Weighing the Risks of Perioperative Aspirin John Serak and Michael Y. Wang
Neurosurgeons are wary of perioperative aspirin use given the potentially catastrophic effects of intraoperative or postoperative bleeding. In a poll of German spine surgeons, only 7 of 142 surgeons would perform elective surgery on a patient taking aspirin (3). With the exception of endovascular procedures, aspirin is generally discontinued 7e10 days before surgery. This time scale is derived from recommendations made by the American College of Chest Physicians and may be adjusted depending on the patient’s specific cardiac risk (2). No recommendations exist at the present time regarding the appropriate time period to restart aspirin postoperatively, leaving this decision to the surgeon. When considering perioperative aspirin use, the objective is to balance the risks of perioperative and postoperative hemorrhage against myocardial infarction and stroke. Neurosurgical literature to guide this decision-making process is sparse, especially in regard to intracranial surgery. In terms of aspirin use in spine surgery, only 2 recent publications address the topic, but these studies evaluated only estimated blood loss intraoperatively and postoperatively via wound drains (4, 5). The studies failed to address whether aspirin use was associated with hemorrhagic complications or if its discontinuation predisposed patients to cardiac events. A recent article in the New England Journal of Medicine (1) attempts to answer this question. Devereaux et al. (1) published their study as part of the POISE-2 (PeriOperative ISchemic Evaluation-2) trial. This prospective, randomized, multicenter, controlled trial sought to determine the effect of perioperatively administered aspirin versus placebo on the 30-day risk of death or nonfatal myocardial infarction in patients undergoing noncardiac surgery. Secondary outcome measures included risk of major bleeding at the surgical site or elsewhere, risk of stroke, and the effect of coadministered clonidine. Only patients with cardiovascular risk factors, who could benefit from aspirin use, were included in the study. Patients were recruited for enrollment from 135 hospitals in 23 countries. Patients undergoing intracranial surgery were excluded. The study enrolled 10,010 patients divided into patients already taking aspirin (continuation stratum; n ¼ 4382 patients) and patients not taking aspirin (initiation stratum; n ¼ 5628 patients) at the start of the trial. Patients from both strata were randomly assigned to either the aspirin group (n ¼ 4998 patients) or the placebo group (n ¼ 5012 patients). Patients received 200 mg of aspirin or placebo just before surgery and continued the medication
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for 30 days postoperatively. In the continuation stratum, the aspirin group resumed preoperative aspirin dose after 7 days if different from the study dose. Additionally, aspirin was stopped 3 days before surgery and replaced with 200 mg of aspirin or placebo. The primary outcome of death or nonfatal myocardial infarction was not significantly different between groups, occurring in 7.0% of patients in the aspirin group and 7.1% of patients in the placebo group (P ¼ 0.92). Major bleeding occurred significantly more often in the aspirin group compared with the placebo group (4.6% vs. 3.8%; P ¼ 0.04). This difference was maintained between subgroups of continuation and initiation strata, respectively. Hemorrhage occurred most commonly at the surgical site (78.3%) and the gastrointestinal tract (9.3%). A post hoc analysis revealed that aspirin produced a 1.2% absolute increase in major bleeding from the immediate postoperative period to 30 days, a 0.9% increase from postoperative day 4 to postoperative day 30 and a 0.3% increase from postoperative day 8 to postoperative day 30. The risk of significant hemorrhage appears to decrease with time throughout the postoperative period. Similar rates of stroke occurred in aspirin and placebo groups as a whole (0.3% vs. 0.4%; P ¼ 0.62); however, there was a significantly greater number of strokes in the aspirin group of the continuation stratum compared with the aspirin group of the initiation stratum (13 strokes vs. 3 strokes; P ¼ 0.01). The authors questioned the validity of this observation because it is derived from a low-powered subgroup analysis that is inconsistent with data from previous studies and opposite of the hypothesized effect of aspirin on stroke. Further subgroup analysis revealed no significant differences between groups. Although patients undergoing spine surgery were included in the study, specific data regarding their enrollment and outcomes were not provided. Whether continued throughout the perioperative period or initiated at the time of surgery, aspirin did not reduce the risk of perioperative or postoperative myocardial infarction or death, but it did increase the risk of major bleeding at the surgical site. This study is reassuring for neurosurgeons. Discontinuing aspirin preoperatively does not appear to increase the risk of perioperative and postoperative cardiac complications. Additionally, the study gives credence to the view that aspirin increases the risk of hemorrhagic complications. Although it excludes intracranial surgery,
82 [6]: 928-935, DECEMBER 2014 WORLD NEUROSURGERY
News items of interest may be forwarded to: Felipe C. Albuquerque, M.D. Section Editor, WORLD NEUROSURGERY News E-mail: [email protected]
does not specify the results of patients undergoing spine surgery, and uses an aspirin dose (200 mg) higher than the typical low dose of 81 mg, the study is a well-designed, large-scale, randomized controlled trial investigating patients with similar characteristics to
REFERENCES 1. Devereaux PJ, Mrkobrada M, Sessler DI, Leslie K, Alonso-Coello P, Kurz A, Villar JC, Sigamani A, Biccard BM, Meyhoff CS, Parlow JL, Guyatt G, Robinson A, Garg AX, Rodseth RN, Botto F, Lurati Buse G, Xavier D, Chan MT, Tiboni M, Cook D, Kumar PA, Forget P, Malaga G, Fleischmann E, Amir M, Eikelboom J, Mizera R, Torres D, Wang CY, VanHelder T, Paniagua P, Berwanger O, Srinathan S, Graham M, Pasin L, Le Manach Y, Gao P, Pogue J, Whitlock R, Lamy A, Kearon C, Baigent C, Chow C, Pettit S, Chrolavicius S, Yusuf S; ; POISE-2 Investigators: Aspirin in patients undergoing non-cardiac surgery. N Engl J Med 370:1494-1503, 2014.
Felipe C. Albuquerque, M.D.
Issam Awad, M.D.
Section Editor, WORLD NEUROSURGERY News
Section Editor, WORLD NEUROSURGERY News
the neurosurgical patient population. This trial provides the best evidence available regarding perioperative aspirin use. This study found no evidence for altering common current practices of preoperative discontinuation of aspirin in neurosurgical patients.
2. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ: American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141 (Suppl):7S-47S, 2012. 3. Korinth MC, Gilsbach JM, Weinzierl MR: Low dose aspirin before spinal surgery: results of a survey among neurosurgeons in Germany. Eur Spine J 16: 365-372, 2007. 4. Park JH, Ahn Y, Choi BS, Choi KT, Lee K, Kim SH, Roh SW: Antithrombotic effects of aspirin on 1- or 2-level lumbar spinal fusion surgery: a comparison between 2 groups discontinuing aspirin use before
and after 7 days prior to surgery. Spine (Phila Pa 1976) 38:1561-1565, 2013. 5. Park HJ, Kwon KY, Woo JH: Comparison of blood loss according to use of aspirin in lumbar fusion patients [published online ahead of print publication date]. Eur Spine J 23:1777-1782, 2014.
The Department of Neurosurgery at the University of Miami Miller School of Medicine, Miami, Florida, USA 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.wneu.2014.10.003
Operative Cytoreduction for Recurrent Glioblastoma Ryan P. Morton1, John D. Nerva1, Isaac Josh Abecassis1, Daniel L. Silbergeld1, Louis J. Kim1,2
The role of upfront surgery for glioblastoma multiforme (GBM) has been well established (2, 3, 5, 9). Gross total resection (best achieved with fluoroscopic 5-aminolevulinic acid guidance (6, 7)) in combination with temozolomide (Temodar) and radiotherapy has improved average survival to >14 months (8). Median and long-term survival may be enhanced if a patient has favorable genetic alterations (i.e., methylguanine methyltransferase promoter methylation) (1). However, if a gross total resection cannot be achieved because of location of tumor in eloquent brain, resection down to 78% of the enhancing portion of the tumor can provide a statistically significant survival benefit (5). However, no matter how effective the primary surgery and adjunctive therapies, GBM is currently an incurable disease with nearly every patient having to confront tumor recurrence. Although never previously proven, most neurosurgeons and neuro-oncologists believe that reoperation can improve mass effect symptoms and steroid dependence and increase
WORLD NEUROSURGERY 82 [6]: 928-935, DECEMBER 2014
progression-free survival and possibly overall survival. Proof of this effect of reoperation would require randomly assigning patients who are deemed operative candidates to surgery or best medical therapy arms. So far, this study has not been undertaken. In lieu of this concrete evidence, we are left with retrospective analyses of patients relegated to surgery only. One of the difficulties with this analysis is the lack of a comparison group. Oppenlander et al. (4) from the Barrow Neurological Institute in Phoenix, Arizona, recently published the largest single-center retrospective study on operative outcomes for recurrent GBM to date. Despite not having a comparison group, this study is extremely important because it provides critical insight to help guide preoperative patient counseling and surgical goals. Oppenlander et al. (4) reviewed 170 consecutive adult patients who had magnetic resonance imaging evidence of new tumor growth and underwent planned resection of recurrent supratentorial GBM at the Barrow Neurological Institute during the
www.WORLDNEUROSURGERY.org
929
Neurosurgeons are wary of perioperative aspirin use given the potentially catastrophic effects of intraoperative or postoperative bleeding. In a poll of German spine surgeons, only 7 of 142 surgeons would perform elective surgery on a patient taking aspirin (3). With the exception of endovascular procedures, aspirin is generally discontinued 7e10 days before surgery. This time scale is derived from recommendations made by the American College of Chest Physicians and may be adjusted depending on the patient’s specific cardiac risk (2). No recommendations exist at the present time regarding the appropriate time period to restart aspirin postoperatively, leaving this decision to the surgeon. When considering perioperative aspirin use, the objective is to balance the risks of perioperative and postoperative hemorrhage against myocardial infarction and stroke. Neurosurgical literature to guide this decision-making process is sparse, especially in regard to intracranial surgery. In terms of aspirin use in spine surgery, only 2 recent publications address the topic, but these studies evaluated only estimated blood loss intraoperatively and postoperatively via wound drains (4, 5). The studies failed to address whether aspirin use was associated with hemorrhagic complications or if its discontinuation predisposed patients to cardiac events. A recent article in the New England Journal of Medicine (1) attempts to answer this question. Devereaux et al. (1) published their study as part of the POISE-2 (PeriOperative ISchemic Evaluation-2) trial. This prospective, randomized, multicenter, controlled trial sought to determine the effect of perioperatively administered aspirin versus placebo on the 30-day risk of death or nonfatal myocardial infarction in patients undergoing noncardiac surgery. Secondary outcome measures included risk of major bleeding at the surgical site or elsewhere, risk of stroke, and the effect of coadministered clonidine. Only patients with cardiovascular risk factors, who could benefit from aspirin use, were included in the study. Patients were recruited for enrollment from 135 hospitals in 23 countries. Patients undergoing intracranial surgery were excluded. The study enrolled 10,010 patients divided into patients already taking aspirin (continuation stratum; n ¼ 4382 patients) and patients not taking aspirin (initiation stratum; n ¼ 5628 patients) at the start of the trial. Patients from both strata were randomly assigned to either the aspirin group (n ¼ 4998 patients) or the placebo group (n ¼ 5012 patients). Patients received 200 mg of aspirin or placebo just before surgery and continued the medication
928
www.SCIENCEDIRECT.com
for 30 days postoperatively. In the continuation stratum, the aspirin group resumed preoperative aspirin dose after 7 days if different from the study dose. Additionally, aspirin was stopped 3 days before surgery and replaced with 200 mg of aspirin or placebo. The primary outcome of death or nonfatal myocardial infarction was not significantly different between groups, occurring in 7.0% of patients in the aspirin group and 7.1% of patients in the placebo group (P ¼ 0.92). Major bleeding occurred significantly more often in the aspirin group compared with the placebo group (4.6% vs. 3.8%; P ¼ 0.04). This difference was maintained between subgroups of continuation and initiation strata, respectively. Hemorrhage occurred most commonly at the surgical site (78.3%) and the gastrointestinal tract (9.3%). A post hoc analysis revealed that aspirin produced a 1.2% absolute increase in major bleeding from the immediate postoperative period to 30 days, a 0.9% increase from postoperative day 4 to postoperative day 30 and a 0.3% increase from postoperative day 8 to postoperative day 30. The risk of significant hemorrhage appears to decrease with time throughout the postoperative period. Similar rates of stroke occurred in aspirin and placebo groups as a whole (0.3% vs. 0.4%; P ¼ 0.62); however, there was a significantly greater number of strokes in the aspirin group of the continuation stratum compared with the aspirin group of the initiation stratum (13 strokes vs. 3 strokes; P ¼ 0.01). The authors questioned the validity of this observation because it is derived from a low-powered subgroup analysis that is inconsistent with data from previous studies and opposite of the hypothesized effect of aspirin on stroke. Further subgroup analysis revealed no significant differences between groups. Although patients undergoing spine surgery were included in the study, specific data regarding their enrollment and outcomes were not provided. Whether continued throughout the perioperative period or initiated at the time of surgery, aspirin did not reduce the risk of perioperative or postoperative myocardial infarction or death, but it did increase the risk of major bleeding at the surgical site. This study is reassuring for neurosurgeons. Discontinuing aspirin preoperatively does not appear to increase the risk of perioperative and postoperative cardiac complications. Additionally, the study gives credence to the view that aspirin increases the risk of hemorrhagic complications. Although it excludes intracranial surgery,
82 [6]: 928-935, DECEMBER 2014 WORLD NEUROSURGERY
News items of interest may be forwarded to: Felipe C. Albuquerque, M.D. Section Editor, WORLD NEUROSURGERY News E-mail: [email protected]
does not specify the results of patients undergoing spine surgery, and uses an aspirin dose (200 mg) higher than the typical low dose of 81 mg, the study is a well-designed, large-scale, randomized controlled trial investigating patients with similar characteristics to
REFERENCES 1. Devereaux PJ, Mrkobrada M, Sessler DI, Leslie K, Alonso-Coello P, Kurz A, Villar JC, Sigamani A, Biccard BM, Meyhoff CS, Parlow JL, Guyatt G, Robinson A, Garg AX, Rodseth RN, Botto F, Lurati Buse G, Xavier D, Chan MT, Tiboni M, Cook D, Kumar PA, Forget P, Malaga G, Fleischmann E, Amir M, Eikelboom J, Mizera R, Torres D, Wang CY, VanHelder T, Paniagua P, Berwanger O, Srinathan S, Graham M, Pasin L, Le Manach Y, Gao P, Pogue J, Whitlock R, Lamy A, Kearon C, Baigent C, Chow C, Pettit S, Chrolavicius S, Yusuf S; ; POISE-2 Investigators: Aspirin in patients undergoing non-cardiac surgery. N Engl J Med 370:1494-1503, 2014.
Felipe C. Albuquerque, M.D.
Issam Awad, M.D.
Section Editor, WORLD NEUROSURGERY News
Section Editor, WORLD NEUROSURGERY News
the neurosurgical patient population. This trial provides the best evidence available regarding perioperative aspirin use. This study found no evidence for altering common current practices of preoperative discontinuation of aspirin in neurosurgical patients.
2. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ: American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141 (Suppl):7S-47S, 2012. 3. Korinth MC, Gilsbach JM, Weinzierl MR: Low dose aspirin before spinal surgery: results of a survey among neurosurgeons in Germany. Eur Spine J 16: 365-372, 2007. 4. Park JH, Ahn Y, Choi BS, Choi KT, Lee K, Kim SH, Roh SW: Antithrombotic effects of aspirin on 1- or 2-level lumbar spinal fusion surgery: a comparison between 2 groups discontinuing aspirin use before
and after 7 days prior to surgery. Spine (Phila Pa 1976) 38:1561-1565, 2013. 5. Park HJ, Kwon KY, Woo JH: Comparison of blood loss according to use of aspirin in lumbar fusion patients [published online ahead of print publication date]. Eur Spine J 23:1777-1782, 2014.
The Department of Neurosurgery at the University of Miami Miller School of Medicine, Miami, Florida, USA 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.wneu.2014.10.003
Operative Cytoreduction for Recurrent Glioblastoma Ryan P. Morton1, John D. Nerva1, Isaac Josh Abecassis1, Daniel L. Silbergeld1, Louis J. Kim1,2
The role of upfront surgery for glioblastoma multiforme (GBM) has been well established (2, 3, 5, 9). Gross total resection (best achieved with fluoroscopic 5-aminolevulinic acid guidance (6, 7)) in combination with temozolomide (Temodar) and radiotherapy has improved average survival to >14 months (8). Median and long-term survival may be enhanced if a patient has favorable genetic alterations (i.e., methylguanine methyltransferase promoter methylation) (1). However, if a gross total resection cannot be achieved because of location of tumor in eloquent brain, resection down to 78% of the enhancing portion of the tumor can provide a statistically significant survival benefit (5). However, no matter how effective the primary surgery and adjunctive therapies, GBM is currently an incurable disease with nearly every patient having to confront tumor recurrence. Although never previously proven, most neurosurgeons and neuro-oncologists believe that reoperation can improve mass effect symptoms and steroid dependence and increase
WORLD NEUROSURGERY 82 [6]: 928-935, DECEMBER 2014
progression-free survival and possibly overall survival. Proof of this effect of reoperation would require randomly assigning patients who are deemed operative candidates to surgery or best medical therapy arms. So far, this study has not been undertaken. In lieu of this concrete evidence, we are left with retrospective analyses of patients relegated to surgery only. One of the difficulties with this analysis is the lack of a comparison group. Oppenlander et al. (4) from the Barrow Neurological Institute in Phoenix, Arizona, recently published the largest single-center retrospective study on operative outcomes for recurrent GBM to date. Despite not having a comparison group, this study is extremely important because it provides critical insight to help guide preoperative patient counseling and surgical goals. Oppenlander et al. (4) reviewed 170 consecutive adult patients who had magnetic resonance imaging evidence of new tumor growth and underwent planned resection of recurrent supratentorial GBM at the Barrow Neurological Institute during the
www.WORLDNEUROSURGERY.org
929
