Duration of Symptoms Is Not Always the Key Modulator of the Choice of Reperfusion for ST-Elevation Myocardial Infarction

Abstract

HomeCirculationVol. 119, No. 9Duration of Symptoms Is Not Always the Key Modulator of the Choice of Reperfusion for ST-Elevation Myocardial Infarction Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBDuration of Symptoms Is Not Always the Key Modulator of the Choice of Reperfusion for ST-Elevation Myocardial Infarction Peter Bogaty, MD Peter BogatyPeter Bogaty From the Quebec Heart Institute/Laval Hospital, Laval University, Quebec City, Quebec, Canada. Search for more papers by this author Originally published10 Mar 2009https://doi.org/10.1161/CIRCULATIONAHA.107.750679Circulation. 2009;119:1304–1310Fibrinolytic therapy (FT) and primary percutaneous coronary intervention (PCI) are both well-accepted reperfusion therapies in ST-segment elevation myocardial infarction (STEMI). The evidence of randomized clinical trials indicates a relatively modest difference in 30-day mortality (≈1%) in favor of primary PCI over fibrin-specific FT and was based on very timely primary PCI (ie, a primary PCI–related delay of 40 minutes [door-to-balloon less door-to-needle time]).1 Longer delays to primary PCI, which are far more frequent in clinical practice,2 are associated with attenuated benefit or no benefit at all, particularly when compared with fibrin-specific FT.3,4 The benefit of timely primary PCI over FT is likely to especially apply to higher-risk patients.5,6 Irrespective of the method of reperfusion, the potential for myocardial salvage and better clinical outcome is inversely proportional to ischemic time or its only available clinical surrogate, symptom duration.7–12 These considerations underpin the notion expressed in the American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the treatment of STEMI that timely reperfusion therapy is likely more important in determining outcome than whether FT or primary PCI is the chosen reperfusion method.13Response by Armstrong et al p 1310The ACC/AHA STEMI guidelines highlight the time point of 3 hours of symptom duration in guiding the choice of reperfusion therapy. They state that if symptom duration is <3 hours, no preference exists between FT and primary PCI provided that treatment is timely (for FT, door-to-needle time <30 minutes; for primary PCI, door-to-balloon time <90 minutes and ≤60 minutes between estimated needle time and estimated balloon time). However, if symptom duration exceeds 3 hours, these guidelines favor primary PCI over FT, again provided that primary PCI can be performed in a timely fashion.13 This article reexamines the evidence that may or may not be the basis for orienting the choice of reperfusion therapy in patients with STEMI according to symptom duration. It is emphasized that this work is not intended to reopen a primary PCI versus FT, “1 size fits all” debate. It rather addresses the question of the extent to which the evidence suggests that symptom duration should modulate the choice of reperfusion therapy.Within the “Golden Hour”Within the “golden hour” for reperfusion (symptom duration <2 hours, ideally <1 hour), the slope of the relation between ischemic time and outcome is extremely steep.8 Both experimentally and clinically, in this critical time frame, a small increment (or decrement) of time to treatment may have dramatic consequences on the quantity of irreversibly damaged myocardium and on clinical outcome.7,8 A substantial proportion of patients who receive reperfusion therapy within this period may actually “abort” their impending myocardial infarction.14 This appears to be more likely with prompt FT than with primary PCI because the latter would necessarily prolong ischemic time at least 30 to 60 minutes more (and often orders of magnitude longer in the real world)2 than the time to FT, substantially augmenting the probability of necrosis and its extent. The better clinical outcomes with FT in the Comparison of Angioplasty and Prehospital Thrombolysis In acute Myocardial infarction (CAPTIM) study in patients with ischemic times <2 hours are consistent with these premises (Figure 1).15 Thus, notwithstanding the notion of equipoise between FT and primary PCI expressed in the ACC/AHA guidelines when symptom duration is <3 hours, data suggest the potential for greater clinical benefit with rapid FT within the first 2 hours of symptom duration, especially in the real world, where door-to-balloon times, particularly for transferred patients, substantially exceed those in the randomized clinical trials.2 The proportion of patients affected by this consideration is substantial; in the National Registry of Myocardial Infarction of nearly 200 000 patients with STEMI, 65% presented within 2 hours of symptom onset.16Download figureDownload PowerPointFigure 1. Prehospital lysis versus primary PCI for STEMI: impact of ischemic symptom time in the CAPTIM study. Adapted from Steg et al15 with permission of the publisher. Copyright © 2003, the American Heart Association.Beyond 3 HoursThe notion that primary PCI should be favored when symptom duration exceeds 3 hours has had the important consequence of leading clinicians, particularly in centers that must transfer patients for primary PCI, to integrate this recommendation into their decisional algorithm. The proportion of patients implicated by an application of this principle is not negligible; in large series of patients receiving reperfusion therapy for STEMI, it has varied from 34% to 66%.17,18It is postulated that longer symptom duration results in older, firmer occlusive fibrin clots more resistant to FT, whereas this would not be a limitation for occlusive clots submitted to the mechanical intervention of angioplasty. What is the strength of the evidence that older clots are more resistant to fibrinolysis?In the Thrombolysis in Myocardial Infarction (TIMI)-1 clinical trial, although patients treated with streptokinase showed a decrease in coronary artery patency (TIMI 2 or 3 flow) from 44% in the 41 patients treated before 4 hours to 24% in the 78 patients treated after 4 hours, no difference was found in coronary artery patency in patients treated with tissue-type plasminogen activator (tPA) within (41 patients) or after 4 hours (72 patients).19 Similarly, in a retrospective analysis of 2 French studies of coronary artery patency in patients receiving FT, Steg et al20 found that when streptokinase was used (244 patients), the achievement of normal flow (TIMI 3) and TIMI 2/3 flow decreased with longer symptom duration (<3 versus ≥3 hours), whereas with tPA (237 patients), coronary artery TIMI flows 3 and 2/3 remained stable regardless of symptom duration.20 This distinction was reinforced by Zeymer et al21 in a retrospective analysis of 6 other angiographic trials in 1111 patients with STEMI treated with FT that examined TIMI flow relative to symptom duration that was dichotomized between 0 to 180 minutes and 181 to 360 minutes (Table). They found that the non–fibrin-specific agents streptokinase, urokinase, and anisoylated plasminogen-streptokinase activator complex achieved significantly less TIMI 3 and TIMI 2/3 flow with longer symptom duration. However, the fibrin-specific agent tPA administered over 3 hours or in accelerated mode and the bolus fibrin-specific agent reteplase did not show a decrease in TIMI 2/3 and TIMI 3 flow when symptom duration was 181 to 360 minutes compared with 0 to 180 minutes.21 Thus, the data strongly suggest that at up to 6 hours of symptom duration, although nonspecific fibrinolytics like streptokinase are less effective in achieving coronary artery patency and normal flow with increasing ischemic time, this limitation does not extend to the fibrin-specific fibrinolytics. Some in vitro data exist consistent with these observations that could be explained by less effective penetration of older clots by non–fibrin-specific fibrinolytic drugs.21,22Table. Effect of Lytic Agent and Symptom Time on TIMI Grade 2 to 3 Flow at 90 Minutes21Substance and Flow0–180 Minutes181–360 MinutesPAPSAC indicates anisoylated plasminogen-streptokinase activator complex.APSAC Patients, n15646 TIMI 2 or 3, n (%)114 (75.1)38 (60.9)0.09 TIMI 3, n (%)95 (59.5)16 (34.8)0.004Streptokinase Patients, n13376 TIMI 2 or 3, n (%)85 (63.9)39 (51.3)0.1 TIMI 3, n (%)49 (36.8)21 (27.6)0.09Urokinase Patients, n6948 TIMI 2 or 3, n (%)48 (69.5)29 (60.5)0.1 TIMI 3, n (%)43 (62.5)20 (41.7)0.03Standard recombinant tPA Patients, n7249 TIMI 2 or 3, n (%)46 (63.9)38 (77.5)0.15 TIMI 3, n (%)35 (48.6)32 (63.5)0.09Front-loaded recombinant tPA Patients, n19086 TIMI 2 or 3, n (%)165 (84.8)75 (84.8)NS TIMI 3, n (%)138 (72.5)66 (76.3)NSReteplase Patients, n11868 TIMI 2 or 3, n (%)90 (76.2)52 (76.4)NS TIMI 3, n (%)75 (63.6)43 (63.2)NSA mechanistic study examined the relationship between myocardial salvage and symptom time with the use of Tc-99m sestamibi scintigraphy in patients with STEMI treated with stenting versus FT with tPA.23 It found that although infarct size expectedly increased in the cohort treated with FT with each increasing tertile of symptom duration, infarct size appeared unaffected by symptom duration in the cohort treated with stenting. Thus, the relative benefit of stenting versus FT in terms of myocardial salvage widened with increasing symptom duration before treatment. On intuitive grounds, it is difficult to understand why the experimentally well-established time dependence of the wave front of necrosis would apply in the FT cohort but would be suspended in an ischemic myocardium faced with an impending stenting intervention.24,25 The apparent constancy of infarct size independent of ischemic time when stenting was used suggests that other factors, such as clinical differences of the patients in the tertiles of symptom duration examined or limitations of the measuring technique (lack of adequate spatial resolution with single-photon emission computed tomography for degree of transmurality),26 may have intervened in the determination of infarct size in the stenting cohort. In support of this, clinical studies have confirmed that, just as with FT, mortality with primary PCI is indeed ischemic time dependent.9,18 Therefore, this mechanistic study appears to be too slender a rationale for triaging patients with longer symptom duration to primary PCI on the assumption that ischemic time does not affect infarct size in patients to be treated with primary PCI.How compelling is the clinical evidence favoring primary PCI over FT when symptom duration exceeds 3 hours? Registry data suggest that with increasing symptom duration, survival outcomes are better with primary PCI than with FT.16,27 Such data may be problematic, however, not only because of the nonrandomized nature of the data but also because either only primary PCI actually performed was considered16,28 or it was unspecified whether it was or not.27 Thus, patients who had long ischemic times and were directed to primary PCI but either did not survive until primary PCI or did not have a completed, generally successful procedure might not have been tallied in the primary PCI arm as they would otherwise have been in the “intention-to-treat” approach that is used in properly conducted randomized clinical trials that compare all patients directed to one or the other reperfusion strategy. On the other hand, patients undergoing fibrinolysis were counted whether or not outcome was favorable. The counting of only completed cases in the primary PCI arm may lead to bias that risks distorting the comparative relationship between symptom duration and outcome in the primary PCI and FT arms.When one turns to the randomized clinical trials, the problem is that none of these trials randomized patients by concomitantly stratifying by symptom duration. Thus, the only means possible to gain insight in this question is to examine post hoc the subgroup analyses of the randomized clinical trials that compared FT with primary PCI by strata of symptom duration time. Thus, the finding of a gradient of increasing relative benefit of primary PCI over FT with increasing symptom duration would be compatible with a greater relative efficacy of primary PCI over FT with increasing ischemic time. The largest single randomized trial that evaluated streptokinase versus primary PCI was the PRimary Angioplasty in patients transferred from General community hospitals to specialized PTCA Units with or without Emergency thrombolysis–2 (PRAGUE-2) trial (850 patients).29 For patients randomized <3 hours from symptom onset, mortality was similar between streptokinase and primary PCI (7.4% and 7.3%, respectively); however, for patients randomized after 3 hours, mortality was 15.3% with streptokinase versus 6.0% for primary angioplasty (P<0.02) (Figure 2). These findings are consistent with a relative loss of fibrinolytic efficacy for streptokinase with longer ischemic time and are supported by the in vitro and angiographic data discussed previously. However, when the large randomized trials that compared accelerated tPA with primary PCI are examined, a different picture is suggested. There appears to be no gradient of increasing relative benefit in terms of mortality reduction for primary PCI over tPA as symptom duration increased in the Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) study or for the primary composite end point of death, reinfarction, or disabling stroke in the Danish Multicenter Randomized Study on Fibrinolytic Therapy Versus Acute Coronary Angioplasty in Acute Myocardial Infarction–2 (DANAMI-2) study (Figure 3).30,31 In the latter study, the benefit of primary PCI over FT at all strata of symptom duration was essentially driven by the reinfarction end point; however, this should be tempered by the fact that <2% of patients treated with FT in DANAMI-2 had rescue angioplasty, that different definitions of reinfarction were applied in the 2 reperfusion arms, and that thienopyridines, known to reduce reinfarction and recurrent ischemia,32,33 were systematically given to patients who had primary PCI and not to those treated with FT. In the CAPTIM study, although the data are compatible with a mortality benefit of tPA over primary PCI for symptom duration <2 hours, no conclusion can be drawn for ischemic time exceeding 2 hours (Figure 1).15 Thus, these data from the 3 largest trials comparing tPA with primary PCI are consistent with the in vitro and angiographic TIMI flow data suggesting that fibrin-specific agents are as effective within the 3- to 6-hour symptom duration window as within the 0- to 3-hour window. Download figureDownload PowerPointFigure 2. Thirty-day mortality in the PRAGUE-2 study of patients (Pts) with STEMI treated with thrombolysis with streptokinase compared with primary PCI. Adapted from Widimsky et al29 with permission of the publisher. Copyright © 2003, Oxford University Press.Download figureDownload PowerPointFigure 3. Absence of increasing gradient of benefit for primary angioplasty over fibrinolysis with the use of tPA with increasing duration of symptoms. Reproduced from the GUSTO-IIb Angioplasty Substudy Investigators30 and Andersen et al31 with permission of the publisher. Copyright © 1997 and 2003, the Massachusetts Medical Society.On the other hand, in a subgroup overview of the randomized trials that compared accelerated tPA with primary PCI and that dichotomized between presentation delays (ie, time from symptom onset to randomization) of >2 versus <2 hours, Boersma18 found that the mortality benefit of primary PCI was confined to the subgroup with >2 hours of presentation delay (odds ratio, 0.72; 95% confidence interval, 0.54 to 0.95). However, an examination of the data from this same publication, showing odds ratios (and 95% confidence intervals) by strata of presentation delay adjusted for patient, hospital, and study level covariates suggests no gradient of increasing relative benefit in favor of primary PCI over tPA, with increasing presentation delay out to 12 hours (Figure 4).18 A limitation of the latter data is that it excludes the robust contingent of the CAPTIM study, a majority of whose patients had <2 hours of symptom duration until treatment. It must also be emphasized that in all of these subgroup analyses, although a time-dependent treatment effect is not suggested, it cannot be excluded, given the width of the confidence intervals. Download figureDownload PowerPointFigure 4. Meta-analysis of adjusted 30-day mortality of primary PCI (PPCI) and fibrinolysis (FL) with accelerated tPA according to presentation delay. Reprinted with permission of the publisher from Boersma et al.18 Copyright © 2006, Oxford University Press.Clinical ImplicationsTherefore, if the fibrinolytic agent used is accelerated tPA or 1 of the fibrin-specific bolus agents, available evidence does not appear compelling in favor of an approach triaging to primary PCI based on symptom duration. The ACC/AHA STEMI guidelines that recommend favoring primary PCI over FT if symptom duration exceeds 3 hours do not appear supported by the available data if fibrin-specific FT is to be used. In the latter context, longer symptom duration should not be grounds for selecting one reperfusion option over another. Factors that should affect the choice of therapy are the timeliness of the 2 options (with, for example, more consideration in favor of primary PCI if delay to balloon time relative to immediate FT is more toward 30 minutes rather than 60 minutes),4 the relative risk of bleeding with both options, and the level of risk of the STEMI with a preference for timely primary PCI in very-high-risk patients such as those in Killip class 3/4.13,34Importantly, beyond consideration of the relative efficacies of FT and primary PCI in “opening up” acutely occluded coronary arteries, studies also suggest that longer ischemic times lessen the chances for successful myocardial reperfusion, as evaluated by ST-segment resolution or myocardial blush grade, whether the method of reperfusion is FT or primary PCI.9,35–38 Thus, late reperfusion therapy, whatever the reperfusion method, adds, to the irreversible injury of an expanded wave front of myocardial necrosis, the insult of an increased likelihood of less successful myocardial reperfusion, even if coronary artery opening and TIMI 3 flow are achieved. This “double jeopardy” of longer ischemic time reinforces the need for ischemic time to be as short as possible.ConclusionShould symptom duration intervene in the choice of which reperfusion therapy to give to patients with STEMI? In the golden hour, when symptom duration is within 1 to 2 hours, prompt FT may provide clinical benefit compared with primary PCI and should be considered as a potentially preferable option. Beyond this critical time window, provided that the fibrinolytic drug considered for use is fibrin specific, the available data suggest that symptom duration need not guide the choice of reperfusion therapy.I am grateful to Dr Gilles R. Dagenais for critical review of this work and to Luce Boyer for expert technical support.DisclosuresNone.FootnotesCorrespondence to Peter Bogaty, MD, Quebec Heart Institute/Laval Hospital, 2725 Chemin Ste-Foy, Quebec, Canada G1V 4G5. E-mail [email protected] References 1 Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003; 361: 13–20.CrossrefMedlineGoogle Scholar2 Nallamothu BK, Bates ER, Herrin J, Wang Y, Bradley EH, Krumholz HM. Times to treatment in transfer patients undergoing primary percutaneous coronary intervention in the United States: National Registry of Myocardial Infarction (NRMI)-3/4 analysis. Circulation. 2005; 111: 761–767.LinkGoogle Scholar3 Nallamothu BK, Bates ER. Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: is timing (almost) everything? Am J Cardiol. 2003; 92: 824–826.CrossrefMedlineGoogle Scholar4 Nallamothu BK, Antman EM, Bates ER. Primary percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: does the choice of fibrinolytic agent impact on the importance of time-to-treatment? Am J Cardiol. 2004; 94: 772–774.CrossrefMedlineGoogle Scholar5 Thune JJ, Hoefsten DE, Lindholm MG, Mortensen LS, Andersen HR, Nielsen TT, Kober L, Kelbaek H. Simple risk stratification at admission to identify patients with reduced mortality from primary angioplasty. Circulation. 2005; 112: 2017–2021.LinkGoogle Scholar6 Tarantini G, Razzolini R, Ramondo A, Napodano M, Bilato C, Iliceto S. Explanation for the survival benefit of primary angioplasty over thrombolytic therapy in patients with ST-elevation acute myocardial infarction. Am J Cardiol. 2005; 96: 1503–1505.CrossrefMedlineGoogle Scholar7 Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront phenomenon of ischemic cell death, 1: myocardial infarct size vs duration of coronary occlusion in dogs. Circulation. 1977; 56: 786–794.CrossrefMedlineGoogle Scholar8 Boersma E, Maas AC, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet. 1996; 348: 771–775.CrossrefMedlineGoogle Scholar9 De Luca G, Suryapranata H, Ottervanger JP, Antman EM. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: every minute of delay counts. Circulation. 2004; 109: 1223–1225.LinkGoogle Scholar10 Berger PB, Ellis SG, Holmes DR Jr, Granger CB, Criger DA, Betriu A, Topol EJ, Califf RM. 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: 14–20.LinkGoogle Scholar11 Brodie BR, Hansen C, Stuckey TD, Richter S, Versteeg DS, Gupta N, Downey WE, Pulsipher M. Door-to-balloon time with primary percutaneous coronary intervention for acute myocardial infarction impacts late cardiac mortality in high-risk patients and patients presenting early after the onset of symptoms. J Am Coll Cardiol. 2006; 47: 289–295.CrossrefMedlineGoogle Scholar12 McNamara RL, Wang Y, Herrin J, Curtis JP, Bradley EH, Magid DJ, Peterson ED, Blaney M, Frederick PD, Krumholz HM. Effect of door-to-balloon time on mortality in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2006; 47: 2180–2186.CrossrefMedlineGoogle Scholar13 Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ, Ornato JP, Pearle DL, Sloan MA, Smith SC Jr, Alpert JS, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Halperin JL, Hiratzka LF, Hunt SA, Jacobs AK. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation. 2004; 110: 588–636.LinkGoogle Scholar14 Taher T, Fu Y, Wagner GS, Goodman SG, Fresco C, Granger CB, Wallentin L, van de Werf F, Verheugt F, Armstrong PW. Aborted myocardial infarction in patients with ST-segment elevation: insights from the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen-3 Trial Electrocardiographic Substudy. J Am Coll Cardiol. 2004; 44: 38–43.CrossrefMedlineGoogle Scholar15 Steg PG, Bonnefoy E, Chabaud S, Lapostolle F, Dubien PY, Cristofini P, Leizorovicz A, Touboul P. Impact of time to treatment on mortality after prehospital fibrinolysis or primary angioplasty: data from the CAPTIM randomized clinical trial. Circulation. 2003; 108: 2851–2856.LinkGoogle Scholar16 Pinto DS, Kirtane AJ, Nallamothu BK, Murphy SA, Cohen DJ, Laham RJ, Cutlip DE, Bates ER, Frederick PD, Miller DP, Carrozza JP Jr, Antman EM, Cannon CP, Gibson CM. Hospital delays in reperfusion for ST-elevation myocardial infarction: implications when selecting a reperfusion strategy. Circulation. 2006; 114: 2019–2025.LinkGoogle Scholar17 Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet. 1994; 343: 311–322.CrossrefMedlineGoogle Scholar18 Boersma E. Does time matter? A pooled analysis of randomized clinical trials comparing primary percutaneous coronary intervention and in-hospital fibrinolysis in acute myocardial infarction patients. Eur Heart J. 2006; 27: 779–788.CrossrefMedlineGoogle Scholar19 Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P. Thrombolysis in Myocardial Infarction (TIMI) Trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase: clinical findings through hospital discharge. Circulation. 1987; 76: 142–154.CrossrefMedlineGoogle Scholar20 Steg PG, Laperche T, Golmard JL, Juliard JM, Benamer H, Himbert D, Aubry P; PERM Study Group: Prospective Evaluation of Reperfusion Markers. Efficacy of streptokinase, but not tissue-type 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.CrossrefMedlineGoogle Scholar21 Zeymer U, Tebbe U, Essen R, Haarmann W, Neuhaus KL; ALKK Study Group. Influence of time to treatment on early infarct-related artery patency after different thrombolytic regimens. Am Heart J. 1999; 137: 34–38.CrossrefMedlineGoogle Scholar22 Collen D, Stassen JM, Verstraete M. Thrombolysis with human extrinsic (tissue-type) plasminogen activator in rabbits with experimental jugular vein thrombosis: effect of molecular form and dose of activator, age of the thrombus, and route of administration. J Clin Invest. 1983; 71: 368–376.CrossrefMedlineGoogle Scholar23 Schomig A, Ndrepepa G, Mehilli J, Schwaiger M, Schuhlen H, Nekolla S, Pache J, Martinoff S, Bollwein H, Kastrati A. Therapy-dependent influence of time-to-treatment interval on myocardial salvage in patients with acute myocardial infarction treated with coronary artery stenting or thrombolysis. Circulation. 2003; 108: 1084–1088.LinkGoogle Scholar24 Garcia-Dorado D, Theroux P, Elizaga J, Galinanes M, Solares J, Riesgo M, Gomez MJ, Garcia-Dorado A, Fernandez Aviles F. Myocardial reperfusion in the pig heart model: infarct size and duration of coronary occlusion. Cardiovasc Res. 1987; 21: 537–544.CrossrefMedlineGoogle Scholar25 Reimer KA, Vander Heide RS, Richard VJ. Reperfusion in acute myocardial infarction: effect of timing and modulating factors in experimental models. Am J Cardiol. 1993; 72: 13G–21G.MedlineGoogle Scholar26 Thiele H, Kappl MJ, Linke A, Erbs S, Boudriot E, Lembcke A, Kivelitz D, Schuler G. Influence of time-to-treatment, TIMI-flow grades, and ST-segment resolution on infarct size and infarct transmurality as assessed by delayed enhancement magnetic resonance imaging. Eur Heart J. 2007; 28: 1433–1439.CrossrefMedlineGoogle Scholar27 Stenestrand U, Lindback J, Wallentin L. Long-term outcome of primary percutaneous coronary intervention vs prehospital and in-hospital thrombolysis for patients with ST-elevation myocardial infarction. JAMA. 2006; 296: 1749–1756.CrossrefMedlineGoogle Scholar28 Tiefenbrunn AJ, Chandra NC, French WJ, Gore JM, Rogers WJ. Clinical experience with primary percutaneous transluminal coronary angioplasty compared with alteplase (recombinant tissue-type plasminogen activator) in patients with acute myocardial infarction: a report from the Second National Registry of Myocardial Infarction (NRMI-2). J Am Coll Cardiol. 1998; 31: 1240–1245.CrossrefMedlineGoogle Scholar29 Widimsky P, Budesinsky T, Vorac D, Groch L, Zelizko M, Aschermann M, Branny M, St'asek J, Formanek P. Long distance transport for primary angioplasty vs immediate thrombolysis in acute myocardial infarction: final results of the randomized national multicentre trial–PRAGUE-2. Eur Heart J. 2003; 24: 94–104.CrossrefMedlineGoogle Scholar30 The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. N Engl J Med. 1997; 336: 1621–1628.CrossrefMedlineGoogle Scholar31 Andersen HR, Nielsen TT, Rasmussen K, Thuesen L, Kelbaek H, Thayssen P, Abildgaard U, Pedersen F, Madsen JK, Grande P, Villadsen AB, Krusell LR, Haghfelt T, Lomholt P, Husted SE, Vigholt E, Kjaergard HK, Mortensen LS. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med. 2003; 349: 733–742.CrossrefMedlineGoogle Scholar32 Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005; 352: 1179–1189.CrossrefMedlineGoogle Scholar33 Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005; 366: 1607–1621.CrossrefMedlineGoogle Scholar34 Armstrong PW, Bogaty P, Buller CE, Dorian P, O'Neill BJ. The 2004 ACC/AHA Guidelines: a perspective and adaptation for Canada by the Canadian Cardiovascular Society Working Group. Can J Cardiol. 2004; 20: 1075–1079.MedlineGoogle Scholar35 Costantini CO, Stone GW, Mehran R, Aymong E, Grines CL, Cox DA, Stuckey T, Turco M, Gersh BJ, Tcheng JE, Garcia E, Griffin JJ, Guagliumi G, Leon MB, Lansky AJ. Frequency, correlates, and clinical implications of myocardial perfusion after primary angioplasty and stenting, with and without glycoprotein IIb/IIIa inhibition, in acute myocardial infarction. J Am Coll Cardiol. 2004; 44: 305–312.CrossrefMedlineGoogle Scholar36 van't Hof AW, Liem A, de Boer MJ, Zijlstra F; Zwolle Myocardial Infarction Study Group. Clinical value of 12-lead electrocardiogram after successful reperfusion therapy for acute myocardial infarction. Lancet. 1997; 350: 615–619.CrossrefMedlineGoogle Scholar37 Mehta RH, Harjai KJ, Cox D, Stone GW, Brodie B, Boura J, O'Neill W, Grines CL. Clinical and angiographic correlates and outcomes of suboptimal coronary flow in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. J Am Coll Cardiol. 2003; 42: 1739–1746.CrossrefMedlineGoogle Scholar38 Gibson CM, Murphy SA, Kirtane AJ, Giugliano RP, Cannon CP, Antman EM, Braunwald E. Association of duration of symptoms at presentation with angiographic and clinical outcomes after fibrinolytic therapy in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2004; 44: 980–987.CrossrefMedlineGoogle ScholarcirculationahaCirculationCirculationCirculation0009-73221524-4539Lippincott Williams & WilkinsResponse to Bogaty10032009Paul W. Armstrong, MD; Cynthia M. Westerhout, PhD; Robert C. Welsh, MDWe are pleased Bogaty concurs that little difference exists between the choices of fibrinolysis and percutaneous coronary intervention (PCI) early after the onset of ST-elevation myocardial infarction symptoms. The lack of prospective randomized data underscores the need for additional data; hence, we and others have begun a trial (STREAM [STrategic Reperfusion Early After Myocardial infarction]) in patients within 3 hours of symptom onset randomized to a strategy of direct PCI or strategic pharmacological therapy with tenecteplase and age- and weight-adjusted concomitant therapy, including enoxaparin and clopidogrel. Rescue PCI is mandatory, and the remainder of the patients will undergo angiography and (where appropriate) revascularization within the subsequent 6 to 24 hours.Although delay attenuates benefit, whatever reperfusion strategy is chosen, the persisting excess hazard posed by fibrinolysis contributes to the narrower margin between benefit and risk, unlike direct PCI. Moreover, PCI-induced late opening of coronary arteries obstructed by clot that is more resistant to fibrinolysis may be beneficial through alternative mechanisms (ie, enhanced left ventricular remodeling, lesser electrical instability, and more potential coronary collateral formation). Although the use of prehospital fibrinolysis–enhanced outcomes compared with primary PCI within the 2-hour window from symptom onset in the Comparison of Angioplasty and Prehospital Thrombolysis In acute Myocardial infarction (CAPTIM) study, patients treated later did less well with fibrinolysis, which attests to the importance of elapsed time when reperfusion therapy is selected.Finally, we would reemphasize the deleterious impact on mortality of each 10-minute reperfusion delay within the Global Registry of Acute Coronary Events (GRACE) for ST-elevation myocardial infarction. For fibrin-specific fibrinolysis, this excess was 0.30% (95% confidence interval 0.22 to 0.40) versus 0.18% (95% confidence interval 0.08 to 0.35%) for PCI.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.This article is Part II of a 2-part article. Part I appears on page 1293. Previous Back to top Next FiguresReferencesRelatedDetailsCited By Park J, Cha K, Shin D, Lee D, Lee H, Oh J, Choi J, Lee H, Hong T, Jeong M, Ahn Y, Chae S and Kim Y (2014) Impact of Non–Chest Pain Complaint as a Presenting Symptom on Door-To-Balloon Time and Clinical Outcomes in Patients With Acute ST-Elevation Myocardial Infarction, The American Journal of Cardiology, 10.1016/j.amjcard.2014.09.017, 114:12, (1801-1809), Online publication date: 1-Dec-2014. Dreyer R, Beltrame J, Tavella R, Air T, Hoffmann B, Pati P, Di Fiore D, Arstall M and Zeitz C (2013) Evaluation of Gender Differences in Door-to-Balloon Time in ST-Elevation Myocardial Infarction, Heart, Lung and Circulation, 10.1016/j.hlc.2013.03.078, 22:10, (861-869), Online publication date: 1-Oct-2013. Kaul P, Armstrong P, Sookram S, Leung B, Brass N and Welsh R (2011) Temporal trends in patient and treatment delay among men and women presenting with ST-elevation myocardial infarction, American Heart Journal, 10.1016/j.ahj.2010.09.016, 161:1, (91-97), Online publication date: 1-Jan-2011. Ramasamy I (2011) Biochemical markers in acute coronary syndrome, Clinica Chimica Acta, 10.1016/j.cca.2011.04.003, 412:15-16, (1279-1296), Online publication date: 1-Jul-2011. March 10, 2009Vol 119, Issue 9 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.107.750679PMID: 19273731 Originally publishedMarch 10, 2009 PDF download Advertisement SubjectsMyocardial InfarctionStentThrombosis