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Anesth Analg 2001;93:573-580
© 2001 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

The Effect of Perioperative Aspirin Therapy in Peripheral Vascular Surgery: A Decision Analysis

David T. Neilipovitz, FRCPC*, Gregory L. Bryson, MSc, FRCPC*{dagger}, and Graham Nichol, MPH, FRCPC{dagger}{ddagger}

Departments of *Anesthesiology and {ddagger}Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada; and the {dagger}Clinical Epidemiology Unit, Loeb Medical Research Institute, Ottawa, Ontario, Canada

Address correspondence and reprint requests to Dr. David T. Neilipovitz, Department of Anesthesiology, The Ottawa Hospital—Civic Campus, 1053 Carling Ave., Ottawa, Ontario K1Y 4E9. Address e-mail to dneilipovitz{at}ottawahospital.on.ca


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Patients who undergo infrainguinal revascularization surgery are at increased risk for perioperative thrombotic complications. Aspirin decreases thrombotic events in the nonoperative setting; however, aspirin is often discontinued to avoid perioperative hemorrhagic complications. We used a decision analysis to determine whether aspirin should be discontinued before infrainguinal revascularization surgery. Two strategies were compared: aspirin cessation 2 wk before surgery and aspirin continuation throughout the perioperative period. Clinical events examined included myocardial infarction, thrombotic cerebrovascular accident, hemorrhagic cerebrovascular accident, gastrointestinal hemorrhage, and incisional hemorrhagic complications. Event rates and effect of aspirin were obtained by using MEDLINE. The outcomes were perioperative mortality, life expectancy, and quality-adjusted life expectancy. According to the model, continued aspirin use decreased perioperative mortality rates from 2.78% to 2.05%. Continued aspirin use increased life expectancy from 14.83 to 14.89 yr and increased quality-adjusted life expectancy from 14.72 to 14.79 yr. Aspirin increased the number of hemorrhagic complications by 2.46%, primarily because of an increased incidence of non-life-threatening complications.

IMPLICATIONS: Decision analysis indicates that continued aspirin use in patients undergoing infrainguinal revascularization surgery is associated with a decreased perioperative mortality and increased life expectancy but may increase the likelihood of minor hemorrhagic complications.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Patients undergoing infrainguinal revascularization surgery (IRS) for peripheral vascular disease are at increased risk of experiencing thrombotic complications in the perioperative period. The incidence of perioperative myocardial infarction (MI) in patients undergoing vascular surgery is as frequent as 15% (1), whereas the risk of a thrombotic cerebrovascular accident (CVA) in these patients undergoing noncarotid surgery is more than 1% (2,3). Platelet hyperaggregability has been implicated as the primary pathophysiologic problem in both of these thrombotic complications (4,5).

Aspirin decreases the risk of thrombotic complications in high-risk population groups in the nonoperative setting. A recent metaanalysis by He et al. (6) reported that aspirin decreased the risk of MI by 31% and decreased the risk of thrombotic CVA by 18%. The use of aspirin to decrease the incidence of MI or thrombotic CVA in the perioperative period has not been prospectively studied. The nonsteroidal antiinflammatory drug (NSAID) ketorolac reduced postoperative myocardial ischemia in patients who underwent total hip or knee arthroplasty (7), but this trial did not have sufficient power to address the influence of ketorolac on the incidence of perioperative MI or thrombotic CVA.

Despite potential reductions in thrombotic complications, antiplatelet drugs have traditionally been discontinued before elective surgery because of concern that they may cause perioperative hemorrhagic complications (8). This recommendation seems to be based on retrospective studies (8,9), case control studies (10), and cardiac surgical studies (11). The relative risks and benefits of continued perioperative aspirin use have not been evaluated in a prospective, randomized trial. However, a trial identifying a 33% relative reduction in MI, assuming a 15% incidence of MI and 80% power, would require 725 patients per group. Decision analysis is an alternative to a large trial. This technique uses the best available evidence to generate results from alternative management strategies. Our study uses this technique to estimate the risks and benefits of perioperative aspirin in patients undergoing elective IRS.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The decision model considered the use of preoperative aspirin in patients with peripheral vascular disease undergoing elective IRS and described the possible outcomes of two different strategies for aspirin for elective IRS. The decision tree illustrated in Figure 1 was analyzed with Data 3.5 (TreeAge Software, Inc.; Williamstown, MA). Strategy one was to discontinue aspirin for 2 wk before elective IRS and throughout the perioperative period. Strategy two was to continue aspirin throughout the perioperative period. The possible outcomes for both strategies were identical, but the probability for each of the outcomes was contingent on whether there was perioperative use of aspirin. The base case patient in the decision model was a 65-yr-old Caucasian man. All patients were assumed to have received epidural anesthesia. It was assumed that the long-term effects of the thrombotic complications were similar to the outcomes of these events in the nonoperative setting.



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  		Figure 1. Decision tree. CVA = cerebrovascular accident; GI = gastrointestinal; OR = operation. A patient presenting for infrainguinal revascularization surgery can either continue aspirin or have it discontinued for the perioperative period. The aspirin tree (not shown) in exactly the same as the no-aspirin tree. The route taken after a circle is determined by event probabilities. A triangle represents an end outcome. Tables 1 and 2 list the probabilities used to generate end outcomes.

 
Seven possible outcomes were considered: intraoperative death, MI, thrombotic CVA, hemorrhagic CVA, gastrointestinal bleed, incisional bleed, and event-free survival. An incisional bleed was defined as a wound hematoma that required reoperation or blood transfusion. Patients experiencing a perioperative complication could succumb or go on to survive with some disability.

For the sake of simplicity, perioperative complications were omitted if it was believed that their incidence was not influenced by the use of aspirin (e.g., pneumonia and urinary tract infections). Further, the decision analysis excluded very rare complications associated with aspirin (e.g., allergic reactions) or those only minimally influenced by the perioperative use of aspirin (e.g., epidural hematoma, deep venous thrombosis). A final assumption was that each of the adverse outcomes was mutually exclusive. The overall results of each strategy arm were expressed in terms of perioperative mortality, crude life expectancy, and quality-adjusted life years (QALYs).

Relevant input data were gathered by performing a systematic literature search with MEDLINE (1966 to February 1999). Relevant articles were identified by using the MESH headings and text words describing the population, intervention, and complications of interest. The search strategy is available from the authors by request. A search filter was used to limit the MEDLINE database to randomized, controlled clinical trials (12). Additional titles were identified by a manual search of the bibliographies of articles from the author’s files, review articles, and each article identified in the MEDLINE search.

The titles and abstracts of more than 1000 articles were subsequently reviewed independently by two investigators (DTN and GLB), who identified studies that were relevant to the purpose of this decision analysis. Disagreement was resolved by consensus of the two reviewers, with preference given to systematic reviews or randomized control trials. If no such studies could be found, then cohort trials, case series, and retrospective studies were identified.

The decision analysis used standardized mortality tables to derive the projected crude life expectancy for each outcome beyond the perioperative period (13). The model incorporated published utility values for the different possible outcomes to quality adjust life expectancy. A "utility" is a quantitative measure that assigns a relative weight to an outcome in an attempt to account for the adverse effect the disease states have on a patient’s life. QALYs for each outcome are the product of the crude life expectancy for each outcome and its respective utility value. The utility value for MI used in this decision analysis was 0.84 (14). The utility value for a stroke was 0.72 (15). The decision analysis used the same utility value for all strokes, regardless of the type of stroke (15). It was assumed that patients who survive a gastrointestinal bleed or an incisional bleed have no long-term adverse sequelae.

Sensitivity analyses were performed to assess the effect of several variables on the long-term results in this decision model. In sensitivity analyses, one or more of the values entered in the decision model are varied to determine their effect on the results. The values that can be varied include the incident rates, mortality rates, and utility values assigned to each outcome. A one-way sensitivity analysis will vary one value, whereas a two-way sensitivity analysis will simultaneously vary two variables. One-way sensitivity analyses were used to assess the effect of patient age and MI rate on outcome. The utility value assigned to incisional bleed was varied from 0 (i.e., worse outcome of death) and 1.0 (i.e., no long-term sequelae) in a one-way sensitivity analysis. A two-way sensitivity analysis was used to examine the effect of simultaneously altering the incidences of the two most common complications (MI and incisional bleed).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
One-hundred-thirty-eight articles were considered eligible and reviewed. Table 1 summarizes the variables used in the base case of the decision model and provides information about the quality of the studies used to calculate these values. The event rates and their associated mortality rates were calculated from the listed studies as a weighted means. The mortality of an incisional bleed was assumed to be 5%. The relative risk for the effect of aspirin on each of the perioperative complications is listed in Table 2, along with the references for each value. A risk ratio >1 implies that aspirin increases the probability of that complication occurring. Conversely, a risk ratio value <1 suggests that aspirin decreases the likelihood of that complication.


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  		Table 1. Articles Used to Calculate Event Rates and Mortality Rates
 

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  		Table 2. Articles Used to Calculate Relative Risk of Aspirin
 
The results of the decision analysis are listed in Table 3. The strategy of continued aspirin administration decreased perioperative mortality from 2.78% to 2.05%. The continued use of aspirin, however, increased the risk of experiencing a hemorrhagic complication from 6.60% to 9.06%. The incidence of incisional bleeds increased from 5.88% to 7.71% with continued aspirin use. Aspirin use increased the crude life expectancy of a base case patient undergoing elective IRS from 14.83 to 14.89 yr. The benefit of aspirin persisted when the crude expectancy was adjusted for quality of life. Patients who continued their aspirin had 14.79 QALYs after surgery, whereas patients who stopped aspirin had 14.72 QALYs.


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  		Table 3. Event Rates and Life Expectancy for the Two Treatment Strategies
 
The influence of the underlying risk of MI on treatment decision was evaluated in a one-way sensitivity analysis. The results in Figure 2 indicate that the benefit of aspirin administration persisted until the chance of MI was <1.3%. The influence of patient age on treatment decision was evaluated in a one-way sensitivity analysis. Continued aspirin administration remains the treatment of choice in patients ranging from 50 to 80 yr of age. A one way sensitivity analysis demonstrated that aspirin use is recommended until the utility value for an incisional bleed is <0.20. A two-way sensitivity analysis (Fig. 3) examined the effect of altering both the MI and incisional bleed rates. Continued aspirin administration remains the favored strategy unless the incidence of MI decreases to <1.3% or the incidence of an incisional bleed exceeds 15%.



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  		Figure 2. One-way sensitivity analysis (effect of myocardial infarction rate on life expectancy). MI = myocardial infarction; LE = life expectancy. The MI was varied from 1% to 10% to determine its effect on crude LE. The MI mortality rate is assumed to be 41.9%. Continued aspirin use is the preferred strategy until the MI rate is <1.3% (threshold value).

 


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  		Figure 3. Two-way sensitivity analysis (myocardial infarction rate versus incisional bleed rate). The incisional bleed rate was varied from 1% to 20% along the ordinate axis, whereas the myocardial infarction rate was varied from 1% to 10% on the abscissa. The shading on the graph represents the preferred strategy at the respective incisional bleed rate and myocardial infarction rate.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The decision to continue preoperative aspirin for patients with peripheral vascular disease who are undergoing elective IRS is a tradeoff between the potential benefits of decreased thrombotic complications and the risk of hemorrhagic complications. The traditional recommendation of stopping aspirin to minimize bleeding problems may therefore preclude patients from experiencing potential benefits (8). This decision analysis suggested that the continued use of aspirin both decreased perioperative mortality and improved the long-term life expectancy, despite causing an increased number of perioperative complications. The increased complication rate in patients who continued to take aspirin was primarily caused by problems with minimal mortality, such as incisional bleed and gastrointestinal hemorrhage (5% and 2.1%, respectively). The overall incidence of hemorrhagic CVA increased from only 0.37% to 0.59% with aspirin and therefore had minimal effect on the outcome of the decision model, despite its associated mortality rate of 35%.

The findings of the model with regard to life expectancy were relatively insensitive to changes in the perioperative MI rate. The benefits of aspirin persisted unless the perioperative MI incidence was <1.3%. The reported MI rates for IRS are variable, but most studies report an MI rate of >1.3%, with some studies reporting incidences >10% (1). As the perioperative MI rate was increased, the benefit conferred by aspirin also increased. The improved outcomes associated with aspirin were not influenced by the patient’s age. It was only once the incisional bleed rate was very frequent or the MI rate was infrequent that the recommendation of this decision model would change.

The effect of the assumption that an incision bleed has no long-term adverse consequences was tested by means of one-way sensitivity analysis. Continued use of aspirin was preferred until the incisional bleed utility value decreased to <0.2. For comparison, the utility value for a CVA is 0.72 (15). Although there is no reported evidence on the long-term sequelae of an incision bleed, it is highly unlikely that it would be three times worse than that of a CVA. Thus, the preferred strategy is continued aspirin administration despite an increased incidence of incisional bleeds.[[(16–38)]]

Aspirin use increased the crude life expectancy by approximately 22 days. Although this difference may not seem to be clinically relevant, it should be noted that this is similar to the benefit offered by other recommended therapies. Routine ß-blocker therapy after an acute MI in patients with a small risk of recurrence increases life expectancy by approximately 36 days (39). Use of the hepatitis B virus vaccine in 12- to 50-year-old patients at high risk for hepatitis increases life expectancy by 4.5 to 7.2 days (39). Perioperative ß-blockade decreases perioperative mortality (40) and improves long term outcome (41). Likewise, continued aspirin use included a 74% relative reduction in perioperative mortality. Because the continuation of preoperative aspirin has a beneficial effect on both short- and long-term outcomes, it would suggest that routine use in IRS should be strongly considered.

The decision analysis has several limitations. The information used to obtain the results came from multiple trials, which included nonrandomized trials, thereby possibly introducing some bias and error. The utility values that were used were derived from a nonoperative population; this may limit applicability to the patients studied in this analysis. This analysis uses a declining exponential approximation to model long-term outcome after the perioperative period, rather than a Markov model. The former method assumes that the mortality rate is constant over time, whereas the Markov model can include changes in risk or recurrent events over time (e.g., alters MI events years after the surgery). Use of a declining exponential approximation is appropriate to the extent that the use of aspirin during the perioperative period modifies only the risk of perioperative events. If such use modifies the risk of future events, then it would be more appropriate to use a Markov model. Although long-term benefits have been demonstrated from some perioperative interventions (41), we cannot conceive of why brief use of aspirin would alter events after the perioperative period.

A further potential weakness is the assumption that aspirin would decrease the incidence of perioperative thrombotic complications in a manner similar to its effects in the nonoperative setting. Plaque rupture and platelet hyperaggregability are the pathophysiologic mechanism in the majority of nonoperative MIs and unstable coronary syndromes (4,42). Evidence now suggests that platelet hyperaggregability is also a primary pathophysiologic problem in the operative setting (42,43). Histopathologic analyses of the coronary arteries and myocardium in cases of fatal perioperative MIs demonstrated virtually identical changes as nonoperative MIs, thus suggesting a common pathophysiology between perioperative and other MIs (44). McDaniel et al. (45) have reported that similar adverse platelet changes occur in patients who undergo IRS. The beneficial effect of aspirin on the incidence and prognosis of nonoperative coronary events seems to be its antiplatelet actions (46). The antiplatelet drug ketorolac decreases perioperative myocardial ischemia, thus further supporting the assumption that platelet hyperaggregability is an important pathophysiologic mechanism for perioperative MI (7).

Considerable evidence suggests that platelets have a primary role in the pathophysiology of a stroke (5). In the nonoperative setting, aspirin decreases the risk of stroke by more than 30% (6,37). Studies on perioperative stroke in procedures other than cardiac or carotid surgery are limited. The available information suggests that the majority of cases occur in the postoperative period and are not related to intraoperative hemodynamic status (3). Because the postoperative period is the time when platelet hyperaggregability is greatest, one would speculate that platelets play a primary role in the pathophysiology of perioperative stroke. Thus, antiplatelet medications such as aspirin could have a preventive role in decreasing postoperative strokes.

The decision model compared only two strategies for preoperative aspirin management: either stopping the drug for the two weeks before surgery or administering it throughout the perioperative period. A third strategy would be to stop aspirin two weeks before surgery but restart the drug in the immediate postoperative period. The advantage of this strategy is that the operative hemorrhagic problems are potentially decreased, but antiplatelet effects are present in the time period that correlates with platelet hyperreactivity. We could not obtain sufficient information from the available literature to be able to test this strategy in our decision model. Further, there are several problems with this third strategy. The stopping of aspirin two weeks before surgery will remove its protective effects in the preoperative period. Although we suspect that some patients may experience a thrombotic complication as a result of aspirin withdrawal before their surgery, we could not find data to support this hypothesis. If there is an increase in preoperative thrombotic events if aspirin is discontinued, it would further strengthen the recommendations of this study. The use of preoperative aspirin may protect against adverse intraoperative platelet changes that contribute to thrombotic complications. Finally, postoperative ileus may delay the restarting of aspirin after surgery, which coincides with the time period when patients are at most risk for thrombotic complications. Therefore, the use of aspirin throughout the entire perioperative period may offer high-risk patients the most protection.

An NSAID to bridge the preoperative and postoperative periods is a potential alternative strategy. The platelet inhibitory effects are reversible, thereby allowing the drug to be given for two weeks before surgery but withheld for 24–48 hours before surgery. This strategy offers some protection against thrombotic events in the preoperative period but decreases the risk for intraoperative hemorrhagic problems. The disadvantages of this approach are that the evidence for beneficial antithrombotic effects of NSAIDs has not been as clearly elucidated as for aspirin, and the approach offers no protection against potentially important intraoperative platelet changes.

Christopherson et al. (16) recommend epidural anesthesia for patients undergoing IRS because of improved graft patency rates. The decision model did not incorporate the complications of epidural anesthesia and the potential adverse effect of aspi-rin on the epidural anesthesia for several reasons. The safety of epidural anesthesia in patients who have received aspirin is controversial (47–49). The present consensus is that epidural anesthesia is safe for patients who have received aspirin (49). Although the concomitant use of heparin may increase the risk (49), there is no evidence to quantify the risk for an epidural hematoma. The reported incidence of an epidural hematoma after epidural anesthesia has been estimated as approximately 1 in 190,000 (50). Even if it is assumed that aspirin increases the risk 100-fold and that all patients die if they develop a hematoma (i.e., worst outcome), the results of the decision analysis are not altered.

An important limitation of this study is the generalizability of its results. This decision analysis addressed the role of continued aspirin administration before elective IRS. The benefit of continued aspirin administration is dependent on the perioperative thrombotic and hemorrhagic complication rates. Vascular surgery patients are at high risk for thrombotic complications, and this accounts for aspirin’s benefit in this group. Procedures for which there is an infrequent incidence of thrombotic complications or a frequent incidence of hemorrhagic complications are less likely to benefit from continued aspirin use. The morbidity and mortality associated with the hemorrhagic complications would also influence the optimal strategy. If the morbidity or mortality of a hemorrhagic complication is particularly high, such as with intracranial surgery, the optimal strategy for preoperative aspirin could be different from the results of this model. Thus, it would be inappropriate to directly extrapolate the results of our decision model to all forms of surgery.

In conclusion, decision analysis suggests that continued use of preoperative aspirin decreases the perioperative mortality and increases life expectancy for patients undergoing elective IRS. Continued perioperative aspirin use would increase the total perioperative complication rate, but the beneficial reductions in mortality from thrombotic problems account for the observed increase in quality-adjusted life expectancy. A randomized, controlled trial should be conducted to confirm that continued aspirin administration increases perioperative and long-term life expectancy without causing a disproportionate increase in perioperative hemorrhagic complications. In lieu of such a trial, the practice of routinely stopping aspirin in the perioperative period should be strongly questioned.[[(51)]]


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 1, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press