- Email: [email protected]
Relation of mortality of primary angioplasty during acute myocardial infarction to door-to-Thrombolysis In Myocardial Infarction (TIMI) time
Relation of Mortality of Primary Angioplasty During Acute Myocardial Infarction to Door-to-Thrombolysis In Myocardial Infarction (TIMI) Time Jean-Michel Juliard, MD, Laurent J. Feldman, MD, PhD, Jean-Louis Golmard, MD, Dominique Himbert, MD, Hakim Benamer, MD, Tinouche Haghighat, MD, Daniel Karila-Cohen, MD, Pierre Aubry, MD, Alec Vahanian, MD, and Ph. Gabriel Steg, MD
PhD,
For primary angioplasty of acute myocardial infarction (AMI), the relation of treatment benefit and time has been debated. The present study aimed to evaluate, in a single-center cohort of patients with ST-segment elevation AMI, which time intervals were carefully and consistently measured, and the relations among ischemic time, in-hospital delays, and in-hospital survival. We included 499 patients (mean age 59 years; 80% men) who underwent successful primary percutaneous transluminal coronary angioplasty (PTCA) for AMI admitted <6 hours after symptom onset. The population was divided into tertiles with respect to time between onset of symptoms and admission, onset of symptoms to Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow, and
time from admission to TIMI grade 3 flow. Univariate analysis followed by multiple logistic regression was performed using the variables linked to mortality in the univariate analysis to assess the relation between predictor variables and in-hospital mortality. The in-hospital mortality rate was 3.2%. There was no significant relation between the various tertiles of time intervals and in-hospital mortality. After linear logistic regression, only age (odds ratio [OR] 1.79 per 10 years), female gender (OR 3.56), and door-to-TIMI 3 time (OR 1.27 per 15 minutes) were independently correlated with in-hospital mortality. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;91:1401–1405)
here is solid evidence that in patients with STsegment elevation acute myocardial infarction T (AMI) who receive thrombolytic therapy, the benefit
studies of the relation between delays and survival have involved multicenter studies, their findings of the prognostic importance of a short in-hospital door-toballoon time has been interpreted to represent a surrogate of hospital performance or expertise, which would be expected to be higher in high-volume centers that are known to be associated with improved outcomes.10,11 The present study aimed to evaluate, in a single-center cohort of patients with acute ST-segment elevation AMI, which time intervals were carefully and consistently measured, and the relations among ischemic time, in-hospital delays, and in-hospital survival.
of treatment decreases with the delay between the onset of symptoms and the administration of lytic therapy.1 However, there is uncertainty as to whether this time dependency of treatment benefit also holds true when reperfusion is obtained by primary percutaneous transluminal coronary angioplasty (PTCA) rather than by pharmacologic means2,3; several studies have suggested that the door-to-balloon time was a better predictor of in-hospital survival than the total duration of ischemia (i.e., the delay between symptom onset and myocardial reperfusion, or at least the start of PTCA).4,5 Others have suggested that in the case of mechanical reperfusion of the myocardium by PTCA, the benefit is somewhat time independent.2,4 This is important because 1 of the main limitations of primary PTCA is the time needed for its implementation; the finding of time-independent benefits would argue for transfer of patients with AMI to PTCA centers, even if this results in reperfusion delays.6 –9 Because previous From the Cardiology Department, Hoˆpital Bichat; and INSERM U436, Hoˆpital Pitie´-Salpe´trie`re, AP-HP, Paris, France. Manuscript received December 30, 2002; revised manuscript received and accepted February 28, 2003. Address for reprints: Jean-Michel Juliard, MD, De´partement de Cardiologie, Hoˆpital Bichat, AP-HP, 46 rue Henri Huchard, 75877 Paris Cedex 18, France. E-mail: [email protected]. fr. ©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 June 15, 2003
METHODS
Study population: Between 1988 and January 2000, 1,200 patients were consecutively admitted to the coronary care unit with a diagnosis of ST-segment elevation AMI, within 6 hours of symptom onset. This cohort has been previously described.12 Of those 1,200 patients, 133 had no attempt at reperfusion therapy, 409 received intravenous thrombolysis, and the remaining 658 were triaged to emergency PTCA. From these 658 patients, we excluded 60 admitted with cardiogenic shock, 28 patients who had a spontaneously patent infarct vessel with Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow, and 71 patients in whom PTCA failed to achieve successful TIMI 3 flow in the infarct-related vessel. Therefore, 499 patients underwent successful primary PTCA 0002-9149/03/$–see front matter doi:10.1016/S0002-9149(03)00388-6
1401
TABLE 1 Clinical Characteristics Survivors (n ⫽ 483) Age (yrs) Men Current smoker Total cholesterol ⱖ220 mg/dl Systemic hypertension Family history of coronary artery disease Diabetes mellitus Anterior wall AMI Contraindication to thrombolysis Prior bypass surgery Prior PTCA Previous AMI Time from pain to admission (min)
58 392 333 197 161 158 53 225 174 11 31 52 180
⫾ 13 (81%) (69%) (41%) (33%) (32%) (11%) (47%) (36%) (2%) (6%) (11%) ⫾ 84
Data are presented as mean ⫾ SD or number (%) of patients.
Statistical analysis: Chest pain-todoor time was defined as the delay Nonsurvivors between the onset of symptoms and (n ⫽ 16) p Value admission to the catheterization laboratory. Door-to-TIMI 3 time was 72 ⫾ 16 0.001 7 (44%) 0.0008 defined by the delay between admis4 (25%) 0.0006 sion and final TIMI grade 3 flow in 2 (12%) 0.04 the infarct-related artery. Chest pain8 (50%) 0.26 to-TIMI 3 time was defined as the 2 (12%) 0.15 3 (19%) 0.77 sum of the 2 previous intervals. TIMI 10 (62%) 0.32 flow grade was assessed according to 8 (50%) 0.38 the TIMI scoring system.13 All con0 — tinuous variables are expressed as 0 — mean ⫾ SD. 0 — 186 ⫾ 93 NS In a first approach, the population was divided into tertiles with respect to time between onset of symptoms and admission, onset of symptoms to TIMI grade 3 flow, and admission to TIMI grade 3 flow. The goal was to evaluate the relation between each subset of patients and the 3 previous intervals. Univariate analysis, using chi-square and Student’s t tests, was performed first to determine the factors associated with in-hospital mortality. Variables examined included age, gender, risk factors for coronary artery disease, medical history and cardiovascular events, type of infarction, presence of a contraindication to thrombolysis, angiographic findings, ventricular arrhythmias, stent placement, use of glycoprotein IIb/IIIa blockers, and the various time intervals. Multiple logistic regression was then performed using the variables linked to mortality in the univariate analysis (p ⬍0.05 was considered significant), to assess the relation between predictor variables and in-hospital mortality. All analyses were performed using SAS (SAS Institute, Cary, North Carolina).
FIGURE 1. In-hospital mortality in patients reperfused during the first hour (included) and those strictly reperfused beyond the first hour after admission.
(i.e., final TIMI flow grade of 3 and residual stenosis ⬍50%). Most of the patients were admitted directly to the catheterization laboratory after prehospital triage, and for those admitted first in the coronary care unit, the transfer time was very short, as our catheterization laboratory is located within the coronary care unit. Treatment protocol: Angioplasty was performed according to standard protocols. All patients received ⱖ250 mg of aspirin on admission and a bolus of 5,000 IU of unfractionated heparin before insertion of the arterial sheath, usually followed by an infusion adjusted to an activated partial thromboplastin time of 2 to 3 times control levels for 48 hours. Beta-adrenergic blocking agents were used first intravenously then orally, unless contraindicated. Stent placement and use of glycoprotein IIb/IIIa blockers were left to the discretion of the operator. All patients who had stents placement received ticlopidine or clopidogrel for ⱖ1 month. 1402 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 91
RESULTS
Clinical characteristics: The patients’ characteristics are listed in Table 1. The average delay between pain and admission was 181 ⫾ 84 minutes (median 180). Infarct location was anterior in 235 patients (47%). Four percent of patients (n ⫽ 21) had had cardiac arrest before admission that was successfully treated with electrical cardioversion. Coronary angioplasty outcome: At baseline angiography, 487 of the 499 patients undergoing PTCA had TIMI 0 to 1 grade flow and 12 had TIMI grade 2 flow in the infarct-related artery. Stents were placed in 36% of the patients, and all patients achieved TIMI grade 3 flow at an average 234 ⫾ 91 minutes (median 215) after pain onset and 54 ⫾ 28 minutes (median 45) after admission to the coronary care unit. Abciximab (bolus plus infusion) was used in 9% of the patients. Finally, 12 patients underwent electrical cardioversion for ventricular fibrillation, which occurred in the catheterization laboratory or immediately after recanalization of the infarct vessel. Clinical outcome and mortality: The in-hospital mortality rate was 3.2% (n ⫽ 16) but it was 1.8% for patients (9 of 394) recanalized within 60 minutes of JUNE 15, 2003
FIGURE 2. Relation between tertiles of time from symptom onset to admission and in-hospital mortality.
FIGURE 4. Relation between tertiles of time from admission to TIMI grade 3 flow and in-hospital mortality.
TABLE 2 Multivariate Risk Factors for In-hospital Mortality Variable Women Age (per 10 yrs) Door-to-TIMI 3 (per 15 min)
OR
95% CI
p Value
3.56 1.79 1.27
1.17–10.86 1.16–2.77 1.06–1.52
0.03 0.009 0.01
CI ⫽ confidence interval.
FIGURE 3. Relation between tertiles of time from symptom onset to TIMI grade 3 flow and in-hospital mortality.
admission, versus 6.7% for patients (7 of 105) recanalized later (p ⱕ0.05) (Figure 1). All deaths were related to left ventricular failure or mechanical complications, except for 1 fatal hemorrhagic stroke and 1 sudden death.
FIGURE 5. Relation between door-to-TIMI grade 3 flow and inhospital mortality. Each unit on the x-axis corresponds to 15minute delay from admission.
Relation between subset of patients and time intervals: There was no relation between tertiles of time
between pain onset and admission and in-hospital mortality (Figure 2). There was a nonsignificant trend toward a higher mortality in relation to the total duration of ischemia (i.e., the time elapse between symptom onset and establishment of TIMI 3 flow) (Figure 3), which was also not significant using the multivariate model. Finally, the relation between time from door to TIMI 3 flow and in-hospital mortality appeared dichotomous with low mortality when the delay was ⬍60 minutes; higher in-hospital mortality was seen when the delay was ⬎60 minutes (Figures 1 and 4). Prognostic factors of in-hospital mortality: Using univariate analysis, the following factors were correlated with in-hospital mortality: age, female gender, lack of smoking history, lack of dyslipidemia, and door-to-TIMI 3 time. After linear logistic regression, only age (odd ratio [OR] 1.79 per 10 years, p ⫽ 0.009), female gender (OR 3.56, p ⫽ 0.03), and doorto-TIMI 3 time (OR 1.27 per 15 minutes, p ⫽ 0.01) were independently correlated with in-hospital mortality (Table 2). A time threshold of 60 minutes was identified; at ⬎60 minutes, mortality significantly increased (Figure 1). After admission, the odds of death
increased 1.27 times per 15 minutes until TIMI 3 flow was achieved (Figure 5).
DISCUSSION Age and female gender are established independent risk factors for early mortality after AMI.14 In the reperfusion era, in which primary PTCA has been increasingly used, it is also important to account for the impact of treatment delays.15 The present study underlines the importance of a short delay between admission and TIMI 3 flow; there is an increase in mortality when TIMI 3 flow is achieved beyond the first hour after admission. Conversely, if TIMI 3 flow is established earlier, in-hospital mortality is very low. Our findings provide independent confirmation of the GUSTO-IIb analysis of time delays in patients treated with primary PTCA; we observed an OR for in-hospital mortality of 1.27 per 15 minutes increase, similar to the OR of 1.6 per 25 minutes in the Global Use of Strategies to Open Occluded Arteries in Actue Coronary Syndromes (GUSTO)-IIb trial.16 Nevertheless, it must be pointed out that the low mortality rate is a
CORONARY ARTERY DISEASE/MORTALITY DURING PTCA FOR AMI
1403
major limitation in the understanding of the statistical analyses. Chest pain-to-TIMI 3 time: Using the model in the 3 subsets, we observed a continuous but nonsignificant trend of higher mortality when chest pain-to-TIMI 3 time increased (Figure 3). Stratifying their population into 2 groups, O’Keefe et al15 showed that early mortality was lower with reperfusion time from pain to reperfusion of ⬍2 hours, and relatively time-independent in patients with reperfusion time ⱖ2 hours. However, the rate of patients successfully treated with primary PTCA within 2 hours after onset of pain remains extremely low; it was only 12% in the cohort of Brodie et al.4 Even in the large cohort of the second National Registry of Myocardial Infarction,2 the adjusted OR of in-hospital mortality did not increase significantly with increasing delay from AMI symptom onset to first balloon inflation (median time 3.9 hours). These results are in contrast with those from thrombolytic trials in which mortality increased with time from pain to treatment. There are several explanations for this discrepancy between lytic therapy and primary PTCA in terms of impact of the total ischemic time. First, the efficacy of primary PTCA to recanalize the infarct-related artery appears to be time independent, whereas this is not the case with lytic therapy, at least with nonfibrin-specific agents.13,17 Even with fibrin-specific agents such as recombinant tissue-type plasminogen activator, angiographic data from the GUSTO trial showed a trend towards a smaller TIMI 3 flow rate with increasing time to lytic therapy (63% at ⬍2 hours, 54% from 2 to 4 hours, and 50% from 4 to 6 hours).18 In addition, the benefit from reperfusion therapy may be the net result of an early “infarctlimiting” effect, confined to the first 2 hours19 and the “open-artery” effect, which is related to recanalization of the infarct-related vessel, independent from myocardial salvage, and therefore, less time sensitive.20 Animal studies suggest that infarct size limitation can only be achieved very early after ischemia. Thrombolytic therapy is more likely to be given in time to achieve such benefit, within the first 2 hours after symptom onset, whereas it is generally rare that primary PTCA can be performed in this time window after symptom onset. In our study, time from pain to reperfusion was on an average 234 ⫾ 91 minutes (median 215), and ⬍2 hours in only 10% of the patients, which explains the lack of correlation with mortality because most patients were reperfused after 2 hours from symptom onset. In the future, even with technology advances, it will be difficult to increase the number of patients treated within the first 2 hours after chest pain onset due to logistic issues. Door-to-TIMI 3 time: Door-to-TIMI grade 3 flow or door-to-balloon time have been adopted as a measure of quality of care for patients treated with primary PTCA during AMI. This delay is clearly influenced by institutional volume and a higher volume being associated with better outcomes.11,21,22 In the American College of Cardiology/American Heart Association guidelines, a door-to-balloon time of ⬍2 hours after 1404 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 91
admission is required for performing primary PTCA.23 The strong relation, even after adjustment for baseline differences, between door-to-TIMI 3 time and short-term mortality, has been interpreted as a surrogate of in-hospital volume and expertise.2– 4 Inhospital volume has been correlated, at least in highrisk patients subsets such as the elderly, to lower mortality.3,10 However, in the present single-center study, this relation between door-to-TIMI 3 time and mortality persists. This suggests that door-to-TIMI 3 time is not simply a surrogate marker of center expertise or quality of care, because these results were obtained in a single center cohort. In the second National Registry of Myocardial Infarction cohort of 27,080 patients treated with primary PTCA, the median door-to-balloon time was 116 minutes, and the odds of short-term mortality increased by 41% for patients with door-to-balloon time of ⬎2 hours and increased 62% for delays of ⬎3 hours.2 Only 8% of patients had a door-to-balloon time of ⱕ60 minutes, with a mortality of 1%. This small reference group is a major shortcoming of this previous study compared with the strength of tertile analysis using groups with a substantial number of patients, and the fact that 75% of patients were successfully treated within 60 minutes. This short delay at our institution has several explanations: most patients were referred to the catheterization laboratory for primary PTCA by mobile intensive care units that are staffed by physicians, and the decision of primary PTCA was most often taken in agreement with the physician in the mobile care unit. Only a small proportion of patients (⬍10%) were transferred in from other hospitals, and most patients were admitted directly into the catheterization laboratory (located within the coronary care unit), bypassing the emergency room. Finally, at night, the catheterization laboratory is staffed by the local coronary care unit nurses team, avoiding calls to outside nurses. This strategy has been adopted in our institution since 1988, with a volume operator of ⬎100 elective PTCAs/year per physician (and ⬎25 myocardial infarction cases annually), and our results are consistent with the guidelines of the French Society of Cardiology, which require a maximal delay of 60 minutes from the admission to the achievement of successful mechanical reperfusion.24 Acknowledgment: We are indebted to the catheterization team and to the nurses of the coronary care unit for their participation in round-the-clock catheterization effort.
1. Fibrinolytic Therapy Trialist’s Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet 1994;343:311–322. 2. Cannon CP, Gibson CM, Lambrew CT, Shoultz DA, Levy D, French WJ, Gore JM, Weaver WD, Rogers WJ, Tiefenbrunn AJ. Relationship of symptom-onsetto-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000;283:2941–2947. 3. Berger PB, Bell MR, Holmes DR, Gersh BJ, Hopfenspirger M, Gibbons R. Time to reperfusion with direct coronary angioplasty and thrombolytic therapy in acute myocardial infarction. Am J Cardiol 1994;73:231–236. 4. Brodie BR, Stuckey TD, Wall TC, Kissling G, Hansen CJ, Muncy DB,
JUNE 15, 2003
Weintraub RA, Kelly TA. Importance of time to reperfusion for 30-day and late survival and recovery of left ventricular function after primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 1998;32:1312–1319. 5. Ward MR, Lo ST, Herity NA, Lee DP, Yeung AC. Effect of audit on door-to-inflation times in primary angioplasty/stenting for acute myocardial infarction. Am J Cardiol 2001;87:336 –338. 6. Ferguson JJ. DANAMI II Danish Multicenter Randomized Study on Thrombolytic Therapy Versus Acute Coronary Angioplasty in Acute Myocardial Infarction-2. Meeting Highlights. Highlights of the 51st Annual Scientific Sessions of the American College of Cardiology. Circulation 2002;106:e24. 7. Grines CL, Westerhausen DR, Grines LL, Hanlon JT, Logemann TL, Niemela M, Weaver WD, Graham M, Boura J, O’Neill WW, Balestrini C, for the AIR PAMI Study Group. A randomized trial of transfer for primary angioplasty versus on-site thrombolysis in patients with high-risk myocardial infarction. The Air Primary Angioplasty in Myocardial Infarction Study. J Am Coll Cardiol 2002; 39:1713–1719. 8. Aversano T, Aversano LT, Passamani E, Knatterud GL, Terrin ML, Williams DO, Foreman SA, for the Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT). Thrombolytic therapy vs primary percutaneous coronary intervention for myocardial intervention for myocardial infarction in patients presenting to hospitals without on-site cardiac surgery. A randomized controlled trial. JAMA 2002;287:1943–1951. 9. Widimsky P, Groch L, Zelizko M, Aschermann M, Bednar S, Suryapranata H, on behalf of the PRAGUE Study Group Investigators. Multicenter randomized trial comparing transport to primary angioplasty versus immediate thrombolysis versus combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory. Eur Heart J 2002;21:823–831. 10. Thiemann DR, Coresh J, Oetgen WJ, Powe NR. The association between hospital volume and survival after acute myocardial infarction in elderly patients. N Engl J Med 1999;340:1640 –1648. 11. Vakili BA, Kaplan R, Brown DL. Volume-outcome relation for physicians and hospitals performing angioplasty for acute myocardial infarction in New York state. Circulation 2001;104:2171–2176. 12. Juliard JM, Himbert D, Golmard JL, Aubry P, Karrillon GJ, Boccara A, Benamer H, Steg PG. Can we provide reperfusion therapy to all unselected patients admitted with acute myocardial infarction? J Am Coll Cardiol 1997;30: 157–164. 13. Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P, et al. Thrombolysis In Myocardial Infarction (TIMI) trial, phase I : a comparison between intravenous plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987;76:142–154. 14. Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J, Simoons ML, Aylward P, Van de Werf F, Califf RM, for the GUSTO-I Investigators. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41 021 patients. Circulation 1995;91:1659 – 1668.
15. O’Keefe JH Jr, Bailey WL, Rutherford BD, Hartzler GO. Primary angioplasty for acute myocardial infarction in 1,000 consecutive patients. Results in an unselected population and high-risk subgroups. Am J Cardiol 1993;72:107G– 115G. 16. Berger PB, Ellis SG, Holmes DR, Granger CB, Griger DA, Betriu A, Topol EJ, Califf RM, for the GUSTO-II Investigators. Relationship between delay in performing direct coronary angioplasty and early clinical outcome in patients with acute myocardial infarction. Results from the Global Use of Strategies to Open Occluded Arteries In Acute Coronary Syndromes (GUSTO-IIb) Trial. Circulation 1999;100:14 –23. 17. Steg PG, Laperche T, Golmard JL, Juliard JM, Benamer H, Himbert D, Aubry P, for the PERM Study Group. Efficacy of streptokinase but not tissue-plasminogen activator in achieving 90-minute, patency after thrombolysis for acute myocardial infarction decreases with time to treatment. J Am Coll Cardiol 1998;31: 776 –779. 18. Newby LK, Rutsch WR, Califf RM, Simoons ML, Aylward TE, Armstrong PW, Woodlief LH, Lee KL, Topol EJ, Van de Werf F, for the GUSTO-I Investigators. Time from symptom onset to treatment and outcomes after thrombolytic therapy. J Am Coll Cardiol 1996;27:1646 –1655. 19. Reimer KA, Jennings RB. The “wavefront phenomenon” of myocardial ischemic cell death, II: transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest 1979;40:633–644. 20. Braunwald E. Myocardial reperfusion, limitation of infarct size, reduction of left ventricular dysfunction, and improved survival: should the paradigm be expanded. Circulation 1989;70:441–444. 21. McGrath PD, Wennberg DE, Malenka DJ, Kellett MA, Ryan TJ, O’Meara JR, Bradley WA, Hearne MJ, Hettleman B, Robb JF, et al, for the Northern New England Cardiovascular Disease Study Group. Operator volume and outcomes in 12,988 percutaneous coronary interventions. J Am Coll Cardiol 1998;31:570 – 576. 22. Tu JV, Austin PC, Chan BTB. Relationship between annual volume of patients treated by admitting physicians and mortality after acute myocardial infarction. JAMA 2001;285:3116 –3122. 23. Ryan TJ, Antman EM, Brooks NH, Califf RM, Hillis LD, Hiratzka LF, Rapaport EL, Riegel B, Russell RO, Smith EE III, Weaver DW. 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee on management of acute myocardial infarction). Circulation 1999;100:1016 –1030. 24. Meyer P, Barragan P, Blanchard D, Chevalier B, Commeau P, Danchin N, Fajadet J, Grand A, Lablanche JM, Machecourt J, et al. Recommandations de la Socie´ te´ Franc¸ aise de Cardiologie concernant la formation des me´ decins coronarographistes et angioplasticiens l’organisation et l’e´ quipement des centres de coronarographie et d’angioplastie coronaire. Arch Mal Cœur 2000;93:147–158.
CORONARY ARTERY DISEASE/MORTALITY DURING PTCA FOR AMI
1405
PhD,
For primary angioplasty of acute myocardial infarction (AMI), the relation of treatment benefit and time has been debated. The present study aimed to evaluate, in a single-center cohort of patients with ST-segment elevation AMI, which time intervals were carefully and consistently measured, and the relations among ischemic time, in-hospital delays, and in-hospital survival. We included 499 patients (mean age 59 years; 80% men) who underwent successful primary percutaneous transluminal coronary angioplasty (PTCA) for AMI admitted <6 hours after symptom onset. The population was divided into tertiles with respect to time between onset of symptoms and admission, onset of symptoms to Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow, and
time from admission to TIMI grade 3 flow. Univariate analysis followed by multiple logistic regression was performed using the variables linked to mortality in the univariate analysis to assess the relation between predictor variables and in-hospital mortality. The in-hospital mortality rate was 3.2%. There was no significant relation between the various tertiles of time intervals and in-hospital mortality. After linear logistic regression, only age (odds ratio [OR] 1.79 per 10 years), female gender (OR 3.56), and door-to-TIMI 3 time (OR 1.27 per 15 minutes) were independently correlated with in-hospital mortality. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;91:1401–1405)
here is solid evidence that in patients with STsegment elevation acute myocardial infarction T (AMI) who receive thrombolytic therapy, the benefit
studies of the relation between delays and survival have involved multicenter studies, their findings of the prognostic importance of a short in-hospital door-toballoon time has been interpreted to represent a surrogate of hospital performance or expertise, which would be expected to be higher in high-volume centers that are known to be associated with improved outcomes.10,11 The present study aimed to evaluate, in a single-center cohort of patients with acute ST-segment elevation AMI, which time intervals were carefully and consistently measured, and the relations among ischemic time, in-hospital delays, and in-hospital survival.
of treatment decreases with the delay between the onset of symptoms and the administration of lytic therapy.1 However, there is uncertainty as to whether this time dependency of treatment benefit also holds true when reperfusion is obtained by primary percutaneous transluminal coronary angioplasty (PTCA) rather than by pharmacologic means2,3; several studies have suggested that the door-to-balloon time was a better predictor of in-hospital survival than the total duration of ischemia (i.e., the delay between symptom onset and myocardial reperfusion, or at least the start of PTCA).4,5 Others have suggested that in the case of mechanical reperfusion of the myocardium by PTCA, the benefit is somewhat time independent.2,4 This is important because 1 of the main limitations of primary PTCA is the time needed for its implementation; the finding of time-independent benefits would argue for transfer of patients with AMI to PTCA centers, even if this results in reperfusion delays.6 –9 Because previous From the Cardiology Department, Hoˆpital Bichat; and INSERM U436, Hoˆpital Pitie´-Salpe´trie`re, AP-HP, Paris, France. Manuscript received December 30, 2002; revised manuscript received and accepted February 28, 2003. Address for reprints: Jean-Michel Juliard, MD, De´partement de Cardiologie, Hoˆpital Bichat, AP-HP, 46 rue Henri Huchard, 75877 Paris Cedex 18, France. E-mail: [email protected]. fr. ©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 June 15, 2003
METHODS
Study population: Between 1988 and January 2000, 1,200 patients were consecutively admitted to the coronary care unit with a diagnosis of ST-segment elevation AMI, within 6 hours of symptom onset. This cohort has been previously described.12 Of those 1,200 patients, 133 had no attempt at reperfusion therapy, 409 received intravenous thrombolysis, and the remaining 658 were triaged to emergency PTCA. From these 658 patients, we excluded 60 admitted with cardiogenic shock, 28 patients who had a spontaneously patent infarct vessel with Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow, and 71 patients in whom PTCA failed to achieve successful TIMI 3 flow in the infarct-related vessel. Therefore, 499 patients underwent successful primary PTCA 0002-9149/03/$–see front matter doi:10.1016/S0002-9149(03)00388-6
1401
TABLE 1 Clinical Characteristics Survivors (n ⫽ 483) Age (yrs) Men Current smoker Total cholesterol ⱖ220 mg/dl Systemic hypertension Family history of coronary artery disease Diabetes mellitus Anterior wall AMI Contraindication to thrombolysis Prior bypass surgery Prior PTCA Previous AMI Time from pain to admission (min)
58 392 333 197 161 158 53 225 174 11 31 52 180
⫾ 13 (81%) (69%) (41%) (33%) (32%) (11%) (47%) (36%) (2%) (6%) (11%) ⫾ 84
Data are presented as mean ⫾ SD or number (%) of patients.
Statistical analysis: Chest pain-todoor time was defined as the delay Nonsurvivors between the onset of symptoms and (n ⫽ 16) p Value admission to the catheterization laboratory. Door-to-TIMI 3 time was 72 ⫾ 16 0.001 7 (44%) 0.0008 defined by the delay between admis4 (25%) 0.0006 sion and final TIMI grade 3 flow in 2 (12%) 0.04 the infarct-related artery. Chest pain8 (50%) 0.26 to-TIMI 3 time was defined as the 2 (12%) 0.15 3 (19%) 0.77 sum of the 2 previous intervals. TIMI 10 (62%) 0.32 flow grade was assessed according to 8 (50%) 0.38 the TIMI scoring system.13 All con0 — tinuous variables are expressed as 0 — mean ⫾ SD. 0 — 186 ⫾ 93 NS In a first approach, the population was divided into tertiles with respect to time between onset of symptoms and admission, onset of symptoms to TIMI grade 3 flow, and admission to TIMI grade 3 flow. The goal was to evaluate the relation between each subset of patients and the 3 previous intervals. Univariate analysis, using chi-square and Student’s t tests, was performed first to determine the factors associated with in-hospital mortality. Variables examined included age, gender, risk factors for coronary artery disease, medical history and cardiovascular events, type of infarction, presence of a contraindication to thrombolysis, angiographic findings, ventricular arrhythmias, stent placement, use of glycoprotein IIb/IIIa blockers, and the various time intervals. Multiple logistic regression was then performed using the variables linked to mortality in the univariate analysis (p ⬍0.05 was considered significant), to assess the relation between predictor variables and in-hospital mortality. All analyses were performed using SAS (SAS Institute, Cary, North Carolina).
FIGURE 1. In-hospital mortality in patients reperfused during the first hour (included) and those strictly reperfused beyond the first hour after admission.
(i.e., final TIMI flow grade of 3 and residual stenosis ⬍50%). Most of the patients were admitted directly to the catheterization laboratory after prehospital triage, and for those admitted first in the coronary care unit, the transfer time was very short, as our catheterization laboratory is located within the coronary care unit. Treatment protocol: Angioplasty was performed according to standard protocols. All patients received ⱖ250 mg of aspirin on admission and a bolus of 5,000 IU of unfractionated heparin before insertion of the arterial sheath, usually followed by an infusion adjusted to an activated partial thromboplastin time of 2 to 3 times control levels for 48 hours. Beta-adrenergic blocking agents were used first intravenously then orally, unless contraindicated. Stent placement and use of glycoprotein IIb/IIIa blockers were left to the discretion of the operator. All patients who had stents placement received ticlopidine or clopidogrel for ⱖ1 month. 1402 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 91
RESULTS
Clinical characteristics: The patients’ characteristics are listed in Table 1. The average delay between pain and admission was 181 ⫾ 84 minutes (median 180). Infarct location was anterior in 235 patients (47%). Four percent of patients (n ⫽ 21) had had cardiac arrest before admission that was successfully treated with electrical cardioversion. Coronary angioplasty outcome: At baseline angiography, 487 of the 499 patients undergoing PTCA had TIMI 0 to 1 grade flow and 12 had TIMI grade 2 flow in the infarct-related artery. Stents were placed in 36% of the patients, and all patients achieved TIMI grade 3 flow at an average 234 ⫾ 91 minutes (median 215) after pain onset and 54 ⫾ 28 minutes (median 45) after admission to the coronary care unit. Abciximab (bolus plus infusion) was used in 9% of the patients. Finally, 12 patients underwent electrical cardioversion for ventricular fibrillation, which occurred in the catheterization laboratory or immediately after recanalization of the infarct vessel. Clinical outcome and mortality: The in-hospital mortality rate was 3.2% (n ⫽ 16) but it was 1.8% for patients (9 of 394) recanalized within 60 minutes of JUNE 15, 2003
FIGURE 2. Relation between tertiles of time from symptom onset to admission and in-hospital mortality.
FIGURE 4. Relation between tertiles of time from admission to TIMI grade 3 flow and in-hospital mortality.
TABLE 2 Multivariate Risk Factors for In-hospital Mortality Variable Women Age (per 10 yrs) Door-to-TIMI 3 (per 15 min)
OR
95% CI
p Value
3.56 1.79 1.27
1.17–10.86 1.16–2.77 1.06–1.52
0.03 0.009 0.01
CI ⫽ confidence interval.
FIGURE 3. Relation between tertiles of time from symptom onset to TIMI grade 3 flow and in-hospital mortality.
admission, versus 6.7% for patients (7 of 105) recanalized later (p ⱕ0.05) (Figure 1). All deaths were related to left ventricular failure or mechanical complications, except for 1 fatal hemorrhagic stroke and 1 sudden death.
FIGURE 5. Relation between door-to-TIMI grade 3 flow and inhospital mortality. Each unit on the x-axis corresponds to 15minute delay from admission.
Relation between subset of patients and time intervals: There was no relation between tertiles of time
between pain onset and admission and in-hospital mortality (Figure 2). There was a nonsignificant trend toward a higher mortality in relation to the total duration of ischemia (i.e., the time elapse between symptom onset and establishment of TIMI 3 flow) (Figure 3), which was also not significant using the multivariate model. Finally, the relation between time from door to TIMI 3 flow and in-hospital mortality appeared dichotomous with low mortality when the delay was ⬍60 minutes; higher in-hospital mortality was seen when the delay was ⬎60 minutes (Figures 1 and 4). Prognostic factors of in-hospital mortality: Using univariate analysis, the following factors were correlated with in-hospital mortality: age, female gender, lack of smoking history, lack of dyslipidemia, and door-to-TIMI 3 time. After linear logistic regression, only age (odd ratio [OR] 1.79 per 10 years, p ⫽ 0.009), female gender (OR 3.56, p ⫽ 0.03), and doorto-TIMI 3 time (OR 1.27 per 15 minutes, p ⫽ 0.01) were independently correlated with in-hospital mortality (Table 2). A time threshold of 60 minutes was identified; at ⬎60 minutes, mortality significantly increased (Figure 1). After admission, the odds of death
increased 1.27 times per 15 minutes until TIMI 3 flow was achieved (Figure 5).
DISCUSSION Age and female gender are established independent risk factors for early mortality after AMI.14 In the reperfusion era, in which primary PTCA has been increasingly used, it is also important to account for the impact of treatment delays.15 The present study underlines the importance of a short delay between admission and TIMI 3 flow; there is an increase in mortality when TIMI 3 flow is achieved beyond the first hour after admission. Conversely, if TIMI 3 flow is established earlier, in-hospital mortality is very low. Our findings provide independent confirmation of the GUSTO-IIb analysis of time delays in patients treated with primary PTCA; we observed an OR for in-hospital mortality of 1.27 per 15 minutes increase, similar to the OR of 1.6 per 25 minutes in the Global Use of Strategies to Open Occluded Arteries in Actue Coronary Syndromes (GUSTO)-IIb trial.16 Nevertheless, it must be pointed out that the low mortality rate is a
CORONARY ARTERY DISEASE/MORTALITY DURING PTCA FOR AMI
1403
major limitation in the understanding of the statistical analyses. Chest pain-to-TIMI 3 time: Using the model in the 3 subsets, we observed a continuous but nonsignificant trend of higher mortality when chest pain-to-TIMI 3 time increased (Figure 3). Stratifying their population into 2 groups, O’Keefe et al15 showed that early mortality was lower with reperfusion time from pain to reperfusion of ⬍2 hours, and relatively time-independent in patients with reperfusion time ⱖ2 hours. However, the rate of patients successfully treated with primary PTCA within 2 hours after onset of pain remains extremely low; it was only 12% in the cohort of Brodie et al.4 Even in the large cohort of the second National Registry of Myocardial Infarction,2 the adjusted OR of in-hospital mortality did not increase significantly with increasing delay from AMI symptom onset to first balloon inflation (median time 3.9 hours). These results are in contrast with those from thrombolytic trials in which mortality increased with time from pain to treatment. There are several explanations for this discrepancy between lytic therapy and primary PTCA in terms of impact of the total ischemic time. First, the efficacy of primary PTCA to recanalize the infarct-related artery appears to be time independent, whereas this is not the case with lytic therapy, at least with nonfibrin-specific agents.13,17 Even with fibrin-specific agents such as recombinant tissue-type plasminogen activator, angiographic data from the GUSTO trial showed a trend towards a smaller TIMI 3 flow rate with increasing time to lytic therapy (63% at ⬍2 hours, 54% from 2 to 4 hours, and 50% from 4 to 6 hours).18 In addition, the benefit from reperfusion therapy may be the net result of an early “infarctlimiting” effect, confined to the first 2 hours19 and the “open-artery” effect, which is related to recanalization of the infarct-related vessel, independent from myocardial salvage, and therefore, less time sensitive.20 Animal studies suggest that infarct size limitation can only be achieved very early after ischemia. Thrombolytic therapy is more likely to be given in time to achieve such benefit, within the first 2 hours after symptom onset, whereas it is generally rare that primary PTCA can be performed in this time window after symptom onset. In our study, time from pain to reperfusion was on an average 234 ⫾ 91 minutes (median 215), and ⬍2 hours in only 10% of the patients, which explains the lack of correlation with mortality because most patients were reperfused after 2 hours from symptom onset. In the future, even with technology advances, it will be difficult to increase the number of patients treated within the first 2 hours after chest pain onset due to logistic issues. Door-to-TIMI 3 time: Door-to-TIMI grade 3 flow or door-to-balloon time have been adopted as a measure of quality of care for patients treated with primary PTCA during AMI. This delay is clearly influenced by institutional volume and a higher volume being associated with better outcomes.11,21,22 In the American College of Cardiology/American Heart Association guidelines, a door-to-balloon time of ⬍2 hours after 1404 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 91
admission is required for performing primary PTCA.23 The strong relation, even after adjustment for baseline differences, between door-to-TIMI 3 time and short-term mortality, has been interpreted as a surrogate of in-hospital volume and expertise.2– 4 Inhospital volume has been correlated, at least in highrisk patients subsets such as the elderly, to lower mortality.3,10 However, in the present single-center study, this relation between door-to-TIMI 3 time and mortality persists. This suggests that door-to-TIMI 3 time is not simply a surrogate marker of center expertise or quality of care, because these results were obtained in a single center cohort. In the second National Registry of Myocardial Infarction cohort of 27,080 patients treated with primary PTCA, the median door-to-balloon time was 116 minutes, and the odds of short-term mortality increased by 41% for patients with door-to-balloon time of ⬎2 hours and increased 62% for delays of ⬎3 hours.2 Only 8% of patients had a door-to-balloon time of ⱕ60 minutes, with a mortality of 1%. This small reference group is a major shortcoming of this previous study compared with the strength of tertile analysis using groups with a substantial number of patients, and the fact that 75% of patients were successfully treated within 60 minutes. This short delay at our institution has several explanations: most patients were referred to the catheterization laboratory for primary PTCA by mobile intensive care units that are staffed by physicians, and the decision of primary PTCA was most often taken in agreement with the physician in the mobile care unit. Only a small proportion of patients (⬍10%) were transferred in from other hospitals, and most patients were admitted directly into the catheterization laboratory (located within the coronary care unit), bypassing the emergency room. Finally, at night, the catheterization laboratory is staffed by the local coronary care unit nurses team, avoiding calls to outside nurses. This strategy has been adopted in our institution since 1988, with a volume operator of ⬎100 elective PTCAs/year per physician (and ⬎25 myocardial infarction cases annually), and our results are consistent with the guidelines of the French Society of Cardiology, which require a maximal delay of 60 minutes from the admission to the achievement of successful mechanical reperfusion.24 Acknowledgment: We are indebted to the catheterization team and to the nurses of the coronary care unit for their participation in round-the-clock catheterization effort.
1. Fibrinolytic Therapy Trialist’s Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet 1994;343:311–322. 2. Cannon CP, Gibson CM, Lambrew CT, Shoultz DA, Levy D, French WJ, Gore JM, Weaver WD, Rogers WJ, Tiefenbrunn AJ. Relationship of symptom-onsetto-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000;283:2941–2947. 3. Berger PB, Bell MR, Holmes DR, Gersh BJ, Hopfenspirger M, Gibbons R. Time to reperfusion with direct coronary angioplasty and thrombolytic therapy in acute myocardial infarction. Am J Cardiol 1994;73:231–236. 4. Brodie BR, Stuckey TD, Wall TC, Kissling G, Hansen CJ, Muncy DB,
JUNE 15, 2003
Weintraub RA, Kelly TA. Importance of time to reperfusion for 30-day and late survival and recovery of left ventricular function after primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 1998;32:1312–1319. 5. Ward MR, Lo ST, Herity NA, Lee DP, Yeung AC. Effect of audit on door-to-inflation times in primary angioplasty/stenting for acute myocardial infarction. Am J Cardiol 2001;87:336 –338. 6. Ferguson JJ. DANAMI II Danish Multicenter Randomized Study on Thrombolytic Therapy Versus Acute Coronary Angioplasty in Acute Myocardial Infarction-2. Meeting Highlights. Highlights of the 51st Annual Scientific Sessions of the American College of Cardiology. Circulation 2002;106:e24. 7. Grines CL, Westerhausen DR, Grines LL, Hanlon JT, Logemann TL, Niemela M, Weaver WD, Graham M, Boura J, O’Neill WW, Balestrini C, for the AIR PAMI Study Group. A randomized trial of transfer for primary angioplasty versus on-site thrombolysis in patients with high-risk myocardial infarction. The Air Primary Angioplasty in Myocardial Infarction Study. J Am Coll Cardiol 2002; 39:1713–1719. 8. Aversano T, Aversano LT, Passamani E, Knatterud GL, Terrin ML, Williams DO, Foreman SA, for the Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT). Thrombolytic therapy vs primary percutaneous coronary intervention for myocardial intervention for myocardial infarction in patients presenting to hospitals without on-site cardiac surgery. A randomized controlled trial. JAMA 2002;287:1943–1951. 9. Widimsky P, Groch L, Zelizko M, Aschermann M, Bednar S, Suryapranata H, on behalf of the PRAGUE Study Group Investigators. Multicenter randomized trial comparing transport to primary angioplasty versus immediate thrombolysis versus combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory. Eur Heart J 2002;21:823–831. 10. Thiemann DR, Coresh J, Oetgen WJ, Powe NR. The association between hospital volume and survival after acute myocardial infarction in elderly patients. N Engl J Med 1999;340:1640 –1648. 11. Vakili BA, Kaplan R, Brown DL. Volume-outcome relation for physicians and hospitals performing angioplasty for acute myocardial infarction in New York state. Circulation 2001;104:2171–2176. 12. Juliard JM, Himbert D, Golmard JL, Aubry P, Karrillon GJ, Boccara A, Benamer H, Steg PG. Can we provide reperfusion therapy to all unselected patients admitted with acute myocardial infarction? J Am Coll Cardiol 1997;30: 157–164. 13. Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P, et al. Thrombolysis In Myocardial Infarction (TIMI) trial, phase I : a comparison between intravenous plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987;76:142–154. 14. Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J, Simoons ML, Aylward P, Van de Werf F, Califf RM, for the GUSTO-I Investigators. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41 021 patients. Circulation 1995;91:1659 – 1668.
15. O’Keefe JH Jr, Bailey WL, Rutherford BD, Hartzler GO. Primary angioplasty for acute myocardial infarction in 1,000 consecutive patients. Results in an unselected population and high-risk subgroups. Am J Cardiol 1993;72:107G– 115G. 16. Berger PB, Ellis SG, Holmes DR, Granger CB, Griger DA, Betriu A, Topol EJ, Califf RM, for the GUSTO-II Investigators. Relationship between delay in performing direct coronary angioplasty and early clinical outcome in patients with acute myocardial infarction. Results from the Global Use of Strategies to Open Occluded Arteries In Acute Coronary Syndromes (GUSTO-IIb) Trial. Circulation 1999;100:14 –23. 17. Steg PG, Laperche T, Golmard JL, Juliard JM, Benamer H, Himbert D, Aubry P, for the PERM Study Group. Efficacy of streptokinase but not tissue-plasminogen activator in achieving 90-minute, patency after thrombolysis for acute myocardial infarction decreases with time to treatment. J Am Coll Cardiol 1998;31: 776 –779. 18. Newby LK, Rutsch WR, Califf RM, Simoons ML, Aylward TE, Armstrong PW, Woodlief LH, Lee KL, Topol EJ, Van de Werf F, for the GUSTO-I Investigators. Time from symptom onset to treatment and outcomes after thrombolytic therapy. J Am Coll Cardiol 1996;27:1646 –1655. 19. Reimer KA, Jennings RB. The “wavefront phenomenon” of myocardial ischemic cell death, II: transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest 1979;40:633–644. 20. Braunwald E. Myocardial reperfusion, limitation of infarct size, reduction of left ventricular dysfunction, and improved survival: should the paradigm be expanded. Circulation 1989;70:441–444. 21. McGrath PD, Wennberg DE, Malenka DJ, Kellett MA, Ryan TJ, O’Meara JR, Bradley WA, Hearne MJ, Hettleman B, Robb JF, et al, for the Northern New England Cardiovascular Disease Study Group. Operator volume and outcomes in 12,988 percutaneous coronary interventions. J Am Coll Cardiol 1998;31:570 – 576. 22. Tu JV, Austin PC, Chan BTB. Relationship between annual volume of patients treated by admitting physicians and mortality after acute myocardial infarction. JAMA 2001;285:3116 –3122. 23. Ryan TJ, Antman EM, Brooks NH, Califf RM, Hillis LD, Hiratzka LF, Rapaport EL, Riegel B, Russell RO, Smith EE III, Weaver DW. 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee on management of acute myocardial infarction). Circulation 1999;100:1016 –1030. 24. Meyer P, Barragan P, Blanchard D, Chevalier B, Commeau P, Danchin N, Fajadet J, Grand A, Lablanche JM, Machecourt J, et al. Recommandations de la Socie´ te´ Franc¸ aise de Cardiologie concernant la formation des me´ decins coronarographistes et angioplasticiens l’organisation et l’e´ quipement des centres de coronarographie et d’angioplastie coronaire. Arch Mal Cœur 2000;93:147–158.
CORONARY ARTERY DISEASE/MORTALITY DURING PTCA FOR AMI
1405