- Email: [email protected]
Sustained favorable long-term prognosis of negative stress echocardiography following uncomplicated myocardial infarction
infarction or angina pectoris. Findings from the Scandinavian Simvastatin Survival Study (4S). Circulation 1997;96:4211–4218. 3. Lewis SJ, Moye LA, Sacks FM, Johnstone DE, Timmis G, Mitchell J, Limacher M, Kell S, Glasser SP, Grant J, et al, for the CARE Investigators. Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial. Ann Intern Med 1998;129:681–689. 4. Hunt D, Young P, Simes J, Hague W, Mann S, Owensby D, Lane G, Tonkin A, for the LIPID Investigators. Benefits of pravastatin on cardiovascular events and mortality in older patients with coronary heart disease are equal to or exceed those seen in younger patients: results from the LIPID trial. Ann Intern Med 2001;134:931–940. 5. Aronow WS, Ahn C. Incidence of new coronary events in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol ⱖ125 mg/dl treated with statins versus no lipid-lowering drug. Am J Cardiol 2002;89: 67–69.
6. Aronow WS, Ahn C, Gutstein H. Incidence of new atherothrombotic brain infarction in older persons with prior myocardial infarction and serum lowdensity lipoprotein cholesterol ⱖ125 mg/dL treated with statins versus no lipidlowering drug. J Gerontol Med Sci 2002:57A:M333–M335. 7. Joint National Committee. The Sixth Report of the Joint National Committee on the Detection Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med 1997;157:2413–2444. 8. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183–1197. 9. Aronow WS, Ahn C, Kronzon I. Prognosis of congestive heart failure in elderly patients with normal versus abnormal left ventricular systolic function associated with coronary artery disease. Am J Cardiol 1990;66:1257–1259. 10. Kjekshus J, Pedersen TR, Olsson AG, Faergeman O, Pyorala K. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail 1997;3:249 –254.
Sustained Favorable Long-Term Prognosis of Negative Stress Echocardiography Following Uncomplicated Myocardial Infarction Riccardo Bigi,
MD,
Lauro Cortigiani,
MD,
obutamine stress echocardiography (DSE) has been increasingly used in the last few years for D risk stratification of patients after acute myocardial infarction (AMI)1– 6 and proved to convey incremental prognostic information compared with standard exercise electrocardiography.7 In particular, a very high negative predictive value has been reported in patients with uncomplicated AMI.2,3 However, most studies have included only short- or medium-term follow-up; therefore, information on long-term negative predictive value is still lacking. The aim of this study was twofold: (1) to verify the duration of the good prognostic implication by a negative DSE after uncomplicated AMI, and (2) to identify possible markers of future cardiac events in this population. •••
Seven hundred two consecutive patients with AMI undergoing predischarge DSE were initially considered for inclusion. One hundred forty-five patients were excluded because of (1) a complicated clinical course (recurrent ischemia, heart failure, major arrhythmias [46 patients]), (2) left ventricular ejection fraction ⬍40% (47 patients), and (3) history of previous AMI and/or revascularization (52 patients). Of the remaining 557 patients, 281 had a negative DSE and formed the study population whose clinical and DSE data are listed in Table 1. The follow-up period lasted
From the Cardiovascular Research Foundation, Castelfranco Veneto, Venice, Italy; Cardiovascular Unit, “Campo di Marte” Hospital, Lucca, Italy; and Department of Cardiology, University Medical Center, Leiden, The Netherlands. Dr. Bigi’s address is: Via Visoli 1, 23037 Tirano (SO), Italy. E-mail: [email protected]. Manuscript received January 23, 2002; revised manuscript received and accepted March 26, 2002. ©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 90 July 15, 2002
Pier R. Mariani,
MD,
and Jeroen J. Bax,
MD
TABLE 1 Clinical and DSE Data Age (yrs) Women Anterior wall AMI Inferior wall AMI Non–Q-wave wall AMI Systemic hypertension Diabetes mellitus Total blood cholesterol ⱖ240 mg/dl Cigarette smokers Risk factors ⱖ3 1 or 2 DSE data Rest WMSI Peak WMSI Max. dobutamine dose (g/kg/min) Atropine administration Peak heart rate (beats/min) % of maximal predicted heart rate Peak systolic blood pressure (mm Hg) Peak diastolic blood pressure (mm Hg) Peak rate-pressure product
61 62 77 151 53 99 46 98 139 237 23 258 1.39 1.38 37.5 160 131 85 154 84 20,119
⫾ 10 (22%) (27%) (54%) (19%) (35%) (16%) (35%) (49%) (84%) (8%) (82%) ⫾ 0.21 ⫾ 0.22 ⫾ 5.4 (57%) ⫾ 20 ⫾ 14 ⫾ 27 ⫾ 10 ⫾ 4,706
Max. ⫽ maximal.
at least 2 years or until the occurrence of death, nonfatal AMI, or coronary revascularization. DSE was performed according to the established protocol8 based on 3-minute stages up to 40 kg/min plus additional atropine (up to 1 mg) if required for achieving 85% of age- and sex-predicted maximum heart rate. Fifteen patients (5%) underwent the test with therapy ( blockers, calcium antagonists, and nitrates, alone or in combination) and 265 underwent testing without therapy. Off-line, computer-assisted analysis of images was used to improve the accuracy of interpretation. In case of disagreement, a third observer reviewed the images without knowledge of previous assessment and a majority decision was achieved. For the semiquantitative assessment, a 160002-9149/02/$–see front matter PII S0002-9149(02)02439-6
149
dobutamine administration (i.e., motion improvement with a low dose Invasive Conservative followed by deterioration with a high Treatment Treatment dose). Improvement with a low dose (n ⫽ 64) (n ⫽ 217) that was maintained with a high Age (yrs) 58.3 ⫾ 9.3 61.7 ⫾ 10.7* dose, identified the presence of viaWomen 12 (19%) 50 (23%) ble myocardium. The test was deAnterior wall AMI 22 (34%) 55 (25%) fined as negative for ischemia in case Inferior wall AMI 28 (44%) 123 (57%) of no worsening or development of Non–Q-wave wall AMI 14 (22%) 39 (18%) Systemic hypertension 23 (36%) 76 (35%) hyperkinetic wall motion. Tests were Diabetes mellitus 13 (20%) 33 (15%) interrupted if there was evidence of Total blood cholesterol ⱖ240 mg/dl 25 (39%) 73 (34%) new wall motion abnormalities. Non† Cigarette smokers 39 (61%) 100 (46%) echocardiographic criteria for interNo. of risk factors 1.6 ⫾ 1.0 1.3 ⫾ 0.8‡ rupting the test were protocol termiⱖ3 risk factors 9 (14%) 14 (6%)§ DSE data nation and achievement of 85% of Rest WMSI 1.42 ⫾ 0.23 1.39 ⫾ 0.21 maximal predicted heart rate. Tests Peak WMSI 1.42 ⫾ 0.23 1.38 ⫾ 0.21 were also discontinued if there was Max. dobutamine dose (g/kg/min) 37.5 ⫾ 5.6 37.6 ⫾ 5.4 severe chest pain, significant arrhythPeak heart rate (beats/min) 130 ⫾ 21 131 ⫾ 20 % of maximal predicted heart rate 83 ⫾ 15 86 ⫾ 14 mias, horizontal or downsloping STPeak systolic blood pressure (mm Hg) 154 ⫾ 23 154 ⫾ 28 segment depression ⬎2 mm, or elePeak diastolic blood pressure (mm Hg) 84 ⫾ 9 84 ⫾ 11 vation ⬎1.5 mm (in no Q-wave Peak rate-pressure product 20,054 ⫾ 4,380 20,138 ⫾ 4,807 leads), hypertension (systolic blood *p ⫽ 0.02; †p ⫽ 0.04; ‡p ⫽ 0.03; §p ⫽ 0.05. pressure ⬎230 mm Hg, diastolic Abbreviation as in Table 1. blood pressure ⱖ130 mm Hg), hypotension (relative or absolute decrease in systolic blood pressure ⱖ30 mm Hg), and intolerable symptoms. Follow-up information was obtained by periodic visits to the outpatient clinic by discharge reports from other hospitals in case of emergency admission and by telephone interview with the patient, a close relative, or a referring physician if the patient was not compliant with the follow-up program. Death was defined as cardiac if strictly related to proven cardiac causes (fatal reinfarction, acute heart failure, or malignant arrhythmias). Nonfatal AMI was diagnosed on the basis of documented electrocardiographic changes and typical cardiac enzyme release. The decision to perFIGURE 1. Distribution of target events over time as percentage of subjects at risk. form coronary angiography and eventual revascularization was independently made by the referring physician, segment, 4-point (1 ⫽ normal, 2 ⫽ hypokinetic, 3 ⫽ who was unaware of the study aim. Continuous variables are expressed as mean ⫾ 1 akinetic, 4 ⫽ dyskinetic) scoring model of the left ventricle was used. A wall motion score index SD and were compared by the unpaired 2-sample t (WMSI) was calculated by adding the numeric value test. The 95% confidence intervals (CIs) are reported assigned to each segment and dividing by the number where appropriate. Proportions were compared by the of visualized segments. Wall motion abnormality was chi-square statistics. The individual effects of clinical defined as worsening of wall motion compared with (age, sex, non–Q-wave AMI, diabetes mellitus, smokthat observed at baseline or at low-dose dobutamine. ing habit, systemic hypertension, total blood cholesChanges from normal wall thickening to hypokinesia, terol ⬎240 mg/dl) and DSE (rest and peak WMSI, akinesia, or dyskinesia, and from hypokinesia to aki- peak dobutamine dose, peak rate-pressure product and nesia or dyskinesia, but not from akinesia to dyskine- evidence of viability) variables on survival were evalsia,9 were considered as worsened wall motion. The uated by Cox’s proportional-hazards model using uniresult of the test was considered positive for ischemia variate and stepwise multivariate procedures. Data if there was worse wall motion in dysfunctional seg- were analyzed for cardiac death only and for the ments, development of new wall motion abnormalities combined end point of cardiac death and nonfatal in normokinetic regions, or a biphasic response to AMI. Patients undergoing myocardial revascularizaTABLE 2 Clinical and DSE Data According to Treatment
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FIGURE 2. Kaplan-Meier overall and infarction-free survival curves.
TABLE 3 Significant Univariate and Multivariate Predictors of Cardiac Death Univariate Variable Age ⬎65 yrs Rest WMSI ⬎1.55 Peak rate-pressure product ⬍18,000 No thrombolysis
Multivariate
HR*
p Value
HR*
p Value
6 (2–128) 25.6 (1.1–641) 4.9 (1.2–19.5)
0.009 0.048 0.026
10 (1.2–83) — —
0.032 — —
8.1 (1.1–65)
0.048
*Hazard ratio (HR) is reported with 95% confidence intervals.
TABLE 4 Significant Univariate and Multivariate Predictors of Cardiac Death and Nonfatal Myocardial Infarction Univariate Variable Age ⬎65 yrs Rest WMSI ⬎1.55
HR*
p Value
HR
2.2 (1–4.6) 5.5 (1–30)
0.037 0.049
— —
*Hazard ratio (HR) is reported with 95% confidence interval.
tion were censored at the time of the procedure to avoid potential referral bias. Cutoff values for assessing risk of cardiac death (determined by receiveroperating characteristics curve analysis of continuous variables) were age 65 years (sensitivity 89%, specificity 68%, area under the curve 0.78, 95% CI 0.73 to 0.83), 18,000 for rate-pressure product (sensitivity 45%, specificity 76%, area under the curve 0.61, 95% CI 0.55 to 0.67), and 1.55 for rest WMSI (sensitivity 67%, specificity 75%, area under the curve 0.68, 95% CI 0.62 to 0.73). The log-rank test was used to compare Kaplan-Meier event-free survival curves. Statistical significance was settled at a p value ⬍0.05. The SPSS statistical package (release 10.0 for Microsoft Windows, SPSS, Inc., Chicago, Illinois) was used. Mean follow-up time was 35.4 months (95% CI 33
to 38). Nine cardiac deaths and 20 nonfatal AMIs were observed. Moreover, 10 patients died of noncardiac reasons and 64 underwent revascularization procedures (35 underwent bypass surgery and 29 percutaneous intracoronary interventions), which were performed within 6 months in 29 and after 6 months in 35 patients. Clinical and DSE data of patients undergoing invasive and conservative treatment are reported in Table 2. The distribution of target events over time as a percentage of subjects at risk is shown in Figure 1. KaplanMeier survival and infarction-free survival curves are reported in Figure 2. Importantly, cardiac death and reinfarction rates were 2% and 6%, respectively, at the minimum required follow-up time of 2 years. Univariate and multivariate predictors of cardiac death alone and cardiac death combined with nonfatal AMI are listed in Tables 3 and 4, respectively. Age was the multivariate predictor of cardiac death, whereas no independent predictor of the combined end point was found. Kaplan-Meier survival curves according to age are shown in Figure 3. Of note, the 5-year cardiac mortality rate of patients aged ⱕ65 years was just 2%. •••
The present study demontrates that a negative DSE is associated Multivariate with a very low incidence of major cardiac events in patients with unp Value complicated AMI. In particular, pa— tients aged ⱕ65 years had an excel— lent prognosis with an extremely low risk of cardiac death that is consistent with previous findings in postinfarction patients.10 In addition, the high discriminant capacity of the test persisted over time, thus making any further gain by an invasive strategy unlikely on Bayesian grounds. This sets the basis for a substantial cost saving by reducing the recourse to revascularization procedures performed just for anatomic reasons. Kuntz et al11 analyzed the cost-effectiveness of routine coronary angiography and treatment guided by its result compared with a conservative strategy. They found the incremental cost-effectiveness ratio per quality-adjusted year of life gained with the invasive approach to be significantly higher in patients with negative than in those with positive stress testing results and/or history of previous AMI. Good clinical practice requires the physician to choose diagnostic procedures in a costeffective manner, in which each procedure individuBRIEF REPORTS
151
FIGURE 3. Kaplan-Meier survival curves according to age.
ally or sequentially may lead to improved diagnosis and management by integrating its results with the previously available information. The evaluation of simple clinical data, such as age, uncomplicated clinical course, and preserved or mildly reduced left ventricular function, combined with DSE results, identifies a post-AMI population at very low risk of cardiac death for which no prognostic benefit could be expected by routine coronary angiography.12,13 On the other hand, no independent predictor of the combined end point of cardiac death and nonfatal AMI was identified in this study. This is in agreement with the known concept that the plaque instability underlying acute coronary events is poorly predicted by clinical data,14 stress echocardiography,15 and even angiographic results.16 On the basis of our findings, patients aged <65 years with negative results on DSE represent the ideal setting in which a conservative strategy could be safely and effectively applied. The wide availability of echocardiographic equipment makes this approach extensively feasible, even in peripheral cardiology centers with limited diagnostic facilities. Furthermore, its application on a large scale could substantially contribute to cost savings, mainly by reducing the recourse to revascularization procedures performed on just an anatomic basis. 1. Carlos ME, Smart SC, Wynse JC, Sagar KB. Dobutamine stress echocardiog-
raphy for risk stratification following acute myocardial infarction. Circulation 1997;95:1402–1410.
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2. Sicari R, Picano E, Landi P, Pingitore A, Bigi R, Coletta C, Heyman J, Casazza F, Previtali M, Mathias W Jr, et al, on Behalf of the Echo Dobutamine International Cooperative (EDIC) Study. The prognostic value of dobutamine-atropine stress echocardiography early after acute myocardial infarction. J Am Coll Cardiol 1997;29:254 –260. 3. Bigi R, Galati A, Curti G, Coletta C, Partesana N, Bordi L, Barlera S, Ceci V, Occhi G, Fiorentini C. Prognostic value of residual ischemia assessed by means of exercise electrocardiography and dobutamine stress echocardiography after uncomplicated myocardial infarction. Eur Heart J 1997;18:1873–1881. 4. Picano E, Sicari R, Landi P, Cortigiani L, Bigi R, Coletta C, Galati A, Heyman J, Mattioli R, Previtali M, et al, on behalf of EDIC (Echo Dobutamine International Cooperative) Study Group. Prognostic value of myocardial viability in medically treated patients with global left ventricular dysfunction early after an acute uncomplicated myocardial infarction: A dobutamine stress echocardiographic study. Circulation 1998;98: 1078 –1084. 5. Previtali M, Fetiveau R, Lanzarini L, Cavalotti C, Klersy C. Prognostic value of myocardial viability and ischemia detected by dobutamine stress echocardiography early after acute myocardial infarction treated with thrombolysis. J Am Coll Cardiol 1998;32:380 – 386. 6. Salustri A, Ciavatti M, Seccareccia F, Palamara A. Prediction of cardiac events after uncomplicated acute myocardial infarction by clinical variables and dobutamine stress test. J Am Coll Cardiol 1999;34:435–440. 7. Bigi R, Galati A, Desideri A, Bax JJ, Coletta C, Fiorentini C, Fioretti PM. Incremental prognostic value of stress echocardiography as adjunctive test to exercise electrocardiography following uncomplicated myocardial infarction. Heart 2001;85:417–423. 8. McNeill AJ, Fioretti PM, El-Said ME, Salustri A, Forster T, Roelandt JRTC. Enhanced sensitivity for detection of coronary artery disease by addition of atropine to dobutamine stress echocardiography. Am J Cardiol 1992;70:41–46. 9. Arnese M, Fioretti PM, Cornel JH, Postma-Tjoa J, Reijs AEM, Roelandt JRTC. Akinesis becoming dyskinesis during high-dose dobutamine stress echocardiography: a marker of myocardial ischemia or a mechanical phenomenon. Am J Cardiol 1994;73:896 –899. 10. Maggioni AP, Maseri A, Fresco C, Franzosi MG, Mauri F, Santoro E, Tognoni G. Age-related increase in mortality among patients with first myocardial infarctions treated with thrombolysis. N Engl J Med 1993;329:1442–1448. 11. Kuntz KM, Tsevat J, Goldman L, Weinstein MC. Cost-effectiveness of routine coronary angiography after acute myocardial infarction. Circulation 1996;94:957–965. 12. Boden WE, O’Rourke RA, Crawford MH, Blaustein AS, Deedwania PC, Zoble RG, Wexler LF, Kleiger RE, Pepine CJ, Ferry DR, Chow BK, Lavori PW. Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial Investigators. N Engl J Med 1998;338:1785–1792. 13. Organisation to Assess Strategies for Ischaemic Syndromes Registry Investigators. Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation. Organisation to Assess Strategies for Ischaemic Syndromes (OASIS). Lancet 1998;352:507–514. 14. Ross J Jr, Gilpin EA, Madsen EB, Henning H, Nicod P, Dittrich H, Engler R, Rittelmeyer J, Smith SC Jr, Viquerat C. A decision scheme for coronary angiography after acute myocardial infarction. Circulation 1989;79:292–303. 15. Varga A, Picano E, Cortgiani L, Petix N, Margaria F, Magaia O, Heymann J, Bigi R, Mathias W Jr, Gigli G, et al, on behalf of EPIC-EDIC Study Group. Is stress echocardiography capable to predict the site of future myocardial infarction? J Am Coll Cardiol 1996;28:45–51. 16. Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows MT, Kahl FR, Santamore WP. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild to moderate coronary artery disease? Circulation 1988;78:1157–1166.
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6. Aronow WS, Ahn C, Gutstein H. Incidence of new atherothrombotic brain infarction in older persons with prior myocardial infarction and serum lowdensity lipoprotein cholesterol ⱖ125 mg/dL treated with statins versus no lipidlowering drug. J Gerontol Med Sci 2002:57A:M333–M335. 7. Joint National Committee. The Sixth Report of the Joint National Committee on the Detection Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med 1997;157:2413–2444. 8. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183–1197. 9. Aronow WS, Ahn C, Kronzon I. Prognosis of congestive heart failure in elderly patients with normal versus abnormal left ventricular systolic function associated with coronary artery disease. Am J Cardiol 1990;66:1257–1259. 10. Kjekshus J, Pedersen TR, Olsson AG, Faergeman O, Pyorala K. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail 1997;3:249 –254.
Sustained Favorable Long-Term Prognosis of Negative Stress Echocardiography Following Uncomplicated Myocardial Infarction Riccardo Bigi,
MD,
Lauro Cortigiani,
MD,
obutamine stress echocardiography (DSE) has been increasingly used in the last few years for D risk stratification of patients after acute myocardial infarction (AMI)1– 6 and proved to convey incremental prognostic information compared with standard exercise electrocardiography.7 In particular, a very high negative predictive value has been reported in patients with uncomplicated AMI.2,3 However, most studies have included only short- or medium-term follow-up; therefore, information on long-term negative predictive value is still lacking. The aim of this study was twofold: (1) to verify the duration of the good prognostic implication by a negative DSE after uncomplicated AMI, and (2) to identify possible markers of future cardiac events in this population. •••
Seven hundred two consecutive patients with AMI undergoing predischarge DSE were initially considered for inclusion. One hundred forty-five patients were excluded because of (1) a complicated clinical course (recurrent ischemia, heart failure, major arrhythmias [46 patients]), (2) left ventricular ejection fraction ⬍40% (47 patients), and (3) history of previous AMI and/or revascularization (52 patients). Of the remaining 557 patients, 281 had a negative DSE and formed the study population whose clinical and DSE data are listed in Table 1. The follow-up period lasted
From the Cardiovascular Research Foundation, Castelfranco Veneto, Venice, Italy; Cardiovascular Unit, “Campo di Marte” Hospital, Lucca, Italy; and Department of Cardiology, University Medical Center, Leiden, The Netherlands. Dr. Bigi’s address is: Via Visoli 1, 23037 Tirano (SO), Italy. E-mail: [email protected]. Manuscript received January 23, 2002; revised manuscript received and accepted March 26, 2002. ©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 90 July 15, 2002
Pier R. Mariani,
MD,
and Jeroen J. Bax,
MD
TABLE 1 Clinical and DSE Data Age (yrs) Women Anterior wall AMI Inferior wall AMI Non–Q-wave wall AMI Systemic hypertension Diabetes mellitus Total blood cholesterol ⱖ240 mg/dl Cigarette smokers Risk factors ⱖ3 1 or 2 DSE data Rest WMSI Peak WMSI Max. dobutamine dose (g/kg/min) Atropine administration Peak heart rate (beats/min) % of maximal predicted heart rate Peak systolic blood pressure (mm Hg) Peak diastolic blood pressure (mm Hg) Peak rate-pressure product
61 62 77 151 53 99 46 98 139 237 23 258 1.39 1.38 37.5 160 131 85 154 84 20,119
⫾ 10 (22%) (27%) (54%) (19%) (35%) (16%) (35%) (49%) (84%) (8%) (82%) ⫾ 0.21 ⫾ 0.22 ⫾ 5.4 (57%) ⫾ 20 ⫾ 14 ⫾ 27 ⫾ 10 ⫾ 4,706
Max. ⫽ maximal.
at least 2 years or until the occurrence of death, nonfatal AMI, or coronary revascularization. DSE was performed according to the established protocol8 based on 3-minute stages up to 40 kg/min plus additional atropine (up to 1 mg) if required for achieving 85% of age- and sex-predicted maximum heart rate. Fifteen patients (5%) underwent the test with therapy ( blockers, calcium antagonists, and nitrates, alone or in combination) and 265 underwent testing without therapy. Off-line, computer-assisted analysis of images was used to improve the accuracy of interpretation. In case of disagreement, a third observer reviewed the images without knowledge of previous assessment and a majority decision was achieved. For the semiquantitative assessment, a 160002-9149/02/$–see front matter PII S0002-9149(02)02439-6
149
dobutamine administration (i.e., motion improvement with a low dose Invasive Conservative followed by deterioration with a high Treatment Treatment dose). Improvement with a low dose (n ⫽ 64) (n ⫽ 217) that was maintained with a high Age (yrs) 58.3 ⫾ 9.3 61.7 ⫾ 10.7* dose, identified the presence of viaWomen 12 (19%) 50 (23%) ble myocardium. The test was deAnterior wall AMI 22 (34%) 55 (25%) fined as negative for ischemia in case Inferior wall AMI 28 (44%) 123 (57%) of no worsening or development of Non–Q-wave wall AMI 14 (22%) 39 (18%) Systemic hypertension 23 (36%) 76 (35%) hyperkinetic wall motion. Tests were Diabetes mellitus 13 (20%) 33 (15%) interrupted if there was evidence of Total blood cholesterol ⱖ240 mg/dl 25 (39%) 73 (34%) new wall motion abnormalities. Non† Cigarette smokers 39 (61%) 100 (46%) echocardiographic criteria for interNo. of risk factors 1.6 ⫾ 1.0 1.3 ⫾ 0.8‡ rupting the test were protocol termiⱖ3 risk factors 9 (14%) 14 (6%)§ DSE data nation and achievement of 85% of Rest WMSI 1.42 ⫾ 0.23 1.39 ⫾ 0.21 maximal predicted heart rate. Tests Peak WMSI 1.42 ⫾ 0.23 1.38 ⫾ 0.21 were also discontinued if there was Max. dobutamine dose (g/kg/min) 37.5 ⫾ 5.6 37.6 ⫾ 5.4 severe chest pain, significant arrhythPeak heart rate (beats/min) 130 ⫾ 21 131 ⫾ 20 % of maximal predicted heart rate 83 ⫾ 15 86 ⫾ 14 mias, horizontal or downsloping STPeak systolic blood pressure (mm Hg) 154 ⫾ 23 154 ⫾ 28 segment depression ⬎2 mm, or elePeak diastolic blood pressure (mm Hg) 84 ⫾ 9 84 ⫾ 11 vation ⬎1.5 mm (in no Q-wave Peak rate-pressure product 20,054 ⫾ 4,380 20,138 ⫾ 4,807 leads), hypertension (systolic blood *p ⫽ 0.02; †p ⫽ 0.04; ‡p ⫽ 0.03; §p ⫽ 0.05. pressure ⬎230 mm Hg, diastolic Abbreviation as in Table 1. blood pressure ⱖ130 mm Hg), hypotension (relative or absolute decrease in systolic blood pressure ⱖ30 mm Hg), and intolerable symptoms. Follow-up information was obtained by periodic visits to the outpatient clinic by discharge reports from other hospitals in case of emergency admission and by telephone interview with the patient, a close relative, or a referring physician if the patient was not compliant with the follow-up program. Death was defined as cardiac if strictly related to proven cardiac causes (fatal reinfarction, acute heart failure, or malignant arrhythmias). Nonfatal AMI was diagnosed on the basis of documented electrocardiographic changes and typical cardiac enzyme release. The decision to perFIGURE 1. Distribution of target events over time as percentage of subjects at risk. form coronary angiography and eventual revascularization was independently made by the referring physician, segment, 4-point (1 ⫽ normal, 2 ⫽ hypokinetic, 3 ⫽ who was unaware of the study aim. Continuous variables are expressed as mean ⫾ 1 akinetic, 4 ⫽ dyskinetic) scoring model of the left ventricle was used. A wall motion score index SD and were compared by the unpaired 2-sample t (WMSI) was calculated by adding the numeric value test. The 95% confidence intervals (CIs) are reported assigned to each segment and dividing by the number where appropriate. Proportions were compared by the of visualized segments. Wall motion abnormality was chi-square statistics. The individual effects of clinical defined as worsening of wall motion compared with (age, sex, non–Q-wave AMI, diabetes mellitus, smokthat observed at baseline or at low-dose dobutamine. ing habit, systemic hypertension, total blood cholesChanges from normal wall thickening to hypokinesia, terol ⬎240 mg/dl) and DSE (rest and peak WMSI, akinesia, or dyskinesia, and from hypokinesia to aki- peak dobutamine dose, peak rate-pressure product and nesia or dyskinesia, but not from akinesia to dyskine- evidence of viability) variables on survival were evalsia,9 were considered as worsened wall motion. The uated by Cox’s proportional-hazards model using uniresult of the test was considered positive for ischemia variate and stepwise multivariate procedures. Data if there was worse wall motion in dysfunctional seg- were analyzed for cardiac death only and for the ments, development of new wall motion abnormalities combined end point of cardiac death and nonfatal in normokinetic regions, or a biphasic response to AMI. Patients undergoing myocardial revascularizaTABLE 2 Clinical and DSE Data According to Treatment
150 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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FIGURE 2. Kaplan-Meier overall and infarction-free survival curves.
TABLE 3 Significant Univariate and Multivariate Predictors of Cardiac Death Univariate Variable Age ⬎65 yrs Rest WMSI ⬎1.55 Peak rate-pressure product ⬍18,000 No thrombolysis
Multivariate
HR*
p Value
HR*
p Value
6 (2–128) 25.6 (1.1–641) 4.9 (1.2–19.5)
0.009 0.048 0.026
10 (1.2–83) — —
0.032 — —
8.1 (1.1–65)
0.048
*Hazard ratio (HR) is reported with 95% confidence intervals.
TABLE 4 Significant Univariate and Multivariate Predictors of Cardiac Death and Nonfatal Myocardial Infarction Univariate Variable Age ⬎65 yrs Rest WMSI ⬎1.55
HR*
p Value
HR
2.2 (1–4.6) 5.5 (1–30)
0.037 0.049
— —
*Hazard ratio (HR) is reported with 95% confidence interval.
tion were censored at the time of the procedure to avoid potential referral bias. Cutoff values for assessing risk of cardiac death (determined by receiveroperating characteristics curve analysis of continuous variables) were age 65 years (sensitivity 89%, specificity 68%, area under the curve 0.78, 95% CI 0.73 to 0.83), 18,000 for rate-pressure product (sensitivity 45%, specificity 76%, area under the curve 0.61, 95% CI 0.55 to 0.67), and 1.55 for rest WMSI (sensitivity 67%, specificity 75%, area under the curve 0.68, 95% CI 0.62 to 0.73). The log-rank test was used to compare Kaplan-Meier event-free survival curves. Statistical significance was settled at a p value ⬍0.05. The SPSS statistical package (release 10.0 for Microsoft Windows, SPSS, Inc., Chicago, Illinois) was used. Mean follow-up time was 35.4 months (95% CI 33
to 38). Nine cardiac deaths and 20 nonfatal AMIs were observed. Moreover, 10 patients died of noncardiac reasons and 64 underwent revascularization procedures (35 underwent bypass surgery and 29 percutaneous intracoronary interventions), which were performed within 6 months in 29 and after 6 months in 35 patients. Clinical and DSE data of patients undergoing invasive and conservative treatment are reported in Table 2. The distribution of target events over time as a percentage of subjects at risk is shown in Figure 1. KaplanMeier survival and infarction-free survival curves are reported in Figure 2. Importantly, cardiac death and reinfarction rates were 2% and 6%, respectively, at the minimum required follow-up time of 2 years. Univariate and multivariate predictors of cardiac death alone and cardiac death combined with nonfatal AMI are listed in Tables 3 and 4, respectively. Age was the multivariate predictor of cardiac death, whereas no independent predictor of the combined end point was found. Kaplan-Meier survival curves according to age are shown in Figure 3. Of note, the 5-year cardiac mortality rate of patients aged ⱕ65 years was just 2%. •••
The present study demontrates that a negative DSE is associated Multivariate with a very low incidence of major cardiac events in patients with unp Value complicated AMI. In particular, pa— tients aged ⱕ65 years had an excel— lent prognosis with an extremely low risk of cardiac death that is consistent with previous findings in postinfarction patients.10 In addition, the high discriminant capacity of the test persisted over time, thus making any further gain by an invasive strategy unlikely on Bayesian grounds. This sets the basis for a substantial cost saving by reducing the recourse to revascularization procedures performed just for anatomic reasons. Kuntz et al11 analyzed the cost-effectiveness of routine coronary angiography and treatment guided by its result compared with a conservative strategy. They found the incremental cost-effectiveness ratio per quality-adjusted year of life gained with the invasive approach to be significantly higher in patients with negative than in those with positive stress testing results and/or history of previous AMI. Good clinical practice requires the physician to choose diagnostic procedures in a costeffective manner, in which each procedure individuBRIEF REPORTS
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FIGURE 3. Kaplan-Meier survival curves according to age.
ally or sequentially may lead to improved diagnosis and management by integrating its results with the previously available information. The evaluation of simple clinical data, such as age, uncomplicated clinical course, and preserved or mildly reduced left ventricular function, combined with DSE results, identifies a post-AMI population at very low risk of cardiac death for which no prognostic benefit could be expected by routine coronary angiography.12,13 On the other hand, no independent predictor of the combined end point of cardiac death and nonfatal AMI was identified in this study. This is in agreement with the known concept that the plaque instability underlying acute coronary events is poorly predicted by clinical data,14 stress echocardiography,15 and even angiographic results.16 On the basis of our findings, patients aged <65 years with negative results on DSE represent the ideal setting in which a conservative strategy could be safely and effectively applied. The wide availability of echocardiographic equipment makes this approach extensively feasible, even in peripheral cardiology centers with limited diagnostic facilities. Furthermore, its application on a large scale could substantially contribute to cost savings, mainly by reducing the recourse to revascularization procedures performed on just an anatomic basis. 1. Carlos ME, Smart SC, Wynse JC, Sagar KB. Dobutamine stress echocardiog-
raphy for risk stratification following acute myocardial infarction. Circulation 1997;95:1402–1410.
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2. Sicari R, Picano E, Landi P, Pingitore A, Bigi R, Coletta C, Heyman J, Casazza F, Previtali M, Mathias W Jr, et al, on Behalf of the Echo Dobutamine International Cooperative (EDIC) Study. The prognostic value of dobutamine-atropine stress echocardiography early after acute myocardial infarction. J Am Coll Cardiol 1997;29:254 –260. 3. Bigi R, Galati A, Curti G, Coletta C, Partesana N, Bordi L, Barlera S, Ceci V, Occhi G, Fiorentini C. Prognostic value of residual ischemia assessed by means of exercise electrocardiography and dobutamine stress echocardiography after uncomplicated myocardial infarction. Eur Heart J 1997;18:1873–1881. 4. Picano E, Sicari R, Landi P, Cortigiani L, Bigi R, Coletta C, Galati A, Heyman J, Mattioli R, Previtali M, et al, on behalf of EDIC (Echo Dobutamine International Cooperative) Study Group. Prognostic value of myocardial viability in medically treated patients with global left ventricular dysfunction early after an acute uncomplicated myocardial infarction: A dobutamine stress echocardiographic study. Circulation 1998;98: 1078 –1084. 5. Previtali M, Fetiveau R, Lanzarini L, Cavalotti C, Klersy C. Prognostic value of myocardial viability and ischemia detected by dobutamine stress echocardiography early after acute myocardial infarction treated with thrombolysis. J Am Coll Cardiol 1998;32:380 – 386. 6. Salustri A, Ciavatti M, Seccareccia F, Palamara A. Prediction of cardiac events after uncomplicated acute myocardial infarction by clinical variables and dobutamine stress test. J Am Coll Cardiol 1999;34:435–440. 7. Bigi R, Galati A, Desideri A, Bax JJ, Coletta C, Fiorentini C, Fioretti PM. Incremental prognostic value of stress echocardiography as adjunctive test to exercise electrocardiography following uncomplicated myocardial infarction. Heart 2001;85:417–423. 8. McNeill AJ, Fioretti PM, El-Said ME, Salustri A, Forster T, Roelandt JRTC. Enhanced sensitivity for detection of coronary artery disease by addition of atropine to dobutamine stress echocardiography. Am J Cardiol 1992;70:41–46. 9. Arnese M, Fioretti PM, Cornel JH, Postma-Tjoa J, Reijs AEM, Roelandt JRTC. Akinesis becoming dyskinesis during high-dose dobutamine stress echocardiography: a marker of myocardial ischemia or a mechanical phenomenon. Am J Cardiol 1994;73:896 –899. 10. Maggioni AP, Maseri A, Fresco C, Franzosi MG, Mauri F, Santoro E, Tognoni G. Age-related increase in mortality among patients with first myocardial infarctions treated with thrombolysis. N Engl J Med 1993;329:1442–1448. 11. Kuntz KM, Tsevat J, Goldman L, Weinstein MC. Cost-effectiveness of routine coronary angiography after acute myocardial infarction. Circulation 1996;94:957–965. 12. Boden WE, O’Rourke RA, Crawford MH, Blaustein AS, Deedwania PC, Zoble RG, Wexler LF, Kleiger RE, Pepine CJ, Ferry DR, Chow BK, Lavori PW. Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial Investigators. N Engl J Med 1998;338:1785–1792. 13. Organisation to Assess Strategies for Ischaemic Syndromes Registry Investigators. Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation. Organisation to Assess Strategies for Ischaemic Syndromes (OASIS). Lancet 1998;352:507–514. 14. Ross J Jr, Gilpin EA, Madsen EB, Henning H, Nicod P, Dittrich H, Engler R, Rittelmeyer J, Smith SC Jr, Viquerat C. A decision scheme for coronary angiography after acute myocardial infarction. Circulation 1989;79:292–303. 15. Varga A, Picano E, Cortgiani L, Petix N, Margaria F, Magaia O, Heymann J, Bigi R, Mathias W Jr, Gigli G, et al, on behalf of EPIC-EDIC Study Group. Is stress echocardiography capable to predict the site of future myocardial infarction? J Am Coll Cardiol 1996;28:45–51. 16. Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows MT, Kahl FR, Santamore WP. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild to moderate coronary artery disease? Circulation 1988;78:1157–1166.
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