The Western Washington and Myocardial Infarction Triage and Intervention Trials of Thrombolytic Therapy: 15 Years of Collaboration in the Pacific Northwest

The Western Washington and Myocardial Infarction Triage and Intervention Trials of Thrombolytic Therapy: 15 Years of Collaboration in the Pacific Northwest

CHARLES MAYNARD, PH.D., NATHAN R. EVERY, M.D., JENNY S. MARTIN, R.N.,

ALFRED P. HALLSTROM, PH.D., J. WARD KENNEDY, M.D., and W. DOUGLAS WEAVER, M.D.

Froin the University of Washington School of Medicine. Department of Medicine and the University of Washington School of P iiblic Health and Cominrinify Medicine, Department of Biosraristics, Seattle, Washington.

Beginning in 1981. collaborative efforts developed between the University of Washington and community hospitals in Washington, British Columbia, Canada, and later outside the Pacific Northwest, have generated important findings about the treatment and outcome of acute myocardial infarction (AMI). These efforts, collectively known as the Western Washington and Myocardial lifarction Triage and Intervention Project trials, have included randomized trials of tlirombolytic drugs, direct antithrombins, platelet receptors, antagonists, and cell adhesion blockers. as well a s the formation of registries ojconsecutive patients admitted to coronary care units with the diagnosis of suspected AMI. Results of these trials have demonstrated that thronibolytic therapy signijicantly reduces mortality and morbidity from AMI with minimal risk to patients, and that early treatment is associated with improved infarct size and better left ventricular function. The efforts of the next decade should be fQcused on the further removal of barriers to rapid treatment and to the evaluation of new agents, so that the devastating effects of myocardial infarction are ri~inirniied to the fullest extent. (J Interven Cardiol 1997; 10: 171- 182)

Introduction

Thrombolytic therapy has been the most important advance in the treatment of acute myocardial infarction (AMI) in the last 15 years. Thrombolytic drugs such as streptokinase, recombinant tissue plasminogen activator (rt-PA) , and now reteplase (r-PA) have dramatically reduced mortality and morbidity from AM1 by reperfusing occluded coronary arteries and halting the process of ischemic necrosis. Beginning in 198 1, collaborative efforts developed between the Univer- sity of Washington School of Medicine and community hospitals in Washington, Idaho, Oregon, British Columbia, Canada, and later outside the Pacific North- west (Table 1) and have generated important new findings about the treatment and outcome of AMI. These efforts have included randomized trials of thrombo-

Address for reprints: Charles Maynard, Ph. D.. MITI Coordinating Center. 1910 Fairview Ave E #204, Seattle. WA 98102. Fax: (206) 543- 1690. E-mail: [email protected]

lytic agents, direct antithrombins, platelet receptors, antagonists, and cell adhesion blockers, as well as the formation of registries of consecutive patients admitted to coronary care units with the diagnosis of suspected AMI.

Although conducted over a 10-year period, these trials have several factors in common. First, the implementation and successful completion of these trials were dependent upon the efforts of investigators, nurses, paramedics, and other personnel at the Univer- sity of Washington and other medical centers and hospitals, and the Seattle and King County emergency medical services. Second, over the years of the early trials, there were national and particularly regional efforts to reduce the time from symptom onset to treatment for AMI, so as to better understand the obstacles to seeking emergency medical care. Third, in addition to assessing conventional clinical and angiographic end points, many trials also used quantitative radionuclide methods to measure ventricular function and infarct size in survivors of the index hospitalization at

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Table 1. Western Washington and Myocardial Infarction Triage and Intervention Trials and Registries

Trial Year5 Comparison Number of Patients Endpoint

WWlC 1981LX3 1C SK vs. control 250 30 day mortality WWIV 1983-xh 1V SK vs. control 368 I4 day mortality WW ED rt-PA 1987-xx IT-PA I60 I4 day mortality WW rt-PA Registry 1987-XX I .028 MITI 1 ')XU-') I Prehospital- vs. hospital-initiated rt-PA 360 Composite endpoint* MITI registry 1988-94 12.33 I

* Composite score combining death. atroke. major bleeding. and infarct size.

ED = emergency department: IC = intracoronary: IV = intravenous: MITI = Myocardial Infarction Triage and Intervention: rt-PA = recombinant tissue plasminogen activator: WW = Western Washington: SK = streptokinase.

the Seattle Department of Veterans Affairs Medical Center and later at the Georgetown University Medical Center. Finally. to better understand the long-term effects of thrombolytic therapy, long-term follow-up of patients enrolled in all four trials was conducted.

Western Washington Intracoronary Streptokinase Trial

Under the leadership of J . Ward Kennedy, MD. the Western Washington Intracoronary Streptokinase Trial began in July 1981 in 14 hospitals in Western Washington and British Columbia. It ended in Febru- ary 1983.'-' This trial, which was supported in part by the W.M. Keck Foundation and the Medical Research Service of the Veterans Administration, was a randomized comparison of intracoronary streptokinase versus standard therapy, with all patients undergoing coronary angiography prior to randomization. The trial enrolled 250 patients who were 5 75 years of age, arrived at the hospital 5 12 hours from symptom onset, had appropriate electrocardiographic changes, and did not have contraindications to anticoagulation therapy. Patients who had treatment of congestive heart failure prior to the onset of AM1 were not eligible for randomization.

The two groups were similar with respect to baseline characteristics (Table 2 ) . The time from symptom onset to hospital arrival was 2.2 hours for 134 treatment patients and 2.3 hours for 116 controls, and the time from symptom onset to treatment was 4.6 hours (Fig. 1. Table 2). The remarkable finding of this study was a threefold reduction in mortality for patients receiving intracoronary streptokinase; 30-day mortality was 3.7% in the treatment group and 11.2% in the

control group (P = 0.02).' It was the first trial of thrombolytic therapy to show a mortality reduction due to treatment. Treatment patients also had better angina and functional class at discharge than did control patients. However, radionuclide ejection fraction at discharge was similar in the two groups.

Follow-up studies were unable to demonstrate differences in key end points that were consistent with the observed mortality difference. For example, radionuclide ejection fraction and thallium infarct size measured approximately 2 months after treatment were similar in treatment and control patients (Fig. 2).? Analysis of echocardiograms performed 2 months after treatment also showed similar outcomes for treatment and control patients.6 The results of a I-year follow-up study demonstrated that intracoronary streptokinase reduced one year mortality, but only in patients with complete coronary artery reperfusion.4 One-year survival was 98% in 80 patients with complete reperfusion, 77% in 14 individuals with partial reperfusion, and 85% in 41 patients with no reperfusion. In comparison, 85% of control patients were alive at 1 year. However, follow-up infarct size and ejection fraction did not differ according to reperfusion status. Again, one is left with the puzzling result of a marked reduction in mortality far greater than expected from a small reduction in infarct size. It is likely that this result is a function of late reperfusion achieved by intracoronary streptokinase; that is, mortality was reduced, but reperfusion was too late to bring about significant reductions in infarct size. From this and other observations has been borne the "open artery hypothesis" that the benefit of coronary artery patency seems to transcend what can be explained by myocardial sal- vage alone.

In addition to these findings, several other analyses

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WESTERN WASHINGTON AND MITI TRIALS

Table 2. Characteristics of Patients Enrolled in the Western Washington and Myocardial Infarction Triage and Intervention Trials

Characteristic WWlC WWIV II-PA MITI

Age Women History MI Anterior MI Delay time (hrs) Time from symptom onset to treatment (hrs) Infarct size (treated patients only) Radionuclide EF (treated patients only)

56 f 10 15% 13% 46%

2.2 f 2.4 4.6 f 2.2 19 f 13 46 f 14

57 f I 1 18% 14% 36%

1.9 i 1.4 3.5 f 1.4 15 t 13 51 f 15

58 2 10 19% 16% 38%

1.6 f 1.1 2.3 f 2.8 13 2 1 1 51 t 15

58 f 10 I X% 20% 39%

1.1 f 0.8 1.8 ? 0.9 6.4 f 8.8 54 f 12

EF = ejection fraction; IC = intracoronary; IV = intravenous; MI = myocardial infarction; MITI = Myocardial Infarction Triage and Intervention; rt-PA = recombinant tissue plasminogen activotor; WW = Western Washington.

utilizing information from the intracoronary trial have produced important findings concerning coronary anatomy and function and risk stratification, as well as the comparability of methods for measuring infarct size and left ventricular f~nc t ion .~ . ' . ~ Since all patients enrolled in the trial had baseline angiograms performed prior to the administration of streptokinase, it was possible to obtain baseline information about infarct location and left ventricular function. All avail- able angiograms were read centrally by a panel of car- diologists, and when possible, quantitative analyses of left ventricular angiograms were performed. An important finding of these analyses was that location of the infarct related occlusion was the most important determinant of global and regional left ventricular function.s In addition, the baseline angiographic ejection fraction was an important predictor of 1-year sur-

5

4

3 VI

i

% 1

0

Figurm

ww IC ww IV W t t - P A MlTl

1. Time from symptom onset to treatment and delay ..me ~. in patients receiving thrombolytic therapy (1981-1991). IC = intracoronary; IV = intravenous; MITI = Myocardial Infarction Triage and Intervention: rt-PA = recombinant tissue plasminogen activator; WW = western Washington.

vival.' These two papers, published over 10 years ago, have contributed to our understanding of the natural history and pathology of AMI.

Western Washington Intravenous Streptokinase Trial

While intracoronary streptokinase reduced hospital mortality, its method of administration has two major limitations. First, it has to be delivered in a cardiac catheterization lab, which is not present in every hospital, and second, the time required to give the drug once the patient arrives at the hospital is frequently too long, particularly during the late evening or early morning hours. In order to achieve the full benefits of reperfusion, the drug must be given to more eligible patients, and it must be given more rapidly than can be done in most cardiac catheterization facilities. As a result, interest shifted to intravenous administration of thrombolytic therapy.

The Western Washington Intravenous Streptokinase Trial began in September 1983 and ended July 3 1, 1986, after enrolling 368 patients in 27 hospitals in Washington, Idaho, and Vancouver, British Colum- biae9-I3 The trial was a randomized comparison of intravenous streptokinase versus standard therapy; it was supported in part by the W.M. Keck Foundation, the National Heart Lung and Blood Institute, and the Seat- tle Veterans Administration Medical Center. Entry criteria were similar to those used in the intracoronary trial, although arrival < 6 hours from symptom onset was required. Patients with history of congestive heart failure were included, although those with prior coronary artery bypass surgery were excluded.

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ICSK ICC I V S K IVC ED PRE HOS

Both groups had similar baseline characteristics, although the mean delay time for the streptokinase group was slightly less (1.8 vs 2.1 hours).' The time from symptom onset to treatment was 3.5 hours. 1 hour less than in the intracoronary trial. Mortality at 14 days was 6.3%, in 191 treatment patients and 9.6% in 177 control patients ( P = 0.23). There appeared to be no survival benefit for those patients with inferior infarction; 14 day mortality was actually higher in treated patients (4.0% vs 1.8'70). although this difference was not statistically significant ( P = 0.32). However, for patients with anterior AMI, mortality was worse for control patients (10.4% vs 22.4%. P = 0.06). Other measures of outcome (including length of stay, angina class, and the presence of congestive heart failure) were similar in treatment and control patients. Intrace- rebral hemorrhage occurred in one (0.5%) patient randomized to streptokinase.

The major conclusion of the trial was that patients with anterior AM1 treated within 6 hours of symptom onset had improved survival. I t was also the case that a higher proportion of treatment patients received coronary angioplasty (6.3% vs 2.8%) and/or coronary artery bypass graft surgery (6.8% vs 5.6%) within 14 days of randomization. The trial was one of many con- firming the benefit of intravenous thrombolytic therapy. As in the intracoronary trial, surviving patients underwent radionuclide and thallium infarct size testing 2 months after infarction." In contrast to findings from the intracoronary trial. where treatment was instituted one hour later, in the intravenous trial the treatment group exhibited both smaller infarct size (19%

Figure 2. Radionuclide ejection fraction and thallium infarct size measurements in patients receiving thrombo- lyt ic therapy ( I98 I - I99 1 ). The error bars represent one standard deviation from the mean. ED = emergency department rt-PA trial: HOS = MlTl hospital initiated therapy: IC SK = intracoronary streptokinase; IC C =

intracoronary control; IS = infarct size: IV SK intravenous streptokinase; IV C = intravenous control; PRE = MlTl prehospital initiated therapy: RNEF = radionuclide ejection fraction.

t 13% vs 15 k 13%. P = 0.03) and improved left ventricular function (51% ? 15% vs 47% t 15%, P = 0.08). This improvement was evident only for patients with anterior infarction who arrived at the hospital within 3 hours of symptom onset. There was no benefit for patients with inferior infarction or for those with anterior infarction of > three hours duration. These results again emphasized the need for early treatment.

Long-term survival was similar for treatment and control patients in the intravenous trial. However, for anterior infarction, 2-year survival was 8 I % for patients receiving streptokinase and only 65% for those receiving standard therapy (P = 0.0S).9 By one year, 27% and 19% of treatment and control patients, respectively, had undergone a revascularization procedure.

As in the first trial, considerable effort was given to examination of coronary anatomy and left ventricular function and comparability of methods for measuring infarct size.'".'' Overall, 68% of patients underwent coronary angiography at an average of 10 days after randomization: 170 films were adequate for analysis of global and regional left ventricular function. Strep- tokinase resulted in better infarct artery patency, better global function as measured by angiographic ejection fraction, and better wall motion in the infarct zone as well as noninfarct areas."'

In a report which combined data from both trials, a higher proportion of streptokinase patients underwent coronary angioplasty within 1 year of randomization (7% vs 3%). but the use of coronary artery bypass

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surgery was similar as was the use of angioplasty for all years after randomization. I 3 Further follow-up of patients in the two trials was accomplished: the mean time to follow-up was almost 5 years for the 618 patients: only 3% were lost to follow-up. Three-year survival was 84% for treated patients and 82% for controls (P = 0.16): for patients with inferior infarction, 3-year survival was 89% and 91% for treatment and control patients, respectively (P = 0.63). For anterior AMI, 3 year survival was 76% for the streptokinase group and 67% for the control group (P = 0.14).

The Western Washington Emergency Department Tissue Plasminogen

Activator Treatment Trial and Registry

Although the time from symptom onset to treatment was reduced by 1 hour to 3.5 hours in the intravenous trial, this was still considered too long to realize the full benefits of early reperfusion. The Western Wash- ington Emergency Department Tissue Plasminogen Activator Treatment Trial was designed to reduce time to treatment by making the emergency department the locus of diagnosis and treatment activities. In addition, a new thrombolytic agent, rt-PA, was used in this non- randomized trial, which was supported by Genentech, Inc. of South San Francisco, CA. The primary objec- tive of the trial was to evaluate initiating administration of rt-PA in the emergency department. A randomized trial was not performed because clear evidence favoring thrombolytic therapy made a placebo controlled trial unethical. Second, there were insufficient resources to enroll the large numbers of patients required for a head-to-head comparison of thrombolytic agents. Entry criteria were similar to those used in the intravenous trial. In a departure from previous Western Washington trials, a registry of all patients with documented AM1 was established to determine the proportion of eligible patients who actually received thrombolytic therapy.

Between January 1987 and January 1988, 160 patients received rt-PA in eight hospitals in Seattle and Tacoma, Wa~hington.'~-'* Characteristics of patients treated with rt-PA were very similar to those of patients enrolled in the intravenous trial.'4 The average delay time was 1.6 hours, and the time from symptom onset to treatment was 2.3 hours, approximately 1 hour shorter than in the intravenous trial, where treatment

Table 3. Cardiac Procedure Utilization Prior to Hospital Discharge (Treated Patients Only)

Procedure WWIC WWIV rt-PA MITI

Coronary angiography - 72% 91% 73%

6% 198 27% Coronary artery bypass 10% 7%- 21% 14%

Days to angiography - 1 0 2 7 S f 3 ? + 2 Coronary angioplasty 2%

surgery

IC = intracoronary; IV = intravenous: MI = myocardial infarction: MITI = Myocardial Infarction Triage and intervention: rt- PA = recombinant tissue plasminogen activator: WW = Western Washington.

was started in the coronary care unit. Mortality at 14 days was 5.6%, and I-year survival was 92% (85% anterior and 96% inferior). Intracerebral hemorrhage occurred in three patients (1.9%). In comparison to the intravenous trial, a much higher proportion of patients underwent coronary angiography, doing so earlier in the course of hospitalization (Table 3). Furthermore, the proportion of patients undergoing revascularization procedures prior to hospital discharge increased dramatically in the emergency department trial.

At the eight participating hospitals, the medical records of all patients who developed AM1 during the course of the trial were reviewed. Of the 1,028 patients with documented AMI, 22% were eligible for thrombolytic therapy under study criteria, and of those eligible, 79% were offered therapy, with 72% enrolled in the trial. Women were less likely to meet eligibility criteria than men, but even among eligible patients, women were less likely to receive thrombolytic therapy."

As in the previous two trials, patients enrolled in the emergency department rt-PA trial had radionuclide ejection fraction and infarct size measurements performed 1 1 weeks after infarction, as well as echocardiographic evaluation of segmental wall motion at 1 I hours, and again at 13 weeks after i n f a r ~ t i o n . ' ~ , ' ~ The results of the first two trials demonstrated a trend to- ward a reduction in infarct size, with shorter time to treatment. However, in the emergency department rt- PA trial there was no association between infarct size or ejection fraction and time to treatment. Echocar- diographic analysis did demonstrate improvement in regional wall motion after early treatment with rt- PA.'5

The emergency department rt-PA trial documented that thrombolytic therapy could be delivered in a safe

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and effective manner in the emergency department. Treatment times were reduced by beginning diagnosis and treatment in the emergency department, as op- posed to the coronary care unit. In the eight hospitals that participated in both the intravenous and emergency department rt-PA trials, the time from hospital arrival to treatment was reduced from 91 to 52 minutes.I6 The trial also showed that the proportion of patients treated could be significantly increased if age restrictions were removed or if patients arriving > 6 hours from symptom onset were offered treatment.I4

The Myocardial Infarction Triage and Intervention Prehospital Treatment

Trial (MITI) and Registry

MITI Prehospital Treatment Trial. During the seven years of the Western Washington trials, the time from symptom onset to treatment was reduced by 50% from 4.6 hours in the intracoronary trial to 2.3 hours in the emergency department rt-PA trial. While it was a significant reduction, this time greatly exceeded the first hour from symptom onset, where the most dra- matic reductions in mortality and infarct size were expected to be achieved. Even with the best emergency medical system and the fastest emergency department, achieving the 1-hour goal is very difficult, since most patients delay at least 30 minutes prior to seeking help for their symptoms. However, identifying and treating patients either at home or at the place of symptom onset could result in shorter treatment times and improved outcomes for patients with AMI. The trial and registry were supported by the National Heart Lung and Blood Institute and by a grant from Genentech Inc., Marquette Electronics (Milwaukee, WI), and Pharmacia Deltec (St. Paul, MN).

The logistical challenges to developing a program for identifying AM1 in the field and for delivering thrombolytic therapy in the prehospital setting are considerable.” As in the previous Western Washington trials, the cooperation of the academic group and community hospitals was critical, but in the MITI trial, the Seattle and King County emergency medical system had significant roles. Whereas previously it was primarily responsible for transporting patients from the place of symptom onset to the hospital, the emergency medical system and its paramedics, under the remote guidance of an emergency physician, were now shar-

ing responsibility for identifying and treating patients with suspected AMI. In this sense, the MITI trial repre- sented a distinct departure from the previous trials.

Under the leadership of W. Douglas Weaver, M.D., the MITI prehospital treatment trial of prehospital versus hospital initiated thrombolytic therapy (rt-PA) was designed to assess the feasibility and efficacy of prehospital thrombolytic therapy.*’-’’ The trial began in 1988 involving 19 hospitals and all 15 paramedic units in Seattle, and suburban King County, Washington. Paramedics evaluated 8,863 patients who complained of chest pain and were considered for inclusion in the trial. This evaluation involved obtaining clinical findings, performing a prehospital ECG (which was transmitted to the hospital), and informing the patient about participation in the trial. The effort was aided in great part by engineers who developed a 12-lead ECG that could be transmitted by cellular telephone to the hospital, and by the Cellular One Division of McCaw Com- munications (Seattle, WA). The decision to randomize was made by a physician who reviewed clinical findings and results of the ECG. The drug was delivered by an infusion pump developed by Pharmacia Deltec. Over a 3-year period, the study enrolled and randomized 360 patients (175 prehospital, 185 in-hospital) who were 75 years of age or younger, had ST segment elevation, symptom duration 5 6 hours, and no risk factors for serious bleeding.

The primary end point of the trial was a composite score, which included death, stroke, serious bleeding, and tomographic thallium infarct size measured 30 days after infarction. The two groups were similar with respect to composite score (406 prehospital vs 400 in- hospital, P = 0.64), mortality (5.7% vs 8.1%, P = 0.49), radionuclide ejection fraction (53 vs 54, P = 0.34) , and infarct size (6.1 vs 6.6, P = 0.72). Hemor- rhagic stroke occurred in six patients (1.7%). A secondary analysis showed that treatment within 70 minutes of symptom onset was associated with a reduction in the in-hospital mortality rate from 8.7% to 1.2% (P = 0.04), a reduction in infarct size from 11.2% to 4.9% (P < 0.001), and an increase in ejection fraction from 49% to 53% (P = 0.03). This finding showed that treatment in the first, or “golden,” hour could essentially abort the infarct; in fact, 40% of the patients treated in the MITI prehospital thrombolytic trial had no measurable infarct by quantitative thallium imaging.

In the MITI trial, the mean time from symptom onset to treatment was 92 & 58 minutes (median, 77

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min) in the prehospital group and 120 2 49 minutes (median, 110 min) in the hospital group; thus, prehos- pita1 therapy resulted in a 33-minute reduction in time to treatment. The time to treatment in the hospital group was more rapid than expected, resulting in minimal variation in treatment time. Virtually all patients were treated within three hours of symptom onset. These rapid treatment times resulted in very small infarct sizes; the overall infarct size was 6% and was approximately 10% for anterior AM1 and 3% for inferior infarcts. These results are vastly different from the much larger infarct sizes obtained in the Western Washington trials (Fig. 2, Table 2).

As in the previous trials, the influence of thrombolytic therapy on long-term survival was examined in the MITI trial.21 Two-year survival was 89% for prehospital and 91% (P = 0.46) for hospital-treated patients. Two-year survival (free of death or readmission to the hospital for angina, myocardial infarction, congestive heart failure, or revascularization) was 56% and 64% for prehospital and hospital patients, respectively (P = 0.42). For patients treated < 70 minutes from symptom onset, 2-year survival was 98%, and it was 88% for those treated later (P = 0.12). Two-year event-free survival was 65% for the early group and 59% for the late group (P = 0.80). Poorer long-term survival was associated with advanced age, history of congestive heart failure, and coronary artery bypass surgery performed before the index hospitalization, but not with time from symptom onset to treatment. Finally, the utilization of cardiac procedures both prior to and after hospital discharge was similar in both randomization groups. In comparison to previous trials, there was an increase in the use of coronary angioplasty prior to hospital discharge (Table 3). This finding is most likely related to advances in the use of angioplasty in patients with AMI.

MITI Registry. The MITI registry, which lists all patients admitted to Seattle metropolitan area hospitals with the diagnosis of suspected AMI, was implemented in part to add perspective to the randomized

Since the trial evaluated only those patients considered to be candidates for thrombolytic therapy (20%-40% of all patients with AMI), study investigators believed it was essential to collect information on patients who were not eligible for thrombolytic therapy, as well as those who were eligible but were not enrolled in the trial. This registry was much more ex- tensive than the emergency department rt-PA registry, in that much more detail was collected on each patient,

and the accrual period was 6.5 years as compared to 1 year. The successful implementation of the registry was due to the efforts of Dr. Mickey Eisenberg, a co- investigator in the MITI prehospital trial, Sherry Schaeffer, the supervisor of individuals who abstracted information from the hospital chart to data collection forms, and Diana Caldwell, who was the lead ab- stractor.

Accrual of patients in the registry began in January 1988 and ended in June 1994, when funding for the registry ceased. Patients were identified from coronary care unit logs as well as hospital discharge listings with appropriate ICD-9 codes. Patients who developed chest pain while admitted to the hospital for another medical condition were not included in the registry. As of June 1994, the registry contained 45,260 patients with suspected AMI. Demographic and outcome data have been abstracted for all patients.

More detailed information was abstracted for the 12,33 1 patients who developed AM1 during the course of hospitalization. Variable collection for these patients has changed over the years of the registry. Ini- tially, a six-page form with information about prior medical conditions, symptoms on admission to the hospital, laboratory data, resource utilization, and outcomes was used for all patients with AMI. In 1991, a more detailed data collection form was instituted for select subsets of patients, including those receiving thrombolytic therapy or primary coronary angioplasty within 6 hours of hospital admission. In 1993, data collection using a simplified form for all admissions was implemented. Most recently, there has been interest in evaluating the long-term outcomes of patients in the MITI registry. This has been accomplished by linking the MITI database to the National Death Index and the state of Washington episode of illness file, which contains information on rehospitalizations in Washington state as well as current vital status from state death records. In addition, socio-economic characteristics of the registry have been obtained by linking patient addresses to 1990 census block data.

Using data from the MITI registry, study investigators have published manuscripts on a variety of topics related to AMI. The effects of age,*'-.'' ge r~de r ,*~ , " .~ r a ~ e , ~ ~ , ' ~ prior coronary bypass surgery,24 cardiac catheterization,31 primary coronary angioplasty,30 clinical risk factors,'" and coronary artery bypass sur- g e ~ ~ ~ ~ on outcomes have been examined. In addition, reports on hospital mortality rates29 and time to treatment,32,40.43 have been published, as have an evalua-

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tion of computer-interpreted electrocardiography'" and several manuscripts examining the ECG as a pre- dictive tool for estimating infarct size and guiding decisions for reperfusion Additional work has focused on a comparison of the epidemiology of AM1 in Girona. Spain, and Seattle," and temporal changes in the use of thrombolytic therapy in Seattle?' In addition, treatment for AM1 in St. Petersburg, Rus- sia and Seattle have also been compared.'l' In topics related to health services research. papers on the effect of cardiac catheterization facilities and health care or- ganization on cardiac procedure utilization3i.3y have been published, as has a recent analysis of hospital length of stay.43 Current activities with respect to the registry are focused on analysis of long-term outcomes, inchding survival and rehospitalization."

Activities Following the MITI Prehospital Treatment Trial

Following the completion of the MITI prehospital thrombolytic trial. there have been investigations of new thrombolytic agents. direct antithrombins, platelet receptors, antagonists, and cell adhesion blockers. as well as efforts to evaluate the prehospital ECG in a wider group of patients than those eligible for thrombolytic therdpy.4x-54 The more recent efforts of MITI have included key investigators in Canada as well as the United States. Investigators at Vancouver General Hospital and St. Paul's Hospital in Vancouver, British Columbia, have been extremely important in recent efforts. The purpose of these efforts, as well as those of the past, has been to implement and test strategies for improving the treatment and outcome of AMI.

Prourokinase trials. The MITI group has done two trials evaluating two separate formulations of prourokinase. In the first study, a new recombinant g l y c ~ ~ y l - ated prourokinase (A-74 I 87 I was evaluated by study- ing coronary artery patency and TIMI 111 flow rates at 90 minutes in patients with AMI. Plasma was collected serially to measure fibrinogen. plasminogen. antithrombin 111. and fibrinopeptide A. The drug was given as either 60 or 80 mg of monotherapy or as 60 mg and "primed" with a bolus of 250,000 IU of recombinant urokinase. Experimental studies have suggested that prourokinase can be "activated" by giving small doses of a second. nonspecific thrombolytic drug which in turn enhances the number of plasminogen

molecules on the clot surface. thus speeding the con- version of prourokinase to clot-sound urokinase. The first study showed that prourokinase in all three dos- ages resulted in TIMI I11 flow rates of approximately 509-60%. Unlike the earlier experimental studies, there was no further enhancement of lytic activity with priming.'x

A second trial studied an unglycosylated formula- tion of prourokinase, evaluating the "priming" con- cept by using an initial bolus of rt-PA (5-10 mg) fol- lowed by a 90 minute infusion of prourokinase (40 mg/hour). Coronary angiography was performed at 90 minutes. and central assessment of patency and flow rates was accomplished. Patency was achieved in 77% of patients. while TIMI I11 flow rates were evident in 60% of patients. The incidence of the reocclusion was almost zero. This study, like many others, suggested that prourokinase in conjunction with another throin- bolytic agent may result in lower rates of reocclusion.4'" These two studies have provided a rationale for large comparative studies of prourokinase. Unfortu- nately, because of commercial concerns about the var- ied mutations of prourokinase and the possible inabil- ity to have a single market presence for one formula- tion, commercialization of prourokinase has been delayed.

RheothRx Trial. Early results from the MITI registry indicated that thrombolytic therapy and primary angioplasty were used i n a relatively small proportion of patients. No more than half of patients with AM1 have ST segment elevation or new bundle branch block on the admission electrocardiogram. Clinical trials and registries have shown that patients with nondiagnostic electrocardiographic changes, particularly ST segment depression, have an equally poor, if not worse, prognosis. Although aspirin and heparin are used commonly in these patients, the support for this approach conies primarily from experience in patients with unstable angina.

RheothRxB or poloxamer 188, is a surfactant which has been experimentally shown to enhance the rate of clot lysis and to attenuate size. possibly by modifying white cell adhesion to damaged microvasculature. It also can change red cell permeability in ischemic tissue. In an effort to determine whether RheothRx reduces infarct size and improves the outcome of patients with nondiagnostic electrocardiographic changes, 196 patients were enrolled and randomized to placebo or RheothRx.5" Two thirds of the patients developed evidence of acute injury by enzyme testing.

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Infarct size was determined prior to discharge by using tomographic thallium imaging, which was interpreted at a core laboratory. Dr. Manual Cerqueira has played the key role in assessing infarct size after AMI; first at the Department of Veterans Affairs Medical Center in Seattle and then at Georgetown University.

The trial was terminated because of evidence of increased transient renal dysfunction in the RheothRx group. Nonetheless, much was learned about the characteristics of patients with nondiagnostic electrocardiographic changes. These patients were older (mean age 67 years) and had more hypertension, diabetes mellitus, and prior cigarette smoking than typical in patients with ST elevation or new bundle branch block on the admission ECG. The average duration of symptoms was 6.2 hours. Infarct size averaged 15% of the left ventricle and was not changed by RheothRx treatment. Mortality rates were 11.3% in the RheothRx group and 7.1 % in control patients (P = 0.30). Treat- ment of this patient population is challenging and will be the subject of future investigations.

r-PA and AM1 (RAPID Trial). A third-generation plasminogen activator, r-PA, is a nonglycosylated deletion mutant of wild type tissue plasminogen activator (t-PA) that is expressed in Escherichia coli. The structural changes of the molecule result in properties markedly different from that of rt-PA. The mutant has less affinity with fibrin, a longer half-life, and a greater thrombolytic potency. RAPID I1 was an angiographic trial evaluating 90-minute patency for double bolus r-PA, compared with a 90-minute or “accelerated” infusion of rt-PA.”.” Three hundred twenty-four patients were enrolled in the trial and angiographic patency was determined at 30, 60, and 90 minutes. The TIMI I11 flow rate was 60% for r-PA compared to 45% for rt-PA (P < 0.05). Treatment with r-PA is convenient, simple to administer, and has minimal complications.

Efegateran and streptokinase can accelerate patency like accelerated rt-PA (ESCALAT trial). ES- CALAT was designed to evaluate whether a direct antithrombin, efegateran, could overcome the initial lag phase of lysis associated with streptokinase. Efeg- ateran is a small, direct thrombin inhibitor produced by chemical synthesis. Experimental evidence sug- gests that efegateran has a greater effect on clot lysis initiated by streptokinase than for rt-PA. The design of this dose ranging study was to determine whether the combination of efegateran and streptokinase could

achieve TIMI 111 flow rates equivalent to those using accelerated rt-PA and heparin.

Two hundred thirty patients were enrolled in the study at medical centers across the United States and Canada.’3 Angiograms were obtained at 90 minutes, and coagulation parameters and clinical events were monitored for 30 days. After exploring four doses ranging from 0.3 mgkg to 1.0 mg/kg, a dose of 0.5 mgkg per hour was chosen. The 90-minute patency rate for efegateran and streptokinase was 73% versus 79% for rt-PA and heparin (P = 0.54). TIMI 111 flow rates. although enhanced at 40%, were not as high as those seen with rt-PA and heparin (5396, P = 0.085). Significantly, there were no cases of intracranial hemorrhage. The result of this trial, similar to those re- ported for other antithrombins, has confirmed that the addition of direct antithrombins appears to enhance patency achieved by streptokinase alone. The thera- peutic range of dose appears narrow if one is to avoid excessive hemorrhage.

Optimal stent trial (OPUS 1). OPUS is an ongoing study evaluating the strategy of optimal balloon angioplasty versus the strategy of primary stenting in patients who are candidates for both. Earlier trials demonstrated that there was less angiographic and clinical restenosis in patients treated with stents compared to balloon angioplasty. However, in a secondary analysis of the studies, coronary arteries of > 3.0 mm with good angioplasty results showed no differences in restenosis compared to the stent strategy. A second limi- tation of the earlier studies is that obligatory follow- up angiograms can lead to repeat procedures that may not be driven totally by clinical indications. The OPUS trial is the first effort by the MITI group to collaborate with interested interventionalists in the United States and Canada. The hypothesis of the trial is that optimal angioplasty (results of < 20% visual stenosis or < 30% stenosis by quantitative coronary angiography) can be achieved in 80% of those undergoing balloon angioplasty and is equivalent to stenting. In the 20% of patients with suboptimal balloon angioplasty results or in those with significant dissection, stents are rec- ommended. In the primary stent strategy, “optimal” stent placement is accomplished without prior balloon angioplasty in order to minimize external injury and to reduce the number of ancillary balloons and use of other equipment. The trial will enroll 2,200 patients, and will evaluate clinical restenosis rates in the two treatment groups. In addition, postprocedure utiliza-

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MlTl ED IV IC I .R 2.3 3.5 4.6 hrs hrs hrs hrs

Figure 3. Ejection fraction and infarct size by trial. This figure displayz the reduction in infarct sire and increase in ejection fraction with dccres\ing time from s!mptoni onset to treatment in each trial. This figure include\ only patients uho received thrombolytic ther- ap!. ED = cmergcnc) department rt-PA trial: 1C = wehtern Wash- ington intracoronary trial: IS = infarct size: IV = western Washing- ton intravenous trial: MITI = M! ocardial Infarction Triage and Intervention: RNEF radionuclide ejection fraction.

tion and qualily o f life will be measured. Completion of the trial is expected in 1997.

Conclusion

In the 10 years from the beginning of the intracoronary trial to the end of the MITI prehospital treatment trial, the time from symptom onset to treatment dropped from 4.6 hours to 1.8 hours (Fig. 1). This remarkable reduction of 60% resulted in improved left ventricular function and infarct size (Fig. 3); the findings for infarct Tize in the MITI trial were particularly striking. as many patients had no detectable defects, It is important to recognize that patients in the MITI trial were highly selected, and that their treatment times were not representative of the overall community. I n 1992 in metropolitan Seattle. 60% of patients received thrombolytic therapy within 3 hours of symptom onset, in comparison to ~ i l l trial patients. Much of this discrepancy is due to differences in patient delay. which is the most significant barrier to rapid treatment. Yet, in the group randomized to hospital therapy, the time from hohpital arrival to treatment was 20 minutes, considerably less than the median of 47 minutes in all

Seattle area hospitals. The rapid treatment time achieved for hospital initiated therapy in the MITI trial is a goal which must be attained to reduce mortality and morbidity from AMI.

The Western Washington and MITI trials have proven that thrombolytic therapy significantly reduces morbidity and mortality from AM1 with minimal risk to patients. Moreover. these trials have clearly indicated that early treatment is associated with improved infarct size and better left ventricular function: in short, this translates to better lives for those who are affected by this all too pervasive condition. The efforts of the next decade should be focused on further removal of barriers to rapid treatment and the evaluation of new agents. so that the devastating effects of myocardial infarction can be minimized to the fullest extent.

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Documents

The Western Washington and Myocardial Infarction Triage and Intervention Trials of Thrombolytic Therapy: 15 Years of Collaboration in the Pacific Northwest