- Email: [email protected]
Effect of an Invasive Strategy on Outcome in Patients ≥75 Years of Age With Non-ST-Elevation Acute Coronary Syndrome
Effect of an Invasive Strategy on Outcome in Patients ‡75 Years of Age With Non-ST-Elevation Acute Coronary Syndrome Gennaro Galasso, MD, PhDa,*, Stefano De Servi, MDb, Stefano Savonitto, MDc, Teresa Strisciuglio, MDa, Raffaele Piccolo, MDa, Nuccia Morici, MDd, Ernesto Murena, MDe, Claudio Cavallini, MDf, Anna Sonia Petronio, MDg, and Federico Piscione, MD, PhDh The Italian Elderly ACS study was the first randomized controlled trial comparing an early aggressive with an initially conservative strategy in patients with noneST-segment elevation acute coronary syndromes aged ‡75 years, with the results showing no significant benefit of early aggressive therapy. The aim of this study was to evaluate the outcomes of trial patients, according to the treatment actually received during hospitalization. The trial enrolled 313 patients. The primary end point was the composite of death, myocardial infarction (MI), disabling stroke, and repeat hospital stay for cardiovascular causes or bleeding within 1 year. All patients in whom coronary angiography was performed during initial hospitalization were defined as having undergone invasive treatment (182 patients), whereas all patients who did not undergo coronary angiography were classified as medically managed (conservative treatment [CT] group, 131 patients). The primary end point occurred in 53 patients (40.5%) in the CT group and 45 patients (24.7%) in the invasive treatment group (hazard ratio 0.56, 95% confidence interval 0.37 to 0.83, p [ 0.003). The invasive treatment group showed significantly lower rates of MI (6% vs 13% in the CT group; hazard ratio 0.43, 95% confidence interval 0.20 to 0.92, p [ 0.034) and the aggregate of death and MI (14.3% vs 27.5% CT group; hazard ratio 0.48, 95% confidence interval 0.29 to 0.81, p [ 0.004). In conclusion, elderly patients with noneST-segment elevation acute coronary syndromes treated invasively experienced significantly better survival free from the composite of all-cause mortality, nonfatal MI, disabling stroke, and repeat hospitalization for cardiovascular causes or bleeding. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;-:-e-) Elderly patients constitute an increasing proportion of those presenting with acute coronary syndromes (ACS), and older age is a major risk factor for adverse outcomes in noneSTsegment elevation ACS (NSTEACS).1 Although several randomized trials have evaluated the effect on outcomes of an early aggressive strategy in comparison with a more selective invasive approach in patients with NSTEACS,2,3 uncertainty remains regarding the benefits of this strategy on short- and long-term outcomes, particularly in elderly patients, who have usually been underrepresented in clinical trials of ACS.4 The Italian Elderly ACS trial was the first randomized study investigating treatment strategies for elderly patients with
a Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy; bDepartment of Cardiovascular Disease, Ospedale Civile, Legnano, Italy; cDivision of Cardiology, A. Manzoni Hospital, Lecco, Italy; dFirst Division of Cardiology, Department Cardio-ToracoVascolare, Ospedale Niguarda Cà Granda, Milan, Italy; eOspedale S. Maria delle Grazie, Pozzuoli, Italy; fAzienda Ospedaliera Ospedale Santa Maria della Misericordia, Perugia, Italy; gAzienda Ospedaliera Universitaria Pisana, Pisa, Italy; and hDepartment of Medicine and Surgery, University of Salerno, Salerno, Italy. Manuscript received October 3, 2014; revised manuscript received and accepted December 5, 2014. See page 5 for disclosure information. *Corresponding author: Tel: þ39-0817462234; fax: þ39-0817462216. E-mail address: [email protected] (G. Galasso).
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.12.005
NSTEACS. The results of the randomized trial showed no significant benefit of an early aggressive approach in the whole population in reducing the primary end point of death, myocardial infarction (MI), stroke, and rehospitalization within 1 year.5 However, the results of the trial could have been affected by the fact that 46 patients (25%) in the conservative-strategy arm underwent coronary angiography during the index hospitalization, followed by revascularization in 36 patients. Indeed, data from a recent meta-analysis, conducted in 7 randomized trials enrolling a very large series of NSTEACS patients, suggest that revascularization itself, rather than the timeliness of invasive therapy, may be the key determinant in improving late clinical outcomes.6 Therefore, we performed an “as-treated” subanalysis of the Italian Elderly ACS trial comparing the outcomes of patients who actually underwent coronary angiography during index hospitalization with those of patients who were treated only medically, irrespective of randomized assignment in the trial. Methods The Italian Elderly ACS randomized trial enrolled patients aged 75 years with NSTEACS who were admitted within 48 hours of the most recent ischemic symptoms and showed ischemic electrocardiographic changes, elevated cardiac markers, or both. The study design has been published www.ajconline.org
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The American Journal of Cardiology (www.ajconline.org)
Figure 1. Study flowchart.
Table 1 Baseline characteristics Variable Age (years) Men Hypertension Hypercholesterolemia Diabetes Mellitus Mean eGFR (mL/min/1.73m2) Prior Myocardial Infarction Prior Percutaneous Coronary Intervention Prior Coronary Bypass Serum Hemoglobin (g/dL) Ejection Fraction TIMI risk score Length of hospital stay
IT (n¼182)
CT (n¼131)
p value
80.57 4.21 96 (52.7%) 152 (83.5%) 82 (45.1%) 70 (38.5%) 53.60 19 54 (29.7%) 25 (13.7%)
82.32 4.83 61 (46.6%) 107(81.7%) 55 (42%) 44 (33.6%) 50.79 18.2 43 (32.8%) 22 (16.8%)
0.001 0.281 0.671 0.589 0.377 0.194 0.552 0.455
19 (10.4%) 13.38 1.72 49.22 9.55 4.08 1.38 8.41 6.02
10 (7.6%) 12.86 1.68 47.81 10.92 4.21 1.38 7.86 5.94
0.398 0.008 0.240 0.403 0.424
Table 2 Antithrombotic treatment during index hospitalization and cardioactive drugs at discharge Variable
previously.7 Patients enrolled in the trial were randomly assigned to either (1) an early aggressive strategy of coronary angiography within 72 hours and, when indicated, coronary revascularization by either percutaneous coronary intervention or coronary artery bypass grafting, or (2) an initially conservative strategy, consisting of medical therapy and coronary angiography during the index hospital stay allowed in the case of refractory ischemia, myocardial reinfarction, heart failure of ischemic origin, or malignant ventricular arrhythmias. After discharge, follow-up visits were planned up to 405 days. In the present analysis we assessed the outcomes of the study population according to the invasive or medical treatment actually received during index hospitalization. To that end, we defined as having undergone “invasive treatment” (IT) all patients in whom coronary angiography, followed by revascularization when suitable, was performed during initial hospitalization; in
During hospital stay Aspirin Thienopiridines GP IIb/IIIa Inhibitors Unfractionated heparin Low molecular weight heparin Bivalirudin At follow up Aspirin Thienopiridines Beta Blocker Ace-inhibitor Statin Nitrates Diuretics
IT (n¼182)
CT (n¼131)
p value
176 171 31 47 113 8
(96.7%) (94%) (17%) (25.8%) (62.1%) (4.4%)
124 118 4 29 74
(94.7%) (90.1%) (3.1%) (22.1%) (56.5%) 0
0.371 0.203 0.0001 0.453 0.319 0.0001
164 142 104 140 147 95 83
(90.1%) (78%) (57.1%) (76.9%) (80.8%) (52.2%) (45.6%)
120 102 81 112 104 86 80
(91.6%) (77.9%) (61.8%) (85.5%) (79.4%) (65.6%) (61.1%)
0.653 0.973 0.405 0.059 0.763 0.047 0.021
contrast, all patients who did not undergo coronary angiography were classified as “medically managed.” The primary end point was the composite of all-cause mortality, nonfatal MI, disabling stroke, and repeat hospital stay for cardiovascular causes or severe bleeding within 12 months.7 Other outcomes of interest were death, MI, the composite of death and MI, and bleedings. The study definitions have been previously described in detail.5,7 Absolute and percentage frequencies are used to describe categorical variables and means and SDs to describe continuous variables. Categorical variables were compared using the c2 test and continuous variables using Student’s t test. Estimations of the cumulative primary event rates were done using the KaplanMeier method, and events time were compared using the log-rank test. The Cox proportional-hazards model was
Coronary Artery Disease/Invasive Strategy in NSTEACS Elderly Patients
3
Table 3 In hospital adverse clinical events Variable
IT (n¼182)
CT (n¼131)
p value
Death Myocardial Infarction Bleeding (Bleeding Academy Research Consortium type 2, 3, or 5) Cardiac Arrhythmia
7 (3.8%) 5 (2.7%) 0 7 (3.8%)
7 3 1 4
(5.3%) (2.3%) (0.8%) (3.1%)
0.527 0.800 0.238 0.707
IT (n¼182)
CT (n¼131)
p value
Table 4 Incidence of primary end point and adverse cardiac events at follow-up Variable Primary composite endpoint Death Cardiac death Myocardial Infarction Death þ Myocardial Infarction Bleeding (Bleeding Academy Research Consortium type 2, 3, or 5) Re-hospitalization
45 19 16 11 26
(24.7%) (10.4%) (8.8%) (6%) (14.3%) 0 18 (9.9%)
53 22 17 17 36 3 22
(40.5%) (16.8%) (13%) (13%) (27.5%) (2.3%) (16.8%)
0.003 0.100 0.234 0.034 0.004 0.040 0.071
Figure 2. Kaplan-Meier survival curves within 12-month follow-up (A) for the primary end point (all-cause mortality, nonfatal MI, disabling stroke, and repeat hospital stay for cardiovascular causes or severe bleeding) and (B) for the combined end point of death and MI.
used to estimate the treatment effect as unadjusted hazard ratios with 95% confidence intervals. Two-sided p values <0.05 were considered significant. Analysis were performed using SPSS version 20 (SPSS, Inc., Chicago, Illinois). Results A total of 313 patients were enrolled in the randomized trial, 154 in the early aggressive arm and 159 in the initially conservative arm. As reported in Figure 1, during the index hospitalization, a total 182 patients (58% of the whole population) underwent coronary angiography, 136 patients initially
randomized to the early aggressive arm and 46 patients randomized to the initially conservative arm. These patients constituted the IT cohort. The conservative treatment (CT) cohort comprised 131 patients who did not undergo coronary angiography during the index hospitalization. The baseline characteristics of the patients are listed in the Table 1. No differences were noted between the 2 groups regarding the common risk factors for cardiovascular disease except for older age and lower hemoglobin levels in the CT compared with IT group. Moreover, no difference between groups was noted in terms of prognostic risk as indicate by a similar Thrombolysis In Myocardial Infarction (TIMI) risk score and left ventricular ejection fraction. As previously reported, the
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reasons for not performing coronary angiography among patients in the early aggressive randomized arm were heart failure in 6 patients, withdrawn consent in 5, bleeding in 2, sepsis in 2, and death, transient ischemic attack, and acute renal insufficiency in 1 case each, whereas the indications for catheterization in patients initially randomized in the conservative cohort of the RCT were recurrent ischemia in 37 cases, heart failure in 6, reinfarction in 1, and sustained ventricular tachycardia in 2.5 The revascularization procedures performed in the IT group were percutaneous coronary intervention in 111 patients (61%) and coronary artery bypass grafting in 10 patients (5.5%). As expected, the use of glycoprotein IIb/IIIa inhibitors was higher in the IT group, whereas no differences were noted regarding the use of other antithrombotic drugs during the index hospitalization (Table 2). Pharmacologic treatments at discharge were similar between groups except for higher use of nitrates and diuretics in the CT group. Length of hospital stay and the rate of adverse events occurred during hospitalization (Table 3) were similar in the 2 groups. Of note, IT was not associated with an increased rate of death or procedure-related MI during the index admission compared with CT. The primary end point occurred in 53 patients in the CT group and 45 patients in the IT group (hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.37 to 0.83, p ¼ 0.003; Table 4). The incidence of nonfatal MI was significantly lower in the IT group (HR 0.43, 95% CI 0.20 to 0.92, p ¼ 0.034). The combined end point of death and MI was significantly lower in the IT group compared with the CT group (HR 0.48, 95% CI 0.29 to 0.81, p ¼ 0.004). No differences were observed for the other primary end point components except for the rate of bleeding that occurred in 3 patients in the CT group compared with none in the IT group (p ¼ 0.040). The Kaplan-Meier curves for the primary end point and the combined end point of death and MI confirmed the better eventfree survival for the invasively treated patients (Figure 2). At Cox regression analysis, the IT performed during index hospitalization was the most important predictor of event-free survival (HR 0.55, 95% CI 0.37 to 0.82, p ¼ 0.004) and was confirmed after correction for univariate differences between groups (HR 0.59, 95% CI 0.39 to 0.88, p ¼ 0.010). We performed an additional analysis evaluating the outcomes of patients initially allocated to the IT or CT group according to the treatment effectively received during index hospitalization. The results of this analysis (249 patients: 136 in the IT group and 113 in the CT group) confirmed our previous observations. Indeed, the primary end point (24.3% in the IT group vs 38.1% in the CT group, p ¼ 0.019) and the combined end point of death and MI (14% vs 24.8%, p ¼ 0.030) were significantly lower in the IT group compared with the CT group. Finally, we evaluated the prognosis of the IT cohort of patients who did not undergo coronary angiography with that of patients in the CT group, both overall (Supplementary Table 1) and divided according to treatment received during initial hospital stay (Supplementary Table 2). No differences were noted in the 2 analyses with regard to the primary outcome or the other primary end point components. Discussion The results of our study show that patients with NSTEACS randomized in the Italian Elderly ACS trial who
actually underwent an invasive strategy during the index hospitalization experienced significantly lower rates of cardiac ischemic events and rehospitalizations at 1 year (a 44% relative difference in the primary end point) compared with patients treated with a conservative, noninvasive approach. This difference was driven mainly by 57% fewer MIs in patients treated invasively compared with the CT cohort. Moreover, there were also consistent trends toward lower mortality and fewer rehospitalizations for cardiovascular causes at follow-up. Our results are in line with the findings of a recent meta-analysis of 9 randomized trials on NSTEACS, including >8,000 patients, indicating that among these patients, the benefit of an invasive strategy in reducing the composite of death and MI and the risk for rehospitalization for cardiovascular causes is more pronounced in elderly rather than younger patients.8 These results were further corroborated by the 5-year follow-up data of the FIR collaboration (including individual data from the FRISC II, ICTUS, and RITA 3 trials)2 demonstrating a significant benefit of a routine invasive strategy in patients >75 years of age, with a 29% reduction in cardiovascular death or MI. Recently, 2 meta-analyses examining the pooled results of 10 randomized trials in about 11,000 patients showed that the invasive strategy was associated with an early hazard, balanced by a reduction of adverse events during followup.3,6 Collectively, the results of these 10 randomized trials showed a significant improvement in survival free from MI, recurrent cardiac ischemia, and rehospitalization.9 However, a mortality benefit from an early routine invasive approach can be observed only in the highest risk patients, whereas the lower risk patients have no mortality benefit at all. Furthermore, age was the strongest predicting factor for improved outcome by a routine invasive strategy.10 Despite these data and the recommendation of current European and American guidelines on NSTEACS,11,12 higher risk patients are paradoxically being treated more conservatively, while low-risk patients are more likely to undergo an invasive strategy. Moreover, although elderly patients represent 1/3 of those with NSTEACS, they are largely excluded from clinical trials on ACS.4 The Italian Elderly ACS study was the first and only trial performed specifically in very elderly patients with NSTEACS. However, the trial did not reach its goal with regard to the number of recruited patients, with significant benefit confined in troponin-positive patients. In the present study, we analyzed the effect of IT as actually received during initial hospitalization in the patients enrolled in the trial. Assessing the effect of invasive therapy irrespectively of randomization arm, we observed a significant difference with regard to the primary end point in favor of the invasively treated patients compared with those receiving conservative therapy. We also show a significant difference in event-free survival from the aggregate of death and MI with lower rates of rehospitalization for cardiovascular causes. The main limitation of present study was the analysis of treatment as received during hospitalization, which led to the inclusion of patients with recurrent ischemia, cardiac arrhythmia, or heart failure in the IT strategy, all patients who are more likely to benefit from an invasive approach, specifically directed at improving myocardial ischemia by performing myocardial revascularization. The inclusion of such patients can explain the positive results of IT as defined
Coronary Artery Disease/Invasive Strategy in NSTEACS Elderly Patients
in the present study compared with the results observed in the parent randomized trial. However, to reduce this bias, we performed an analysis in patients initially allocated to the IT or CT group analyzed according to the treatment received during index hospitalization. A further analysis was performed to analyze the outcome of the IT cohort of patients elected for medical management after coronary angiography versus the prognosis of the patients in the CT arm considered overall or divided according to patients receiving coronary angiography. Taken together, the similar results of these analyses support the observation of our main analysis confirming the favorable effects on outcome of an invasive strategy, whenever not contraindicated in our study population. Although an intention-to-treat analysis is the gold standard to analyze the results of an RCT,5 the results of an as-treated analysis can provide some idea about the maximum treatment efficacy in patients who actually received the treatment. However, these results should be interpreted as only hypothesis generating.
5.
6.
7.
8.
Disclosures The authors have no conflicts of interest to disclose. Supplementary Data
9. 10.
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.amjcard.2014.12.005. 11. 1. Halon DA, Adawi S, Dobrecky-Mery I, Lewis BS. Importance of increasing age on the presentation and outcome of acute coronary syndromes in elderly patients. J Am Coll Cardiol 2004;43:346e352. 2. Damman P, Clayton T, Wallentin L, Lagerqvist B, Fox KA, Hirsch A, Windhausen F, Swahn E, Pocock SJ, Tijssen JG, de Winter RJ. Effects of age on long-term outcomes after a routine invasive or selective invasive strategy in patients presenting with non-ST segment elevation acute coronary syndromes: a collaborative analysis of individual data from the FRISC II - ICTUS - RITA-3 (FIR) trials. Heart 2012;98:207e213. 3. Mehta SR, Cannon CP, Fox KA, Wallentin L, Boden WE, Spacek R, Widimsky P, McCullough PA, Hunt D, Braunwald E, Yusuf S. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA 2005;293:2908e2917. 4. 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; American Heart Association Council
12.
5
on Clinical Cardiology; Society of Geriatric Cardiology. 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. Savonitto S, Cavallini C, Petronio AS, Murena E, Antonicelli R, Sacco A, Steffenino G, Bonechi F, Mossuti E, Manari A, Tolaro S, Toso A, Daniotti A, Piscione F, Morici N, Cesana BM, Jori MC, De Servi S; Italian Elderly ACS Trial Investigators. Early aggressive versus initially conservative treatment in elderly patients with non-ST-segment elevation acute coronary syndrome: a randomized controlled trial. JACC Cardiovasc Interv 2012;5:906e916. Bavry AA, Kumbhani DJ, Rassi AN, Bhatt DL, Askari AT. Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of contemporary randomized clinical trials. J Am Coll Cardiol 2006;48: 1319e1325. Savonitto S, De Servi S, Petronio AS, Bolognese L, Cavallini C, Greco C, Indolfi C, Visconti LO, Piscione F, Ambrosio G, Galvani M, Marzocchi A, Santilli I, Steffenino G, Maseri A. Early aggressive vs. initially conservative treatment in elderly patients with non-ST-elevation acute coronary syndrome: the Italian Elderly ACS study. J Cardiovasc Med (Hagerstown) 2008;9:217e226. Angeli F, Verdecchia P, Savonitto S, Morici N, De Servi S, Cavallini C. Early invasive versus selectively invasive strategy in patients with nonST-segment elevation acute coronary syndrome: impact of age. Catheter Cardiovasc Interv 2014;83:686e701. Stone GW. Non-ST-elevation acute coronary syndromes. Lancet 2007;369:801e803. Fox KA, Clayton TC, Damman P, Pocock SJ, de Winter RJ, Tijssen JG, Lagerqvist B, Wallentin L; FIR Collaboration. Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome a metaanalysis of individual patient data. J Am Coll Cardiol 2010;55: 2435e2445. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, Caso P, Dudek D, Gielen S, Huber K, Ohman M, Petrie MC, Sonntag F, Uva MS, Storey RF, Wijns W, Zahger D; ESC Committee for Practice Guidelines. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the Management of Acute Coronary Syndromes (ACS) in Patients Presenting Without Persistent STSegment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999e3054. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2012;60:645e681.
a Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy; bDepartment of Cardiovascular Disease, Ospedale Civile, Legnano, Italy; cDivision of Cardiology, A. Manzoni Hospital, Lecco, Italy; dFirst Division of Cardiology, Department Cardio-ToracoVascolare, Ospedale Niguarda Cà Granda, Milan, Italy; eOspedale S. Maria delle Grazie, Pozzuoli, Italy; fAzienda Ospedaliera Ospedale Santa Maria della Misericordia, Perugia, Italy; gAzienda Ospedaliera Universitaria Pisana, Pisa, Italy; and hDepartment of Medicine and Surgery, University of Salerno, Salerno, Italy. Manuscript received October 3, 2014; revised manuscript received and accepted December 5, 2014. See page 5 for disclosure information. *Corresponding author: Tel: þ39-0817462234; fax: þ39-0817462216. E-mail address: [email protected] (G. Galasso).
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.12.005
NSTEACS. The results of the randomized trial showed no significant benefit of an early aggressive approach in the whole population in reducing the primary end point of death, myocardial infarction (MI), stroke, and rehospitalization within 1 year.5 However, the results of the trial could have been affected by the fact that 46 patients (25%) in the conservative-strategy arm underwent coronary angiography during the index hospitalization, followed by revascularization in 36 patients. Indeed, data from a recent meta-analysis, conducted in 7 randomized trials enrolling a very large series of NSTEACS patients, suggest that revascularization itself, rather than the timeliness of invasive therapy, may be the key determinant in improving late clinical outcomes.6 Therefore, we performed an “as-treated” subanalysis of the Italian Elderly ACS trial comparing the outcomes of patients who actually underwent coronary angiography during index hospitalization with those of patients who were treated only medically, irrespective of randomized assignment in the trial. Methods The Italian Elderly ACS randomized trial enrolled patients aged 75 years with NSTEACS who were admitted within 48 hours of the most recent ischemic symptoms and showed ischemic electrocardiographic changes, elevated cardiac markers, or both. The study design has been published www.ajconline.org
2
The American Journal of Cardiology (www.ajconline.org)
Figure 1. Study flowchart.
Table 1 Baseline characteristics Variable Age (years) Men Hypertension Hypercholesterolemia Diabetes Mellitus Mean eGFR (mL/min/1.73m2) Prior Myocardial Infarction Prior Percutaneous Coronary Intervention Prior Coronary Bypass Serum Hemoglobin (g/dL) Ejection Fraction TIMI risk score Length of hospital stay
IT (n¼182)
CT (n¼131)
p value
80.57 4.21 96 (52.7%) 152 (83.5%) 82 (45.1%) 70 (38.5%) 53.60 19 54 (29.7%) 25 (13.7%)
82.32 4.83 61 (46.6%) 107(81.7%) 55 (42%) 44 (33.6%) 50.79 18.2 43 (32.8%) 22 (16.8%)
0.001 0.281 0.671 0.589 0.377 0.194 0.552 0.455
19 (10.4%) 13.38 1.72 49.22 9.55 4.08 1.38 8.41 6.02
10 (7.6%) 12.86 1.68 47.81 10.92 4.21 1.38 7.86 5.94
0.398 0.008 0.240 0.403 0.424
Table 2 Antithrombotic treatment during index hospitalization and cardioactive drugs at discharge Variable
previously.7 Patients enrolled in the trial were randomly assigned to either (1) an early aggressive strategy of coronary angiography within 72 hours and, when indicated, coronary revascularization by either percutaneous coronary intervention or coronary artery bypass grafting, or (2) an initially conservative strategy, consisting of medical therapy and coronary angiography during the index hospital stay allowed in the case of refractory ischemia, myocardial reinfarction, heart failure of ischemic origin, or malignant ventricular arrhythmias. After discharge, follow-up visits were planned up to 405 days. In the present analysis we assessed the outcomes of the study population according to the invasive or medical treatment actually received during index hospitalization. To that end, we defined as having undergone “invasive treatment” (IT) all patients in whom coronary angiography, followed by revascularization when suitable, was performed during initial hospitalization; in
During hospital stay Aspirin Thienopiridines GP IIb/IIIa Inhibitors Unfractionated heparin Low molecular weight heparin Bivalirudin At follow up Aspirin Thienopiridines Beta Blocker Ace-inhibitor Statin Nitrates Diuretics
IT (n¼182)
CT (n¼131)
p value
176 171 31 47 113 8
(96.7%) (94%) (17%) (25.8%) (62.1%) (4.4%)
124 118 4 29 74
(94.7%) (90.1%) (3.1%) (22.1%) (56.5%) 0
0.371 0.203 0.0001 0.453 0.319 0.0001
164 142 104 140 147 95 83
(90.1%) (78%) (57.1%) (76.9%) (80.8%) (52.2%) (45.6%)
120 102 81 112 104 86 80
(91.6%) (77.9%) (61.8%) (85.5%) (79.4%) (65.6%) (61.1%)
0.653 0.973 0.405 0.059 0.763 0.047 0.021
contrast, all patients who did not undergo coronary angiography were classified as “medically managed.” The primary end point was the composite of all-cause mortality, nonfatal MI, disabling stroke, and repeat hospital stay for cardiovascular causes or severe bleeding within 12 months.7 Other outcomes of interest were death, MI, the composite of death and MI, and bleedings. The study definitions have been previously described in detail.5,7 Absolute and percentage frequencies are used to describe categorical variables and means and SDs to describe continuous variables. Categorical variables were compared using the c2 test and continuous variables using Student’s t test. Estimations of the cumulative primary event rates were done using the KaplanMeier method, and events time were compared using the log-rank test. The Cox proportional-hazards model was
Coronary Artery Disease/Invasive Strategy in NSTEACS Elderly Patients
3
Table 3 In hospital adverse clinical events Variable
IT (n¼182)
CT (n¼131)
p value
Death Myocardial Infarction Bleeding (Bleeding Academy Research Consortium type 2, 3, or 5) Cardiac Arrhythmia
7 (3.8%) 5 (2.7%) 0 7 (3.8%)
7 3 1 4
(5.3%) (2.3%) (0.8%) (3.1%)
0.527 0.800 0.238 0.707
IT (n¼182)
CT (n¼131)
p value
Table 4 Incidence of primary end point and adverse cardiac events at follow-up Variable Primary composite endpoint Death Cardiac death Myocardial Infarction Death þ Myocardial Infarction Bleeding (Bleeding Academy Research Consortium type 2, 3, or 5) Re-hospitalization
45 19 16 11 26
(24.7%) (10.4%) (8.8%) (6%) (14.3%) 0 18 (9.9%)
53 22 17 17 36 3 22
(40.5%) (16.8%) (13%) (13%) (27.5%) (2.3%) (16.8%)
0.003 0.100 0.234 0.034 0.004 0.040 0.071
Figure 2. Kaplan-Meier survival curves within 12-month follow-up (A) for the primary end point (all-cause mortality, nonfatal MI, disabling stroke, and repeat hospital stay for cardiovascular causes or severe bleeding) and (B) for the combined end point of death and MI.
used to estimate the treatment effect as unadjusted hazard ratios with 95% confidence intervals. Two-sided p values <0.05 were considered significant. Analysis were performed using SPSS version 20 (SPSS, Inc., Chicago, Illinois). Results A total of 313 patients were enrolled in the randomized trial, 154 in the early aggressive arm and 159 in the initially conservative arm. As reported in Figure 1, during the index hospitalization, a total 182 patients (58% of the whole population) underwent coronary angiography, 136 patients initially
randomized to the early aggressive arm and 46 patients randomized to the initially conservative arm. These patients constituted the IT cohort. The conservative treatment (CT) cohort comprised 131 patients who did not undergo coronary angiography during the index hospitalization. The baseline characteristics of the patients are listed in the Table 1. No differences were noted between the 2 groups regarding the common risk factors for cardiovascular disease except for older age and lower hemoglobin levels in the CT compared with IT group. Moreover, no difference between groups was noted in terms of prognostic risk as indicate by a similar Thrombolysis In Myocardial Infarction (TIMI) risk score and left ventricular ejection fraction. As previously reported, the
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The American Journal of Cardiology (www.ajconline.org)
reasons for not performing coronary angiography among patients in the early aggressive randomized arm were heart failure in 6 patients, withdrawn consent in 5, bleeding in 2, sepsis in 2, and death, transient ischemic attack, and acute renal insufficiency in 1 case each, whereas the indications for catheterization in patients initially randomized in the conservative cohort of the RCT were recurrent ischemia in 37 cases, heart failure in 6, reinfarction in 1, and sustained ventricular tachycardia in 2.5 The revascularization procedures performed in the IT group were percutaneous coronary intervention in 111 patients (61%) and coronary artery bypass grafting in 10 patients (5.5%). As expected, the use of glycoprotein IIb/IIIa inhibitors was higher in the IT group, whereas no differences were noted regarding the use of other antithrombotic drugs during the index hospitalization (Table 2). Pharmacologic treatments at discharge were similar between groups except for higher use of nitrates and diuretics in the CT group. Length of hospital stay and the rate of adverse events occurred during hospitalization (Table 3) were similar in the 2 groups. Of note, IT was not associated with an increased rate of death or procedure-related MI during the index admission compared with CT. The primary end point occurred in 53 patients in the CT group and 45 patients in the IT group (hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.37 to 0.83, p ¼ 0.003; Table 4). The incidence of nonfatal MI was significantly lower in the IT group (HR 0.43, 95% CI 0.20 to 0.92, p ¼ 0.034). The combined end point of death and MI was significantly lower in the IT group compared with the CT group (HR 0.48, 95% CI 0.29 to 0.81, p ¼ 0.004). No differences were observed for the other primary end point components except for the rate of bleeding that occurred in 3 patients in the CT group compared with none in the IT group (p ¼ 0.040). The Kaplan-Meier curves for the primary end point and the combined end point of death and MI confirmed the better eventfree survival for the invasively treated patients (Figure 2). At Cox regression analysis, the IT performed during index hospitalization was the most important predictor of event-free survival (HR 0.55, 95% CI 0.37 to 0.82, p ¼ 0.004) and was confirmed after correction for univariate differences between groups (HR 0.59, 95% CI 0.39 to 0.88, p ¼ 0.010). We performed an additional analysis evaluating the outcomes of patients initially allocated to the IT or CT group according to the treatment effectively received during index hospitalization. The results of this analysis (249 patients: 136 in the IT group and 113 in the CT group) confirmed our previous observations. Indeed, the primary end point (24.3% in the IT group vs 38.1% in the CT group, p ¼ 0.019) and the combined end point of death and MI (14% vs 24.8%, p ¼ 0.030) were significantly lower in the IT group compared with the CT group. Finally, we evaluated the prognosis of the IT cohort of patients who did not undergo coronary angiography with that of patients in the CT group, both overall (Supplementary Table 1) and divided according to treatment received during initial hospital stay (Supplementary Table 2). No differences were noted in the 2 analyses with regard to the primary outcome or the other primary end point components. Discussion The results of our study show that patients with NSTEACS randomized in the Italian Elderly ACS trial who
actually underwent an invasive strategy during the index hospitalization experienced significantly lower rates of cardiac ischemic events and rehospitalizations at 1 year (a 44% relative difference in the primary end point) compared with patients treated with a conservative, noninvasive approach. This difference was driven mainly by 57% fewer MIs in patients treated invasively compared with the CT cohort. Moreover, there were also consistent trends toward lower mortality and fewer rehospitalizations for cardiovascular causes at follow-up. Our results are in line with the findings of a recent meta-analysis of 9 randomized trials on NSTEACS, including >8,000 patients, indicating that among these patients, the benefit of an invasive strategy in reducing the composite of death and MI and the risk for rehospitalization for cardiovascular causes is more pronounced in elderly rather than younger patients.8 These results were further corroborated by the 5-year follow-up data of the FIR collaboration (including individual data from the FRISC II, ICTUS, and RITA 3 trials)2 demonstrating a significant benefit of a routine invasive strategy in patients >75 years of age, with a 29% reduction in cardiovascular death or MI. Recently, 2 meta-analyses examining the pooled results of 10 randomized trials in about 11,000 patients showed that the invasive strategy was associated with an early hazard, balanced by a reduction of adverse events during followup.3,6 Collectively, the results of these 10 randomized trials showed a significant improvement in survival free from MI, recurrent cardiac ischemia, and rehospitalization.9 However, a mortality benefit from an early routine invasive approach can be observed only in the highest risk patients, whereas the lower risk patients have no mortality benefit at all. Furthermore, age was the strongest predicting factor for improved outcome by a routine invasive strategy.10 Despite these data and the recommendation of current European and American guidelines on NSTEACS,11,12 higher risk patients are paradoxically being treated more conservatively, while low-risk patients are more likely to undergo an invasive strategy. Moreover, although elderly patients represent 1/3 of those with NSTEACS, they are largely excluded from clinical trials on ACS.4 The Italian Elderly ACS study was the first and only trial performed specifically in very elderly patients with NSTEACS. However, the trial did not reach its goal with regard to the number of recruited patients, with significant benefit confined in troponin-positive patients. In the present study, we analyzed the effect of IT as actually received during initial hospitalization in the patients enrolled in the trial. Assessing the effect of invasive therapy irrespectively of randomization arm, we observed a significant difference with regard to the primary end point in favor of the invasively treated patients compared with those receiving conservative therapy. We also show a significant difference in event-free survival from the aggregate of death and MI with lower rates of rehospitalization for cardiovascular causes. The main limitation of present study was the analysis of treatment as received during hospitalization, which led to the inclusion of patients with recurrent ischemia, cardiac arrhythmia, or heart failure in the IT strategy, all patients who are more likely to benefit from an invasive approach, specifically directed at improving myocardial ischemia by performing myocardial revascularization. The inclusion of such patients can explain the positive results of IT as defined
Coronary Artery Disease/Invasive Strategy in NSTEACS Elderly Patients
in the present study compared with the results observed in the parent randomized trial. However, to reduce this bias, we performed an analysis in patients initially allocated to the IT or CT group analyzed according to the treatment received during index hospitalization. A further analysis was performed to analyze the outcome of the IT cohort of patients elected for medical management after coronary angiography versus the prognosis of the patients in the CT arm considered overall or divided according to patients receiving coronary angiography. Taken together, the similar results of these analyses support the observation of our main analysis confirming the favorable effects on outcome of an invasive strategy, whenever not contraindicated in our study population. Although an intention-to-treat analysis is the gold standard to analyze the results of an RCT,5 the results of an as-treated analysis can provide some idea about the maximum treatment efficacy in patients who actually received the treatment. However, these results should be interpreted as only hypothesis generating.
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Disclosures The authors have no conflicts of interest to disclose. Supplementary Data
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