Author + information
- Received February 14, 2012
- Revision received April 6, 2012
- Accepted April 10, 2012
- Published online November 13, 2012.
- Sandeep Singla, MD,
- Rajesh Sachdeva, MD and
- Barry F. Uretsky, MD⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Barry F. Uretsky, Department of Cardiology, University of Arkansas for Medical Sciences, CAVHS, 4300 West Seventh Street, Little Rock, Arkansas 72205
Noncardiac surgery (NCS) may be required within the first year after percutaneous coronary intervention (PCI) in approximately 4% of patients and is the second most common reason for premature discontinuation of antiplatelet therapy (APT),which may, in turn, increase the risk of perioperative ischemic events, particularly stent thrombosis. Its continuation may increase the risk of perioperative bleeding. We review current information on the incidence of these events, particularly related to APT, describe potentially useful strategies to minimize the risks of adverse outcomes, and provide recommendations on APT use.
- antiplatelet therapy
- cardiac risk
- percutaneous coronary intervention
- perioperative period
- noncardiac surgery
- stent thrombosis
Percutaneous coronary intervention (PCI) is the most common strategy for myocardial revascularization, with more than a million procedures performed annually in the United States alone (1). Enthusiasm has been tempered by the potentially lethal complication of stent thrombosis (ST) (2). The most important ST predictor is premature discontinuation of dual antiplatelet therapy (DAPT) (3,4). Apart from noncompliance, the second most common reason for early discontinuation of either DAPT or single antiplatelet therapy (APT) is the need for noncardiac surgery (NCS), accounting for one-third of cases (4).
In both retrospective (5) and prospective (6) studies, approximately 4% of patients undergo NCS within the first year after index PCI (approximately 40,000 patients in the United States by current PCI usage). This large cohort presents a challenge for the treating surgeon, anesthesiologist, and cardiologist in managing APT in the perioperative period. On the basis of current American College of Cardiology/American Heart Association guidelines, approximately two-thirds of all NCS procedures in the first year after index PCI are classified as moderate to high risk for major adverse cardiac events (MACE) (5–7). Surgical stress creates a prothrombotic state due to increased platelet activation and decreased fibrinolysis, explaining in part the well-described MACE increase in the perioperative period (8–10).
The small, but persistent, ST risk long after PCI raises the important issue of perioperative management. On the one hand, MACE, particularly ST, is a concern after APT discontinuation; with its continuation, bleeding looms as a persistent danger. In this paper, we review studies of NCS outcomes following PCI with either bare-metal stents (BMS) or drug-eluting stents (DES), particularly in relation to APT, and potential strategies to decrease these risks.
We performed a PubMed search for full-length articles published within the last 10 years in the English language (abstracts were excluded) with the following key terms: “noncardiac surgery, coronary stent” and “noncardiac surgery, percutaneous coronary intervention.” We identified 6 studies with BMS (11–16), 13 with DES (6,17–28), and 6 with both BMS and DES (5,29–33). In 1 study of 103 patients (34), stent type (BMS vs. DES) was unavailable in 75% of patients; we excluded this study except to discuss it relative to anticoagulation strategies. Another paper was excluded because the myocardial infarction (MI) endpoint, although well defined, was not clearly presented (23). We reviewed each study for definitions and incidence of MACE and bleeding, APT status, and factors associated with adverse outcomes. We also performed an extensive English literature search for strategies to prevent MACE. In this presentation, the ischemic risk of surgery was defined as “low,” “intermediate,” or “high,” using the American College of Cardiology/American Heart Association guidelines (7).
Current guidelines for management of patients undergoing NCS after PCI
The 2009 American College of Cardiology/American Heart Association and 2010 European Society of Cardiology/European Association of Cardio-Thoracic Surgery guidelines provide a framework for APT management in the perioperative period following PCI (7,35). Given the lack of prospective randomized clinical trials, recommendations are based primarily on expert opinion and relatively small, and mostly retrospective, studies.
Four important variables cited in decision making regarding APT use in the perioperative period include urgency of surgery, PCI type (balloon angioplasty [BA] vs. stenting), stent type (DES vs. BMS), and the duration between PCI and NCS.
Guidelines recommend that elective surgery be postponed for at least 2 weeks after BA, 1 month after BMS, and 1 year after DES. The rationale relates to the time frame for vascular healing and re-endothelialization in animal studies (36). Current guidelines recommend that aspirin (ASA) (81 to 325 mg/day) be continued through the perioperative period if the risk of surgical bleeding is not prohibitive. The decision regarding APT continuation with urgent or emergent surgery is governed by the relative risks of bleeding versus ST in an individual patient. This consideration is reflected in the 2010 European Society of Cardiology/European Association of Cardio-Thoracic Surgery guidelines, where a “case by case” approach is suggested (35).
Limitations of current guidelines and studies
Most published studies are retrospective, single center, and/or with small sample size, limiting generalizability of the results (Table 1). In addition, definition of adverse events, both cardiac and bleeding, details of perioperative APT, and duration of post-operative monitoring vary, making comparisons among studies difficult. Thus, the reader must take these caveats into consideration in drawing conclusions about the risks and efficacy of APT in PCI patients undergoing NCS. In addition, current guidelines provide APT recommendations for only the first year after PCI. The small, but persistent, MACE risk including ST beyond the first year is not addressed. Finally, it should be mentioned that MACE definitions vary in each study; thus, the reader should refer to Tables 2 to 4⇓⇓ to determine what constitutes MACE in each study.
Cardiac risks from NCS in patients with prior PCI
NCS Following PCI With BMS
MACE following NCS with BMS was first reported by Kaluza et al. (11) who found a 17.5% (7 of 40) incidence of MI presumed to be secondary to ST. Total mortality (ischemic + bleeding) was 20%. All MACE occurred within the first 2 weeks after PCI. Subsequent studies provide evidence that the high-risk period for MACE may extend to 6 weeks, though the risk seems to be lower between 3 to 6 weeks as compared with the initial 2 weeks (12–14) (Fig. 1, Tables 2 to 5).⇓
Nuttal et al. (16) in 899 patients showed an overall MACE rate of 5.2%. APT (single vs. dual not specified) was used perioperatively in 72% when the interval between PCI and NCS was <30 days and in approximately 60% >30 days. NCS within 1 month of PCI carried the highest MACE risk (10.5%). The risk between 30 and 90 days was 3.8%, with a persistent 2.8% risk between 90 and 360 days. Other risk factors included general anesthesia (odds ratio: 2.79, 95% confidence interval: 1.27 to 6.13, p < 0.01) and shock before the index PCI (odds ratio: 8.06, 95% confidence interval: 3.53 to 18.41, p < 0.001). A small study (32 patients) suggested that the high-risk period may extend to 3 months because 2 of 3 ST occurred >30 days after PCI (15).
There are case reports of very late ST, that is, >1 year from BMS implantation following NCS; the incidence of these events, however, and their relationship to APT use is uncertain (37–39).
NCS Following PCI With DES
There is a wide variation in the reported MACE risk in DES patients (Fig. 1, Tables 3 and 5). Two early studies suggested it was low (<2%) (17,18). These studies were notable for a long interval between PCI and NCS (>6 months), frequent APT use in the perioperative period (17), and relatively low-risk NCS. Similarly, in a questionnaire-based study, a low MACE risk (1.5%) was reported (24).
Other studies, however, suggest a higher MACE rate. Rhee et al. (20) reported a 5% ST incidence following NCS within 1 year of PCI. In this series, all oral APT agents were withheld. Assali et al. (26) identified a 7.7% MACE risk following NCS at least 6 months after PCI despite continuation of single or dual APT in approximately 80% of cases.
The incidence of late ST (31 to 365 days after implantation) in real-world practice in non-NCS patients is approximately 0.6% (40). A prospective registry reported 2% incidence of ST following NCS (21). In a single-center retrospective study (N = 520), MACE was 5.4% within the first year of PCI and 3.3% thereafter (22). There was no significant MACE difference whether NCS was performed <90, 90 to 180, 181 to 360, or >365 days from PCI. There was a significant univariate association between MACE and advanced age, emergent surgery, shock at index PCI, and thienopyridine use in the perioperative period. However, thienopyridine use was not associated with MACE after adjustment for emergency surgery. ASA was used within 7 days of NCS in 70% of cases and thienopyridine in 33%, whereas DAPT usage was not reported.
In another relatively large retrospective study (481 patients, 606 procedures), the risk of definite and probable ST with an average delay between PCI and surgery of about a year was 2% (25). ST risk was 6% if NCS was performed within 1 month of PCI and 1.5% thereafter (p = 0.04). Other ST predictors were NCS being emergent, previous MI, pre-operative heparin use, and longer stent length. ASA and/or clopidogrel in the perioperative period was not associated with either improved or worsened MACE risk.
In a prospective registry of 206 patients, MACE was 1.9% (6). However, the incidence was 27 times higher if NCS was performed <1 week of index PCI as compared with any time period thereafter. A history of heart failure and serum creatinine >2.0 mg/dl also predicted MACE. In the same registry, MACE associated with minor NCS (defined as surgery without a large surgical incision) <1 year after DES was very low, with only 1 ST case in the first week following NCS among 164 subjects (28). APT status was not described.
NCS beyond 1 year of index PCI may have a lower MACE risk. A study of 135 DES patients undergoing 191 NCS procedures with an average delay of 18 months had a low MACE rate (ST: 0.5%, MI: 2%) (27). ASA was continued during the perioperative period in 54% and clopidogrel in 30%. It was stated that there was no MACE difference between patients who received clopidogrel versus who did not, but the DAPT rates in the perioperative period were not reported. Of all reported complications (ischemic + bleeding), 74% occurred within the first 3 days following NCS, highlighting the first post-operative week as carrying the highest MACE risk.
Individual very late ST cases with DES after NCS have been described, but the incidence is uncertain (19,21,25,41–43).
NCS Following PCI With Either BMS or DES
The relative MACE incidence with BMS and DES following NCS has been compared in a few studies (Tables 4 and 5). Cruden et al. (5) compared BMS (n = 1,383) with DES (n = 570), with a median interval between PCI and NCS >1 year. APT use was not reported. MACE frequency was 13.3% for BMS and 14.6% with DES (p = 0.3). High MACE rates in this study likely reflected broad endpoint criteria (primary endpoint: in-hospital death or ischemic cardiac event, ICD-10 (International Classification of Diseases-10) codes 120.0, 120.1, 120.8–121.4, 121.9–122.1, 122.8, 122.9, 124.0, and 124.9–125.1; secondary endpoint: in-hospital death and MI, codes 121.0–121.4, 121.9–122.1, 122.8, and 122.9). Similar, but smaller, studies have also failed to link MACE risk to stent type (30,33). By contrast, a relatively small study (BMS = 101, DES = 138) identified higher MACE with DES (2.2%) versus BMS (0%) (29), probably reflecting higher baseline comorbidity in the DES cohort (increased prevalence of hypertension and diabetes mellitus, longer stent length, and multivessel intervention) (29). In these studies, a short period (<4 to 6 weeks) between PCI and NCS was associated with higher MACE regardless of stent type (31,33).
In a prospective multicenter observational study of 1,134 NCS procedures (82% performed >1 year after PCI), MACE risk was 10.9% (32). This study did not report complications by stent type. A multivariate analysis did identify complete APT interruption >5 days prior to NCS as well as creatinine clearance <30 ml/min, pre-operative hemoglobin <10 g/dl, and urgent and high-risk surgery as significant predictors for MACE.
Table 5 lists the incidence of ST in studies in which it was specifically stated. The apparently lower DES ST rate may reflect a lack of studies during the very-high-risk period as compared with BMS studies, where many were performed during this time, as seen in Figure 1.
NCS following BA
BA is rarely used as an isolated procedure. However, it may have some utility as a “holding” procedure for NCS in certain circumstances. In a retrospective study of 350 patients undergoing NCS <2 months of BA, Brilakis et al. (44) reported 3 adverse events (0.9%) including one death and 2 MI. All events occurred among the 188 patients undergoing NCS within 2 weeks of BA. Aspirin was used in 78% and thienopyridine in 4%. Leibowitz et al. (45) comparing BA (n = 122) with stenting (n = 94) did not identify any significant difference in MACE risk regardless of NCS timing (<2 or >2 weeks). MI incidence was 6% in the BA group. It should be noted that the relatively high MI rate may have been related to the fact that MACE incidence included events up to 6 months after NCS.
Risk of bleeding in the setting of NCS following PCI
It is intuitive that APT, particularly DAPT, continued in the perioperative period increases the bleeding risk, but the level of risk remains uncertain.
Results from multiple studies report a variable frequency of significant bleeding, in part due to different bleeding endpoint definitions. Timing of NCS following PCI has been variably associated with the bleeding risk with either single APT or DAPT (Figs. 2A and 2B, Tables 2 to 4 and 6).⇓ Though some studies (11,13) suggest higher bleeding risk if NCS is performed within 2 to 3 weeks of PCI, a large retrospective study (16) did not identify any significant association, although there was a trend toward a higher bleeding risk if NCS was <30 days of PCI (<30: 6.9%, 30 to 90: 4.6%, >90: 3.6%). In a prospective study of 103 stented patients, there were only 4 major bleeding episodes, defined as “unusually high post-operative blood loss as assessed by the surgeon” despite APT continuation (84% ASA, 44% clopidogrel) or discontinuation for <3 days, in addition to either the use of unfractionated or low-molecular-weight heparin (LMWH) (34). Other retrospective studies also have not identified a significant relationship between APT use and with the risk of perioperative bleeding (13,22).
There seems to be a higher bleeding risk with DAPT versus single APT, although very few studies, even retrospective ones, provide this comparison. Table 6 lists the incidence of bleeding in the perioperative period following NCS with the use of either single or dual APT. The mean bleeding risk from studies in which adequate information was available was 4.1% for single APT versus 14.7% for DAPT, driven in large part by the study of Van Kuijk et al. (31). They reported significant bleeding in 21% of DAPT and 4% of single APT patients (p ≤ 0.001). These results differ from the expected 1% increase in bleeding risk with DAPT (vs. ASA alone) in the nonsurgical setting (46).
That being said, DAPT may have an acceptable bleeding risk if future data provide evidence that there is a MACE decrease compared with DAPT discontinuation pre-operatively. At least 1 surgical series suggests that DAPT may be used with an acceptable bleeding risk. In 108 non-PCI patients (47), the bleeding risk with limb ischemia surgery in patients maintained on 75 mg of aspirin in the perioperative period and then randomly assigned to either clopidogrel or matched placebo was evaluated. There was no increase in major bleeding, but the transfusion requirement was increased with DAPT (28%) versus ASA alone (12.6%) (p = 0.037). Though this study does not specifically address patients with previous PCI undergoing NCS, it does provide evidence that DAPT may not increase major bleeding even in patients undergoing high-risk surgery.
Given the lack of large randomized studies, current guidelines recommend a case-by-case approach, weighing MACE versus bleeding risk (7,35).
Strategies to reduce adverse cardiac ischemic complications in stented patients following NCS
Given the high frequency of NCS in the year after PCI and potential increase in MACE (including ST) with both DES and BMS, it has become imperative to develop better strategies to decrease the risk of stent-related MACE. Potential strategies include the following:
DAPT Continuation in the Perioperative Period
DAPT continuation in the perioperative period is 1 strategy to prevent or reduce MACE. As previously noted, ASA is recommended by guidelines unless the bleeding risk is prohibitive. It should be noted that there have been conflicting data from previous studies whether DAPT continuation is actually effective in preventing ST and/or MACE (please see the preceding text). Current data suggest that minor bleeding and bleeding severe enough to warrant transfusion may be more frequent with DAPT, but major or life-threatening bleeds, depending on the bleeding definition, may not be more frequent. Therefore, adoption of DAPT as a “fallback” position for NCS in patients who have an “acceptable” pre-operative bleeding risk may improve cardiac outcomes. Further data are required to determine whether such a fallback position carries a favorable risk–benefit ratio.
We provide a suggested approach to APT use in Figure 3. It assumes that APT, and particularly DAPT, decrease MACE and ST and increase perioperative bleeding. The flow diagram is presented as a suggested approach for the clinician to individualize treatment in the absence of definitive data.
Heparin and LMWH
ST prevention likely requires some degree of platelet inhibition. Thus, it remains unclear whether DAPT cessation and anticoagulation therapy alone is a useful strategy. A 103-patient study (unknown stent type: 77%) undergoing NCS <1 year after PCI evaluated addition of either unfractionated or LMWH perioperatively in addition to continuation of some type of APT (ASA 85%, clopidogrel 44%) (34). Though the incidence of significant bleeding was low, the risk of overall adverse events was high (approximately 44%), likely due in part to the primary composite endpoint definition that included cardiac death, MI, revascularization (PCI or coronary artery bypass grafting), congestive heart failure, unstable angina, significant arrhythmias, biochemical evidence of myocardial necrosis, sepsis, surgical bleeding, and nonsurgically related bleeding. Given the paucity of data, the value of heparin or LMWH is uncertain, and further data are required.
Intravenous Glycoprotein IIb/IIIa Therapy
DAPT discontinuation preoperatively and use of a short-acting intravenous APT in addition to ASA is another potential strategy. Savonitto et al. (48) used tirofiban in 30 DES patients undergoing urgent surgery <1 year after DES implantation. Clopidogrel was stopped 5 days pre-operatively and tirofiban continued up to 4 h before surgery. There was no MACE and only 1 major bleeding episode. This study may have underestimated the bleeding risk because patients with high baseline bleeding risk were excluded. A similar protocol was tested in 36 DES patients (ASA continued in 80%) undergoing cardiac surgery (n = 15) or NCS (n = 21) (49). There was no MACE and 6 bleeding episodes (5 transfusions, 1 re-operation). Based on these small studies, a “bridging strategy” using short-acting intravenous APT may be an alternative to prevent MACE in high-risk patients, but further data are required.
Newer antiplatelet agents and NCS
The TIMI-38 (Thrombolysis In Myocardial Infarction 38) trial demonstrated that in acute coronary syndrome patients, prasugrel had a lower ST risk versus clopidogrel, whereas bleeding complications were more frequent (50). Although there are no studies of prasugrel in the NCS setting, the same considerations as with clopidogrel regarding bleeding complications are applicable. Because of its longer half-life, it is recommended to withhold prasugrel 7 days before surgery.
Ticagrelor is a reversible P2Y12 inhibitor that has been shown to compare favorably with clopidogrel in terms of both efficacy and safety (51). This agent may be useful during NCS because it is reversible and has a rapid onset of action; however, its action offset may be as long as 5 to 7 days and thus does not appear to offer an advantage over other P2Y12 inhibitors in allowing NCS with a minimal break in platelet inhibition from an oral agent (52). At present, there are no published data in patients undergoing NCS.
Cangrelor, currently investigational, is an intravenous non-thienopyridine P2Y12 receptor inhibitor, with a 3-min half-life (52). The recently reported BRIDGE (Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery) trial (53) demonstrated that cangrelor could provide adequate platelet inhibition before surgery after oral thienopyridine discontinuation. Bleeding events were not increased in patients who received cangrelor compared with placebo nor was there any difference in ischemic events. It should be noted that at the time of surgery, the cangrelor group did not demonstrate any difference in platelet inhibition compared with placebo; as such, the BRIDGE study showed a means to maintain platelet inhibition before, but not during, surgery. Cangrelor's value in reducing MACE with an acceptable bleeding risk during surgery requires a large-scale randomized study.
Conclusions and Recommendations
The current, rather limited, data suggest the following regarding the MACE and bleeding risks after NCS, and methods to decrease them:
1. The actual MACE risk after NCS remains uncertain, with wide variations reported (Fig. 1, Tables 2 to 5). There does seem to be a consensus, however, that the highest-risk period for ST after PCI with either BMS or DES following NCS is the first 4 weeks. Therefore, it seems reasonable to withhold NCS, if possible, for at least 4 weeks after PCI.
2. In the non-NCS situation, it is recommended that DAPT be continued for 1 to 12 months with BMS and at least 12 months for DES. Should NCS be required during this period, consideration to continue DAPT during NCS should be given, understanding that the risks and benefits of such an approach remain unclear based on current data (Fig. 3). However, it seems reasonable until more definitive data are forthcoming to recommend ASA in most cases as per guidelines unless the risk of bleeding is prohibitive and to recommend DAPT when the risk of bleeding is less than severe.
3. An important issue that has emerged is the persistent MACE risk even beyond the conventional “high-risk” period. The value of APT is uncertain. It seems reasonable to consider ASA unless the risk of bleeding is more than moderate, although further data are required to strengthen this recommendation.
4. The frequency of the combination of prior stent implantation and NCS recommends a randomized prospective trial to determine whether, and to what extent, APT, either single or dual, affects MACE, ST, and bleeding incidence after NCS.
5. At present, decision making regarding APT in the perioperative period in an individual patient will have to balance bleeding versus MACE risk. Recent strategies evaluating use of glycoprotein IIb/IIIa inhibitor or newer P2Y12 receptor antagonists look promising, but further studies are required. A coordinated treatment plan by the cardiologist, anesthesiologist, and surgeon is essential.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- antiplatelet therapy
- balloon angioplasty
- bare-metal stent(s)
- dual antiplatelet therapy
- drug-eluting stent(s)
- low-molecular-weight heparin
- major adverse cardiac event(s)
- myocardial infarction
- noncardiac surgery
- percutaneous coronary intervention
- stent thrombosis
- Received February 14, 2012.
- Revision received April 6, 2012.
- Accepted April 10, 2012.
- American College of Cardiology Foundation
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