Chronic aspirin therapy plays a prominent role in cardiovascular health maintenance and preventive therapy for thromboembolic disease. For those with elevated risk of coronary artery disease (CAD), chronic low-dose aspirin is recommended as primary prevention by both American Heart Association guidelines1 and by the US Preventive Services Task Force2 based on a large body of data suggesting a favorable risk to benefit ratio.3–8 Patients receiving percutaneous coronary stents are another group of patients for whom lifelong chronic aspirin therapy is recommended,9 as antiplatelet therapy is crucial for prevention of in-stent thrombosis.10–12 Additionally, most patients with atrial fibrillation receive aspirin or anticoagulant therapy for prevention of stroke.13
Despite these established benefits of aspirin therapy, it is unclear how this should be balanced against the perioperative concern of increased bleeding risk for patients undergoing noncardiac surgery. Much of the published data on perioperative aspirin consists of case reports or case series14 documenting adverse incidents related to continuation or discontinuation of antiplatelet therapy before surgery. While 2 meta-analyses have reported an increased risk of bleeding complications with continuation of preoperative aspirin in noncardiac surgery,15,16 some trials suggest that discontinuation is associated with increased incidence of major adverse cardiac events and no advantage in terms of bleeding risk.17–19 A recent randomized controlled trial20 on perioperative aspirin administration in patients undergoing noncardiac surgeries suggested that initiating aspirin before surgery can be associated with an increased risk of postoperative major bleeding complications. However, this study did not sufficiently address the management of patients receiving chronic aspirin treatment and excluded intracranial neurosurgery.
Because bleeding is a potentially dangerous complication after intracranial procedures, aspirin is routinely discontinued 7 days or longer before elective intracranial neurosurgery.21,22 Yet, there are no data as to whether this practice is necessary or improves outcomes. Moreover, preoperative cessation of aspirin is impossible in emergency situations when patients undergoing emergency craniotomies or Burr hole procedures for intracranial bleeding have been receiving chronic aspirin treatment until the time of surgery. While platelet therapy may reverse thrombasthenia associated with aspirin, its use and effectiveness in preventing perioperative complications in emergency neurosurgery is not known. Patients older than 65 years of age form a population of particular interest in which to study neurosurgery for traumatic bleeding, as the incidence of hospitalization for traumatic brain injury doubles at 65 years old compared to the general population, and falls become a more frequent mechanism of injury at this age threshold.23 The purpose of this study was to examine whether aspirin exposure before emergency neurosurgery for traumatic intracranial hemorrhage is associated with worse perioperative bleeding and postoperative outcomes in the elderly.
The study was approved by the Institutional Review Board of the University of Washington, and need for informed consent was waived.
This was a retrospective cohort study using a combination of electronic and manual hospital medical record review. The electronic hospital and anesthesia medical record system databases were used to identify all cases of emergency craniotomy, craniectomy, and Burr hole procedures (International Classification of Diseases, 9th Revision codes: 61108, 61154, 61156, 61312, 61313, 61314, 61315) for the indications of traumatic intracranial hemorrhage at a level 1 Trauma Center (Harborview Medical Center, Seattle, WA) during a 5-year period between January 1, 2008, and December 31, 2012. This center has been using a computerized electronic anesthetic record system since 2007.
Inclusion criteria were: (1) patients ≥65 years, (2) emergency neurosurgery for traumatic intracranial hemorrhage, and (3) emergency code recorded in the electronic anesthesia record. Transfer patients were included.
Exclusion criteria were: (1) patients undergoing craniotomy for primary indication other than subdural, extradural, or intraparenchymal hemorrhage, (2) patients who were preoperatively receiving clopidogrel, warfarin, low-molecular-weight heparin, or any of the novel oral anticoagulant medications—direct thrombin inhibitors or anti-factor X medication (Figure 1), (3) polytrauma, defined as presence of other injuries upon admission requiring surgical intervention during the hospital stay, and (4) cases representing subsequent neurosurgical procedures for re-bleeding in the same admission as an initial included case.
Demographic data, clinical course, and outcomes were abstracted by a combination of electronic database searches and manual data abstraction by 5 investigators (A.L., A.G., S.P., I.R., and A.Z.). Patient characteristics included age, gender, American Society of Anesthesiologists Physical Status classification, admission Glasgow Coma Scale (GCS) score, and history of any of the following: CAD, myocardial infarction, atrial fibrillation, cerebrovascular accident or transient ischemic attack, diabetes mellitus, congestive heart failure, and peripheral vascular disease. These perioperative data were abstracted: type of surgery (craniotomy, craniectomy, or Burr hole procedure), duration of surgery (minutes), admission radiographic diagnoses by computed tomography and/or magnetic resonance imaging (subdural epidural, subarachnoid, intraparenchymal hemorrhage), intraoperative estimated blood loss (EBL) and perioperative transfusion of blood products (units).
Perioperative period was defined as a time period starting at 48 hours before surgery or shorter, if admission to the hospital occurred closer to surgery start time, and ending at 48 hours after surgery or shorter, if death or discharge occurred sooner than that after surgery end time.
Patients who were receiving preoperative aspirin therapy were included in the aspirin group, while patients not receiving aspirin were included in the non-aspirin group.
Study outcomes were: (1) estimated intraoperative blood loss, (2) aggregate incidence of repeat neurosurgery for postoperative intracranial re-bleeding or death in hospital during the same admission, (3) length of stay in the intensive care unit (ICU), (4) length of stay in the hospital, and (5) in-hospital death and perioperative blood product transfusion volume of (6) packed red blood cells (PRBCs) (7), fresh frozen plasma (FFP), (8) platelets, and (9) cryoprecipitate.
Baseline patient characteristics such as demographic variables and comorbidities were compared with respect to the aspirin and non-aspirin groups using Student t test for continuous variables. Fisher exact test for binary variables, and χ2 test were used for categorical variables with more than two categories. P < .05 was considered significant.
Two of the outcome variables (death and the combined outcome of postoperative intracranial hemorrhage or death) are binary, and we have dichotomized the other measures as well. The distribution of values for each continuous outcome was analyzed by 2 investigators (A.L. and I.R) and a threshold value was chosen for each, to define a clinical dichotomy between a routine and typical versus an uncommon and adverse outcome for that measure. There are several reasons for dichotomizing outcomes in this manner rather than analyzing as continuous outcome measures. First, these outcomes all have a very skewed distribution. For the perioperative transfusion variables, 72% to 99% of patients have a value of zero making transformation to a normally distributed measure impossible. Furthermore, since some patients died during the hospitalization, dichotomizing hospital and ICU length of stay allows the appropriate inclusion of these patients as being in the adverse outcome category, even if their lengths of stay were short due to early mortality.
However, as an alternative to the dichotomized analyses, linear regression analyses were also done for EBL, hospital length of stay, and ICU length of stay, giving results consistent with those from the dichotomized versions of these outcomes (results not shown).
To examine whether preoperative or intraoperative platelet transfusion was associated with outcomes in those patients taking aspirin, we divided the aspirin group into the no platelet and platelet transfusion groups, and the same outcomes were compared as in the primary analysis except that intraoperative and postoperative PRBCs, FFP and cryoprecipitate and postoperative platelets were taken as transfusion outcomes to more specifically capture the effect of preoperative or intraoperative platelet transfusion. Among those not taking aspirin, only 5 patients received preoperative or intraoperative platelet transfusion and hence a similar analysis was not conducted among non-aspirin patients.
Binary logistic regression analysis was used to estimate the association between preoperative aspirin exposure and patient outcome categories. Because the number of events is very small for some outcomes, Firth’s method for bias reduction in logistic regression was used, as implemented in the logistic function in R.24 The statistical model was adjusted for admission GCS score and prevalence of CAD between the aspirin and non-aspirin groups. Adjusted odds ratios, 95% confidence intervals, and P value are presented.
Overall, 182 of 871 patients met inclusion criteria. From the remaining sample, data from 171 patients were abstracted after identifying surgeries that represented a repeat neurosurgical procedure within the same admission. There were 87 patients in the aspirin group, and 84 patients in the non-aspirin group (Figure 1) who were included in the final analysis.
Patient characteristics and demographic data are reported in Table 1. Admission computed tomography findings of subdural hematoma, traumatic subarachnoid hemorrhage, intraparenchymal hemorrhage, and extradural hemorrhage were similar in the aspirin and non-aspirin groups, as were the proportion of patients undergoing Burr hole procedures rather than craniotomy or craniectomy.
Patients receiving preoperative aspirin had higher mean GCS scores on admission (13 ± 3 vs 11 ± 4, P= .02) and were more likely to have a history of CAD (17% vs 7%, P< .05).
Eighty-three patients (95.4%) in the aspirin group were receiving low-dose (81 mg/d) aspirin. Four patients had aspirin doses of more than 81 mg/d (3 patients on 325 mg/d, and 1 patient on 500 mg/d), with a mean age of 80.5 years and a mean GCS score of 12.3.
Figures 2 and 3 illustrate the distribution of volume of perioperative PRBC transfusion and number of hospital days, respectively. These, along with the values for ICU length of stay and EBL, follow a non-normal pattern of distribution; Figure 2 for instance shows that the majority of patients receiving blood transfusion during an intracranial neurosurgery received only one unit of PRBCs, but there is an outlying tail consisting of a few patients receiving more units for large EBL. Based on the distributions of values, a routine outcome versus an adverse outcome was defined as: perioperative PRBC transfusion >350 mL (adverse) versus ≤350 mL (routine) (Figure 2), hospital length of stay >15 days (adverse outcome) versus ≤ 15 days (routine outcome) (Figure 3), ICU length of stay >5 days (adverse) versus ≤5 days (routine), and EBL >500 mL (adverse) versus <500 mL (routine).
Preoperative aspirin exposure was not associated with intraoperative EBL >500 mL (adjusted odds ratio [aOR] 0.99; 95% confidence interval [CI], 0.23–3.99) or subsequent neurosurgical intervention (aOR 0.69; 95% CI, 0.32–1.47). There was no difference in length of hospitalization, length of ICU stay, or in-hospital mortality between the 2 groups (Table 2).
Aspirin patients were more likely to receive perioperative platelet transfusion than non-aspirin patients (aOR 9.89; 95% CI, 4.24–26.25), but there was no difference in transfusion of any other blood products. Forty-six percent of patients in the aspirin group received perioperative platelets compared to 8.3% in the non-aspirin group.
Outcomes for the 4 patients receiving preoperative aspirin greater than 81 mg/d were similar to those of the remainder of the cohort, with no patients having an EBL of greater than 500 mL and in-hospital death and re-bleeding each being 25%; 1 of the 4 patients received perioperative platelets.
Table 3 shows that adjusted for GCS score and CAD, preoperative or intraoperative platelet transfusion was not associated with EBL, in-hospital mortality, postoperative intracranial bleeding or hospital length of stay, nor with intra- or postoperative transfusion of other blood products in aspirin group patients.
In this study, we aimed to examine the association between preoperative aspirin exposure and outcomes after emergency neurosurgery. The main findings are that low-dose preoperative aspirin exposure was not associated with postoperative intracranial re-bleeding, higher procedural blood loss or increased transfusion of red blood cells after emergency neurosurgery. There were no differences in length of ICU stay, length of hospitalization, or in-hospital death between the aspirin and non-aspirin groups. These results suggest that chronic low-dose aspirin therapy may not be associated with adverse perioperative outcomes in emergent neurosurgery for traumatic intracranial hemorrhage.
In this study, patients receiving preoperative aspirin therapy were more likely to receive perioperative platelet transfusion than patients not receiving aspirin. At our institution, the decision to transfuse platelets preoperatively is made by the neurosurgeons, and is not typically guided by platelet function or bleeding assays. Intraoperative and postoperative platelet transfusion is usually decided by the neurosurgery providers in conjunction with anesthesiology providers. Factors that clinicians often cite empirically in making this decision include presence of preoperative antiplatelet or anticoagulant therapy and degree of surgeon satisfaction with the gross appearance of hemostasis intraoperatively. There is, however, no universal protocol at our hospital governing the administration of platelets in the neurosurgical setting, given the paucity of data on this topic, and this situation did not change during the period of our study. Since the greater incidence of platelet transfusion in the aspirin group may have reversed the antiplatelet effect in many patients and reduced their perioperative bleeding, our results might be interpreted as corroborating the efficacy of perioperative platelet transfusion for patients receiving chronic aspirin before emergency neurosurgery. However, less than half of the patients in the aspirin group actually received platelet transfusion. Furthermore, results of our secondary analysis show that within the aspirin group, patients receiving either preoperative or intraoperative platelet transfusion had the same likelihood of having higher EBL, longer hospital or ICU lengths of stay and hospital mortality compared to patients not receiving platelets. These findings suggest that other factors such as brain injury severity may play a more important role in perioperative outcomes than low-dose preoperative aspirin exposure. We also did not identify any clearly protective effect that can be attributed to platelet transfusion in aspirin-exposed patients.
Published literature does not shed clear light on the association between aspirin exposure and outcomes after neurosurgery.25,26 A recent small study27 on time interval to surgery in acute traumatic subdural hematoma noted a curious association between preinjury aspirin therapy and reduced mortality, but had only 6 aspirin patients to compare with the remainder of the cohort. In contrast, a retrospective cohort with 179 patients suggested that antiplatelet medication in the elderly is associated with increased mortality after traumatic brain hemorrhage, but included patients on clopidogrel and warfarin in the antiplatelet therapy group.28 The recent POISE 2 trial aroused great interest because it suggested that initiation of aspirin could cause increased postoperative bleeding after elective surgery, but was less generalizable to the population of patients already on preoperative aspirin, since the study’s “continuation of aspirin” stratum was required to stop aspirin at least 3 days before surgery and then restart it on the day of surgery with a larger load of aspirin.20 Also, this study excluded patients undergoing intracranial surgery as well as those with a history of coronary stents. The present study is the first to examine perioperative outcomes of neurosurgical patients receiving preoperative monotherapy primarily with low-dose aspirin for a variety of indications.
While our study only focused on emergency neurosurgery for traumatic intracranial hemorrhage, these findings may have implications for elective neurosurgery. If bleeding, reoperation and mortality are not increased by preoperative continuation of aspirin, it is possible that patients at higher risk for cardiac morbidity, such as those with coronary stents,29,30 an elevated revised cardiac risk index31 score or American College of Surgeons National Surgical Quality Improvement risk calculation would derive benefit from continuation before elective neurosurgery.32 The elevated incidence of platelet transfusion and therefore reversal of aspirin effect in the aspirin group makes it difficult to generalize as to what the significance of unreversed antiplatelet therapy would be in the elective surgery population. While we cannot draw a firm conclusion on this point from these data, we feel that further study of the practice of low-dose aspirin continuation on outcomes after neurosurgery is warranted.
As expected, the non-aspirin group tended to have less CAD than the aspirin group. We believe that matching patients to obtain an equal incidence of CAD in both groups would not have reduced confounding. Non-aspirin group patients with CAD are not receiving an optimal and indicated antiplatelet therapy for their coronary disease for a variety of reasons that may range from medical non-compliance to significant bleeding propensity. Matching the 2 groups to have CAD equally represented in their comorbidities would introduce the additional confounding factor of having a disproportionate number of patients in the non-aspirin group who are not optimally treated for an important comorbidity. We opted instead to adjust for the greater prevalence of CAD in the aspirin group in our logistic regression model, and on the basis of this comparison found no difference in outcomes between aspirin and non-aspirin patients.
This study has some limitations worth discussing. As a retrospective chart analysis, the data are susceptible to errors in recording and charting; for instance, the proper accounting of perioperative and preoperative blood product transfusion depends on the correct recording of time of administration for any given blood product. Being a study that is not blinded, the possibility of observer bias influencing the retrieval and interpretation of data manually must also be considered. This is a single center study, and despite adjustments, there may be residual confounding. We cannot exclude the possibility of Type II error given the relatively small size of our sample. In particular, the outcome of cryoprecipitate transfusion was found to be rare enough that no firm conclusions can be drawn on the impact of aspirin on administration of this blood product. Its rarity however does help exclude the possibility that aspirin patients in our study were somehow not receiving FFP but did receive more cryoprecipitate as a substitute. In addition, we cannot exclude the possibility that there are other baseline characteristic differences between aspirin and non-aspirin patients that were not detected and adjusted for in our logistic regression model. For instance, one could speculate that the slightly higher admission GCS score in the aspirin group might reflect less severe mechanisms of injury among patients on aspirin (eg, mechanical falls versus motor vehicle accidents), or similar factors that may not sort independently between the 2 groups but potentially affect patient outcomes. Also, because we confined our analysis to elderly patients of 65 years of age or greater, our conclusions may not be applicable to younger patients. Finally, since the majority of our patients were taking low-dose aspirin, we cannot generalize our findings to patients receiving larger doses. Despite these limitations, the present study findings provide new information regarding the potential safety of chronic low-dose aspirin therapy in neurosurgery for intracranial hemorrhage.
In summary, this study found that low-dose aspirin therapy without preoperative cessation in the context of emergency neurosurgery for traumatic hemorrhage in elderly patients was not associated with adverse postoperative outcomes. Patients on aspirin were more frequently transfused with platelets in the perioperative period, but platelet transfusion during or before neurosurgery did not improve outcomes for aspirin group patients.
Name: Alex T. Lee, MD.
Contribution: This author helped design the study, analyze and collect the data, and write the manuscript.
Name: Arni Gagnidze, BS.
Contribution: This author helped collect the data and write the manuscript.
Name: Sharon R. Pan, BS.
Contribution: This author helped collect the data and write the manuscript.
Name: Pimwan Sookplung, MD.
Contribution: This author helped conceive the study design and write the study protocol.
Name: Bala Nair, PhD.
Contribution: This author helped collect the electronic data and analyze the data.
Name: Shu-Fang Newman, MS.
Contribution: This author helped collect the electronic data and analyze the data.
Name: Alon Ben-Ari, MD.
Contribution: This author helped analyze the statistics and collect the data.
Name: Ahmed Zaky, MD, MPH.
Contribution: This author helped collect and analyze the data.
Name: Kevin Cain, PhD.
Contribution: This author helped design the study and analyze the statistics.
Name: Monica S. Vavilala, MD.
Contribution: This author helped design the study, write the manuscript, and gave senior editorial input.
Name: Irene Rozet, MD.
Contribution: This author helped conceive the study, write the manuscript, and gave senior editorial input.
This manuscript was handled by: Richard P. Dutton, MD.
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© 2017 International Anesthesia Research Society
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