The Incidence of Non-Cardiac Surgery in Patients Treated With Drug-Eluting Stents According to Age

Abstract: Objectives. The impact of age on the incidence and timing of non-cardiac surgery after coronary stent implantation is unknown. We evaluated the incidence and timing of non-cardiac surgery after drug-eluting stent (DES) implantation according to patient age. Methods. A total of 37,915 consecutive patients treated by DES implantation between February 2003 and April 2014 were included in this study. The number of patients who underwent non-cardiac surgery were as follows: 4263 (11.2%) within 1 year, 5357 (14.1%) within 2 years, and 6311 (16.6%) within 3 years of DES implantation. Patients were divided into four groups according to age: <50 years (n = 5785), between 50 and 59 years (n = 9639), between 60 and 69 years (n = 13,566), and between 70 and 79 years (n = 8925). Results. The rates of non-cardiac surgery within 1 year among patients aged <50 years, 50-59 years, 60-69 years, and 70-79 years were 8.0% (461/5785), 8.9% (855/9639), 12.1% (1636/13,566), and 14.7% (1311/8925), respectively (P-value for trend <.01). The cut-off age at which non-cardiac surgery was more likely to occur within 1 year of DES implantation was 62 years. The rate of non-cardiac surgery within 3 years of DES implantation reached a peak among patients who were 73 years old (23.9%). Conclusions. Non-cardiac surgery with requests for cessation of dual-antiplatelet treatment was frequently performed in patients ≥62 years old who were treated with DES implantation in a real-world clinical practice.

J INVASIVE CARDIOL 2019;31(2):E9-E14.

Key words: drug-eluting stents, percutaneous coronary intervention, surgery

While drug-eluting stent (DES) implantation lowered the incidence of in-stent restenosis compared to bare-metal stenting by inhibiting neointimal hyperplasia,¹ DES thrombosis was a rare but serious complication causing acute myocardial infarction and high risk of subsequent mortality, particularly in patients who prematurely discontinued antiplatelet therapy.^2,3 Discontinuation of antiplatelet therapy was commonly associated with non-cardiac surgery in DES-treated patients. Surgeons usually advised DES-treated patients to discontinue antiplatelet therapy for bleeding control during non-cardiac surgery. However, current guidelines recommend that elective non-cardiac surgery should be postponed at least 3 or 6 months, and up to 12 months after DES implantation for prevention of DES thrombosis.^4,5 Several studies reported that non-cardiac surgery was frequently performed after coronary stent implantation.^6-8 As patients age, non-cardiac surgery is performed more frequently. However, the impact of age on the incidence and timing of non-cardiac surgery after coronary stent implantation remains unknown. In particular, there are no data identifying specific patient ages (ie, cut-off or reference values) at which clinicians should discontinue antiplatelet therapy due to the risk of non-cardiac surgery in the current DES era. Therefore, we evaluated the incidence and timing of non-cardiac surgery after DES implantation according to age.

Methods

Study population. A total of 37,915 consecutive patients treated with DES implantation at our institute between February 2003 and April 2014 were enrolled in this retrospective study. It was more likely for older patients and their guardians to refuse surgery due to the higher prevalence of surgical complications and poor physical performance; therefore, elderly patients (defined as those ≥80 years old) were excluded from this study. Patients with follow-up duration <3 years or loss of follow-up were excluded from this study. The remaining patients were arbitrarily divided into four groups according to age: <50 years, between 50 and 59 years, between 60 and 69 years, and between 70 and 79 years. This study was approved by the institutional review board of our institute, and written informed consent was obtained from all patients included in this retrospective analysis.

Data collection. Data were reported using standard case report forms. Baseline clinical information was collected for all patients, including age, gender, traditional risk factors, and past medical history. Patients visited the outpatient clinic at 30 days and 3 months after DES implantation, and every 3-6 months thereafter. Non-cardiac surgeries were categorized into three groups according to low, intermediate, or high surgical risk, based on the European Society of Cardiology and European Society of Anaesthesiology recommendations.⁹ Time to non-cardiac surgery was defined as the time from the date of DES implantation to the date of the non-cardiac surgery. Time interval from DES implantation to non-cardiac surgery was categorized as 0-12 months, 0-24 months, and 0-36 months. The incidence and timing of non-cardiac surgery after DES implantation were evaluated according to patient age. The cut-off age at which the number of non-cardiac surgery increased after DES implantation was also evaluated.

Statistical analysis. Continuous variables are expressed as mean ± standard deviation, and categorical data are presented as number (%). Categorical variables were analyzed by Chi-square or Fisher’s exact test, as appropriate, and continuous variables were analyzed by ANOVA test or Kruskall-Wallis test, as indicated. The linear-by-linear association Chi-square test was performed to evaluate the significance of linear relationship between age group and number of patients who underwent non-cardiac surgery. The relationship between age group and number of non-cardiac surgeries was assessed using Spearman’s non-parametric correlation analysis. Receiver operator characteristic analysis was performed to determine the best cut-off values for patient age to demonstrate increased risk of non-cardiac surgery.¹⁰ A two-sided P-value <.05 was considered statistically significant. Statistical analyses were performed with SPSS statistical software, version 23.0 for Windows (SPSS, Inc).     

Results

The baseline demographic and clinical characteristics are presented in Table 1. The mean patient age was 60.8 ± 10.9 years (range, 18-79 years). As the patient age increased, the prevalence of male gender and current smoker decreased, as did mean body mass index (P<.01). On the other hand, the prevalence of diabetes mellitus, chronic renal failure, prior stroke history, prior percutaneous coronary intervention, prior myocardial infarction, prior coronary artery bypass graft, and congestive heart failure significantly increased as patient age increased (P<.01).

The absolute numbers and percentages of patients who underwent non-cardiac surgery within 3 years are shown in Figure 1. The percentage of non-cardiac surgery within 3 years of DES implantation reached a peak among patients 73 years old (251/1050; 23.9%). As the patients aged, the number of patients who underwent non-cardiac surgery tended to increase. The detailed incidence of non-cardiac surgery according to patient age and time interval between DES implantation and non-cardiac surgery are summarized in Table 2. The number of patients who underwent non-cardiac surgery within 1 year, 2 years, and 3 years of DES implantation was 4263 (11.2%), 5357 (14.1%), and 6311 (16.6%), respectively. The incidence rates of non-cardiac surgery within 1 year for the patient groups <50 years, 50-59 years, 60-69 years, and 70-79 years were 8.0%, 8.9%, 12.1%, and 14.7%, respectively (P-value for trend <.01). Sensitivity and specificity curves were used to identify the optimal age cut-off value that best predicted an increase in the number of non-cardiac surgeries within 1 year of DES implantation, and determined it to be 62 years (Figure 2), with sensitivity of 60.7% and specificity of 51.9%. Detailed incidence and timing of surgery classified according to the surgical risks are summarized in Table 3.

Discussion

The principal findings of the present study were that non-cardiac surgery with subsequent requests for cessation of dual-antiplatelet therapy was frequently performed in patients who were treated by DES. As the patients increased in age, the number of patients who underwent non-cardiac surgery also increased in a real-world clinical practice. The percentage of non-cardiac surgeries within 3 years after DES implantation reached a peak when patients were 73 years old. The cut-off age at which the number of non-cardiac surgeries performed within 1 year of DES implantation increased was 62 years old.

Current guidelines recommend that elective non-cardiac surgery should be delayed until completion of the full duration of recommended dual-antiplatelet therapy, and that non-cardiac surgery should be performed without discontinuation of aspirin, if possible, in DES-treated patients in order to prevent DES thrombosis.^9,11 However, most non-cardiac surgeons are reluctant to perform non-cardiac surgery with simultaneous antiplatelet therapy, which increases bleeding events during surgery.

Iakovou et al demonstrated that premature antiplatelet therapy discontinuation was an independent predictor of DES thrombosis.² Ferreira-González et al¹² reported that interruption of at least one antiplatelet therapy (predominantly clopidogrel) was observed in 14.4% during the first year after DES implantation, while Schoos et al¹³ reported that interruption of dual-antiplatelet therapy due to minor and major surgery occurred in 4.1% of patients during the first year after DES implantation in their study group. The majority of dual-antiplatelet therapy interruptions occurred due to minor surgery (68.4%) rather than major surgery (31.6%), and interruptions were frequently recommended by non-cardiologists.¹³ The risk of perioperative major adverse cardiac events, such as stent thrombosis, myocardial infarction, or death, was related to the early cessation of dual-antiplatelet therapy or prothrombotic and proinflammatory effects induced by the surgery.^14-17 The perioperative prothrombotic state may be mediated by increased platelet aggregation and decreased fibrinolysis.¹⁸ Physiological stress, such as anemia and hypotension, were another possible mechanism of myocardial ischemia in the patients with coronary artery disease.¹⁹

The incidence of non-cardiac surgery in the current study (11.2% at 1 year, 14.1% at 2 years, 16.6% at 3 years) was comparable with those in previous studies (4.4%-18.0% at 1 year, 18.0%-29.3% at 2 years, and 13%-21% at 3 years after coronary stent implantation).^7,8,20,21 Until now, only very limited data regarding the incidence and timing of non-cardiac surgery according to patient age were available. Two previous studies reported that older patients were more likely to undergo subsequent surgeries, but did not include specific data and detailed analysis.^21,22 In the present study, the incidence rates of non-cardiac surgery were 8.0%, 8.9%, 12.1%, and 14.7% within 1 year of DES implantation for patients <50 years, between 50 and 59 years, between 60 and 69 years, and between 70 and 79 years, respectively. The cut-off age after which the number of non-cardiac surgeries performed within 1 year after DES implantation increased was 62 years. The percentage of non-cardiac surgeries within 3 years of DES implantation reached a peak in patients 73 years old (23.9%). The clinical implication for real-world practice is that elderly patients (specifically, ≥62 years old) were identified as more likely to interrupt dual-antiplatelet therapy than younger patients.

Recent studies showed short-term dual-antiplatelet therapy (≤3 or ≤6 months) showed a similar ischemic event rate and a lower bleeding rate when stable angina patients were treated with new-generation DES implantation compared to prolonged dual-antiplatelet therapy.^23-25 Therefore, interventionists should carefully select new-generation DES options for the treatment of elderly patients, especially those ≥62 years old, considering the possibility of unexpected cessation of dual-antiplatelet therapy. When coronary revascularization is required prior to planned non-cardiac surgery, bare-metal stent implantation or balloon angioplasty, followed by 4-6 weeks of dual-antiplatelet therapy, is usually preferred to DES implantation.^26,27 In addition, new-generation DES options with shorter duration of dual-antiplatelet therapy might be an alternative for these patients.^24,28

Study limitations. This study had several limitations. First, this was a retrospective analysis. Second, we did not investigate whether or not antiplatelet agents were stopped in the perioperative period and whether such stoppage was related to clinical outcomes such as stent thrombosis or myocardial infarction.

Conclusion

Elderly patients underwent non-cardiac surgery more often than younger patients. Thus, physicians are advised to carefully select the type of DES used to treat patients ages ≥62 years old while considering the possibility of cessation of dual-antiplatelet therapy.

References

1. Kirtane AJ, Gupta A, Iyengar S, et al. Safety and efficacy of drug-eluting and bare metal stents: comprehensive meta-analysis of randomized trials and observational studies. Circulation. 2009;119:3198-3206.
2. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293:2126-2130.
3. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement. Circulation. 2006;113:2803-2809.
4. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2016;68:1082-1115.
5. Valgimigli M, Bueno H, Byrne R, et al. ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. The task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39:213-260.
6. Anwaruddin S, Askari AT, Saudye H, et al. Characterization of post-operative risk associated with prior drug-eluting stent use. JACC Cardiovasc Interv. 2009;2:542-549.
7. Gandhi NK, Abdel-Karim ARR, Banerjee S, Brilakis ES. Frequency and risk of noncardiac surgery after drug-eluting stent implantation. Catheter Cardiovasc Interv. 2011;77:972-976.
8. Cruden NL, Harding SA, Flapan AD, et al. Previous coronary stent implantation and cardiac events in patients undergoing noncardiac surgery. Circ Cardiovasc Interv. 2010;3:236-242.
9. Kristensen SD, Knuuti J, Saraste A, et al. 2014 ESC/ESA guidelines on non-cardiac surgery: cardiovascular assessment and management: the joint task force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). Eur Heart J. 2014;35:2383-2431.
10. Perkins NJ, Schisterman EF. The inconsistency of “optimal” cutpoints obtained using two criteria based on the receiver operating characteristic curve. Am J Epidemiol. 2006;163:670-675.
11. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. J Am Coll Cardiol. 2014;64:e77-e137.
12. Ferreira-González I, Marsal JR, Ribera A, et al. Background, incidence, and predictors of antiplatelet therapy discontinuation during the first year after drug-eluting stent implantation. Circulation. 2010;122:1017-1025.
13. Schoos M, Chandrasekhar J, Baber U, et al. Causes, timing, and impact of dual antiplatelet therapy interruption for surgery (from the patterns of non-adherence to anti-platelet regimens in stented patients registry). Am J Cardiol. 2017;120:904-910.
14. Diamantis T, Tsiminikakis N, Skordylaki A, et al. Alterations of hemostasis after laparoscopic and open surgery. Hematology. 2007;12:561-570.
15. Li N, Astudillo R, Ivert T, Hjemdahl P. Biphasic pro-thrombotic and inflammatory responses after coronary artery bypass surgery. J Thromb Haemost. 2003;1:470-476.
16. Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation. 2005;111:3481-3488.
17. Rajagopalan S, Ford I, Bachoo P, et al. Platelet activation, myocardial ischemic events and postoperative non-response to aspirin in patients undergoing major vascular surgery. J Thromb Haemost. 2007;5:2028-2035.
18. Mahla E, Lang T, Vicenzi MN, et al. Thromboelastography for monitoring prolonged hypercoagulability after major abdominal surgery. Anesth Analg. 2001;92:572-577.
19. Kunadian V, Mehran R, Lincoff AM, et al. Effect of anemia on frequency of short-and long-term clinical events in acute coronary syndromes (from the acute catheterization and urgent intervention triage strategy trial). Am J Cardiol. 2014;114:1823-1829.
20. Tokushige A, Shiomi H, Morimoto T, et al. Incidence and outcome of surgical procedures after coronary bare-metal and drug-eluting stent implantation: a report from the CREDO-Kyoto PCI/CABG registry cohort-2. Circ Cardiovasc Interv. 2012;5:237-246.
21. Hawn MT, Graham LA, Richman JR, et al. The incidence and timing of noncardiac surgery after cardiac stent implantation. J Am Coll Surg. 2012;214:658-666.
22. To AC, Armstrong G, Zeng I, Webster NW. Non-cardiac surgery and bleeding after percutaneous coronary intervention. Circ Cardiovasc Interv. 2009;2:213-221.
23. Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET trial (real safety and efficacy of 3-month dual antiplatelet therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol. 2012;60:1340-1348.
24. Urban P, Meredith IT, Abizaid A, et al. Polymer-free drug-coated coronary stents in patients at high bleeding risk. N Engl J Med. 2015;373:2038-2047.
25. Palmerini T, Della Riva D, Benedetto U, et al. Three, six, or twelve months of dual antiplatelet therapy after DES implantation in patients with or without acute coronary syndromes: an individual patient data pairwise and network meta-analysis of six randomized trials and 11,473 patients. Eur Heart J. 2017;38:1034-1043.
26. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease. J Am Coll Cardiol. 2012;60:e44-e164.
27. Windecker S, Kolh P, Windecker S, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35:2541-2619.
28. Varenne O, Cook S, Sideris G, et al. Drug-eluting stents in elderly patients with coronary artery disease (SENIOR): a randomised single-blind trial. Lancet. 2018;391:41-50. Epub 2017 Nov 1.

From the ¹Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; ²Severance Cardiovascular Hospital, Yonsei University Health System, Seoul, Korea; ³Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea; and ⁴Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.

Funding: This study was supported by a grant from the Korea Healthcare Technology Research & Development Project, Ministry for Health & Welfare, Republic of Korea (Nos. A085136 and HI15C1277), the Mid-Career Research Program through an NRF grant funded by the NEST, Republic of Korea (No. 2015R1A2A2A01002731), and the Cardiovascular Research Center, Seoul, Korea.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted September 19, 2018 and accepted October 2, 2018.

Address for correspondence: Myeong-Ki Hong, MD, PhD, Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722 South Korea. Email: mkhong61@yuhs.ac