(Circulation. 1995;91:1905-1907.)
© 1995 American Heart Association, Inc.
Articles |
Optimal Management of Acute Myocardial Infarction Requires Early and Complete Reperfusion
From the Division of Cardiology, University of Washington, Seattle, Wash.
Correspondence to J. Ward Kennedy, MD, University of Washington, Division of Cardiology, RG-22, 1959 NE Pacific Street, Seattle, WA 98195.
Key Words: Editorials • myocardial infarction • reperfusion
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Thrombolytic therapy for the treatment of acute myocardial infarction (AMI) began more than 15 years ago with the initial observations of Rentrop et al1 and others2 that demonstrated the feasibility of reperfusing totally occluded coronary arteries in patients with AMI with the infusion of intracoronary streptokinase (ICSK). The intracoronary route of administration was hampered by the need for early cardiac catheterization, delaying the initiation of therapy, which many believed made this approach to treatment impractical. Despite this limitation, intracoronary thrombolytic therapy resulted in patency rates that were generally higher and achieved more rapidly than intravenous therapy once treatment was begun. One of the earliest trials of intracoronary therapy, which randomized patients early in the course of AMI, demonstrated improved left ventricular function as compared with control patients, a finding that many randomized trials of intravenous thrombolytic therapy have failed to demonstrate.3 One of the great advantages of intracoronary administration over the intravenous route is the immediate angiographic demonstration of the success or failure of the therapy. In our Western Washington ICSK trial,4 5 we randomized 250 patients to either ICSK or no thrombolytic therapy. All patients underwent immediate coronary angiography and were randomized after the identification of a partially or totally occluded infarct-related coronary artery. Of the vessels that were totally occluded at the time of the initiation of the streptokinase infusion, 67% completely reperfused at an average of 31 minutes after the onset of therapy. The adequacy of coronary artery reperfusion was judged by an angiographic reading committee that classified patients as having complete, partial, or no reperfusion. Although the 30-day survival in this trial was significantly better in the treatment than in the control patients (3.7% versus 11.2%, P<.02), by 1 year this difference was no longer significant. However, when the survival of all patients was analyzed by their status of reperfusion immediately after therapy, there was much better 1-year survival for patients with complete reperfusion (98%) as compared with those who had either partial (77%) or no reperfusion (85%). Although the difference in 1-year survival was not statistically different between patients with no reperfusion as compared with those with partial reperfusion, there is a clear trend toward reduced survival for those with partial reperfusion, suggesting that partial reperfusion is harmful. This trial has been referred to as one of the early demonstrations of the influence that an "open artery" has on the outcome of patients after AMI, since the demonstrated reduction in early mortality could not be accounted for by improved left ventricular function in the treatment group. This also may be the first demonstration that partial reperfusion is harmful, although we did not recognize this possible phenomenon at the time we reported these findings.
After completion of the early intracoronary thrombolytic trials and the development of effective intravenous thrombolytic therapy, a great deal of activity was directed toward the development of better intravenous thrombolytic agents. Among the most important of these efforts was the development of the Thrombolysis in Myocardial Infarction (TIMI) studies. TIMI I was designed to evaluate the relative effectiveness of a new intravenous thrombolytic agent, rTPA, which was compared with intravenous streptokinase.6 These patients underwent coronary angiography before beginning the infusion of the study drug, and the results of therapy were monitored by serial coronary angiograms. TIMI I demonstrated that rTPA resulted in a much higher rate of reperfusion as compared with streptokinase. The TIMI protocol defined the degree of reperfusion into four grades (0, absent antigrade flow; 1, penetration of the thrombus by contrast material but incomplete filling of the distal vessel; 2, complete opacification of the distal vessel with delayed filling or washout; and 3, normal vessel flow). This classification scheme is more complex than the system used in the Western Washington Studies because it incorporated two levels of partial reperfusion (grades 1 and 2). However, both the TIMI investigators and many others who have used the TIMI classification of reperfusion have usually combined grades 0 and 1 in their analysis, so that in reality only three grades of reperfusion have been used, similar to the Western Washington reperfusion grading system.
A recent report from the TEAM investigators7 and two reports from the GUSTO investigators,8 9 including that of Simes et al,9 which appears in this issue of Circulation, provides convincing evidence in a very large number of patients with AMI that only those who achieve complete reperfusion benefit from thrombolytic therapy. It is also now apparent, in retrospect, that the small Western Washington ICSK trial provided the first evidence that partial reperfusion does not benefit patients with AMI and may be harmful.5
Anderson et al7 have done an analysis of the results of the Thrombolysis Trial of Eminase Versus Activase in Myocardial Infarction (TEAM 3) investigation. In this study, 298 patients with AMI were randomized within 4 hours from the onset of symptoms to receive either intravenous Activase or Eminase. On the following day, the patency of the infarct-related artery was evaluated by coronary angiography. In this study, 74% of patients at day-1 angiography had TIMI 3 flow as compared with 13% with grade 2 flow and 12% with grade 0 or 1 flow. Patients with TIMI 2 flow had a similar outcome as those with TIMI 0 and 1 flow in regard to ejection fraction, enzyme peak, ECG markers of infarct size, and index of morbidity. By comparison, TIMI 3 flow on the day after thrombolytic therapy was significantly associated with improved ejection fraction, earlier enzyme peak, greater infarct zone ejection fraction, and a trend toward a lower morbidity index. Thus, this study convincingly demonstrates the superior outcome of patients with complete reperfusion after thrombolytic therapy. The TEAM 3 investigators did not perform early coronary arteriography and therefore could not evaluate the relative value of early reperfusion on the outcome of their patients.
The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) is a large trial of 41 021 patients who were randomized within 6 hours of the onset of symptoms of AMI to one of four thrombolytic regimens: IVSK with subcutaneous heparin, IVSK with intravenous heparin, front-loaded tissue plasminogen activator (rTPA), or a combination of streptokinase and rTPA.10 The trial included a mechanistic substudy in which patients were randomized to 90-minute angiography to classify the success of reperfusion therapy using the TIMI criteria.11 Kleiman and colleagues8 have carried out a detailed analysis of the relation between the patient's status of 90-minute reperfusion and mortality within the first 24 hours after thrombolytic therapy. In the overall trial, there were 2851 deaths in the first 30 days, with 1125 (38%) of these occurring within the first 24 hours after therapy. In the patients in the angiographic substudy, there was little difference in mortality during the first 6 hours between those with grade 0 or 1 and those with grade 3 flow, whereas mortality was 3 to 4 times higher in those with grade 2 flow, suggesting that partial reperfusion at 90 minutes after thrombolytic therapy is harmful. After 6 hours, there was little additional mortality during the next 18 hours in the patients with complete reperfusion, whereas mortality continued to increase in those with partial or no reperfusion. By 24 hours, the mortality was highest in the patients with TIMI 2 flow being 2.93%, 2.35% in those with grade 0 or 1 flow, and lowest, 0.89%, in the patients who had normal flow at 90 minutes. These results demonstrate that mortality within the first 6 hours after AMI is largely determined by the baseline condition of the patient and is largely unaffected by the early success or failure of thrombolytic therapy. By 24 hours, mortality is greatly reduced by successful reperfusion but is higher in those with partial reperfusion than those without reperfusion, suggesting that partial reperfusion results in additional damage to the left ventricle.
One of the most important features of the GUSTO trial was the inclusion of a mechanistic angiographic substudy, which makes it possible to relate the findings on early angiography to the outcome of patients both in the substudy and in the study as a whole.11 The angiographic substudy consisted of 2431 patients, of whom 1210 were randomized to undergo coronary angiography at 90 minutes after the initiation of one of the four thrombolytic protocols. The perfusion grade was determined for patients in each treatment group, and their outcome was used to develop a model to predict mortality for the large trial. The model was developed with the assumption that any difference in outcome between treatment groups was due to a difference in the adequacy of reperfusion as determined at 90 minutes. The mortality of each treatment group was then predicted based on the proportion of each group achieving each level of reperfusion (TIMI grades 0 to 3) and the mortality associated with that level of patency averaged over all treatment groups.
Among the 1210 patients who were randomized to a 90-minute angiogram, grade 3 flow was significantly higher in the patients who received TPA (54%) as compared with the other treatment groups. Over all four treatment groups, 452 (37%) of the patients achieved grade 3 flow and had a 30-day mortality of 4.0%. Those with grades 0, 1, and 2 flow had a 30-day mortality of 8.4%, 9.2%, and 7.8%, respectively. The 34 patients who failed to have their assigned 90-minute angiogram had a 30-day mortality of 18.2%. When the predictive model was applied to each of the treatment groups in the entire study, the observed mortality and the predicted mortality had a very high correlation. The predicted versus the observed mortality for the streptokinase and subcutaneous heparin group was 7.46 versus 7.28; for streptokinase and intravenous heparin, 7.26 versus 7.39; for TPA, 6.31 versus 6.37; and for TPA and streptokinase, 6.98 versus 6.96. The close relation between the predicted and observed 30-day mortality for each treatment group clearly demonstrates that the variation in the success of early reperfusion is the primary determinant of the differences in 30-day outcome between the treatment groups.
From the data that I have briefly reviewed and from numerous other studies not cited, I believe that early and complete reperfusion must be the goal when applying reperfusion therapy for patients with AMI. In addition, it now seems very likely that incomplete reperfusion at 90 minutes is harmful. Since GUSTO has demonstrated that incomplete reperfusion is a frequent outcome of various thrombolytic regimens, ranging from 25% to 35%, major efforts must be made to both reduce the incidence of incomplete reperfusion while increasing the proportion of patients who achieve complete reperfusion. It is not clear how this goal can be achieved with the use of currently available thrombolytic agents. It has been clearly demonstrated that complete reperfusion is the usual outcome after direct angioplasty for the treatment of AMI, with patency rates in the range of 90% to 95%.12 In addition, partial or incomplete reperfusion is an unusual outcome of angioplasty performed in the setting of AMI.13 Small and medium-sized randomized trials of angioplasty versus thrombolytic therapy for AMI are now reporting reduced mortality and, very importantly, a reduction in the risk of total and hemorrhagic strokes.12 14 It appears very likely that these superior outcomes are the result of both a high rate of early and complete reperfusion and a low rate of partial reperfusion, with its associated harmful effects.
Today, many cardiologists are selecting direct angioplasty as the therapy of choice in the management of high-risk patients with AMI. The economic and social consequences of a major shift away from thrombolytic therapy in favor of direct angioplasty for the treatment of AMI are great and need to be based on better information than is currently available. The GUSTO 2 investigators are making an effort to further evaluate this important question. I believe that the National Institutes of Health should support a large sample trial to better define the appropriate role of these two important therapies. It must be appreciated that very early and expertly performed direct angioplasty is unavailable for the treatment of the majority of patients with AMI in the United States today and is even less available in most other developed countries. Early intravenous thrombolytic therapy remains an excellent treatment for many patients with AMI and must be vigorously applied when expert angioplasty is not immediately available as an alternative treatment. It can be anticipated that advances in angioplasty, thrombolytic agents, and adjunctive therapies for both of these methods of reperfusion will be made in the near future, which will further reduce the overall current high mortality that results from AMI.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Received January 31, 1995; accepted February 2, 1995.
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References |
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TopIntroductionReferences |
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1. Rentrop P, Blanke H, Karsch KR, Kaise H, Kostering H, Leitz K. Selective intracoronary thrombolysis in acute myocardial infarction and unstable angina pectoris. Circulation. 1981;63:307-317.
2. Ganz W, Buchbinder M, Marcus H, Mondkar A, Maddahi J, Charuzi Y, O'Connor L, Shell W, Fishbein MC, Kass R, Miyamoto A, Swan HJC. Intracoronary thrombolysis in evolving myocardial infarction. Am Heart J. 1981;101:4-13. [Medline] [Order article via Infotrieve]
3. Anderson JL, Marshall HW, Bray BE, et al. A randomized trial of intracoronary streptokinase in the treatment of acute myocardial infarction. N Engl J Med. 1983;308:1312-1318. [Abstract]
4. Kennedy JW, Ritchie JL, Davis KB, Fritz JK. Western Washington Randomized Trial of Intracoronary Streptokinase in Acute Myocardial Infarction. N Engl J Med. 1983;309:1477-1482.[Abstract]
5. Kennedy JW, Ritchie JL, Davis KB, Stadius ML, Maynard C, Fritz JK. The Western Washington Randomized Trial of Intracoronary Streptokinase in Acute Myocardial Infarction. N Engl J Med. 1985;312:1073-1078. [Abstract]
6. TIMI Special Report. The Thrombolysis in Myocardial Infarction (TIMI) trial: phase I findings. N Engl J Med. 1985;312:932-936. [Medline] [Order article via Infotrieve]
7.
Anderson JL, Karagounis LA, Becker LC, Sorensen SG, Menlove
RL, TEAM-3 Investigators. TIMI perfusion grade 3 but not grade 2
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8.
Kleiman NL, White HD, Ohman EM, Ross AM, Woodlief LH, Califf
RM, Holmes DR, Bates E, Pfisterer M, Vahanian A, Topol EJ, GUSTO
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9.
Simes RJ, Topol EJ, Holmes DR, White HD, Rutsch WR, Vahanian
A, Simoons ML, Morris D, Betriu A, Califf RM, Ross AM, GUSTO-I
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Circulation. 1995;91:1923-1928.
10.
GUSTO-I Investigators. An international randomized trial
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11.
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13.
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