Usefulness of Primary Angioplasty in Nonagenarians With Acute Myocardial Infarction

Usefulness of Primary Angioplasty in Nonagenarians With Acute Myocardial Infarction Gian Battista Danzi, MDa,*, Marco Centola, MDa, Guido A. Pomidossi, MDa, Dario Consonni, MDb, Sara De Matteis, MDb, Amerigo Stabile, MDc, Marco Sesana, MDd, Angelo Anzuini, MDe, Paolo Sganzerla, MDf, Bernardo Cortese, MDg, Angela Migliorini, MDh, and David Antoniucci, MDh The optimal reperfusion strategy in very elderly patients with ST-segment elevation myocardial infarction is still a subject of debate. The aim of this multicenter study was to determine the medium-term outcomes of nonagenarians after primary percutaneous intervention for ST-segment elevation myocardial infarction. A systematic review of the databases of 7 Italian centers showed that these had performed 5,023 primary angioplasties over the previous 5 years, 100 of which (2%) involved patients >90 years old. Thirty-five subjects were in Killip class III or IV at time of presentation, 78 had multivessel coronary artery disease, and mean ejection fraction was 0.40 ⴞ 0.12%. In-hospital mortality was 19% and was significantly higher in patients with shock (58% vs 10%, p <0.001). Survival rate after 6 months was 68%: 16% in those with Killip class IV at admission and 81% in the remaining patients (p <0.001). Cox regression analysis identified 3 independent predictors of 6-month mortality: cardiogenic shock at presentation (hazard ratio [HR] 10.82, 95% confidence interval [CI] 4.51 to 25.93, p <0.001), Thrombolysis In Myocardial Infarction myocardial flow after percutaneous coronary intervention (HR 0.19, 95% CI 0.07 to 0.50, p ⴝ 0.001), and abciximab administration (HR 0.32, 95% CI 0.13 to 0.78, p ⴝ 0.01). In conclusion, the results of this multicenter study suggest that selected nonagenarians with acute myocardial infarction benefit from successful primary angioplasty. The treatment does not affect the poor prognosis of patients presenting with cardiogenic shock, but the administration of abciximab seems to have a positive effect on 6-month mortality. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;106:770 –773) The aim of this multicenter study was to evaluate the short- and medium-term outcomes of nonagenarians with ST-segment elevation myocardial infarction (STEMI) systematically treated with primary angioplasty. Methods The study involved 7 Italian centers that systematically use primary percutaneous coronary intervention (PCI) in patients with STEMI regardless of their age. A systematic review of their databases showed that they had performed 5,023 primary PCIs over the previous 5 years, 100 of which (2%) involved subjects ⱖ90 years old and formed the subject of this analysis. Inclusion criteria for direct PCI were chest pain persisting for ⬎30 minutes with electrocardiographic ST-segment elevation ⱖ0.1 mV in ⱖ2 contiguous

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Divisione di Cardiologia and bServizio di Epidemiologia, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico; cDivisione di Cardiologia Ospedale Civico ARNAS, Palermo, Italy; dDivisione di Cardiologia, Fondazione Poliambulanza, Brescia, Italy; eDivisione di Cardiologia, Casa di Cura Città Studi, Milan, Italy; fDivisione di Cardiologia, Cliniche Gavazzeni–Humanitas, Bergamo, Italy; gDivisione di Cardiologia, Ospedale di Grosseto, Grosseto, Italy; and hDivisione di Cardiologia, Ospedale di Careggi, Florence, Italy. Manuscript received March 25, 2010; revised manuscript received and accepted April 26, 2010. *Corresponding author: Tel: 39-02-5503-3532; fax: 39-02-5503-3530. E-mail address: [email protected] (G.B. Danzi). 0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.04.041

leads and admission within 6 hours of symptom onset (from 6 to 24 hours for patients with evidence of continuing ischemia). Exclusion criteria were severe cognitive impairment, an inability to obtain informed consent, and a history of bleeding diathesis.1 Cardiac catheterization and PCI were performed using the standards of each center. All patients received aspirin (325 to 500 mg) before the procedure and clopidogrel (300 to 600 mg). The choice of anticoagulation or the use of glycoprotein IIb/IIIa inhibitor (abciximab) was left to the physician’s judgment. Cardiogenic shock was determined by conventional clinical criteria of hypotension and signs of peripheral hypoperfusion in the presence of pulmonary congestion that did not resolve with inotropic agents or possibly mechanical support. A successful procedure was defined as (1) achievement of Thrombolysis In Myocardial Infarction (TIMI) grade 2 or 3 flow, (2) ⬍50% residual stenosis, and (3) absence of any major clinical adverse cardiac events within 24 hours. A failed procedure was defined as resulting in TIMI grade 0 to 1 flow regardless of residual stenosis, with the absence of any major clinical adverse cardiac events within 24 hours. A complicated procedure was defined as resulting in death, reinfarction, emergent revascularization, or cerebrovascular accident within 24 hours. Reinfarction was defined as an increase in creatinine kinase to ⬎2 times the initial value, associated with a creatinine kinase-MB fraction ⬎10% of total creatinine kinase. www.ajconline.org

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Table 1 Clinical data (n ⫽ 100) Variable Age (years) Men Body/mass index (kg/m2) Hypertension Hyperlipidemia Diabetes mellitus Previous myocardial infarction Previous coronary bypass Previous percutaneous coronary intervention Left ventricular ejection fraction on admission (%) ST-segment elevation myocardial infarction location Anterior Nonanterior Killip class before percutaneous coronary intervention I II III IV Time from symptoms to percutaneous coronary intervention (minutes) Hemoglobin at admission (g/L) Creatinine at admission (mg/dl) Infarct-related artery stenting

92.1 ⫾ 2.1 44 24.3 ⫾ 5.2 58 68 19 18 9 16 0.40 ⫾ 0.12 43 57 51 14 16 19 248 ⫾ 122 10.8 ⫾ 1.1 1.4 ⫾ 0.4 94

Table 2 Procedural characteristics Variable Door-to-balloon time (minutes) Single-vessel coronary artery disease Multivessel coronary artery disease Single-lesion percutaneous coronary intervention Multilesion percutaneous coronary intervention Infarct-related coronary artery Left anterior descending Left circumflex Right Left main Thrombolysis In Myocardial Infarction grade flow after procedure 0 1 2 3 Successful percutaneous coronary intervention Failed percutaneous coronary intervention Complicated percutaneous coronary intervention Use of protection device Intra-aortic balloon pumping Creatinine kinase peak (mg/dl) Abciximab administration

148 ⫾ 137 22 78 73 18 40 24 30 6

7 2 9 82 85 4 11 10 7 1,782 ⫾ 1,455 45

Major and minor bleeding events were defined using the criteria of the TIMI trial group,2 and acute renal failure as an increase in serum creatinine ⱖ25% within 72 hours of angioplasty, with a peak creatinine level ⱖ2.0 mg/dl. Severe clinical events, such as death, cardiac death, cerebrovascular accident, reinfarction, new revascularization (with PCI or coronary artery bypass surgery), and

Figure 1. Kaplan-Meier estimated probability of survival after 6 months by shock at admission, postprocedural TIMI myocardial flow, and abciximab administration.

severe bleeding were evaluated during hospitalization and at follow-up. At least 6 months’ follow-up data were available for all surviving patients; these data were obtained during a patient visit to outpatient clinics or by a telephone interview. Continuous variables are expressed as mean ⫾ 1 SD, and discrete variables as absolute values and percentages. Sixmonth survival/mortality was first evaluated with KaplanMeier estimators and log-rank tests and then with a multiple Cox proportional hazard model that included the covariates center and gender and the variables associated with mortality at univariate analysis. Data were statisti-

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cally analyzed using STATA 11 (STATA Corp. LP, College Station, Texas). Results Patients’ mean age was 92.1 ⫾ 2.1 years (range 90 to 98); their clinical and procedural characteristics are presented in Tables 1 and 2. Forty-three of the 100 patients had an anterior wall acute MI (AMI), 19 presented with cardiogenic shock, and 16 were in Killip class III. Mean left ventricular ejection fraction recorded during echocardiographic examination in the emergency department was 0.40 ⫾ 0.12%. Seventy-eight percent of patients had multivessel coronary artery disease. Mean time from symptom onset to PCI was 248 ⫾ 122 minutes, and door-to-balloon time was 148 ⫾ 137 minutes. The procedure was successful in 85 patients, complicated in 11, and failed in 4; abciximab was administered in 45% of cases. Preprocedural minimal lumen diameter of the stenotic segment was 0.13 ⫾ 0.02 mm and increased to 2.98 ⫾ 0.47 mm after angioplasty. Mean lesion length was 14.9 ⫾ 8.2 mm. In-hospital mortality rate was 19%; 11 of 19 patients presented with cardiogenic shock (58%) and 8 of 81 (10%) without shock (p ⬍0.001). Major bleeding complications occurred in 3 patients who developed groin hematoma with a decrease in hemoglobin levels to ⱖ4.0 g/L and received blood transfusions; none of these patients had received a glycoprotein IIb/IIIa receptor inhibitor. Reversible acute renal failure also occurred in 3 patients. Mean length of hospitalization was 7 ⫾ 5 days. Six-month survival rate was 68%. One patient died from pneumonia 1 month after discharge, and 31 had cardiac death; mortality rates were 84% in patients in Killip class IV at admission and 19% in the other patients (p ⬎0.001; Figure 1). Two subjects were rehospitalized because of congestive heart failure, and 1 developed a new episode of AMI. Multivariate Cox regression analysis identified 3 independent predictors of 6-month mortality: cardiogenic shock at presentation (hazard ratio [HR] 10.82, 95% confidence interval [CI] 4.51 to 25.93, p ⬍0.001), TIMI myocardial flow after PCI (HR 0.19, 95% CI 0.07 to 0.50, p ⫽ 0.001), and abciximab administration (HR 0.32, 95% CI 0.13 to 0.78, p ⫽ 0.01; Figure 1). Discussion The findings of this study show that (1) selected nonagenarians presenting with STEMI without cardiogenic shock benefit from successful primary angioplasty and (2) administration of abciximab seems to be associated with a decrease in 6-month mortality. Results of published studies on AMI indicate that age is a strong predictor of mortality and, in nonagenarians, is associated with a high rate of 30-day and 1-year mortalities even when the guideline recommendations are followed.3,4 Factors contributing to adverse outcomes are extent of coronary artery disease (as shown in most patients) and frequent presence of co-morbidities known to be associated with an increased risk of death. Most nonagenarians in our

study were women, which is consistent with the generally longer life expectancy of women. As expected, most had multivessel coronary artery disease and left ventricular dysfunction, and ⬎1/3 were in Killip class III or IV. Primary PCI is particularly attractive in high-risk patients, and previous studies have shown that the long-term benefit of angioplasty over fibrinolysis is not affected by age.5–7 Furthermore, because the relative risk decrease provided by angioplasty is the same in elderly and younger patients, the absolute benefit may be greater. However, there are no published data concerning outcomes of nonagenarians who have undergone primary PCI, although Moreno et al8 reported a 100% success rate in a series of 28 nonagenarian patients undergoing elective PCI in different clinical settings, with in-hospital mortality occurring in patients with cardiogenic shock and those receiving primary PCI. Our results seem to support the benefit of using PCI as the default strategy even in very elderly patients presenting with an AMI without cardiogenic shock; the high initial success rate was sustained for up to 6 months when the survival rate was 81%. Six-month mortality was closely associated with an inability to restore optimal TIMI flow after the intervention, and unsuccessful myocardial reperfusion has been previously associated with a poor prognosis, especially in elderly patients.9 Our findings are consistent with those reported for the Primary Angioplasty in Myocardial Infarction (PAMI) trials10 and by Valente et al11 who carried out a trial in a small series of patients ⬎85 years old. Incidence of cardiogenic shock was very high in our patients (19%), and Shah et al12 reported similar findings. We found that 6-month mortality rate remained very high (about 85%) in this subgroup of patients, even after an angiographically successful procedure, and this confirms that a very advanced age is a strong predictor of early and late death in patients with AMI presenting with cardiogenic shock. A number of randomized trials have shown that use of glycoprotein IIb/IIIa receptor blockers decreases death or MI when used as adjunctive therapy to PCI.13 However, in patients with non–ST-segment acute coronary syndromes undergoing PCI, the efficacy of abciximab seems to be age dependent, with the greatest benefit being observed in younger patients.14 In our study, use of abciximab was left to the discretion of the investigators, and it was given to an unexpectedly large proportion of patients (45%), if we consider the European standard and the age of the treated population.15 In our limited experience, procedural administration of abciximab was safe and did not lead to any episodes of major bleeding or thrombocytopenia. It also significantly correlated with 6-month survival. The role of effective myocardial perfusion as a determinant of prognosis in older patients with STEMI undergoing mechanical reperfusion has been previously demonstrated,16,17 and many experimental data have shown that aging is associated with a greater susceptibility to ischemia– reperfusion injury.18 As observed in previous studies, administration of glycoprotein IIb/IIIa receptor blockers to higher-risk patients ameliorates myocardial perfusion and may explain our findings; however, this point needs to be further explored in larger series of elderly patients. Further-

Coronary Artery Disease/Primary PCI in Nonagenarians

more, we cannot exclude a bias in favor of abciximab treatment because the patients who did not receive the drug may have had a worse baseline risk profile associated with an increased risk of bleeding. Times from symptoms to PCI and door-to-balloon-times were prolonged in our experience. These results are consistent with those of Sheifer et al19 who examined time to presentation with AMI in elderly patients and showed that delayed presentation depends not only on clinical and logistical issues but also on older age, female gender, and socioeconomic characteristics. Furthermore, a longer delay from symptom onset to hospital presentation has been associated with a lesser likelihood of receiving reperfusion therapies and longer door-to-balloon times.20 This relation could be explained by the fact that older patients who present late may exhibit more atypical or no symptoms that subsequently lead to a missed or late diagnosis. The main limitation of this study is the limited sample size; nonagenarians account for only 2% of the patients treated at 7 Italian centers that routinely use primary PCI in all patients with STEMI, regardless of age or clinical status at presentation. This suggests that many very elderly patients with AMI are not referred for primary PCI. However, to the best of our knowledge, ours is the only study concerning the safety and efficacy of primary angioplasty in nonagenarians that has complete information relating to a follow-up of up to 6 months after hospital admission. 1. Choe JY, Youn JC, Park JH, Jeong JW, Lee WH, Park YS, Jhoo JH, Lee DY, Kim KW. The severe cognitive impairment rating scale: an instrument for the assessment of cognition in moderate to severe dementia patients. Dement Geriatr Cogn Disord 2008;25:321–328. 2. TIMI Study Group. The Thrombolysis In Myocardial Infarction (TIMI) trial: phase 1 findings. N Engl J Med 1985;312:932–936. 3. Hovanesyan A, Rich MW. Outcomes of acute myocardial infarction in nonagenarians. Am J Cardiol 2008;101:1379 –1383. 4. Metha RH, Granger CB, Alexander KP, Bossone E, White HD, Sketch MH. Reperfusion strategies for acute myocardial infarction in the elderly: benefit and risks. J Am Coll Cardiol 2005;45:471– 478. 5. Fosbol EL, Thune JJ, Kelbaek H, Andersen HR, Saunamaki K, Nielsen TT, Mortensen LS, Kober L for the DANAMI-2 Investigators. Longterm outcome of primary angioplasty compared with fibrinolysis across age groups: a Danish multicenter randomized study on fibrinolytic therapy versus acute coronary angioplasty in acute myocardial infarction (DANAMI-2) substudy. Am Heart J 2008;156:391–396. 6. de Boer MJ, Ottervanger JP, van’t Hof AW, Hoorntje JC, Suryapranata H, Zijlstra F; Zwolle Myocardial Infarction Study Group. Reperfusion therapy in elderly patients with acute myocardial infarction: a randomized comparison of primary angioplasty and thrombolytic therapy. J Am Coll Cardiol 2002;39:1723–1728. 7. Antoniucci D, Valenti R, Santoro GM, Bolognese L, Moschi G, Trapani M, Taddeucci E, Fazzini PF. Systematic primary angioplasty in octogenarian and older patients. Am Heart J 1999;138:670 – 674.

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8. Moreno R, Salazr A, Banuelos C, Hernandez R, Alfonso F, Sabatè M, Escaned J, Perez MJ, Azcona L, Macaya C. Effectiveness of percutaneous coronary interventions in nonagenarians. Am J Cardiol 2004; 94:1058 –1060. 9. De Luca G, van’t Hof AW, Ottervanger JP, Hoorntje JC, Gosselink AT, Dambrink JH, Zijlstra F, de Boer MJ, Suryapranata H. Unsuccessful reperfusion in patients with ST-segment elevation myocardial infarction treated by primary angioplasty. Am Heart J 2005;150:557– 562. 10. Mehta RH, Harjai KJ, Cox D, Stone GW, Brodie B, Boura J, O’Neill W, Grines CL; Primary Angioplasty in Myocardial Infarction (PAMI) Investigators. Clinical and angiographic correlates and outcomes of suboptimal coronary flow inpatients with acute myocardial infarction undergoing primary percutaneous coronary intervention. J Am Coll Cardiol 2003;42:1739 –1746. 11. Valente S, Lazzeri C, Salvadori C, Chiostri M, Giglioli C, Poli S, Gensini GF. Effectiveness and safety of routine primary angioplasty in patients aged ⬎85 years with acute myocardial infarction. Circ J 2008;72:67–70. 12. Shah P, Najafi AH, Panza JA, Cooper HA. Outcomes and quality of life in patients ⱖ85 years of age with ST-elevation myocardial infarction. Am J Cardiol 2009;103:170 –174. 13. De Luca G, Suryapranata H, Stone GW, Antoniucci D, Tcheng JE, Neumann FJ, Van de Werf F, Antman EM, Topol EJ. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. JAMA 2005; 293:1759 –1765. 14. Ndrepepa G, Kastrati A, Mehilli J, Neumann FJ, ten Berg J, Bruskina O, Dotzer F, Seyfarth M, Pache J, Dirscinger J, Ulm K, Berger PB, Schomig A. Age-dependent effect of abciximab in patients with acute coronary syndromes treated with percutaneous coronary intervention. Circulation 2006;114:2040 –2046. 15. Dabbous OH, Anderson FA Jr, Gore JM, Eagle KA, Fox KA, Mehta RH, Goldberg RJ, Agnelli G, Steg PG; GRACE Investigators. Outcomes with the use of glycoprotein IIb/IIIa inhibitors in non–STsegment elevation acute coronary syndromes. Heart 2008;94:159 – 165. 16. Neumann FJ, Blasini R, Schmitt C, Alt E, Dirschinger J, Gawaz M, Kastrati A, Schömig A. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after placement of coronary artery stents in acute myocardial infarction. Circulation 1998;98:2695–2701. 17. De Luca G, van’t Hof AWJ, Ottervanger JP, Hoorntje JCA, Gosselink ATM, Dambrink JE, de Boer M, Suryapranata H. Ageing, impaired myocardial perfusion, and mortality in patients with ST-segment elevation myocardial infarction treated by primary angioplasty. Eur Heart J 2005;26:662– 666. 18. Headrick JP. Aging impairs functional, metabolic and ionic recovery from ischemia-reperfusion and hypoxia-reoxygenation. J Mol Cell Cardiol 1998;30:1415–1430. 19. Sheifer SE, Rathore SS, Gersh BJ, Weinfurt KP, Oetgen WJ, Breall JA, Schulman KA. Time to presentation with acute myocardial infarction in the elderly: associations with race, sex, and socioeconomic characteristics. Circulation 2000;102:1651–1656. 20. Ting HH, Bradley EH, Wang Y, Nallamothu BK, Gersh BJ, Roger VL, Lichtman JH, Curtis JP, Krumholz HM. Delay in presentation and reperfusion therapy in ST-elevation myocardial infarction. Am J Med 2008;121:316 –323.