Comparison Among Patients ‡75 Years Having Percutaneous Coronary Angioplasty Using Drug-Eluting Stents Versus Bare Metal Stents Fabio Mangiacapra, MD, PhDa,b,*, Elisabetta Ricottini, MDa, Giuseppe Di Gioia, MDa, Aaron Peace, MD, PhDa, Giuseppe Patti, MDa, Bernard De Bruyne, MD, PhDb, William Wijns, MD, PhDb, Emanuele Barbato, MD, PhDb, and Germano Di Sciascio, MDa Limited data are available on long-term efficacy and safety of drug-eluting stents (DES) in elderly patients who underwent PCI. A total of 635 consecutive patients aged ‡75 years who underwent PCI were enrolled at 2 European centers. Of these, 170 patients received at least 1 DES, whereas 465 patients received bare metal stent (BMS) only. Primary end point was the incidence of net adverse clinical events (NACE), defined as the occurrence of ischemic events or bleeding events, and was compared at a median follow-up of 31.2 months. Clinical follow-up information was available in 593 patients (93.4%). The duration of dual antiplatelet therapy was 12.3 – 5.1 months in the DES group and 3.8 – 7.4 months in the BMS group. The Kaplan-Meier estimate of NACE at 5 years was significantly lower in DES-treated patients (40.5%) than in BMS-treated patients (55.7%; p [ 0.009). This benefit was driven by a significant reduction in myocardial infarction (8.6% vs 16.6%; p [ 0.038) and target vessel revascularization rates (7.9% vs 21.9%; p [ 0.003) in the DES group, with no significant increase in the incidence of bleeding events (13.8% vs 12.2%; p [ 0.882). These results were confirmed at propensity scoree adjusted Cox proportional hazard analysis. In conclusion, in patients ‡75 years, the use of DES compared with BMS seems to reduce myocardial infarction and repeat revascularization rates at long-term follow-up, without an increase in bleeding despite longer duration of dual antiplatelet therapy. This net clinical benefit, resulting from persistent efficacy and safety over time, may support the use of DES as a reasonable option in patients ‡75 years. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;115:1179e1184)
Drug-eluting stents (DES) are effective in reducing the incidence of restenosis and repeat revascularization especially in the subset of complex lesion, such as multivessel disease, small-vessel disease, long lesions, and in patients with diabetes.1e5 Older patients may benefit more from DES implantation because of their greater anatomical complexity. Although the safety of second-generation DES regarding stent thrombosis (ST) has been largely documented,6,7 concerns about the need of prolonged dual antiplatelet therapy (DAPT) in a population with high incidence of co-morbidities and high bleeding risk continue to constrain the use of DES in elderly patients. Limited evidence is available on long-term outcomes of such patients who underwent PCI with DES, especially regarding safety data on bleeding events. Aim of the present study was to assess long-term net clinical outcomes of elderly patients treated with DES compared with bare metal stent (BMS).
a Department of Cardiovascular Medicine, Campus Bio-Medico University of Rome, Rome, Italy and bCardiovascular Center Aalst, OLV Clinic, Aalst, Belgium. Manuscript received December 10, 2014; revised manuscript received and accepted January 29, 2015. See page 1183 for disclosure information. *Corresponding author: Tel: þ39-06-225411612; fax: þ39-06225411638. E-mail address: [email protected] (F. Mangiacapra).
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.01.557
Methods Consecutive elderly patients (75 years) who underwent elective or urgent PCI were enrolled at the Department of Cardiovascular Sciences, Campus Bio-Medico University of Rome, Rome, Italy, and at the Cardiovascular Center Aalst, Aalst, Belgium, over a 2-year period (2008 to 2010). Exclusion criteria were PCI performed without stent implantation or with both DES and BMS, left ventricular ejection fraction 1 bleeding (13.8% vs 12.2%; p ¼ 0.882; Figure 1). The temporal distribution of bleeding events in the 2 study groups according to BARC classes is shown in Figure 2. Results of the propensity scoreeadjusted Cox proportional hazard analysis are reported in Table 3. The use of DES remained significantly associated with lower rates of MACE (hazard ratio [HR] 0.622, 95% confidence interval [CI] 0.426 to 0.910; p ¼ 0.015), nonfatal MI (HR 0.406, 95% CI 0.182 to 0.903; p ¼ 0.027), TVR (HR 0.315, 95% CI 0.150 to 0.662; p ¼ 0.002), and NACE (HR 0.632, 95% CI 0.450 to 0.887; p ¼ 0.008). Similar results were obtained after entering enrolling center as a covariate in the model. Discussion The present study suggests that the use of DES seems to be safe and effective in reducing the incidence of NACE in elderly patients who underwent PCI for various clinical syndromes, supporting DES as the “first-line” therapy for coronary interventions in this group of patients. Older patients represent a growing population among those who underwent PCI. These patients usually present high-risk features, which depend on greater incidence of co-morbidities and on more complex coronary anatomy and are often undertreated.11e14 Current guidelines are based on randomized trials in which the elderly population is only marginally represented.15 In
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Table 3 Cox proportional hazard analysis for 5-year clinical outcomes Cumulative event rates
Ischemic events Major adverse cardiac events Death Non-fatal myocardial infarction Target vessel revascularization Definite/probable stent thrombosis Bleeding events Net adverse clinical events
Unadjusted
Propensity score-adjusted
HR
95% CI
p value
HR
95% CI
p value
0.628 0.941 0.442 0.351 0.897 1.051 0.642
0.431-0.914 0.597-1.483 0.200-0.976 0.168-0.731 0.331-2.432 0.547-2.021 0.459-0.897
0.015 0.739 0.043 0.005 0.830 0.882 0.009
0.622 1.042 0.406 0.315 0.754 1.178 0.632
0.426-0.910 0.656-1.657 0.182-0.903 0.150-0.662 0.273-2.085 0.450-3.080 0.450-0.887
0.015 0.861 0.027 0.002 0.586 0.821 0.008
fact, little evidence is available regarding treatment options for this subset of patients. In recent years, several developments, such as adjuvant drug therapies, use of coronary stents, and transradial access have led to a general improvement in PCI outcome.12,16e18 The advent of DES has markedly reduced the incidence of restenosis with a decrease in the need for repeated myocardial revascularization, especially in the case of complex coronary lesions, which are frequently found in elderly subjects.1e5 Previous investigations about DES use in elderly patients have shown an increased incidence of death among this population compared with younger patients but have also demonstrated the efficacy in reducing restenosis and, therefore, repeat revascularization.19e21 Because the clinical presentation of restenosis is an ACS in the vast majority of cases, this clinical entity cannot be considered as a benign phenomenon. In a series of 12,492 patients treated with BMS, 25.3% only of those with restenosis presented stable angina, whereas the vast majority presented with ACS (52.2% unstable angina/noneST-elevation MI; 18.5% ST-elevation MI).22 Therefore, decreasing restenosis rates by DES implantation could be a mean to reduce the incidence of potentially threatening events in a population already at high risk, such as elderly patients. Marcolino et al21 found greater mortality rates at mid- and long-term follow-up among 291 octogenarians treated with DES compared with younger patients; however, TLR and TVR rates were lower among older patients, suggesting that the benefit from DES in reducing revascularization rate could be extended also to an older population. Similar results have been confirmed more recently in a large population of patients treated with zotarolimus-eluting stent (ZES).19 Costa et al20 have also shown higher rates of cardiac and noncardiac death among elderly patients compared with a younger population, nonetheless with very low rates of ST (1.5%) at 1-year follow-up, denoting the safety of DES use in these patients. Despite these encouraging data, the use of DES in elderly population continues to be often limited by the presence of co-morbidities and higher bleeding risk leading to concerns about prolonged DAPT.23 Advanced age itself is a risk factor for periprocedural bleeding complications, and in patients >75 years, occurrence after PCI bleeding is associated with subsequent increased risk of death or MI.24 In addition, bleeding events are in most cases directly related to the occurrence of death.19 Given the prognostic importance of both, it seems reasonable to take into account ischemic and
bleeding events together for the evaluation of clinical outcomes of patients who underwent PCI, especially when at higher risk, as it is the case of an aged population. In the present study, we have, hence, decided to investigate a composite end point of NACE, including both ischemic events and bleedings, with the aim to have a more complete assessment of patients’ outcomes. We have shown, after adjustment for propensity score, that DES implantation compared with BMS is associated with a 37% reduction of NACE at 5 years after the index procedure. The benefit from DES implantation derived from lower TVR and MI rates at 5-year follow-up. At the same time, in our population, no difference was observed in terms of bleeding events, supporting the safety of a DES strategy in an elderly population. Although the optimal duration of DAPT is still a matter of debate, recent studies suggest that even a 6-month period is associated with favorable outcomes, with no increase in thrombotic events after implantation of new-generation DES.25,26 In this view, the use of DES seems an even more reasonable option in patients with potentially increased risk of bleeding. Our data agree with previous studies comparing DES and BMS.4,27,28 Cheng et al27 showed in octogenarians that DES use was associated with a reduction of MACE, in particular TVR at 5-year follow-up. Wang et al28 documented in a large series of elderly patients a significant reduction in the risk of death and hospitalization for MI in DES-treated patients with no difference in bleeding risk compared with those treated with BMS. The reduction in the rates of MI besides TVR could be related that in elderly patients restenosis is often not as benign as in younger patients, presenting as an ACS. Therefore, preventing restenosis with DES may also result in a reduction of harder events. The efficacy and safety of DES implantation have also been recently demonstrated for the treatment of small coronary lesions in a population of patients aged 75 years.29 Moreover, in a study of 800 patients aged 80 years randomized to receive either everolimus-eluting stent or BMS, it was found at 1-year follow-up a reduced incidence of MI and TVR in DES-treated patients with no significant difference in the composite end point of death, MI, TVR, cerebrovascular accident, and major hemorrhage.30 In our study, a reduction of NACE was observed at 5-year follow-up in favor of DES. Although an initial split of the survival curves at Kaplan-Meier analysis is observed at 6 months after PCI in terms of NACE (mainly driven by higher incidence of TVR in patients who received BMS), a
Coronary Artery Disease/DES Versus BMS in Elderly Patients
continuous separation is seen for the remaining time course up to 5 years, suggesting a persistent benefit from DES beyond the classical time frame of BMS restenosis. Principal limitations of our study are inherent to its observational nonrandomized nature. It was performed in a nonselected population with unequal clinical characteristics and involved multiple operators. A propensity scoree adjusted multiple regression analysis was carried out to mitigate potential bias, but unmeasured indicators affecting the results cannot be excluded. Interestingly, despite unfavorable clinical and procedural characteristics compared with BMS, DES use was still associated with better clinical outcomes after statistical adjustment. Furthermore, the definition of elderly in our study (75 years) is lower than in some others, for example >80 years, and could have reduced event rates. Patients with reduced ejection fraction, severe renal impairment, and high bleeding risk were excluded to reduce potential selection bias, and therefore, the results of the present study cannot be extrapolated to these groups of patients.
9.
10.
11.
12.
Disclosures The authors report no relations that could be construed as a conflict of interest. 1. Colombo F, Biondi-Zoccai G, Infantino V, Omede P, Moretti C, Sciuto F, Siliquini R, Chiado S, Trevi GP, Sheiban I. A long-term comparison of drug-eluting versus bare metal stents for the percutaneous treatment of coronary bifurcation lesions. Acta Cardiol 2009;64:583e588. 2. Kim YH, Park SW, Lee SW, Park DW, Yun SC, Lee CW, Hong MK, Kim HS, Ko JK, Park JH, Lee JH, Choi SW, Seong IW, Cho YH, Lee NH, Kim JH, Chun KJ, Park SJ. Sirolimus-eluting stent versus paclitaxel-eluting stent for patients with long coronary artery disease. Circulation 2006;114:2148e2153. 3. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315e1323. 4. Puymirat E, Mangiacapra F, Peace A, Sharif F, Conte M, Bartunek J, Vanderheyden M, Wijns W, de Bruyne B, Barbato E. Long-term clinical outcome in patients with small vessel disease treated with drugeluting versus bare-metal stenting. Am Heart J 2011;162:907e913. 5. Sabate M, Jimenez-Quevedo P, Angiolillo DJ, Gomez-Hospital JA, Alfonso F, Hernandez-Antolin R, Goicolea J, Banuelos C, Escaned J, Moreno R, Fernandez C, Fernandez-Aviles F, Macaya C. Randomized comparison of sirolimus-eluting stent versus standard stent for percutaneous coronary revascularization in diabetic patients: the diabetes and sirolimus-eluting stent (DIABETES) trial. Circulation 2005;112: 2175e2183. 6. Palmerini T, Biondi-Zoccai G, Della Riva D, Stettler C, Sangiorgi D, D’Ascenzo F, Kimura T, Briguori C, Sabate M, Kim HS, De Waha A, Kedhi E, Smits PC, Kaiser C, Sardella G, Marullo A, Kirtane AJ, Leon MB, Stone GW. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet 2012;379:1393e1402. 7. Palmerini T, Biondi-Zoccai G, Della Riva D, Mariani A, Sabate M, Valgimigli M, Frati G, Kedhi E, Smits PC, Kaiser C, Genereux P, Galatius S, Kirtane AJ, Stone GW. Clinical outcomes with drug-eluting and bare-metal stents in patients with ST-segment elevation myocardial infarction: evidence from a comprehensive network meta-analysis. J Am Coll Cardiol 2013;62:496e504. 8. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Katus HA, Lindahl B, Morrow DA, Clemmensen PM, Johanson P, Hod H, Underwood R, Bax JJ, Bonow RO, Pinto F, Gibbons RJ, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W, Bassand JP, Menasche P, Ravkilde J, Ohman EM,
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Antman EM, Wallentin LC, Armstrong PW, Simoons ML, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D, Smith SC, Hu D, Lopez-Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S. Third universal definition of myocardial infarction. Circulation 2012;126:2020e2035. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115: 2344e2351. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736e2747. Alexander KP, Newby LK, Cannon CP, Armstrong PW, Gibler WB, Rich MW, Van de Werf F, White HD, Weaver WD, Naylor MD, Gore JM, Krumholz HM, Ohman EM. Acute coronary care in the elderly, part I: non-ST-segment-elevation acute coronary syndromes: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology: in collaboration with the Society of Geriatric Cardiology. Circulation 2007;115:2549e2569. Batchelor WB, Anstrom KJ, Muhlbaier LH, Grosswald R, Weintraub WS, O’Neill WW, Peterson ED. Contemporary outcome trends in the elderly undergoing percutaneous coronary interventions: results in 7, 472 octogenarians. National Cardiovascular Network Collaboration. J Am Coll Cardiol 2000;36:723e730. Gerber Y, Rihal CS, Sundt TM, Killian JM, Weston SA, Therneau TM, Roger VL. Coronary revascularization in the community. A population-based study, 1990 to 2004. J Am Coll Cardiol 2007;50: 1223e1229. Thomas MP, Moscucci M, Smith DE, Aronow H, Share D, Kraft P, Gurm HS. Outcome of contemporary percutaneous coronary intervention in the elderly and the very elderly: insights from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium. Clin Cardiol 2011;34:549e554. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head SJ, Juni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ, Richter DJ, Schauerte P, Sousa Uva M, Stefanini GG, Taggart DP, Torracca L, Valgimigli M, Wijns W, Witkowski A. 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;35:2541e2619. Alexander KP, Roe MT, Chen AY, Lytle BL, Pollack CVJ, Foody JM, Boden WE, Smith SCJ, Gibler WB, Ohman EM, Peterson ED. Evolution in cardiovascular care for elderly patients with non-STsegment elevation acute coronary syndromes: results from the CRUSADE National Quality Improvement Initiative. J Am Coll Cardiol 2005;46:1479e1487. Johnman C, Oldroyd KG, Mackay DF, Slack R, Pell AC, Flapan AD, Jennings KP, Eteiba H, Irving J, Pell JP. Percutaneous coronary intervention in the elderly: changes in case-mix and periprocedural outcomes in 31,758 patients treated between 2000 and 2007. Circ Cardiovasc Interv 2010;3:341e345. Schoenenberger AW, Radovanovic D, Stauffer JC, Windecker S, Urban P, Eberli FR, Stuck AE, Gutzwiller F, Erne P. Age-related differences in the use of guideline-recommended medical and interventional therapies for acute coronary syndromes: a cohort study. J Am Geriatr Soc 2008;56:510e516. Belardi J, Manoharan G, Albertal M, Widimsky P, Neumann FJ, Silber S, Leon MB, Saito S. The influence of age on clinical outcomes in patients treated with the resolute zotarolimus-eluting stent. Catheter Cardiovasc Interv 2013 [Epub ahead of print]. Costa JRJ, Sousa A, Moreira AC, Costa RA, Maldonado G, Cano MN, Egito ET, Romano ER, Barbosa M, Pavanello R, Jardim C, Cury A, Berwanger O, Sousa JE. Drug-eluting stents in the elderly: long-term (> one year) clinical outcomes of octogenarians in the DESIRE (Drug-Eluting Stents in the REal world) registry. J Invasive Cardiol 2008;20:404e410.
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21. Marcolino MS, Simsek C, de Boer SP, van Domburg RT, van Geuns RJ, de Jaegere P, Akkerhuis KM, Daemen J, Serruys PW, Boersma E. Shortand long-term outcomes in octogenarians undergoing percutaneous coronary intervention with stenting. EuroIntervention 2012;8:920e928. 22. Bainey KR, Norris CM, Graham MM, Ghali WA, Knudtson ML, Welsh RC. Clinical in-stent restenosis with bare metal stents: is it truly a benign phenomenon? Int J Cardiol 2008;128:378e382. 23. Spertus JA, Kettelkamp R, Vance C, Decker C, Jones PG, Rumsfeld JS, Messenger JC, Khanal S, Peterson ED, Bach RG, Krumholz HM, Cohen DJ. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation 2006;113: 2803e2809. 24. Ndrepepa G, Neumann FJ, Schulz S, Fusaro M, Cassese S, Byrne RA, Richardt G, Laugwitz KL, Kastrati A. Incidence and prognostic value of bleeding after percutaneous coronary intervention in patients older than 75 years of age. Catheter Cardiovasc Interv 2014;83:182e189. 25. Colombo A, Chieffo A, Frasheri A, Garbo R, Masotti-Centol M, Salvatella N, Oteo Dominguez JF, Steffanon L, Tarantini G, Presbitero P, Menozzi A, Pucci E, Mauri J, Cesana BM, Giustino G, Sardella G. Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol 2014;64:2086e2097. 26. Gilard M, Barragan P, Noryani AA, Noor HA, Majwal T, Hovasse T, Castellant P, Schneeberger M, Maillard L, Bressolette EE, Wojcik J, Delarche N, Blanchard D, Jouve B, Ormezzano O, Paganelli F, Levy G, Sainsous J, Carrie D, Furber A, Berland J, Darremont O, Le Breton H, Lyuycx-Bore A, Gommeaux A, Cassat C, Kermarrec A, Cazaux P,
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Druelles P, Dauphin R, Armengaud J, Dupouy P, Champagnac D, Ohlmann P, Endresen KK, Benamer H, Kiss RG, Ungi I, Boschat JJ, Morice MC. Six-month versus 24-month dual antiplatelet therapy after implantation of drug eluting stents in patients non-resistant to aspirin: ITALIC, a randomized multicenter trial. J Am Coll Cardiol 2015;65:777e786. Cheng JM, Onuma Y, Piazza N, Nuis RJ, Van Domburg RT, Serruys PW. Comparison of five-year outcome of octogenarians undergoing percutaneous coronary intervention with drug-eluting versus bare-metal stents (from the RESEARCH and T-SEARCH Registries). Am J Cardiol 2010;106:1376e1381. Wang TY, Masoudi FA, Messenger JC, Shunk KA, Boyle A, Brennan JM, Anderson HV, Anstrom KJ, Dai D, Peterson ED, Douglas PS, Rumsfeld JS. Percutaneous coronary intervention and drug-eluting stent use among patients 85 years of age in the United States. J Am Coll Cardiol 2012;59:105e112. Puymirat E, Mangiacapra F, Peace A, Ntarladimas Y, Conte M, Bartunek J, Vanderheyden M, Wijns W, de Bruyne B, Barbato E. Safety and effectiveness of drug-eluting stents versus bare-metal stents in elderly patients with small coronary vessel disease. Arch Cardiovasc Dis 2013;106:554e561. de Belder A, de la Torre Hernandez JM, Lopez-Palop R, O’Kane P, Hernandez Hernandez F, Strange J, Gimeno F, Cotton J, Diaz Fernandez JF, Carrillo Saez P, Thomas M, Pinar E, Curzen N, Baz JA, Cooter N, Lozano I, Skipper N, Robinson D, Hildick-Smith D. A prospective randomized trial of everolimus-eluting stents versus bare-metal stents in octogenarians: the XIMA Trial (Xience or Vision Stents for the Management of Angina in the Elderly). J Am Coll Cardiol 2014;63:1371e1375.
Drug-eluting stents (DES) are effective in reducing the incidence of restenosis and repeat revascularization especially in the subset of complex lesion, such as multivessel disease, small-vessel disease, long lesions, and in patients with diabetes.1e5 Older patients may benefit more from DES implantation because of their greater anatomical complexity. Although the safety of second-generation DES regarding stent thrombosis (ST) has been largely documented,6,7 concerns about the need of prolonged dual antiplatelet therapy (DAPT) in a population with high incidence of co-morbidities and high bleeding risk continue to constrain the use of DES in elderly patients. Limited evidence is available on long-term outcomes of such patients who underwent PCI with DES, especially regarding safety data on bleeding events. Aim of the present study was to assess long-term net clinical outcomes of elderly patients treated with DES compared with bare metal stent (BMS).
a Department of Cardiovascular Medicine, Campus Bio-Medico University of Rome, Rome, Italy and bCardiovascular Center Aalst, OLV Clinic, Aalst, Belgium. Manuscript received December 10, 2014; revised manuscript received and accepted January 29, 2015. See page 1183 for disclosure information. *Corresponding author: Tel: þ39-06-225411612; fax: þ39-06225411638. E-mail address: [email protected] (F. Mangiacapra).
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.01.557
Methods Consecutive elderly patients (75 years) who underwent elective or urgent PCI were enrolled at the Department of Cardiovascular Sciences, Campus Bio-Medico University of Rome, Rome, Italy, and at the Cardiovascular Center Aalst, Aalst, Belgium, over a 2-year period (2008 to 2010). Exclusion criteria were PCI performed without stent implantation or with both DES and BMS, left ventricular ejection fraction 1 bleeding (13.8% vs 12.2%; p ¼ 0.882; Figure 1). The temporal distribution of bleeding events in the 2 study groups according to BARC classes is shown in Figure 2. Results of the propensity scoreeadjusted Cox proportional hazard analysis are reported in Table 3. The use of DES remained significantly associated with lower rates of MACE (hazard ratio [HR] 0.622, 95% confidence interval [CI] 0.426 to 0.910; p ¼ 0.015), nonfatal MI (HR 0.406, 95% CI 0.182 to 0.903; p ¼ 0.027), TVR (HR 0.315, 95% CI 0.150 to 0.662; p ¼ 0.002), and NACE (HR 0.632, 95% CI 0.450 to 0.887; p ¼ 0.008). Similar results were obtained after entering enrolling center as a covariate in the model. Discussion The present study suggests that the use of DES seems to be safe and effective in reducing the incidence of NACE in elderly patients who underwent PCI for various clinical syndromes, supporting DES as the “first-line” therapy for coronary interventions in this group of patients. Older patients represent a growing population among those who underwent PCI. These patients usually present high-risk features, which depend on greater incidence of co-morbidities and on more complex coronary anatomy and are often undertreated.11e14 Current guidelines are based on randomized trials in which the elderly population is only marginally represented.15 In
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Table 3 Cox proportional hazard analysis for 5-year clinical outcomes Cumulative event rates
Ischemic events Major adverse cardiac events Death Non-fatal myocardial infarction Target vessel revascularization Definite/probable stent thrombosis Bleeding events Net adverse clinical events
Unadjusted
Propensity score-adjusted
HR
95% CI
p value
HR
95% CI
p value
0.628 0.941 0.442 0.351 0.897 1.051 0.642
0.431-0.914 0.597-1.483 0.200-0.976 0.168-0.731 0.331-2.432 0.547-2.021 0.459-0.897
0.015 0.739 0.043 0.005 0.830 0.882 0.009
0.622 1.042 0.406 0.315 0.754 1.178 0.632
0.426-0.910 0.656-1.657 0.182-0.903 0.150-0.662 0.273-2.085 0.450-3.080 0.450-0.887
0.015 0.861 0.027 0.002 0.586 0.821 0.008
fact, little evidence is available regarding treatment options for this subset of patients. In recent years, several developments, such as adjuvant drug therapies, use of coronary stents, and transradial access have led to a general improvement in PCI outcome.12,16e18 The advent of DES has markedly reduced the incidence of restenosis with a decrease in the need for repeated myocardial revascularization, especially in the case of complex coronary lesions, which are frequently found in elderly subjects.1e5 Previous investigations about DES use in elderly patients have shown an increased incidence of death among this population compared with younger patients but have also demonstrated the efficacy in reducing restenosis and, therefore, repeat revascularization.19e21 Because the clinical presentation of restenosis is an ACS in the vast majority of cases, this clinical entity cannot be considered as a benign phenomenon. In a series of 12,492 patients treated with BMS, 25.3% only of those with restenosis presented stable angina, whereas the vast majority presented with ACS (52.2% unstable angina/noneST-elevation MI; 18.5% ST-elevation MI).22 Therefore, decreasing restenosis rates by DES implantation could be a mean to reduce the incidence of potentially threatening events in a population already at high risk, such as elderly patients. Marcolino et al21 found greater mortality rates at mid- and long-term follow-up among 291 octogenarians treated with DES compared with younger patients; however, TLR and TVR rates were lower among older patients, suggesting that the benefit from DES in reducing revascularization rate could be extended also to an older population. Similar results have been confirmed more recently in a large population of patients treated with zotarolimus-eluting stent (ZES).19 Costa et al20 have also shown higher rates of cardiac and noncardiac death among elderly patients compared with a younger population, nonetheless with very low rates of ST (1.5%) at 1-year follow-up, denoting the safety of DES use in these patients. Despite these encouraging data, the use of DES in elderly population continues to be often limited by the presence of co-morbidities and higher bleeding risk leading to concerns about prolonged DAPT.23 Advanced age itself is a risk factor for periprocedural bleeding complications, and in patients >75 years, occurrence after PCI bleeding is associated with subsequent increased risk of death or MI.24 In addition, bleeding events are in most cases directly related to the occurrence of death.19 Given the prognostic importance of both, it seems reasonable to take into account ischemic and
bleeding events together for the evaluation of clinical outcomes of patients who underwent PCI, especially when at higher risk, as it is the case of an aged population. In the present study, we have, hence, decided to investigate a composite end point of NACE, including both ischemic events and bleedings, with the aim to have a more complete assessment of patients’ outcomes. We have shown, after adjustment for propensity score, that DES implantation compared with BMS is associated with a 37% reduction of NACE at 5 years after the index procedure. The benefit from DES implantation derived from lower TVR and MI rates at 5-year follow-up. At the same time, in our population, no difference was observed in terms of bleeding events, supporting the safety of a DES strategy in an elderly population. Although the optimal duration of DAPT is still a matter of debate, recent studies suggest that even a 6-month period is associated with favorable outcomes, with no increase in thrombotic events after implantation of new-generation DES.25,26 In this view, the use of DES seems an even more reasonable option in patients with potentially increased risk of bleeding. Our data agree with previous studies comparing DES and BMS.4,27,28 Cheng et al27 showed in octogenarians that DES use was associated with a reduction of MACE, in particular TVR at 5-year follow-up. Wang et al28 documented in a large series of elderly patients a significant reduction in the risk of death and hospitalization for MI in DES-treated patients with no difference in bleeding risk compared with those treated with BMS. The reduction in the rates of MI besides TVR could be related that in elderly patients restenosis is often not as benign as in younger patients, presenting as an ACS. Therefore, preventing restenosis with DES may also result in a reduction of harder events. The efficacy and safety of DES implantation have also been recently demonstrated for the treatment of small coronary lesions in a population of patients aged 75 years.29 Moreover, in a study of 800 patients aged 80 years randomized to receive either everolimus-eluting stent or BMS, it was found at 1-year follow-up a reduced incidence of MI and TVR in DES-treated patients with no significant difference in the composite end point of death, MI, TVR, cerebrovascular accident, and major hemorrhage.30 In our study, a reduction of NACE was observed at 5-year follow-up in favor of DES. Although an initial split of the survival curves at Kaplan-Meier analysis is observed at 6 months after PCI in terms of NACE (mainly driven by higher incidence of TVR in patients who received BMS), a
Coronary Artery Disease/DES Versus BMS in Elderly Patients
continuous separation is seen for the remaining time course up to 5 years, suggesting a persistent benefit from DES beyond the classical time frame of BMS restenosis. Principal limitations of our study are inherent to its observational nonrandomized nature. It was performed in a nonselected population with unequal clinical characteristics and involved multiple operators. A propensity scoree adjusted multiple regression analysis was carried out to mitigate potential bias, but unmeasured indicators affecting the results cannot be excluded. Interestingly, despite unfavorable clinical and procedural characteristics compared with BMS, DES use was still associated with better clinical outcomes after statistical adjustment. Furthermore, the definition of elderly in our study (75 years) is lower than in some others, for example >80 years, and could have reduced event rates. Patients with reduced ejection fraction, severe renal impairment, and high bleeding risk were excluded to reduce potential selection bias, and therefore, the results of the present study cannot be extrapolated to these groups of patients.
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