reflective of the general risk factors in this population. Indeed, a number of studies support our finding that most of the postoperative strokes were delayed (68%; n = 75).4,36,37 The definition of early versus delayed stroke varies slightly in the above studies, yet this distinction may highlight important differences in postoperative stroke mechanisms. Several reports suggest that cardioembolic events38 and ischemic events resulting from intraoperative hypotension cause most early strokes.39 In contrast, underpinnings of delayed strokes may be significantly influenced by the activation of systemic inflammation and hypercoagulability.36 Of note, off-pump CABG is associated with a small reduction in stroke events compared to on-pump CABG; however, this difference was notable for early stroke only, which is consistent with reduced manipulation of the aorta.40 Interestingly, as part of our ongoing study, we recently reported a similar pattern of perioperative nadir platelet counts in on-pump versus off-pump CABG, raising the question about the role of platelets in postoperative stroke in off-pump CABG surgery.41
Our finding that moderate to severe thrombocytopenia was associated with delayed but not early stroke is intriguing and supports the hypothesis that a postoperative prothrombotic state with associated platelet activation is an important factor in delayed stroke. Defining the mechanisms that drive these events will be crucial to the development of improved strategies to prevent postoperative stroke.
Risk Factors for Stroke
We confirmed the value of many previously described risk factors for predicting postoperative stroke and timing of stroke after CABG surgery.1,4,42,43 In particular, advanced age, PVD, absence of preoperative statin use, intraoperative insertion of IABP, and administration of packed red blood cell transfusions were consistently significant predictors of postoperative stroke in our risk-adjusted analysis. Further, when we studied the predictors of timing of postoperative stroke, we found that prior cerebrovascular accident was a predictor of early postoperative stroke, whereas advanced age and intraoperative insertion of IABP were associated with delayed postoperative stroke. Importantly, we found that most of these risk factors were also associated with postoperative thrombocytopenia.
Advanced age, prior cerebrovascular accident, and PVD have previously been found to increase the risk for postoperative stroke. Patients with these risk factors often have widespread systemic vascular and cerebrovascular disease resulting in impaired cerebral blood flow and increased susceptibility to atheroembolism and thromboembolism in the perioperative period.1,4,42 Because platelets play a central role in the pathophysiology of most vascular diseases and their associated ischemic complications, perioperative management of high-risk patients should include an evaluation of the benefits of dual antiplatelet therapy27,44 or novel monotherapy, the latter of which may offer a better bleeding risk profile in the post-CABG surgery setting.26
Our finding that statin use was associated with a lower risk for postoperative stroke highlights the importance of adhering to current guidelines on initiation and maintenance of statin use for primary and secondary prevention of cardiovascular events in patients with ischemic heart disease.45 In addition to their well-known favorable effect on lipid profile, statins affect platelet activation and aggregation, endothelial cell function, and proliferation and migration of vascular smooth muscle cells.44,45 All of these so-called pleiotropic properties of statins may substantially attenuate postoperative platelet activation and aggregation, and stabilize unstable atherosclerotic plaques, thereby reducing the risk for postoperative cardiovascular complications including stroke.
The use of IABP has been linked to platelet activation and increased microthrombi generation due to mechanical stress during the IABP cycle and prolonged exposure of blood components to the synthetic surface of the polyurethane balloon.46 Thus, our finding that the use of IABP is associated with both low platelet counts and an increased risk for postoperative stroke calls into question the appropriateness of using heparin alone for anticoagulation in these patients and suggests the need for a personalized and more comprehensive anticoagulation strategy, such as using heparin in combination of a glycoprotein IIb/IIIa inhibitor, or a glycoprotein IIb/IIIa inhibitor alone.47
Furthermore, our results support previous findings that link transfusion of packed red blood cells to increased risk for postoperative stroke in cardiac surgery.43,48 As in these studies, our data cannot provide evidence of the causative effect of blood transfusion and thus the increased risk for stroke may stem from the effects of preceding anemia as well as from specific abnormalities introduced by the transfusion itself.49 It is noteworthy that transfused blood may trigger prothrombotic and inflammatory responses and also may have limited oxygen-carrying capabilities, especially if stored over longer periods.50 However, irrespective of such considerations, evidence such as ours further highlights the importance of ongoing efforts to avoid excessive hemodilution and to establish clear blood transfusion guidelines for patients undergoing CABG surgery.
Our study has several limitations due to its retrospective design. Information on clinical risk factors for postoperative stroke was not prospectively collected. Instead, potentially relevant risk factors, medication use, and laboratory values were retrieved from electronic health records, electronic intraoperative charts, physician documentation, and neuroimaging reports. Therefore, effects and the magnitude of effects of certain risk factors, medication use, and laboratory data may have been biased. However, the magnitude of their predictive values was similar to published findings from other studies.4,42
All patients were screened routinely during the postoperative period for evidence of postoperative stroke. While detailed preoperative baseline neurologic and neurocognitive assessments of these patients were not performed, the diagnosis of postoperative stroke was substantiated by neuroimaging, such as a CT or MRI head scan, in 91% of affected patients.
It has been suggested that intraoperative epiaortic ultrasound may reduce cerebral emboli during CABG surgery by reducing aortic manipulation in atheroma-rich sites.51 However, such intervention predominantly affected early postoperative stroke occurrence and not the more common delayed stroke as observed in several other reports including ours.4,52
This study was performed at a single tertiary center, and therefore, our findings may not be fully applicable to other institutions with different perioperative practices and levels of experience. However, our reported incidences of postoperative stroke and risk factors were similar to other studies.1,4
In our study, we did not have a specific recorded time on perioperative blood product administration, and thus, we could not accommodate perioperative blood product administration in our extended Cox regression analysis as a time-dependent variable to model its potential effect on postoperative stroke. Consequently, its effect on postoperative stroke may have been biased. Nevertheless, perioperative blood product administration in CABG surgery most frequently occurs intraoperatively through day 2 after surgery; hence, the potential for observing a bias estimate of perioperative blood product administration on postoperative stroke is likely minimal.
Finally, no protocols were used to guide perioperative management of transfusion and anticoagulation therapies. Routine postoperative testing for HIT was left to the discretion of the intensive care unit team. Antiplatelet factor 4 antibodies are common after cardiac surgery with CPB, but only 3% of these patients develop HIT based on thrombotic sequel or serotonin-release assay.53 As indicated by previous studies,13,54 early-onset and persisting thrombocytopenia in cardiac surgery patients is seldom caused by HIT. Nevertheless, our sensitivity analysis indicated that after excluding patients with HIT, the association between postoperative thrombocytopenia and stroke persisted.
In summary, our findings suggest an independent association between moderate to severe postoperative thrombocytopenia and the development of postoperative stroke, and timing of stroke after CABG surgery. Our findings highlight the need for further studies to define mechanisms of perioperative platelet activation and its influence on adverse outcomes.
APPENDIX: MEMBERS OF THE CARE GROUP
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina:
Solomon Aronson, MD; Raquel R. Bartz, MD; Brandi A. Bottiger, MD; Anne D. Cherry, MD; Brian J. Colin, MD; J. Mauricio Del Rio, MD; Michael Fierro, MD; Kamrouz Ghadimi, MD; Nicole R. Guinn, MD; Ehimemen Iboaya, MD; Mandisa Jones-Haywood, MD; Jörn A. Karhausen, MD; Miklos D. Kertai, MD; Rebecca Y. Klinger, MD; Ryan Konoske, MD; Jerrold H. Levy, MD; F. Willem Lombard, MD; Yasmin Maisonave, MD; Michael W. Manning, MD; Joseph P. Mathew, MD; Corry D. Maxwell, MD; Grace C. McCarthy, MD; Mark F. Newman, MD; Alina Nicoara, MD; Mihai V. Podgoreanu, MD; Quintin J. Quinones, MD; Mark Stafford-Smith, MD; Madhav Swaminathan, MD; Annemarie Thompson, MD; Eleanor A. Vega, MD; and Ian J. Welsby, MD.
Department of Anesthesiology Clinical Research Services, Duke University Medical Center, Durham, North Carolina:
Narai Balajonda, MD; Tiffany Bisanar, RN; Rachele Brassard, BSW; Bonita L. Funk, RN; Roger L. Hall, AAS; Kathleen Lane, RN, BSN; Yi-Ju Li, PhD; Galdwell Mbocchi, AAS; Greg Pecora, BA; Michelle Pender, BA, MPH; Barbara Phillips-Bute, PhD; Prometheus T. Solon, MD; Yanne Toulgoat-Dubois, BA; Peter Waweru, CCRP; and William D. White, MPH.
Perfusion Services, Duke University Medical Center, Durham, North Carolina:
Kevin Collins, BS, CCP; Ian Shearer, BS, CCP; and Greg Smigla, BS, CCP.
Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina:
Thomas A. D’Amico, MD; Mani A. Daneshmand, MD; R. Duane Davis, MD; Jeffrey G. Gaca, MD; Donald D. Glower, MD; John Haney, MD; R. David Harpole, MD; Matthew G. Hartwig, MD; G. Chad Hughes, MD; Robert D.B. Jaquiss, MD; Shu S. Lin, MD; Andrew J. Lodge, MD; Carmelo A. Milano, MD; Mark W. Onaitis, MD; Jacob N. Schroeder, MD; Peter K. Smith, MD; and Betty C. Tong, MD.
The authors thank Betsy W. Hale, BSc, Alec Graham, BSc (Data Analysts, Department of Anesthesiology, Duke University Medical Center, Durham, NC) and Aimen El-Manafi, MD (Cardiothoracic Fellow 2015–2016, Department of Anesthesiology, Duke University Medical Center) for their help with data retrieval and database building. Finally, we thank Kathy Gage (Research Development Associate, Department of Anesthesiology, Duke University Medical Center) for her editorial contributions to the manuscript.
Name: Jörn A. Karhausen, MD.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Name: Alan M. Smeltz, MD.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Name: Igor Akushevich, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Name: Mary Cooter, MSc.
Contribution: This author helped analyze the data and write the manuscript.
Name: Mihai V. Podgoreanu, MD.
Contribution: This author helped write the manuscript.
Name: Mark Stafford-Smith, MD.
Contribution: This author helped write the manuscript.
Name: Susan M. Martinelli, MD.
Contribution: This author helped write the manuscript.
Name: Manuel L. Fontes, MD.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Name: Miklos D. Kertai, MD, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
This manuscript was handled by: Roman M. Sniecinski, MD.
1. Stamou SC, Hill PC, Dangas G, et al. Stroke after coronary artery bypass: incidence, predictors, and clinical outcome. Stroke. 2001;32:1508–1513.
2. Demaerschalk BM, Hwang HM, Leung G. US cost burden of ischemic stroke: a systematic literature review. Am J Manag Care. 2010;16:525–533.
3. Likosky DS, Marrin CA, Caplan LR, et al.; Northern New England Cardiovascular Disease Study Group. Determination of etiologic mechanisms of strokes secondary to coronary artery bypass graft surgery. Stroke. 2003;34:2830–2834.
4. Hogue CW Jr, Murphy SF, Schechtman KB, Dávila-Román VG. Risk factors for early or delayed stroke after cardiac surgery. Circulation. 1999;100:642–647.
5. Abu-Omar Y, Balacumaraswami L, Pigott DW, Matthews PM, Taggart DP. Solid and gaseous cerebral microembolization during off-pump, on-pump, and open cardiac surgery procedures. J Thorac Cardiovasc Surg. 2004;127:1759–1765.
6. Gold JP, Charlson ME, Williams-Russo P, et al. Improvement of outcomes after coronary artery bypass. A randomized trial comparing intraoperative high versus low mean arterial pressure. J Thorac Cardiovasc Surg. 1995;110:1302–1311.
7. Parolari A, Mussoni L, Frigerio M, et al. Increased prothrombotic state lasting as long as one month after on-pump and off-pump coronary surgery. J Thorac Cardiovasc Surg. 2005;130:303–308.
8. Grünenfelder J, Zünd G, Schoeberlein A, et al. Expression of adhesion molecules and cytokines after coronary artery bypass grafting during normothermic and hypothermic cardiac arrest. Eur J Cardiothorac Surg. 2000;17:723–728.
9. Reilly SJ, Li N, Liska J, Ekström M, Tornvall P. Coronary artery bypass graft surgery up-regulates genes involved in platelet aggregation. J Thromb Haemost. 2012;10:557–563.
10. Nannizzi-Alaimo L, Rubenstein MH, Alves VL, Leong GY, Phillips DR, Gold HK. Cardiopulmonary bypass induces release of soluble CD40 ligand. Circulation. 2002;105:2849–2854.
11. Ioannou A, Kannan L, Tsokos GC. Platelets, complement and tissue inflammation. Autoimmunity. 2013;46:1–5.
12. Williamson DR, Lesur O, Tétrault JP, Nault V, Pilon D. Thrombocytopenia in the critically ill: prevalence, incidence, risk factors, and clinical outcomes. Can J Anaesth. 2013;60:641–651.
13. Kertai MD, Zhou S, Karhausen JA, et al. Platelet counts, acute kidney injury, and mortality after coronary artery bypass grafting surgery. Anesthesiology. 2016;124:339–352.
14. Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg. 1999;16:9–13.
15. Beyersmann J, Wolkewitz M, Schumacher M. The impact of time-dependent bias in proportional hazards modelling. Stat Med. 2008;27:6439–6454.
16. Klein JP, Moeschberger ML. Survival Analysis: Techniques for Censored and Truncated Data. 2003.2nded. New York: Springer
17. Therneau TM, Grambsch PM. Modelling Survival Data: Extended the Cox Model. 2000.1st ed. New York: Springer-Verlag
18. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.
19. Austin PC, Lee DS, Fine JP. Introduction to the analysis of survival data in the presence of competing risks. Circulation. 2016;133:601–609.
20. Mangano DT; Multicenter Study of Perioperative Ischemia Research GroupAspirin and mortality from coronary bypass surgery. N Engl J Med. 2002;347:1309–1317.
21. Mathew JP, Podgoreanu MV, Grocott HP, et al.; PEGASUS Investigative Team. Genetic variants in P-selectin and C-reactive protein influence susceptibility to cognitive decline after cardiac surgery. J Am Coll Cardiol. 2007;49:1934–1942.
22. Emani S, Trainor B, Zurakowski D, et al. Aspirin unresponsiveness predicts thrombosis in high-risk pediatric patients after cardiac surgery. J Thorac Cardiovasc Surg. 2014;148:810–814.
23. Antiplatelet Trialists’ Collaboration.Collaborative overview of randomised trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81–106.
24. Myles PS, Smith JA, Forbes A, et al.; ATACAS Investigators of the ANZCA Clinical Trials Network. Stopping vs. continuing aspirin before coronary artery surgery. N Engl J Med. 2016;374:728–737.
25. Biancari F, Airaksinen KE, Lip GY. Benefits and risks of using clopidogrel before coronary artery bypass surgery: systematic review and meta-analysis of randomized trials and observational studies. J Thorac Cardiovasc Surg. 2012;143:665–675 e4.
26. Whellan DJ, Tricoci P, Chen E, et al. Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome). J Am Coll Cardiol. 2014;63:1048–1057.
27. Saw J, Wong GC, Mayo J, et al. Ticagrelor and aspirin for the prevention of cardiovascular events after coronary artery bypass graft surgery. Heart. 2016;102:763–769.
28. Dvir D, Généreux P, Barbash IM, et al. Acquired thrombocytopenia after transcatheter aortic valve replacement: clinical correlates and association with outcomes. Eur Heart J. 2014;35:2663–2671.
29. Monreal M, Lafoz E, Casals A, Ruíz J, Arias A. Platelet count and venous thromboembolism. A useful test for suspected pulmonary embolism. Chest. 1991;100:1493–1496.
30. Cil H, Yavuz C, Islamoglu Y, et al. Platelet count and mean platelet volume in patients with in-hospital deep venous thrombosis. Clin Appl Thromb Hemost. 2012;18:650–653.
31. Monreal M, Lafoz E, Ruiz J, Gimenez G. Platelet count in acute pulmonary embolism: its relationship to recurrences. Haemostasis. 1993;23:263–268.
32. Ly HQ, Kirtane AJ, Murphy SA, et al.; TIMI Study Group. Association of platelet counts on presentation and clinical outcomes in ST-elevation myocardial infarction (from the TIMI Trials). Am J Cardiol. 2006;98:1–5.
33. Sico JJ, Phipps MS, Concato J, et al. Thrombocytopenia and in-hospital mortality risk among ischemic stroke patients. J Stroke Cerebrovasc Dis. 2013;22:e99–e102.
34. Gore JM, Spencer FA, Gurfinkel EP, et al.; GRACE Investigators. Thrombocytopenia in patients with an acute coronary syndrome (from the Global Registry of Acute Coronary Events [GRACE]). Am J Cardiol. 2009;103:175–180.
35. Kobzar G, Mardla V, Rätsep I, Samel N. Platelet activity before and after coronary artery bypass grafting. Platelets. 2006;17:289–291.
36. Tarakji KG, Sabik JF 3rd, Bhudia SK, Batizy LH, Blackstone EH. Temporal onset, risk factors, and outcomes associated with stroke after coronary artery bypass grafting. JAMA. 2011;305:381–390.
37. Peel GK, Stamou SC, Dullum MK, et al. Chronologic distribution of stroke after minimally invasive versus conventional coronary artery bypass. J Am Coll Cardiol. 2004;43:752–756.
38. Clark RE, Brillman J, Davis DA, Lovell MR, Price TR, Magovern GJ. Microemboli during coronary artery bypass grafting. Genesis and effect on outcome. J Thorac Cardiovasc Surg. 1995;109:249–257.
39. Siepe M, Pfeiffer T, Gieringer A, et al. Increased systemic perfusion pressure during cardiopulmonary bypass is associated with less early postoperative cognitive dysfunction and delirium. Eur J Cardiothorac Surg. 2011;40:200–207.
40. Nishiyama K, Horiguchi M, Shizuta S, et al. Temporal pattern of strokes after on-pump and off-pump coronary artery bypass graft surgery. Ann Thorac Surg. 2009;87:1839–1844.
41. Kigwana S, Schonberger RB, Nwozuzu A, et al. Nadir postoperative platelet counts in off pump vs. on pump coronary artery bypass surgery and associated risk of acute kidney injury. 2016: SCA 38th Annual Meeting and Workshops. San Diego, CA, SCA66.
42. Toumpoulis IK, Anagnostopoulos CE, Chamogeorgakis TP, et al. Impact of early and delayed stroke on in-hospital and long-term mortality after isolated coronary artery bypass grafting. Am J Cardiol. 2008;102:411–417.
43. Mikkola R, Gunn J, Heikkinen J, et al. Use of blood products and risk of stroke after coronary artery bypass surgery. Blood Transfus. 2012;10:490–501.
44. Hillis LD, Smith PK, Anderson JL, et al.; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; American Association for Thoracic Surgery; Society of Cardiovascular Anesthesiologists; Society of Thoracic Surgeons. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;58:e123–e210.
45. Sadowitz B, Maier KG, Gahtan V. Basic science review: statin therapy – Part I: The pleiotropic effects of statins in cardiovascular disease. Vasc Endovascular Surg. 2010;44:241–251.
46. Ficek SJ, Stammers A, Deligonul U, Shurmur SW, Alonso A, Galbraith T. Hemostatic assessment of patients undergoing intraaortic balloon pump therapy. J Extra Corpor Technol. 1997;29:78–82.
47. Pucher PH, Cummings IG, Shipolini AR, McCormack DJ. Is heparin needed for patients with an intra-aortic balloon pump? Interact Cardiovasc Thorac Surg. 2012;15:136–139.
48. Brascia D, Garcia-Medina N, Kinnunen EM, Tauriainen T, Airaksinen J, Biancari F. Impact of transfusion on stroke after cardiovascular interventions: Meta-analysis of comparative studies. J Crit Care. 2017;38:157–163.
49. Biancari F, Tauriainen T, Perrotti A, et al. Bleeding, transfusion and the risk of stroke after coronary surgery: a prospective cohort study of 2357 patients. Int J Surg. 2016;32:50–57.
50. Silvain J, Abtan J, Kerneis M, et al. Impact of red blood cell transfusion on platelet aggregation and inflammatory response in anemic coronary and noncoronary patients: the TRANSFUSION-2 study (impact of transfusion of red blood cell on platelet activation and aggregation studied with flow cytometry use and light transmission aggregometry). J Am Coll Cardiol. 2014;63:1289–1296.
51. Yamaguchi A, Adachi H, Tanaka M, Ino T. Efficacy of intraoperative epiaortic ultrasound scanning for preventing stroke after coronary artery bypass surgery. Ann Thorac Cardiovasc Surg. 2009;15:98–104.
52. Mathew JP, Fontes ML, Tudor IC, et al.; Investigators of the Ischemia Research and Education Foundation; Multicenter Study of Perioperative Ischemia Research Group. A multicenter risk index for atrial fibrillation after cardiac surgery. JAMA. 2004;291:1720–1729.
53. Hui P, Cook DJ, Lim W, Fraser GA, Arnold DM. The frequency and clinical significance of thrombocytopenia complicating critical illness: a systematic review. Chest. 2011;139:271–278.
54. Selleng S, Malowsky B, Strobel U, et al. Early-onset and persisting thrombocytopenia in post-cardiac surgery patients is rarely due to heparin-induced thrombocytopenia, even when antibody tests are positive. J Thromb Haemost. 2010;8:30–36.