- Email: [email protected]
Usefulness of the presenting electrocardiogram in predicting successful reperfusion with Streptokinase in acute myocardial infarction
Usefulness of the Presenting Electrocardiogram in Predicting Successful Reperfusion With Streptokinase in Acute Myocardial Infarction Cheuk-Kit Wong, MD, John K. French, MB, PhD, Philip E. Aylward, BM, PhD, Martin J. Frey, MD, A. A. Jennifer Adgey, MD, and Harvey D. White, MB, DSc The presenting electrocardiogram may contain information indicating the probability of successful reperfusion. The relation between 3 parameters in the presenting electrocardiogram (pathologic Q waves, T-wave inversion, and the slope of ST elevation) and Thrombolysis in Myocardial Infarction trial (TIMI) grade 3 flow in the infarct-related artery was assessed angiographically 90 minutes after beginning streptokinase in 362 patients. TIMI grade 3 flow was more common in patients without Q waves (55%) than in those with Q waves (35%; p <0.001), and more common in patients without T-wave inversion (50%) than in those with T-wave inversion (30%; p <0.002). There was no relation between the slope of the ST segment or the magnitude of its deviation and the achievement of TIMI grade 3 flow. Only 20% of the 59 patients with both Q waves and T-wave inversion had TIMI grade 3 flow, compared with 50% of the remaining patients (p <0.0001). Among patients
treated within 3 hours, TIMI grade 3 flow was seen in 68% of those without versus 44% of those with Q waves (p <0.01), and in 62% of those without versus 43% of those with T-wave inversion (p 5 0.06). Among patients treated after 3 hours, TIMI grade 3 flow was seen in 38% of those without versus 30% of those with Q waves (p 5 NS), and in 38% of those without versus 23% of those with T-wave inversion (p <0.05). On multivariate analysis, the absence of Q waves, the time from the onset of chest pain to treatment, and age were independent predictors of TIMI grade 3 flow. Pathologic Q waves in the presenting electrocardiogram provide valuable information as to the probability of achieving successful reperfusion following administration of streptokinase, and may be helpful for triage of patients to alternative reperfusion strategies, including percutaneous revascularization. Q1999 by Excerpta Medica, Inc. (Am J Cardiol 1999;83:164 –168)
uring the evolution of acute myocardial infarction, changes occur in the extent and the slope of D ST elevation, and pathologic Q waves and T-wave
over 30 to 60 minutes) and aspirin (150 to 325 mg daily) for acute myocardial infarction.1 In brief, patients with acute myocardial infarction were recruited into HERO within 12 hours of the onset of chest pain, with the usual exclusion criteria for administration of thrombolytic therapy, including a history of bleeding and recent surgery. For this angiographic trial, patients with cardiogenic shock or previous use of streptokinase were also excluded. Patients with previous infarction or revascularization were eligible for the study. Coronary angiography was performed 90 to 120 minutes after the initiation of streptokinase therapy. Angiograms were analyzed by cardiologists, who were blinded to patient treatment, at the Green Lane Hospital core laboratory. Infarct-related artery flow was quantitated using the Thrombolysis in Myocardial Infarction trial (TIMI) flow grades: TIMI 0 (no perfusion) 5 no flow beyond the occlusion; TIMI 1 (penetration without perfusion) 5 slow and incomplete opacification of the vascular bed by contrast material; TIMI 2 (partial perfusion) 5 slow but complete opacification of the vascular bed by contrast material, with slower clearance; and TIMI 3 (complete perfusion) 5 prompt and complete opacification of the vascular bed by contrast material, with rapid clearance, as in an uninvolved artery.2 Achievement of TIMI 3 flow was the primary end point of the study,
inversion develop, reflecting the duration of the coronary occlusion. In this study, we hypothesized that these parameters in the presenting electrocardiogram might indicate the probability of successful thrombolysis. We examined patients with acute myocardial infarction who had received streptokinase in our recent angiographic trial1 to investigate the relation between the presenting electrocardiographic changes and the likelihood of successful reperfusion.
METHODS
Study patients: The study population consisted of patients from the multicenter Hirulog Early Reperfusion/Occlusion (HERO) trial, a randomized, doubleblind comparison of hirulog (bivalirudin) versus heparin in patients receiving streptokinase (1.5 million U From the Cardiovascular Research Unit, Green Lane Hospital, Auckland, New Zealand; Flinders Cardiovascular Centre, Adelaide, South Australia, Australia; Heart Center of Sarasota, Sarasota, Florida; and Regional Medical Cardiology Centre, Royal Victoria Hospital, Belfast, Northern Ireland. Manuscript received July 27, 1998; revised manuscript received and accepted August 17, 1998. Address for reprints: Harvey White, DSc, Cardiology Department, Green Lane Hospital, Private Bag 92 189, Auckland 1030, New Zealand. Email: [email protected].
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©1999 by Excerpta Medica, Inc. All rights reserved.
0002-9149/99/$–see front matter PII S0002-9149(98)00818-2
because TIMI 2 flow indicates suboptimal coronary reperfusion.3–5 Electrocardiographic analysis: The qualifying electrocardiogram recorded on entry to the study was sent to the core laboratory at Green Lane Hospital. Those analyzing the electrocardiograms were blinded to the TIMI flow data. ST segment deviation was measured at 60 ms after the J point. Any deviation of $1 mm (0.1 mV) was considered significant. Three additional parameters in the lead with the maximum ST elevation were analyzed as categoric variables. 1. The presence of Q waves: (a) No pathologic Q waves; (b) shallow pathologic Q waves, defined as a depth .25% of the R wave, and width $40 ms; and (c) deep pathologic Q waves, defined as either Q waves with total loss of the R wave or deep Q waves of .5 mm (0.5 mV) in the inferior or lateral limb leads and .10 mm (1 mV) in the chest leads. Isolated Q waves in lead III were not read as pathologic Q waves. 2. T-wave inversion: (a) No T-wave inversion; (b) shallow T-wave inversion including biphasic T waves; and (c) deep T-wave inversion of .5 mm (0.5 mV) in the inferior or lateral limb leads and .10 mm (1 mV) in the chest leads. 3. The slope of the ST segment as measured by a protractor: (a) Upsloping ST elevation of .30°; (b) ST elevation with a slope of 10° to 30°; and (c) planar ST elevation with a slope of ,10°. Statistical analysis: The relation between TIMI 3 flow and the electrocardiographic parameters, including the presence of Q waves, T-wave inversion, and ST-segment slope, were prespecified and examined using chi-square tests and Fisher’s exact tests where appropriate. Group means were compared using t tests. p Values (2-tailed) of ,0.05 were considered significant. Stepwise logistic regression, incorporating age, gender, infarct site, smoking history, electrocardiographic variables and the duration from the onset of chest pain to therapy, was used to determine the predictors of TIMI 3 flow. This analysis was repeated with the treatment group (heparin vs hirulog) entered as a categoric variable in the prediction model.
TABLE I Baseline Characteristics (n 5 362) Age (yrs) Men Smokers Anterior wall AMI Nonanterior wall AMI Previous AMI Previous CABG Previous PTCA History of heart failure History of hypertension
62 268 232 112 250 40 9 15 4 108
6 12 (74%) (64%) (31%) (69%) (11%) (2%) (4%) (1%) (30%)
AMI 5 acute myocardial infarction; CABG 5 coronary artery bypass grafting; PTCA 5 percutaneous transluminal coronary angioplasty.
TABLE II Relation Between TIMI 3 Flow and the Presence of Q Waves
Whole cohort (n 5 362) No. of patients TIMI 0–2 flow TIMI 3 flow Patients with first infarction (n 5 322) No. of patients TIMI 0–2 flow TIMI 3 flow
No Q Waves
Shallow Q Waves
Deep Q Waves
186 84 (45%) 102 (55%)*
96 60 (63%) 36 (37%)
80 54 (68%) 26 (32%)
172 78 (45%) 94 (55%)†
80 50 (63%) 30 (37%)
70 46 (66%) 24 (34%)
*p ,0.001 versus the other 2 groups combined. † p ,0.01 versus the other 2 groups combined.
TABLE III Relation Between TIMI 3 Flow and T-wave Inversion
Whole cohort (n 5 362) No. of patients TIMI 0–2 flow TIMI 3 flow Patients with first infarction (n 5 322) No. of patients TIMI 0–2 flow TIMI 3 flow
No T-wave Inversion
Shallow T-wave Inversion
Deep T-wave Inversion
276 138 (50%) 138 (50%)*
82 56 (68%) 26 (32%)
4 4 (100%) 0 (0%)
249 123 (49%) 126 (51%)*
69 47 (68%) 22 (32%)
4 4 (100%) 0 (0%)
*p ,0.01 versus the other 2 groups combined.
RESULTS Four hundred patients underwent 90 to 120 minute angiography, and the presenting 12-lead electrocardiograms of 385 patients were available for analysis in the present study. Of the remaining 15 patients, the electrocardiograms were missing in 10 and 5 had insufficient baseline data. Of the 385 patients, 23 were excluded because of suboptimal electrocardiographic recordings, complete bundle branch block, intraventricular conduction defects, and multiple ventricular ectopic beats. This study is based on the remaining 362 patients, 164 with TIMI grade 3 flow and 198 with TIMI grade 0 to 2 flow. The baseline characteristics are reported in Table I. The results for the following electrocardiographic parameters were similar irrespective of whether the 40 patients with previous myocardial infarction were included or not.
Pathologic Q waves and TIMI 3 flow (Table II) TIMI grade 3 flow occurred more commonly in patients without Q waves (55%) than in those with Q waves (35%; p ,0.001). However, there was no difference in the TIMI 3 flow rates between patients with deep Q waves and those with shallow Q waves. T-wave inversion and TIMI 3 flow (Table III): TIMI 3 flow occurred more commonly in patients without T-wave inversion (50%) than in those with T-wave inversion (30%; p ,0.01). Only 4 patients had deep T-wave inversion. ST-segment changes and TIMI 3 flow (Table IV):
There was no relation between the slope of the ST segment and achievement of TIMI 3 flow. There were no differences between patients with TIMI 3 flow and
CORONARY ARTERY DISEASE/REPERFUSION WITH STREPTOKINASE IN AMI
165
TABLE IV. Relation Between TIMI 3 Flow and ST-Segment Slope
Whole cohort (n 5 362) No. of patients TIMI 0–2 flow TIMI 3 flow Patients with first infarction (n 5 322) No. of patients TIMI 0–2 flow TIMI 3 flow
ST Slope .30°
ST Slope 10–30°
ST Slope ,10°
165 87 (53%) 78 (47%)
145 81 (56%) 64 (44%)
52 30 (58%) 22 (42%)
151 78 (52%) 73 (48%)
128 72 (56%) 56 (44%)
43 24 (56%) 19 (44%)
P 5 NS for all comparisons.
those with TIMI 0 to 2 flow in the presenting electrocardiograms with respect to the number of leads with ST elevation (3.6 6 1.4 vs 3.5 6 1.2), the number of leads with ST depression (2.5 6 1.9 vs 2.4 6 2.3), the maximum ST elevation (3.4 6 2.1 vs 3.3 6 2.0 mm), and the maximum ST depression (1.8 6 1.6 vs 1.6 6 1.7 mm) (p 5 NS for all comparisons).
Presence of pathologic Q waves, T-wave inversion, and TIMI 3 flow: Fifty-nine patients had both Q waves
(shallow or deep) and T-wave inversion (shallow or deep). TIMI 3 flow was found in only 20% of these patients versus 50% of the remaining patients (p ,0.0001). In patients with anterior infarction and in those with $4 leads showing ST elevation, TIMI 3 flow rates were low (21% and 24%, respectively) when both Q waves and T-wave inversion were present. Time from onset of chest pain and TIMI 3 flow: TIMI 3 flow was seen in 59% of the 168 patients treated within 3 hours of the onset of chest pain, compared with 34% of the 194 patients treated after 3 hours (p ,0.0001). For the 168 patients treated within 3 hours, TIMI 3 flow was seen in 68% of those without Q waves versus 44% of those with Q waves (p ,0.01), and in 62% of patients without T-wave inversion versus 43% of those with T-wave inversion (p 5 0.06). For the 194 patients treated after 3 hours, TIMI 3 flow was seen in 38% of those without Q waves versus 30% of those with Q waves (p 5 NS); and 38% of patients without T-wave inversion versus 23% of those with T-wave inversion (p ,0.05). On multivariate analysis, the independent predictors of TIMI 3 flow were age (p ,0.01), time to streptokinase therapy (p ,0.01), and the absence of Q waves in the presenting electrocardiogram (p ,0.01). The same predictors persisted when the treatment group was entered into the prediction model. Subgroup analysis in patients receiving different antithrombin therapies: Two hundred forty patients
received hirulog and 122 received heparin. For the comparison of patients without versus those with pathologic Q waves, TIMI 3 flow was seen in 56% versus 39% of those treated with hirulog (p ,0.01) and 52% versus 27% of those treated with heparin (p ,0.01). 166 THE AMERICAN JOURNAL OF CARDIOLOGYT
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DISCUSSION This study shows that pathologic Q waves in the presenting electrocardiogram can predict the probability of successful reperfusion following the administration of streptokinase. Although ST elevation is an electrocardiographic criterion for administration of thrombolytic therapy,6 the presence of pathologic Q waves predicts a low success rate for reperfusion. Time to thrombolytic therapy and angiographic outcome: Previous studies have reported a decreasing rate
of reperfusion with increasing time to streptokinase therapy.2 In a multicenter reperfusion trial of intravenous anistreplase in acute myocardial infarction,7 60% of patients receiving anistreplase within 4 hours of chest pain had TIMI 2 or 3 flow versus 33% of those treated after 4 hours.2 In the TIMI-1 study, which included only patients with TIMI 0 to 1 flow at baseline, 44% of those treated with streptokinase within 4 hours of chest pain had TIMI 2 to 3 flow at 90 minutes versus 24% of those treated after 4 hours. In the current study, treatment after 3 hours was associated with a lower TIMI 3 flow rate than earlier treatment (34% vs 59%). Older clots with more mature, crosslinked fibrin may be more resistant to streptokinase.8 In addition to the time to therapy, the presence of pathologic Q waves was also an independent predictor of TIMI 3 flow in the present study. In patients treated within 3 hours, the presence of Q waves was associated with a much lower rate of successful reperfusion (44% vs 68%, p ,0.01). These patients may benefit most from alternative reperfusion strategies, including primary angioplasty. Angioplasty versus thrombolytics as the reperfusion strategy: Angioplasty has been shown to achieve a
higher TIMI 3 flow rate than intravenous thrombolysis does,9 –11 but generally with some delay. In the Global Utilization of Streptokinase and TPA for Occluded arteries (GUSTO-IIb) trial, comparing primary angioplasty and accelerated tissue plasminogen activator (t-PA) in acute myocardial infarction,10 the primary end point of death, nonfatal myocardial infarction, or nonfatal stroke occurred in 9.6% of the angioplasty group versus 13.7% of the t-PA group (p 5 0.033). There was a trend toward a greater early benefit in the angioplasty group in patients presenting $4 hours after the onset of chest pain. At 6 months, however, the advantage of angioplasty over t-PA was not statistically significant. In the second Primary Angioplasty in Myocardial Infarction (PAMI-2) trial,11 inhospital mortality was similar at all time points up to 12 hours after the onset of chest pain. These observations may relate to restoration of TIMI 3 flow by angioplasty, regardless of the time elapsed since the onset of chest pain.11 In contrast, greater delay from symptom onset to commencement of thrombolytic therapy may result in decreased TIMI grade 3 flow2,7,12 and increased mortality.13,14 The treatment option of primary angioplasty is not available in many communities, and thrombolytic therapy is the only option for reperfusion. Streptokinase continues to be used widely in many parts of the world, not only because it is cheaper, but partly also because it is JANUARY 15, 1999
associated with a lower incidence of intracerebral bleeding than t-PA.15–17 This study shows that the absence of Q waves in the presenting electrocardiogram and a short time interval from the onset of symptoms to therapy independently correlate with a high TIMI 3 flow rate when streptokinase is used. Why is the presence of Q waves useful in predicting TIMI flow? The use of these evolving electrocardio-
graphic changes in predicting successful clot lysis may be explained by their relation to the duration of occlusion. Their importance, even when the duration of chest pain is known, would imply that the latter is only a crude estimate of the duration of occlusion. Perception of pain is subjective, particularly in diabetic patients18 and the elderly, and some patients have episodes of silent ischemia, masking the precise definition of the onset of coronary artery occlusion. Also, many patients with acute myocardial infarction have prodromal angina,19 –21 which may be protective through the mechanism of ischemic preconditioning19,20 or enhanced recanalization with thrombolytic administration.21 These episodes of prodromal angina could also cause difficulty in defining the duration of coronary occlusion. This may partly explain our finding that the absence of Q waves was an independent predictor of TIMI 3 flow even when the duration of chest pain was taken into account. Despite its limitations, the duration of chest pain is one of the main factors used to determine patients’ eligibility for thrombolytic therapy.6,22 Animal studies have shown that coronary occlusion produces a wavefront of myocardial necrosis that progresses with time from the subendocardium towards the epicardium.23 The size of the infarct is also influenced by other factors, including spontaneous intermittent reperfusion,24 collateral coronary circulation,25 and the level of myocardial demands.26 New pathologic Q waves generally reflect myocardial necrosis, although ischemia-induced intramyocardial conduction delay, which causes a shift in early electrical force, may also be important.27 The presence of pathologic Q waves is a direct indication of the late phase of ischemic insult after coronary occlusion, whereas the time from the onset of chest pain may be only indirectly related. In the Late Assessment of Thrombolytic Efficacy (LATE) trial, where mortality decreased with thrombolytic therapy was seen to extend to 12 hours, over half of the patients recruited did not have pathologic Q waves in their initial electrocardiograms.28 In the current study, about half of the patients had pathologic Q waves. The finding of improved reperfusion rates when Q waves were absent in the presenting electrocardiogram suggests that the time window for the benefits of thrombolytic therapy could be widened. Other factors associated with infarct artery patency:
About a quarter of the patients in this study had T-wave inversion in their presenting electrocardiogram. On its own, T-wave inversion was associated with a low TIMI 3 flow rate, but this association was largely explained by other covariates, including patho-
logic Q waves and time to therapy. In situations where the precise onset of chest pain cannot be determined, T-wave inversion may also be a helpful feature, in addition to pathologic Q waves, in predicting successful reperfusion. In this study, age was also a significant predictor of the TIMI 3 flow rate, whereas in the GUSTO report, combining the results of different thrombolytic regimens, age had no relation to the 90-minute TIMI 3 flow rate.29 This study was based on the use of streptokinase as the thrombolytic agent in the HERO trial, with co-administration of aspirin and either heparin or hirulog. It is possible that the electrocardiographic relation with patency rates could be different with other thrombolytic regimens. 1. White HD, Aylward PE, Frey MJ, Adgey AAJ, Nair R, Hillis WS, Shalev Y, Brown MA, French JK, Collins R, Maraganore J, Adelman B, on behalf of the Hirulog Early Reperfusion/Occlusion (HERO) Trial Investigators. Randomized, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Circulation 1997; 96:2155–2161. 2. Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, et al. 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. 3. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction [published erratum appears in N Engl J Med 1994;330:516]. N Engl J Med 1993;329:1615–1622. 4. Karagounis L, Sorenson SG, Menlove RL, Moreno F, Anderson JL. Does thrombolysis in myocardial infarction (TIMI) perfusion grade 2 represent a mostly patent artery or a mostly occluded artery? Enzymatic and electrocardiographic evidence from the TEAM-2 study. J Am Coll Cardiol 1992;19:1–10. 5. Vogt A, von Essen R, Tebbe U, Feuerer W, Appel K-F, Neuhaus K-L. Impact of early perfusion status of the infarct-related artery on short-term mortality after thrombolysis for acute myocardial infarction: retrospective analysis of four German multicenter studies. J Am Coll Cardiol 1993;21:1391–1395. 6. French JK, Williams BF, Hart HH, Wyatt S, Poole JE, Ingram C, Ellis CJ, Williams MG, White HD. Prospective evaluation of eligibility for thrombolytic therapy in acute myocardial infarction. Br Med J 1996;312:1637–1641. 7. Anderson JL, Rothbard RL, Hackworthy RA, Sorensen SG, Fitzpatrick PG, Dahl CF, Hagan AD, Browne KF, Symkoviak GP, Menlove RL, Barry WH, Eckerson HW, Marder VJ. Multicenter reperfusion trial of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial infarction: controlled comparison with intracoronary streptokinase. J Am Coll Cardiol 1988;11:1153–1163. 8. Anderson JL. Why does thrombolysis fail? Breaking through the reperfusion ceiling. Am J Cardiol 1997;80:1588 –1590. 9. Grines CL, Browne KF, Marco J, Rothbaum D, Stone GW, O’Keefe J, Overlie P, Donohue B, Chelliah N, Timmis GC, Vlietstra RE, Strzelecki M, PuchrowiczOchocki S, O’Neill WW, for the Primary Angioplasty in Myocardial Infarction Study Group. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993;328:673– 679. 10. 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. 11. Stone GW, Brodie B, Griffin J, Donohue B, Costantini C, Jones D, Graham M, Grines C. Should the risk of delaying reperfusion prohibit inter-hospital transfer to perform primary PTCA in acute myocardial infarction? (abstr). Circulation 1996;94(suppl I):I-331. 12. Stewart JT, French JK, The´roux P, Ramanathan K, Solymoss BC, Johnson R, White HD. Early noninvasive identification of failed reperfusion after intravenous thrombolytic therapy in acute myocardial infarction. J Am Coll Cardiol 1998;31: 1499 –1505. 13. 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. 14. Boersma E, Maas ACP, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet 1996;348:771–775. 15. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329: 673– 682.
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16. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico.
GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12 490 patients with acute myocardial infarction. Lancet 1990;336:65–71. 17. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41 299 cases of suspected acute myocardial infarction. Lancet 1992;339:753–770. 18. Kannel WB. Lipids, diabetes, and coronary heart disease: insights from the Framingham study. Am Heart J 1985;110:1100 –1107. 19. Kloner RA, Shook T, Przyklenk K, Davis VG, Junio L, Matthews RV, Burstein S, Gibson M, Poole WK, Cannon CP, McCabe CH, Braunwald E. Previous angina alters in-hospital outcome in TIMI 4: a clinical correlate to preconditioning? Circulation 1995;91:37– 45. 20. Ottani F, Galvani M, Ferrini D, Sorbello F, Limonetti P, Pantoli D, Rusticali F. Prodromal angina limits infarct size: a role for ischemic preconditioning. Circulation 1995;91:291–297. 21. Andreotti F, Pasceri V, Hackett DR, Davies GJ, Haider AW, Maseri A. Preinfarction angina as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infarction. N Engl J Med 1996;334:7–12. 22. White HD. Thrombolytic therapy for patients with myocardial infarction presenting after six hours. Lancet 1992;340:221–222. 23. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wave-front
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phenomenon of ischemic cell death. I. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation 1977;56:786 –794. 24. Hackett D, Davies G, Chierchia S, Maseri A. Intermittent coronary occlusion in acute myocardial infarction: value of combined thrombolytic and vasodilator therapy. N Engl J Med 1987;317:1055–1059. 25. Christian TF, Schwartz RS, Gibbons RJ. Determinants of infarct size in reperfusion therapy for acute myocardial infarction. Circulation 1992;86:81–90. 26. Reimer KA, Jennings RB, Cobb FR, Murdock RH, Greenfield JC Jr, Becker LC, Bulkley BH, Hutchins GM, Schwartz RP Jr, Bailey KR, Passamani ER. Animal models for protecting ischemic myocardium: results of the NHLBI cooperative study: comparison of unconscious and conscious dog models. Circ Res 1985;56:651– 665. 27. Selvester RH, Wagner NB, Wagner GS. Ventricular excitation during percutaneous transluminal angioplasty of the left anterior descending coronary artery. Am J Cardiol 1988;62:1116 –1121. 28. Langer A, Goodman SG, Topol EJ, Charlesworth A, Skene AM, Wilcox RG, Armstrong PW, for the LATE Study Investigators. Late Assessment of Thrombolytic Efficacy (LATE) Study: prognosis in patients with non-Q wave myocardial infarction. J Am Coll Cardiol 1996;27:1327–1332. 29. Lesnefsky EJ, Lundergan CF, Hodgson JM, Nair R, Reiner JS, Greenhouse SW, Califf RM, Ross AM. Increased left ventricular dysfunction in elderly patients despite successful thrombolysis: the GUSTO-I angiographic experience. J Am Coll Cardiol 1996;28:331–337.
JANUARY 15, 1999
treated within 3 hours, TIMI grade 3 flow was seen in 68% of those without versus 44% of those with Q waves (p <0.01), and in 62% of those without versus 43% of those with T-wave inversion (p 5 0.06). Among patients treated after 3 hours, TIMI grade 3 flow was seen in 38% of those without versus 30% of those with Q waves (p 5 NS), and in 38% of those without versus 23% of those with T-wave inversion (p <0.05). On multivariate analysis, the absence of Q waves, the time from the onset of chest pain to treatment, and age were independent predictors of TIMI grade 3 flow. Pathologic Q waves in the presenting electrocardiogram provide valuable information as to the probability of achieving successful reperfusion following administration of streptokinase, and may be helpful for triage of patients to alternative reperfusion strategies, including percutaneous revascularization. Q1999 by Excerpta Medica, Inc. (Am J Cardiol 1999;83:164 –168)
uring the evolution of acute myocardial infarction, changes occur in the extent and the slope of D ST elevation, and pathologic Q waves and T-wave
over 30 to 60 minutes) and aspirin (150 to 325 mg daily) for acute myocardial infarction.1 In brief, patients with acute myocardial infarction were recruited into HERO within 12 hours of the onset of chest pain, with the usual exclusion criteria for administration of thrombolytic therapy, including a history of bleeding and recent surgery. For this angiographic trial, patients with cardiogenic shock or previous use of streptokinase were also excluded. Patients with previous infarction or revascularization were eligible for the study. Coronary angiography was performed 90 to 120 minutes after the initiation of streptokinase therapy. Angiograms were analyzed by cardiologists, who were blinded to patient treatment, at the Green Lane Hospital core laboratory. Infarct-related artery flow was quantitated using the Thrombolysis in Myocardial Infarction trial (TIMI) flow grades: TIMI 0 (no perfusion) 5 no flow beyond the occlusion; TIMI 1 (penetration without perfusion) 5 slow and incomplete opacification of the vascular bed by contrast material; TIMI 2 (partial perfusion) 5 slow but complete opacification of the vascular bed by contrast material, with slower clearance; and TIMI 3 (complete perfusion) 5 prompt and complete opacification of the vascular bed by contrast material, with rapid clearance, as in an uninvolved artery.2 Achievement of TIMI 3 flow was the primary end point of the study,
inversion develop, reflecting the duration of the coronary occlusion. In this study, we hypothesized that these parameters in the presenting electrocardiogram might indicate the probability of successful thrombolysis. We examined patients with acute myocardial infarction who had received streptokinase in our recent angiographic trial1 to investigate the relation between the presenting electrocardiographic changes and the likelihood of successful reperfusion.
METHODS
Study patients: The study population consisted of patients from the multicenter Hirulog Early Reperfusion/Occlusion (HERO) trial, a randomized, doubleblind comparison of hirulog (bivalirudin) versus heparin in patients receiving streptokinase (1.5 million U From the Cardiovascular Research Unit, Green Lane Hospital, Auckland, New Zealand; Flinders Cardiovascular Centre, Adelaide, South Australia, Australia; Heart Center of Sarasota, Sarasota, Florida; and Regional Medical Cardiology Centre, Royal Victoria Hospital, Belfast, Northern Ireland. Manuscript received July 27, 1998; revised manuscript received and accepted August 17, 1998. Address for reprints: Harvey White, DSc, Cardiology Department, Green Lane Hospital, Private Bag 92 189, Auckland 1030, New Zealand. Email: [email protected].
164
©1999 by Excerpta Medica, Inc. All rights reserved.
0002-9149/99/$–see front matter PII S0002-9149(98)00818-2
because TIMI 2 flow indicates suboptimal coronary reperfusion.3–5 Electrocardiographic analysis: The qualifying electrocardiogram recorded on entry to the study was sent to the core laboratory at Green Lane Hospital. Those analyzing the electrocardiograms were blinded to the TIMI flow data. ST segment deviation was measured at 60 ms after the J point. Any deviation of $1 mm (0.1 mV) was considered significant. Three additional parameters in the lead with the maximum ST elevation were analyzed as categoric variables. 1. The presence of Q waves: (a) No pathologic Q waves; (b) shallow pathologic Q waves, defined as a depth .25% of the R wave, and width $40 ms; and (c) deep pathologic Q waves, defined as either Q waves with total loss of the R wave or deep Q waves of .5 mm (0.5 mV) in the inferior or lateral limb leads and .10 mm (1 mV) in the chest leads. Isolated Q waves in lead III were not read as pathologic Q waves. 2. T-wave inversion: (a) No T-wave inversion; (b) shallow T-wave inversion including biphasic T waves; and (c) deep T-wave inversion of .5 mm (0.5 mV) in the inferior or lateral limb leads and .10 mm (1 mV) in the chest leads. 3. The slope of the ST segment as measured by a protractor: (a) Upsloping ST elevation of .30°; (b) ST elevation with a slope of 10° to 30°; and (c) planar ST elevation with a slope of ,10°. Statistical analysis: The relation between TIMI 3 flow and the electrocardiographic parameters, including the presence of Q waves, T-wave inversion, and ST-segment slope, were prespecified and examined using chi-square tests and Fisher’s exact tests where appropriate. Group means were compared using t tests. p Values (2-tailed) of ,0.05 were considered significant. Stepwise logistic regression, incorporating age, gender, infarct site, smoking history, electrocardiographic variables and the duration from the onset of chest pain to therapy, was used to determine the predictors of TIMI 3 flow. This analysis was repeated with the treatment group (heparin vs hirulog) entered as a categoric variable in the prediction model.
TABLE I Baseline Characteristics (n 5 362) Age (yrs) Men Smokers Anterior wall AMI Nonanterior wall AMI Previous AMI Previous CABG Previous PTCA History of heart failure History of hypertension
62 268 232 112 250 40 9 15 4 108
6 12 (74%) (64%) (31%) (69%) (11%) (2%) (4%) (1%) (30%)
AMI 5 acute myocardial infarction; CABG 5 coronary artery bypass grafting; PTCA 5 percutaneous transluminal coronary angioplasty.
TABLE II Relation Between TIMI 3 Flow and the Presence of Q Waves
Whole cohort (n 5 362) No. of patients TIMI 0–2 flow TIMI 3 flow Patients with first infarction (n 5 322) No. of patients TIMI 0–2 flow TIMI 3 flow
No Q Waves
Shallow Q Waves
Deep Q Waves
186 84 (45%) 102 (55%)*
96 60 (63%) 36 (37%)
80 54 (68%) 26 (32%)
172 78 (45%) 94 (55%)†
80 50 (63%) 30 (37%)
70 46 (66%) 24 (34%)
*p ,0.001 versus the other 2 groups combined. † p ,0.01 versus the other 2 groups combined.
TABLE III Relation Between TIMI 3 Flow and T-wave Inversion
Whole cohort (n 5 362) No. of patients TIMI 0–2 flow TIMI 3 flow Patients with first infarction (n 5 322) No. of patients TIMI 0–2 flow TIMI 3 flow
No T-wave Inversion
Shallow T-wave Inversion
Deep T-wave Inversion
276 138 (50%) 138 (50%)*
82 56 (68%) 26 (32%)
4 4 (100%) 0 (0%)
249 123 (49%) 126 (51%)*
69 47 (68%) 22 (32%)
4 4 (100%) 0 (0%)
*p ,0.01 versus the other 2 groups combined.
RESULTS Four hundred patients underwent 90 to 120 minute angiography, and the presenting 12-lead electrocardiograms of 385 patients were available for analysis in the present study. Of the remaining 15 patients, the electrocardiograms were missing in 10 and 5 had insufficient baseline data. Of the 385 patients, 23 were excluded because of suboptimal electrocardiographic recordings, complete bundle branch block, intraventricular conduction defects, and multiple ventricular ectopic beats. This study is based on the remaining 362 patients, 164 with TIMI grade 3 flow and 198 with TIMI grade 0 to 2 flow. The baseline characteristics are reported in Table I. The results for the following electrocardiographic parameters were similar irrespective of whether the 40 patients with previous myocardial infarction were included or not.
Pathologic Q waves and TIMI 3 flow (Table II) TIMI grade 3 flow occurred more commonly in patients without Q waves (55%) than in those with Q waves (35%; p ,0.001). However, there was no difference in the TIMI 3 flow rates between patients with deep Q waves and those with shallow Q waves. T-wave inversion and TIMI 3 flow (Table III): TIMI 3 flow occurred more commonly in patients without T-wave inversion (50%) than in those with T-wave inversion (30%; p ,0.01). Only 4 patients had deep T-wave inversion. ST-segment changes and TIMI 3 flow (Table IV):
There was no relation between the slope of the ST segment and achievement of TIMI 3 flow. There were no differences between patients with TIMI 3 flow and
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TABLE IV. Relation Between TIMI 3 Flow and ST-Segment Slope
Whole cohort (n 5 362) No. of patients TIMI 0–2 flow TIMI 3 flow Patients with first infarction (n 5 322) No. of patients TIMI 0–2 flow TIMI 3 flow
ST Slope .30°
ST Slope 10–30°
ST Slope ,10°
165 87 (53%) 78 (47%)
145 81 (56%) 64 (44%)
52 30 (58%) 22 (42%)
151 78 (52%) 73 (48%)
128 72 (56%) 56 (44%)
43 24 (56%) 19 (44%)
P 5 NS for all comparisons.
those with TIMI 0 to 2 flow in the presenting electrocardiograms with respect to the number of leads with ST elevation (3.6 6 1.4 vs 3.5 6 1.2), the number of leads with ST depression (2.5 6 1.9 vs 2.4 6 2.3), the maximum ST elevation (3.4 6 2.1 vs 3.3 6 2.0 mm), and the maximum ST depression (1.8 6 1.6 vs 1.6 6 1.7 mm) (p 5 NS for all comparisons).
Presence of pathologic Q waves, T-wave inversion, and TIMI 3 flow: Fifty-nine patients had both Q waves
(shallow or deep) and T-wave inversion (shallow or deep). TIMI 3 flow was found in only 20% of these patients versus 50% of the remaining patients (p ,0.0001). In patients with anterior infarction and in those with $4 leads showing ST elevation, TIMI 3 flow rates were low (21% and 24%, respectively) when both Q waves and T-wave inversion were present. Time from onset of chest pain and TIMI 3 flow: TIMI 3 flow was seen in 59% of the 168 patients treated within 3 hours of the onset of chest pain, compared with 34% of the 194 patients treated after 3 hours (p ,0.0001). For the 168 patients treated within 3 hours, TIMI 3 flow was seen in 68% of those without Q waves versus 44% of those with Q waves (p ,0.01), and in 62% of patients without T-wave inversion versus 43% of those with T-wave inversion (p 5 0.06). For the 194 patients treated after 3 hours, TIMI 3 flow was seen in 38% of those without Q waves versus 30% of those with Q waves (p 5 NS); and 38% of patients without T-wave inversion versus 23% of those with T-wave inversion (p ,0.05). On multivariate analysis, the independent predictors of TIMI 3 flow were age (p ,0.01), time to streptokinase therapy (p ,0.01), and the absence of Q waves in the presenting electrocardiogram (p ,0.01). The same predictors persisted when the treatment group was entered into the prediction model. Subgroup analysis in patients receiving different antithrombin therapies: Two hundred forty patients
received hirulog and 122 received heparin. For the comparison of patients without versus those with pathologic Q waves, TIMI 3 flow was seen in 56% versus 39% of those treated with hirulog (p ,0.01) and 52% versus 27% of those treated with heparin (p ,0.01). 166 THE AMERICAN JOURNAL OF CARDIOLOGYT
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DISCUSSION This study shows that pathologic Q waves in the presenting electrocardiogram can predict the probability of successful reperfusion following the administration of streptokinase. Although ST elevation is an electrocardiographic criterion for administration of thrombolytic therapy,6 the presence of pathologic Q waves predicts a low success rate for reperfusion. Time to thrombolytic therapy and angiographic outcome: Previous studies have reported a decreasing rate
of reperfusion with increasing time to streptokinase therapy.2 In a multicenter reperfusion trial of intravenous anistreplase in acute myocardial infarction,7 60% of patients receiving anistreplase within 4 hours of chest pain had TIMI 2 or 3 flow versus 33% of those treated after 4 hours.2 In the TIMI-1 study, which included only patients with TIMI 0 to 1 flow at baseline, 44% of those treated with streptokinase within 4 hours of chest pain had TIMI 2 to 3 flow at 90 minutes versus 24% of those treated after 4 hours. In the current study, treatment after 3 hours was associated with a lower TIMI 3 flow rate than earlier treatment (34% vs 59%). Older clots with more mature, crosslinked fibrin may be more resistant to streptokinase.8 In addition to the time to therapy, the presence of pathologic Q waves was also an independent predictor of TIMI 3 flow in the present study. In patients treated within 3 hours, the presence of Q waves was associated with a much lower rate of successful reperfusion (44% vs 68%, p ,0.01). These patients may benefit most from alternative reperfusion strategies, including primary angioplasty. Angioplasty versus thrombolytics as the reperfusion strategy: Angioplasty has been shown to achieve a
higher TIMI 3 flow rate than intravenous thrombolysis does,9 –11 but generally with some delay. In the Global Utilization of Streptokinase and TPA for Occluded arteries (GUSTO-IIb) trial, comparing primary angioplasty and accelerated tissue plasminogen activator (t-PA) in acute myocardial infarction,10 the primary end point of death, nonfatal myocardial infarction, or nonfatal stroke occurred in 9.6% of the angioplasty group versus 13.7% of the t-PA group (p 5 0.033). There was a trend toward a greater early benefit in the angioplasty group in patients presenting $4 hours after the onset of chest pain. At 6 months, however, the advantage of angioplasty over t-PA was not statistically significant. In the second Primary Angioplasty in Myocardial Infarction (PAMI-2) trial,11 inhospital mortality was similar at all time points up to 12 hours after the onset of chest pain. These observations may relate to restoration of TIMI 3 flow by angioplasty, regardless of the time elapsed since the onset of chest pain.11 In contrast, greater delay from symptom onset to commencement of thrombolytic therapy may result in decreased TIMI grade 3 flow2,7,12 and increased mortality.13,14 The treatment option of primary angioplasty is not available in many communities, and thrombolytic therapy is the only option for reperfusion. Streptokinase continues to be used widely in many parts of the world, not only because it is cheaper, but partly also because it is JANUARY 15, 1999
associated with a lower incidence of intracerebral bleeding than t-PA.15–17 This study shows that the absence of Q waves in the presenting electrocardiogram and a short time interval from the onset of symptoms to therapy independently correlate with a high TIMI 3 flow rate when streptokinase is used. Why is the presence of Q waves useful in predicting TIMI flow? The use of these evolving electrocardio-
graphic changes in predicting successful clot lysis may be explained by their relation to the duration of occlusion. Their importance, even when the duration of chest pain is known, would imply that the latter is only a crude estimate of the duration of occlusion. Perception of pain is subjective, particularly in diabetic patients18 and the elderly, and some patients have episodes of silent ischemia, masking the precise definition of the onset of coronary artery occlusion. Also, many patients with acute myocardial infarction have prodromal angina,19 –21 which may be protective through the mechanism of ischemic preconditioning19,20 or enhanced recanalization with thrombolytic administration.21 These episodes of prodromal angina could also cause difficulty in defining the duration of coronary occlusion. This may partly explain our finding that the absence of Q waves was an independent predictor of TIMI 3 flow even when the duration of chest pain was taken into account. Despite its limitations, the duration of chest pain is one of the main factors used to determine patients’ eligibility for thrombolytic therapy.6,22 Animal studies have shown that coronary occlusion produces a wavefront of myocardial necrosis that progresses with time from the subendocardium towards the epicardium.23 The size of the infarct is also influenced by other factors, including spontaneous intermittent reperfusion,24 collateral coronary circulation,25 and the level of myocardial demands.26 New pathologic Q waves generally reflect myocardial necrosis, although ischemia-induced intramyocardial conduction delay, which causes a shift in early electrical force, may also be important.27 The presence of pathologic Q waves is a direct indication of the late phase of ischemic insult after coronary occlusion, whereas the time from the onset of chest pain may be only indirectly related. In the Late Assessment of Thrombolytic Efficacy (LATE) trial, where mortality decreased with thrombolytic therapy was seen to extend to 12 hours, over half of the patients recruited did not have pathologic Q waves in their initial electrocardiograms.28 In the current study, about half of the patients had pathologic Q waves. The finding of improved reperfusion rates when Q waves were absent in the presenting electrocardiogram suggests that the time window for the benefits of thrombolytic therapy could be widened. Other factors associated with infarct artery patency:
About a quarter of the patients in this study had T-wave inversion in their presenting electrocardiogram. On its own, T-wave inversion was associated with a low TIMI 3 flow rate, but this association was largely explained by other covariates, including patho-
logic Q waves and time to therapy. In situations where the precise onset of chest pain cannot be determined, T-wave inversion may also be a helpful feature, in addition to pathologic Q waves, in predicting successful reperfusion. In this study, age was also a significant predictor of the TIMI 3 flow rate, whereas in the GUSTO report, combining the results of different thrombolytic regimens, age had no relation to the 90-minute TIMI 3 flow rate.29 This study was based on the use of streptokinase as the thrombolytic agent in the HERO trial, with co-administration of aspirin and either heparin or hirulog. It is possible that the electrocardiographic relation with patency rates could be different with other thrombolytic regimens. 1. White HD, Aylward PE, Frey MJ, Adgey AAJ, Nair R, Hillis WS, Shalev Y, Brown MA, French JK, Collins R, Maraganore J, Adelman B, on behalf of the Hirulog Early Reperfusion/Occlusion (HERO) Trial Investigators. Randomized, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Circulation 1997; 96:2155–2161. 2. Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, et al. 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. 3. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction [published erratum appears in N Engl J Med 1994;330:516]. N Engl J Med 1993;329:1615–1622. 4. Karagounis L, Sorenson SG, Menlove RL, Moreno F, Anderson JL. Does thrombolysis in myocardial infarction (TIMI) perfusion grade 2 represent a mostly patent artery or a mostly occluded artery? Enzymatic and electrocardiographic evidence from the TEAM-2 study. J Am Coll Cardiol 1992;19:1–10. 5. Vogt A, von Essen R, Tebbe U, Feuerer W, Appel K-F, Neuhaus K-L. Impact of early perfusion status of the infarct-related artery on short-term mortality after thrombolysis for acute myocardial infarction: retrospective analysis of four German multicenter studies. J Am Coll Cardiol 1993;21:1391–1395. 6. French JK, Williams BF, Hart HH, Wyatt S, Poole JE, Ingram C, Ellis CJ, Williams MG, White HD. Prospective evaluation of eligibility for thrombolytic therapy in acute myocardial infarction. Br Med J 1996;312:1637–1641. 7. Anderson JL, Rothbard RL, Hackworthy RA, Sorensen SG, Fitzpatrick PG, Dahl CF, Hagan AD, Browne KF, Symkoviak GP, Menlove RL, Barry WH, Eckerson HW, Marder VJ. Multicenter reperfusion trial of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial infarction: controlled comparison with intracoronary streptokinase. J Am Coll Cardiol 1988;11:1153–1163. 8. Anderson JL. Why does thrombolysis fail? Breaking through the reperfusion ceiling. Am J Cardiol 1997;80:1588 –1590. 9. Grines CL, Browne KF, Marco J, Rothbaum D, Stone GW, O’Keefe J, Overlie P, Donohue B, Chelliah N, Timmis GC, Vlietstra RE, Strzelecki M, PuchrowiczOchocki S, O’Neill WW, for the Primary Angioplasty in Myocardial Infarction Study Group. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993;328:673– 679. 10. 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. 11. Stone GW, Brodie B, Griffin J, Donohue B, Costantini C, Jones D, Graham M, Grines C. Should the risk of delaying reperfusion prohibit inter-hospital transfer to perform primary PTCA in acute myocardial infarction? (abstr). Circulation 1996;94(suppl I):I-331. 12. Stewart JT, French JK, The´roux P, Ramanathan K, Solymoss BC, Johnson R, White HD. Early noninvasive identification of failed reperfusion after intravenous thrombolytic therapy in acute myocardial infarction. J Am Coll Cardiol 1998;31: 1499 –1505. 13. 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. 14. Boersma E, Maas ACP, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet 1996;348:771–775. 15. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329: 673– 682.
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GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12 490 patients with acute myocardial infarction. Lancet 1990;336:65–71. 17. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41 299 cases of suspected acute myocardial infarction. Lancet 1992;339:753–770. 18. Kannel WB. Lipids, diabetes, and coronary heart disease: insights from the Framingham study. Am Heart J 1985;110:1100 –1107. 19. Kloner RA, Shook T, Przyklenk K, Davis VG, Junio L, Matthews RV, Burstein S, Gibson M, Poole WK, Cannon CP, McCabe CH, Braunwald E. Previous angina alters in-hospital outcome in TIMI 4: a clinical correlate to preconditioning? Circulation 1995;91:37– 45. 20. Ottani F, Galvani M, Ferrini D, Sorbello F, Limonetti P, Pantoli D, Rusticali F. Prodromal angina limits infarct size: a role for ischemic preconditioning. Circulation 1995;91:291–297. 21. Andreotti F, Pasceri V, Hackett DR, Davies GJ, Haider AW, Maseri A. Preinfarction angina as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infarction. N Engl J Med 1996;334:7–12. 22. White HD. Thrombolytic therapy for patients with myocardial infarction presenting after six hours. Lancet 1992;340:221–222. 23. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wave-front
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phenomenon of ischemic cell death. I. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation 1977;56:786 –794. 24. Hackett D, Davies G, Chierchia S, Maseri A. Intermittent coronary occlusion in acute myocardial infarction: value of combined thrombolytic and vasodilator therapy. N Engl J Med 1987;317:1055–1059. 25. Christian TF, Schwartz RS, Gibbons RJ. Determinants of infarct size in reperfusion therapy for acute myocardial infarction. Circulation 1992;86:81–90. 26. Reimer KA, Jennings RB, Cobb FR, Murdock RH, Greenfield JC Jr, Becker LC, Bulkley BH, Hutchins GM, Schwartz RP Jr, Bailey KR, Passamani ER. Animal models for protecting ischemic myocardium: results of the NHLBI cooperative study: comparison of unconscious and conscious dog models. Circ Res 1985;56:651– 665. 27. Selvester RH, Wagner NB, Wagner GS. Ventricular excitation during percutaneous transluminal angioplasty of the left anterior descending coronary artery. Am J Cardiol 1988;62:1116 –1121. 28. Langer A, Goodman SG, Topol EJ, Charlesworth A, Skene AM, Wilcox RG, Armstrong PW, for the LATE Study Investigators. Late Assessment of Thrombolytic Efficacy (LATE) Study: prognosis in patients with non-Q wave myocardial infarction. J Am Coll Cardiol 1996;27:1327–1332. 29. Lesnefsky EJ, Lundergan CF, Hodgson JM, Nair R, Reiner JS, Greenhouse SW, Califf RM, Ross AM. Increased left ventricular dysfunction in elderly patients despite successful thrombolysis: the GUSTO-I angiographic experience. J Am Coll Cardiol 1996;28:331–337.
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