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Comparison of thrombolytic therapy for acute myocardial infarction in rural and urban settings
VOLUME 82
The
American
Journal
NUMBER 6
JUNE 1987
of Medicine@ CLINICAL STUDIES
Comparison of Thrombolytic Therapy for Acute Myocardial Infarction in Rural and Urban Settings
COLEEN A. McNAMARA, M.D. MARK W. BURKET, M.D. PAMELA S. BREWSTER, M.A. RICHARD F. LEIGHTON, M.D. THEODORE D. FRAKER, Jr., M.D. Toledo, Ohio
From the Department of Medicine, Medical College of Ohio, Toledo, Ohio. This work was supported in part by a grant from the Northwestern Ohio Chapter of the American Heart Association and by a grant from the Medical College of Ohio Foundation. Requests for reprints should be addressed to Dr. Theodore D. Fraker, Jr., Department of Medicine, Medical College of Ohio, C.S. 10008, Toledo, Ohio 43699. Manuscript submitted September 29, 1986, and accepted December 5, 1986.
In this study, a tertiary care hospital served as a registry and information source to rural hospitals in northwestern Ohio where thrombolytic therapy had not previously been used. The study was designed to compare the safety and efficacy of intravenous thrombolytic therapy for acute myocardial infarction in the two settings. Fifty-five patients in eight rural hospitals and 36 patients in the urban tertiary care center received intravenous streptokinase. Of the 67 patients whose symptoms first occurred out of the hospital, 63 percent were treated within three hours. There were no significant differences in rates of clinically determined coronary artery recanalization (63 percent versus 69 percent for rural and tertiary hospitals, respectively), in-hospital mortality (5.4 percent versus 11 percent), bleeding complications (3.6 percent versus 5.5 percent), or time from the onset of pain to infusion of streptokinase (3.4 hours versus 2.9 hours). There were also no differences in the completeness of collection of serial coagulation data and cardiac enzyme values, or in the documentation of chest pain onset and cessation. Major differences between rural centers and the tertiary care center involved the use of serial electrocardiography (56 percent versus 69 percent, respectively), subsequent cardiac catheterization (49 percent versus 66 percent), and the timing of catheterization, when performed (30.4 days versus 4.6 days) (p <0.005 for all values). Thrombolytic therapy for acute myocardial infarction can be administered quickly, safely, and effectively in rural hospital settings even by physicians previously unfamiliar with this form of treatment. To be most effective, thrombolytic therapy for acute myocardial infarction must be instituted early after symptoms appear [l-6]. In fact, the most dramatic benefit in terms of salvage of left ventricular function may be derived only in those patients treated in less than two hours from the onset of symptoms [I]. For patients living in rural areas, transfer to tertiary care centers may involve an unacceptable delay in treatment. The availability of thrombolytic therapy for acute myocardial infarction in rural areas of the United States without angiographic facilities is unknown. We hypothesized that physicians in rural hospitals without prior experience with thrombolytic therapy for acute myocardial infarction could safely provide prompt treatment and achieve acceptable rates of coronary artery reperfusion. Since immediate angiography would not be available in these remote areas, we also examined the possibility that
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noninvasive clinical parameters co~~ld be used to determine coronary artery recanalization. To study the impact of thrombolytic therapy for acute myocardial infarction in rural areas, 19 physicians (four cardiologists, five internists, and 10 family practitioners) from eight rural hospitals contributed information on 55 patients. This group was then compared with 36 patients treated in an urban referral center by the same protocol. PATIENTS
AND
creatine kinase and 12-lead electrocardiography every four hours for 24 hours and at 36 and 4% hours were also recommended. Cardiac catheterization was encouraged within 48 to 96 hours after the acute myocardial infarction or sooner if the patient had recurrent chest pain or new ischemic electrocardiographic changes. The decision for subsequent treatment including antiplatelet therapy was at the discretion of the private physician. The foregoing information as well as age, sex, location of myocardial infarction, history of previous myocardial infarction, presence of all bleeding complications, hospital survival, and catheterization data were requested. Clinical Assessment of Reperfusion. To determine whether or not coronary artery recanalization took place as a result of thrombolytic therapy, the following information was requested: time of onset of pain, time of onset of streptokinase infusion, time of the highest creatine kinase value, time of resolution of pain, and time of the first electrocardiographic evidence of a decrease in ST segment abnormalities compared with the admission findings. Recanalization of the infarct-related vessel was identified by clinical assessment when the creatine kinase value peaked at 16 hours or less from the onset of chest pain (which was usually 13 hours or less from the onset of the streptokinase infusion) [5-g]. Resolution of ischemic electrocardiographic changes and a decrease in the patients’ perception of chest pain, both subjective end-points, were used as adjuncts to the creatine kinase data to predict reperfusion. Angiographic patency of the infarct-related vessel was determined at subsequent catheterization and was defined as the presence of antegrade blood flow throughout the course of the entire vessel as confirmed by experienced observers. Vessel reocclusion was defined as an occluded infarct-related artery at angiography when clinical criteria were consistent with vessel patency. Statistical Analysis. Contingency tables were developed to compare the rural and urban study groups in which the rate of occurrence was used to differentiate the groups. The chi-square statistic was used to determine the significance of difference between these rates. The average time to treatment from onset of symptoms for each group was compared using the two-sample t test.
METHODS
Community Participation. Physicians in rural communities who were contacted to enter patients in the thrombolytic protocol were those from towns or cities of less than 50,000 population, those with no immediate coronary angiographic services available, and those more than 30 miles from the nearest fully operational cardiac catheterization facility. Each hospital had a fully equipped coronary care unit. Intravenous streptokinase had not previously been used in these communities for treatment of acute myocardial infarction. One of us traveled to each community at least once to discuss the cjinical protocol with physicians and hospital staff. A toll-free number was provided so that problems or concerns could be addressed at the parent institution 24 hours a day. Data forms were filled out by physicians or nursing staff in the rural communities and forwarded to the parent institution at the conclusion of each patient’s hospital stay. Patient Selection. Criteria for patient selection for the thrombolytic protocol included (1) symptoms of acute myocardial infarction of less than six hours’ duration, (2) acute electrocardiographic ST segment elevation characteristic of myocardial infarction, and (3) absence of Q waves on the 12-lead electrocardiogram in at least one lead with ST segment elevation. Criteria for patient exclusion were (1) coexisting terminal illness or (2) contraindications to thrombolytic therapy such as recent surgery, gastrointestinal bleeding within the prior three months or active peptic ulcer disease, recent cardiopulmonary resuscitation, severe hypertension (systolic blood pressure of more than 200 mm Hg), recent stroke or cerebral hemorrhage, severe renal or hepatic dysfunction, known hypofibrinogenemia, recent trauma, or known adverse reaction to streptokinase. Patient selection was nonrandomized and was at the discretion of the private physician based upon the foregoing criteria. Thrombolytic Protocol. Informed consent approved by the institutional review board at the Medical College of Ohio was obtained. A dose of 750,000 units of streptokinase given over 15 to 30 minutes was recommended, but the dose and duration of infusion could be modified at the discretion of the treating physician. Recommended baseline laboratory studies included complete blood cell count, determination of the activated partial thromboplastin time, and measurement of fibrinogen, creatine kinase, MB fraction of creatine kinase, and antistreptolysin 0 titer. Followup laboratory studies included determination of the partial thromboplastin time and fibrinogen level 30 minutes after streptokinase and every four hours for 24 hours. Heparin was started after these laboratory data were obtained and was to be continued for at least 48 hours. Measurement of
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RESULTS Ninety-one patients in the northwestern Ohio area (55 from rural centers and 36 from the urban center) were given intravenous streptokinase. The average dose was 805,000 f 197,000 units in the rural centers and 693,000 f 137,000 units in the urban center (p <0.002). The clinical characteristics of the rural and urban groups were similar (Table I); the mean age was 58 years for patients in rural communities and 60 years for patients in the urban center. The majority of the patients were male. The location of the myocardial infarction had a similar distribution in both settings, with more than half of infarctions being in the inferior wall. The time from the onset of chest pain until the initiation of streptokinase infusion was similar; however, the urban
62
THROMBOLYTIG
TABLE I
center had a somewhat shorter delay in initiating therapy. Four patients in the urban center had onset of chest pain of acute myocardial infarction while they were already hospitalized. The remaining urban patients and all of the rural patients had the onset of chest pain prior to hospitalization. The average time from the onset of chest pain to the initiation of streptokinase therapy was 3.4 f 2.3 hours in the rural centers and 2.9 f 1.1 hours in the urban center (Table II). The four patients in the urban center who had the onset of chest pain related to acute myocardial infarction while they were in the hospital were not included in the calculation of these times. A further breakdown of the time from the onset of chest pain to initiation of thrombolytic therapy shows that the time from onset of chest pain to arrival in the emergency department was 1.6 f 1.8 hours and 1.5 f 1.2 hours for the rural and urban centers, respectively. The time from arrival in the emergency department to initiation of thrombolytic therapy was 1.8 f 1.4 hours and 1.4 f 0.6 hours for the rural and urban centers, respectively. Sixty-nine percent (22 of 32) of the urban patients and 60 percent (33 of 55) of the rural patients were treated with thrombolytic therapy for acute myocardial infarction in three hours or less after the onset of symptoms (Table II). Although there was a tendency for patients to arrive in the emergency department somewhat sooner in the urban center, and for these patients to receive thrombolytic therapy somewhat more quickly, the differences in time were not significantly different. Coronary Artery Reperfusion. Coronary artery reperfusion was determined clinically solely by a peak in creatine
TABLE
II
Time from Symptoms
to Thrombolytic
TABLE III
Recanalization
3.2 f 21187 55187
Clinical
INFARCTION-McNAMARA
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Characteristics
Number of patients Age (years) Sex Female Male Infarct location Anterior inferior
91 59f
12
Rural 55 58 f
Urban 36 60f
12
11
16 (18%) 75 (82%)
11(20%) 44 (80%)
5 (14%) 31(86%)
41(45%) 50 (55%)
24 (44%) 31 (56%)
17 (47%) 19 (53%)
kinase activity that occurred 16 hours or less from the onset of symptoms of acute myocardial infarction. Additional information including chest pain resolution and rapid return of electrocardiographic ST segment abnormalities to baseline was frequently not available (particularly from rural centers). Because this information was so subjective (particularly chest pain relief), we chose not to use these data in clinical determination of reperfusion. Among those patients with early peaking creatine kinase activity after thrombolytic therapy, the mean interval from onset of symptoms to the peak of creatine kinase activity was 10.7 f 5.4 hours. Patients without clinical evidence of reperfusion had a mean interval from symptoms to peak enzyme activity of 20.9 f 8.1 hours. Table Ill compares the coronary artery recanalization rate achieved in patients who received thrombolytic therapy in the rural and urban settings. DeWood et al [IO] found that only 13 percent of patients with acute myocardial
Therapy Rural
2.0
3.4 f
(24%) (63%)
14/55 33/S
and Catheterization
Urban 2.3
2.9 f
(25%) (60%)
7/32 22/32
p Value 1.1
NS
(22 %) (69 % )
NS NS
Data
Total Recanalization By clinical criteria By angiographic findings Catheterization Number of patients Time from infarction (days) Range Mean Median
FOR MYOCARDIAL
Total
Total Average (hours) Patients treated Within 2 hours Within 3 hours
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Rural
Urban
p Value
54/83 42/60
(65%) (70%)
30148 24129
(63 %) (83 %)
24/35 18/31
(69 % ) (58%)
NS <0.05
60/91
(66%)
29/55
(53%)
31/36
(86%)
<0.005
o-229 15.8 3
l-229 30.4 11
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TABLE IV
Concordance in Patency Related Vessel
Clinical Assessment
Total Patent
Patent Closed
TABLE V
4 13
16 2
underwent
TABLE
death
VI
1 6
15 7
versus physician reluctance to pursue catheterization is unknown. In contrast, 86 percent of the patients who received thrombolytic therapy in the urban center subsequently underwent cardiac catheterization. Four patients refused catheterization after thrombolytic therapy, and one patient was discovered to have a terminal malignancy and was therefore not subjected to catheterization. The mean time to catheterization for this group was 4.6 days. The median time from myocardial infarction to catheterization was 11 and 2.0 days for the rural and urban centers, respectively. Both the mean and median time differences were highly significant (p
underwent
catheterization
3 7
within
two days
more
than
after
two days
Compllcatlons Rural
7791 (7.6%) 4/91 (4.4%)
Urban
3155 (5.4%) 2/55 (3.6%)
Completeness
4136 2/36
Fibrinogen Partial thromboplastin time Creatine kinase Resolution of chest pain Resolution of electrocardiographic abnormalities died before
p Value
(11%) (5.5%)
NS NS
of Data Collection Rural*
“Two patients obtained.
ET AL
of Infarct-
catheterization
Total Hospital Bleeding
INFARCTION-McNAMARA
Angiographic Findings Group I* Group Ilt Closed Patent Closed Patent Closed
31 9
* Group I patients infarction. t Group II patients after infarction.
FOR MYOCARDIAL
Urban
p Value
43153 46153
(81%) (87%)
34136 34136
(94%) (94%)
NS NS
48/53 34/53
(9 1%) (64%)
35/36 28/36
(97 %) (78%)
NS NS
31/53
(58%)
32/36
(89%)
any laboratory
or clinical
data could
be
infarction studied in the first four hours had patent infarctrelated vessels in the absence of thrombolytic therapy. By clinical criteria (an early peak of creatine kinase), the average recanalization rate (spontaneous and streptokinase-related) was 65 percent and was similar in both settings and similar to other reported rates [8,1 I-141. Eight patients were not classified clinically as demonstrating reperfusion or occlusion. Two of these patients died of ventricular arrhythmias, and the remainder had insufficient creatine kinase values or other clinical data to make a determination. By angiographic criteria, patients in rural communities who underwent catheterization achieved a higher recanalization rate (83 percent) than patients in the urban setting who underwent catheterization (58 percent). This discrepancy may be related to the difference in the interval from myocardial infarction to catheterization in the two groups. There was apparent reluctance on the part of rural physicians to subject patients to catheterization soon after myocardial infarction. Only 53 percent of the patients treated with thrombolytic therapy in rural centers eventually underwent cardiac catheterization, and the mean time from myocardial infarction to catheterization was approximately one month. The extent of patient 1098
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COMMENTS and Efficacy. The results of this study indicate that thrombolytic therapy for acute myocardial infarction can be instituted in rural communities safely and with an
Safety
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THROMBOLYTIC
apparent effectiveness of coronary artery recanalization equal to that in other published series [8,1 l-141. Only four of 91 patients had a bleeding complication necessitating transfusion, and all of these patients had received heparin [ 1,6,12,15]. An additional two patients demonstrated guaiac-positive nasogastric aspirates but had otherwise uncomplicated courses. There was no increase in bleeding risk in rural hospitals. In this study, there were no deaths attributable to thrombolytic therapy, and the overall hospital mortality rate was only 7.6 percent. The hospital mortality rate in the rural community hospitals was only 5.4 percent. Both values compare favorably to the published coronary care unit mortality rate for patients with acute myocardial infarction of 12 to 15 percent [ 16- 191. Since this was not a randomized study, comparable hospital mortality rates for communities in northwestern Ohio were unknown and may not have been equivalent to published rates. A randomized trial of thrombolytic versus conventional therapy for acute myocardial infarction was proposed to physicians practicing in rural communities, but was unacceptable to them because of widespread belief in the efficacy of thrombolytic therapy. Despite this limitation, this study shows that physicians unfamiliar with the use of streptokinase could employ this potentially hazardous therapy with safety and completeness of data collection comparable to physicians who were already experienced in its use. We were aware of no instances in which patients received thrombolytic therapy inappropriately. Clinical versus Angiographic Determination of Patency. Despite delayed catheterization in many patients, the concordance between clinical and angiographic patency of the infarct-related vessel was 77 percent (Table IV). There was a nonsignificant trend (p = 0.09) for a higher rate of concordance in the group undergoing early catheterization (group I, 88 percent) than in the group undergoing late catheterization (group II, 69 percent). Although the number of patients in these groups is small, it appears that the rate of reocclusion of infarct-related coronary arteries increases with time. In this study, reocclusion occurred in only four of 35 patients (11 percent), which is comparable to the results in other published series [S, 14,151. Vessel patency appears to be maintained in the vast majority of patients. These preliminary results (low hospital mortality and reocclusion rate) imply that not all patients who receive thrombolytic therapy for acute myocardial infarction need an early coronary artery revascularization procedure (bypass surgery or coronary angioplasty), or even early coronary angiography. O’Neill et al [20] have recently reported that acute coronary angioplasty achieved increases in coronary artery luminal diameter superior to those following treatment with intracoronary streptokinase in patients seen within 12 hours of acute myocardial infarction. They saw a trend toward greater improvement in left ventricular function in those patients undergoing acute angioplasty. June
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Since a very aggressive and invasive approach to management of patients with acute myocardial infarction will not be available in many rural communities and probably could not be supported by the national health care budget if applied to all patients, a large-scale study of patients in rural areas who receive thrombolytic therapy must be undertaken to determine the patients who need subsequent intervention and the patients who can be treated medically, at least initially. Clinical Criteria for Vessel Patency. In this study, the major clinical criterion for determination of coronary artery reperfusion was an early peak in creatine kinase values. Several other investigators have found a close correlation between early creatine kinase peaks and coronary vessel recanalization. Ong et al [5] used an arbitrary time of 12 hours from the first abnormal value of the MB creatine kinase fraction to the peak value to separate patients with acute myocardial infarction who had early spontaneous coronary recanalization from those who had presumed fixed occlusion. Using this criterion, patients with an early peak of creatine kinase activity had spontaneous improvement in left ventricular function, whereas patients with a delayed creatine kinase peak had no improvement. Ganz et al [6] used a value of 13 hours from the abrupt rise in the MB fraction to the peak value to identify those patients with successful coronary reperfusion after streptokinase administration. Schwarz et al [7] found the peak creatine kinase activity to occur at an average of 15.7 hours after onset of chest pain in 10 patients with proved coronary artery recanalization after intracoronary streptokinase, whereas the peak creatine kinase activity occurred at an average of 23.6 hours after chest pain in patients without recanalization. Alderman et al [8] showed that an interval from initiation of thrombolytic therapy to peak creatine kinase activity of 15 hours or less separated patients with proved (by angiography) recanalization from those without recanalization with a sensitivity of 95 percent and a specificity of 88 percent. Blanke et al [9] found that the mean interval from onset of symptoms to peak creatine kinase activity was 13.5 hours for patients with angiographically proved coronary reperfusion after streptokinase, whereas the mean time from symptoms to peak creatine kinase activity was 22.9 hours in those patients without reperfusion. Using our criterion for clinical evidence of reperfusion (peak creatine kinase activity 16 hours or less after symptom onset), the mean time to peak creatine kinase activity was 10.7 f 5.4 hours for patients with successful reperfusion and 20.9 f 8.1 hours for patients without recanalization. Given the variability in the way various investigators have looked at time to peak creatine kinase activity (whether from symptom onset, infusion onset, or first abnormal creatine kinase value) in patients with proved recanalization, our data are very comparable. This similarity suggests to us the value of this simple and readily available method of determining coronary artery 1997
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recanalization in rural centers where definitive evidence of recanalization may not be available. Decrease in the patients’ perception of chest pain and resolution of ischemic electrocardiographic changes were not always reliable predictors of vessel recanalization. The subjective nature of these parameters and the difficulty in rural settings of obtaining complete data in these categories may have contributed to this unreliability. The use of an early creatine kinase peak may be useful in selecting subsequent management for patients who have had thrombolytic therapy for acute myocardial infarction. In particular, those patients whose creatine kinase activity peaked late should be considered to have had completed infarcts and hence would benefit little from intervention on the infarct-related vessel, unless there was later evidence of reversible ischemia in the same vascular bed. Cardiac catheterization might be recommended for those patients with an early peak of creatine kinase activity, particularly if recurrent ischemic episodes ensue after completion of thrombolytic therapy. Spontaneous Late Recanalization. Discordance between clinical criteria for coronary artery recanalization and the findings at late angiography (Table IV) indicates a high rate of spontaneous recanalization. Previous angiographic studies are consistent with this process. DeWood et al [lo] reported an 87 percent prevalence of total coronary artery occlusion in patients who underwent catheterization in the first four hours of myocardial infarction, whereas between 12 and 24 hours after myocardial infarction only 65 percent of patients had total coronary artery occlusion. Bertrand et al [21] showed that, at an average of 16 days after acute myocardial infarction, only 53 percent of patients had a completely occluded infarctrelated artery. Betriu et al [22] reported a 45 percent prevalence of complete coronary artery obstruction among 259 survivors of acute myocardial infarction who underwent catheterization 30 days after onset of symptoms. Our patients in group II (Table IV) had a 50 percent prevalence of patent infarct-related vessels at late angi-
ography, even though clinical criteria for coronary reperfusion were not met early after thrombolytic therapy. These data suggest an increasing prevalence of spontaneous coronary artery recanalization occurring well past any potential for myocardial salvage. The data also indicate that the presence of a patent infarct-related coronary artery at catheterization does not necessarily prove that thrombolytic therapy has been successful in salvaging ischemic myocardium. The decision to revascularize a coronary artery should be based upon evidence of early reperfusion by clinical criteria (e.g., an early peak of creatine kinase activity) or upon evidence of reversible ischemia in that vascular bed. We have shown that physicians in rural hospitals without prior experience with thrombolytic therapy for acute myocardial infarction can safely provide prompt treatment and achieve acceptable rates of coronary artery reperfusion. In addition, our data would suggest that reocclusion of an infarct-related vessel occurs in a minority of patients. Furthermore, we believe that successful early reperfusion can be detected reliably by analysis of the timing of the creatine kinase activity peak relative to the onset of symptoms. Since this information is readily available in rural centers, prudent choices for subsequent coronary angiography and eventual myocardial revascularization could be made by rural-based physicians. Given the inordinate manpower and monetary costs of acute angiographic intervention proposed for patients receiving thrombolytic therapy [23], a trial of more conservative management of patients receiving thrombolytic therapy for acute myocardial infarction is warranted. In particular, a trend toward treatment of acute myocardial infarction only in tertiary care centers may be unacceptable to some patients, referring physicians, and health care insurers. ACKNOWLEDGMENT We wish to express our appreciation to Ms. Karen Haase for preparation of the manuscript.
REFERENCES 1.
2.
3.
1100
4.
Koren G, Weiss AT, Hasin Y, et al: Prevention of myocardial damage in acute myocardial ischemia by early treatment with intravenous streptokinase. N Engl J Med 1985; 313: 1384-1389. Mathey DG, Sheehan FH, Schafer J, Dodge HT: Time from onset of symptoms to thrombolytic therapy: a major determinant of myocardial salvage in patients with acute transmural infarction. J Am Coll Cardiol 1985; 6: 518-525. Simoons ML, Serruys PW, van den Brand M, et al: Early thrombolysis in acute myocardial infarction: limitation of infarct size and improved survival. J Am Coll Cardiol 1986; 7: 717-728.
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Bergmann SR, Lerch RA, Fox KAA, et al: Temporal dependence of beneficial effects of coronary thrombolysis characterized by positron tomography. Am J Med 1982; 73: 573-581. Ong L, Reiser P, Coromilas J, Scherr L, Morrison J: Left ventricular function and rapid release of creatine kinase MB in acute myocardial infarction. N Engl J Med 1983; 309: 1-6. Ganz W, Geft I, Shah PK. et al: Intravenous streptokinase in evolving acute myocardial infarction. Am J Cardiol 1984; 53: 1209-1216. Schwarz F, Schuler G, Katus H, et al: lntracoronary thrombolysis in acute myocardial infarction: correlations among
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serum enzyme, scintigraphic and hemodynamic findings. Am J Cardiol 1982; 50: 32-38. Alderman EL, Jutzy KR, Berte LE, et al: Randomized comparison of intravenous versus intracoronary streptokinase for myocardial infarction. Am J Cardiol 1984; 54: 14-19. Blanke H, von Hardenberg D, Cohen M, et al: Patterns of creatine kinase release during acute myocardial infarction after nonsurgical reperfusion: comparison with conventional treatment and correlation with infarct size. J Am Coil Cardiol 1984; 3: 675-680. DeWood MA, Spores J, Notske R, et al: Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980; 303: 897-902. Schroder R, Biamino G, v. Leitner ER, et al: intravenous short-term infusion of streptokinase in acute myocardial infarction. Circulation 1983; 67: 5366548. Spann JF, Sherry S, Carabello BA, et al: High-dose, brief intravenous streptokinase early in acute myocardial infarction. Am Heart J 1982; 104: 939-945. Taylor GJ, Mikell FL, Moses W, et al: Intravenous versus intracoronary streptokinase therapy for acute myocardial infarction in community hospitals. Am J Cardiol 1984; 54: 256-260. Rogers WJ, Mantle JA, Hood WP, et al: Prospective randomized trial of intravenous and intracoronary streptokinase in acute myocardial infarction. Circulation 1983; 68: 1051-1061. TIMI Study Group: The thrombolysis in myocardial infarction
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(TIMI) trial. N Engl J Med 1985; 312: 932-936. Morris AL, Nernberg V, Roos NP, Henteleff P, Roos L: Acute myocardial infarction; survey of urban and rural hospital mortality. Am Heart J 1983; 105: 44-53. Stross JK, Willis PW, Reynolds EW, et al: Effectiveness of coronary care units in small community hospitals. Ann Intern Med 1976; 85: 709-713. Blanke H, Schicha H, Cohen M, et al: Long-term follow-up after intracoronary streptokinase therapy for acute myocardial infarction. Am Heart J 1985; 110: 736-741. 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. O’Neill W, Timmis GC, Bourdillon PD, et al: A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty for acute myocardial infarction. N Engl J Med 1986; 314: 812-818. Bertrand ME, Lefebvre JM, Laisne CL, Rousseau MF, Carre AG, Lekieffre JP: Coronary arteriography in acute transmural myocardial infarction. Am Heart J 1979; 97: 61-69. Betriu A, Castaner A, Sanz GA, et al: Angiographic findings 1 month after myocardial infarction: a prospective study of 259 survivors. Circulation 1982; 65: 1099-l 105. Top01 EJ, Fung AY, Kline E, et al: Safety of helicopter transport and out-of-hospital intravenous fibrinolytic therapy in patients with evolving myocardial infarction. Cathet Cardiovasc Diagn 1986; 12: 151-15.5.
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NUMBER 6
JUNE 1987
of Medicine@ CLINICAL STUDIES
Comparison of Thrombolytic Therapy for Acute Myocardial Infarction in Rural and Urban Settings
COLEEN A. McNAMARA, M.D. MARK W. BURKET, M.D. PAMELA S. BREWSTER, M.A. RICHARD F. LEIGHTON, M.D. THEODORE D. FRAKER, Jr., M.D. Toledo, Ohio
From the Department of Medicine, Medical College of Ohio, Toledo, Ohio. This work was supported in part by a grant from the Northwestern Ohio Chapter of the American Heart Association and by a grant from the Medical College of Ohio Foundation. Requests for reprints should be addressed to Dr. Theodore D. Fraker, Jr., Department of Medicine, Medical College of Ohio, C.S. 10008, Toledo, Ohio 43699. Manuscript submitted September 29, 1986, and accepted December 5, 1986.
In this study, a tertiary care hospital served as a registry and information source to rural hospitals in northwestern Ohio where thrombolytic therapy had not previously been used. The study was designed to compare the safety and efficacy of intravenous thrombolytic therapy for acute myocardial infarction in the two settings. Fifty-five patients in eight rural hospitals and 36 patients in the urban tertiary care center received intravenous streptokinase. Of the 67 patients whose symptoms first occurred out of the hospital, 63 percent were treated within three hours. There were no significant differences in rates of clinically determined coronary artery recanalization (63 percent versus 69 percent for rural and tertiary hospitals, respectively), in-hospital mortality (5.4 percent versus 11 percent), bleeding complications (3.6 percent versus 5.5 percent), or time from the onset of pain to infusion of streptokinase (3.4 hours versus 2.9 hours). There were also no differences in the completeness of collection of serial coagulation data and cardiac enzyme values, or in the documentation of chest pain onset and cessation. Major differences between rural centers and the tertiary care center involved the use of serial electrocardiography (56 percent versus 69 percent, respectively), subsequent cardiac catheterization (49 percent versus 66 percent), and the timing of catheterization, when performed (30.4 days versus 4.6 days) (p <0.005 for all values). Thrombolytic therapy for acute myocardial infarction can be administered quickly, safely, and effectively in rural hospital settings even by physicians previously unfamiliar with this form of treatment. To be most effective, thrombolytic therapy for acute myocardial infarction must be instituted early after symptoms appear [l-6]. In fact, the most dramatic benefit in terms of salvage of left ventricular function may be derived only in those patients treated in less than two hours from the onset of symptoms [I]. For patients living in rural areas, transfer to tertiary care centers may involve an unacceptable delay in treatment. The availability of thrombolytic therapy for acute myocardial infarction in rural areas of the United States without angiographic facilities is unknown. We hypothesized that physicians in rural hospitals without prior experience with thrombolytic therapy for acute myocardial infarction could safely provide prompt treatment and achieve acceptable rates of coronary artery reperfusion. Since immediate angiography would not be available in these remote areas, we also examined the possibility that
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noninvasive clinical parameters co~~ld be used to determine coronary artery recanalization. To study the impact of thrombolytic therapy for acute myocardial infarction in rural areas, 19 physicians (four cardiologists, five internists, and 10 family practitioners) from eight rural hospitals contributed information on 55 patients. This group was then compared with 36 patients treated in an urban referral center by the same protocol. PATIENTS
AND
creatine kinase and 12-lead electrocardiography every four hours for 24 hours and at 36 and 4% hours were also recommended. Cardiac catheterization was encouraged within 48 to 96 hours after the acute myocardial infarction or sooner if the patient had recurrent chest pain or new ischemic electrocardiographic changes. The decision for subsequent treatment including antiplatelet therapy was at the discretion of the private physician. The foregoing information as well as age, sex, location of myocardial infarction, history of previous myocardial infarction, presence of all bleeding complications, hospital survival, and catheterization data were requested. Clinical Assessment of Reperfusion. To determine whether or not coronary artery recanalization took place as a result of thrombolytic therapy, the following information was requested: time of onset of pain, time of onset of streptokinase infusion, time of the highest creatine kinase value, time of resolution of pain, and time of the first electrocardiographic evidence of a decrease in ST segment abnormalities compared with the admission findings. Recanalization of the infarct-related vessel was identified by clinical assessment when the creatine kinase value peaked at 16 hours or less from the onset of chest pain (which was usually 13 hours or less from the onset of the streptokinase infusion) [5-g]. Resolution of ischemic electrocardiographic changes and a decrease in the patients’ perception of chest pain, both subjective end-points, were used as adjuncts to the creatine kinase data to predict reperfusion. Angiographic patency of the infarct-related vessel was determined at subsequent catheterization and was defined as the presence of antegrade blood flow throughout the course of the entire vessel as confirmed by experienced observers. Vessel reocclusion was defined as an occluded infarct-related artery at angiography when clinical criteria were consistent with vessel patency. Statistical Analysis. Contingency tables were developed to compare the rural and urban study groups in which the rate of occurrence was used to differentiate the groups. The chi-square statistic was used to determine the significance of difference between these rates. The average time to treatment from onset of symptoms for each group was compared using the two-sample t test.
METHODS
Community Participation. Physicians in rural communities who were contacted to enter patients in the thrombolytic protocol were those from towns or cities of less than 50,000 population, those with no immediate coronary angiographic services available, and those more than 30 miles from the nearest fully operational cardiac catheterization facility. Each hospital had a fully equipped coronary care unit. Intravenous streptokinase had not previously been used in these communities for treatment of acute myocardial infarction. One of us traveled to each community at least once to discuss the cjinical protocol with physicians and hospital staff. A toll-free number was provided so that problems or concerns could be addressed at the parent institution 24 hours a day. Data forms were filled out by physicians or nursing staff in the rural communities and forwarded to the parent institution at the conclusion of each patient’s hospital stay. Patient Selection. Criteria for patient selection for the thrombolytic protocol included (1) symptoms of acute myocardial infarction of less than six hours’ duration, (2) acute electrocardiographic ST segment elevation characteristic of myocardial infarction, and (3) absence of Q waves on the 12-lead electrocardiogram in at least one lead with ST segment elevation. Criteria for patient exclusion were (1) coexisting terminal illness or (2) contraindications to thrombolytic therapy such as recent surgery, gastrointestinal bleeding within the prior three months or active peptic ulcer disease, recent cardiopulmonary resuscitation, severe hypertension (systolic blood pressure of more than 200 mm Hg), recent stroke or cerebral hemorrhage, severe renal or hepatic dysfunction, known hypofibrinogenemia, recent trauma, or known adverse reaction to streptokinase. Patient selection was nonrandomized and was at the discretion of the private physician based upon the foregoing criteria. Thrombolytic Protocol. Informed consent approved by the institutional review board at the Medical College of Ohio was obtained. A dose of 750,000 units of streptokinase given over 15 to 30 minutes was recommended, but the dose and duration of infusion could be modified at the discretion of the treating physician. Recommended baseline laboratory studies included complete blood cell count, determination of the activated partial thromboplastin time, and measurement of fibrinogen, creatine kinase, MB fraction of creatine kinase, and antistreptolysin 0 titer. Followup laboratory studies included determination of the partial thromboplastin time and fibrinogen level 30 minutes after streptokinase and every four hours for 24 hours. Heparin was started after these laboratory data were obtained and was to be continued for at least 48 hours. Measurement of
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RESULTS Ninety-one patients in the northwestern Ohio area (55 from rural centers and 36 from the urban center) were given intravenous streptokinase. The average dose was 805,000 f 197,000 units in the rural centers and 693,000 f 137,000 units in the urban center (p <0.002). The clinical characteristics of the rural and urban groups were similar (Table I); the mean age was 58 years for patients in rural communities and 60 years for patients in the urban center. The majority of the patients were male. The location of the myocardial infarction had a similar distribution in both settings, with more than half of infarctions being in the inferior wall. The time from the onset of chest pain until the initiation of streptokinase infusion was similar; however, the urban
62
THROMBOLYTIG
TABLE I
center had a somewhat shorter delay in initiating therapy. Four patients in the urban center had onset of chest pain of acute myocardial infarction while they were already hospitalized. The remaining urban patients and all of the rural patients had the onset of chest pain prior to hospitalization. The average time from the onset of chest pain to the initiation of streptokinase therapy was 3.4 f 2.3 hours in the rural centers and 2.9 f 1.1 hours in the urban center (Table II). The four patients in the urban center who had the onset of chest pain related to acute myocardial infarction while they were in the hospital were not included in the calculation of these times. A further breakdown of the time from the onset of chest pain to initiation of thrombolytic therapy shows that the time from onset of chest pain to arrival in the emergency department was 1.6 f 1.8 hours and 1.5 f 1.2 hours for the rural and urban centers, respectively. The time from arrival in the emergency department to initiation of thrombolytic therapy was 1.8 f 1.4 hours and 1.4 f 0.6 hours for the rural and urban centers, respectively. Sixty-nine percent (22 of 32) of the urban patients and 60 percent (33 of 55) of the rural patients were treated with thrombolytic therapy for acute myocardial infarction in three hours or less after the onset of symptoms (Table II). Although there was a tendency for patients to arrive in the emergency department somewhat sooner in the urban center, and for these patients to receive thrombolytic therapy somewhat more quickly, the differences in time were not significantly different. Coronary Artery Reperfusion. Coronary artery reperfusion was determined clinically solely by a peak in creatine
TABLE
II
Time from Symptoms
to Thrombolytic
TABLE III
Recanalization
3.2 f 21187 55187
Clinical
INFARCTION-McNAMARA
ET AL
Characteristics
Number of patients Age (years) Sex Female Male Infarct location Anterior inferior
91 59f
12
Rural 55 58 f
Urban 36 60f
12
11
16 (18%) 75 (82%)
11(20%) 44 (80%)
5 (14%) 31(86%)
41(45%) 50 (55%)
24 (44%) 31 (56%)
17 (47%) 19 (53%)
kinase activity that occurred 16 hours or less from the onset of symptoms of acute myocardial infarction. Additional information including chest pain resolution and rapid return of electrocardiographic ST segment abnormalities to baseline was frequently not available (particularly from rural centers). Because this information was so subjective (particularly chest pain relief), we chose not to use these data in clinical determination of reperfusion. Among those patients with early peaking creatine kinase activity after thrombolytic therapy, the mean interval from onset of symptoms to the peak of creatine kinase activity was 10.7 f 5.4 hours. Patients without clinical evidence of reperfusion had a mean interval from symptoms to peak enzyme activity of 20.9 f 8.1 hours. Table Ill compares the coronary artery recanalization rate achieved in patients who received thrombolytic therapy in the rural and urban settings. DeWood et al [IO] found that only 13 percent of patients with acute myocardial
Therapy Rural
2.0
3.4 f
(24%) (63%)
14/55 33/S
and Catheterization
Urban 2.3
2.9 f
(25%) (60%)
7/32 22/32
p Value 1.1
NS
(22 %) (69 % )
NS NS
Data
Total Recanalization By clinical criteria By angiographic findings Catheterization Number of patients Time from infarction (days) Range Mean Median
FOR MYOCARDIAL
Total
Total Average (hours) Patients treated Within 2 hours Within 3 hours
THERAPY
Rural
Urban
p Value
54/83 42/60
(65%) (70%)
30148 24129
(63 %) (83 %)
24/35 18/31
(69 % ) (58%)
NS <0.05
60/91
(66%)
29/55
(53%)
31/36
(86%)
<0.005
o-229 15.8 3
l-229 30.4 11
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TABLE IV
Concordance in Patency Related Vessel
Clinical Assessment
Total Patent
Patent Closed
TABLE V
4 13
16 2
underwent
TABLE
death
VI
1 6
15 7
versus physician reluctance to pursue catheterization is unknown. In contrast, 86 percent of the patients who received thrombolytic therapy in the urban center subsequently underwent cardiac catheterization. Four patients refused catheterization after thrombolytic therapy, and one patient was discovered to have a terminal malignancy and was therefore not subjected to catheterization. The mean time to catheterization for this group was 4.6 days. The median time from myocardial infarction to catheterization was 11 and 2.0 days for the rural and urban centers, respectively. Both the mean and median time differences were highly significant (p
underwent
catheterization
3 7
within
two days
more
than
after
two days
Compllcatlons Rural
7791 (7.6%) 4/91 (4.4%)
Urban
3155 (5.4%) 2/55 (3.6%)
Completeness
4136 2/36
Fibrinogen Partial thromboplastin time Creatine kinase Resolution of chest pain Resolution of electrocardiographic abnormalities died before
p Value
(11%) (5.5%)
NS NS
of Data Collection Rural*
“Two patients obtained.
ET AL
of Infarct-
catheterization
Total Hospital Bleeding
INFARCTION-McNAMARA
Angiographic Findings Group I* Group Ilt Closed Patent Closed Patent Closed
31 9
* Group I patients infarction. t Group II patients after infarction.
FOR MYOCARDIAL
Urban
p Value
43153 46153
(81%) (87%)
34136 34136
(94%) (94%)
NS NS
48/53 34/53
(9 1%) (64%)
35/36 28/36
(97 %) (78%)
NS NS
31/53
(58%)
32/36
(89%)
any laboratory
or clinical
data could
be
infarction studied in the first four hours had patent infarctrelated vessels in the absence of thrombolytic therapy. By clinical criteria (an early peak of creatine kinase), the average recanalization rate (spontaneous and streptokinase-related) was 65 percent and was similar in both settings and similar to other reported rates [8,1 I-141. Eight patients were not classified clinically as demonstrating reperfusion or occlusion. Two of these patients died of ventricular arrhythmias, and the remainder had insufficient creatine kinase values or other clinical data to make a determination. By angiographic criteria, patients in rural communities who underwent catheterization achieved a higher recanalization rate (83 percent) than patients in the urban setting who underwent catheterization (58 percent). This discrepancy may be related to the difference in the interval from myocardial infarction to catheterization in the two groups. There was apparent reluctance on the part of rural physicians to subject patients to catheterization soon after myocardial infarction. Only 53 percent of the patients treated with thrombolytic therapy in rural centers eventually underwent cardiac catheterization, and the mean time from myocardial infarction to catheterization was approximately one month. The extent of patient 1098
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COMMENTS and Efficacy. The results of this study indicate that thrombolytic therapy for acute myocardial infarction can be instituted in rural communities safely and with an
Safety
82
THROMBOLYTIC
apparent effectiveness of coronary artery recanalization equal to that in other published series [8,1 l-141. Only four of 91 patients had a bleeding complication necessitating transfusion, and all of these patients had received heparin [ 1,6,12,15]. An additional two patients demonstrated guaiac-positive nasogastric aspirates but had otherwise uncomplicated courses. There was no increase in bleeding risk in rural hospitals. In this study, there were no deaths attributable to thrombolytic therapy, and the overall hospital mortality rate was only 7.6 percent. The hospital mortality rate in the rural community hospitals was only 5.4 percent. Both values compare favorably to the published coronary care unit mortality rate for patients with acute myocardial infarction of 12 to 15 percent [ 16- 191. Since this was not a randomized study, comparable hospital mortality rates for communities in northwestern Ohio were unknown and may not have been equivalent to published rates. A randomized trial of thrombolytic versus conventional therapy for acute myocardial infarction was proposed to physicians practicing in rural communities, but was unacceptable to them because of widespread belief in the efficacy of thrombolytic therapy. Despite this limitation, this study shows that physicians unfamiliar with the use of streptokinase could employ this potentially hazardous therapy with safety and completeness of data collection comparable to physicians who were already experienced in its use. We were aware of no instances in which patients received thrombolytic therapy inappropriately. Clinical versus Angiographic Determination of Patency. Despite delayed catheterization in many patients, the concordance between clinical and angiographic patency of the infarct-related vessel was 77 percent (Table IV). There was a nonsignificant trend (p = 0.09) for a higher rate of concordance in the group undergoing early catheterization (group I, 88 percent) than in the group undergoing late catheterization (group II, 69 percent). Although the number of patients in these groups is small, it appears that the rate of reocclusion of infarct-related coronary arteries increases with time. In this study, reocclusion occurred in only four of 35 patients (11 percent), which is comparable to the results in other published series [S, 14,151. Vessel patency appears to be maintained in the vast majority of patients. These preliminary results (low hospital mortality and reocclusion rate) imply that not all patients who receive thrombolytic therapy for acute myocardial infarction need an early coronary artery revascularization procedure (bypass surgery or coronary angioplasty), or even early coronary angiography. O’Neill et al [20] have recently reported that acute coronary angioplasty achieved increases in coronary artery luminal diameter superior to those following treatment with intracoronary streptokinase in patients seen within 12 hours of acute myocardial infarction. They saw a trend toward greater improvement in left ventricular function in those patients undergoing acute angioplasty. June
THERAPY
FOR MYOCARDIAL
INFARCTION-McNAMARA
ET AL
Since a very aggressive and invasive approach to management of patients with acute myocardial infarction will not be available in many rural communities and probably could not be supported by the national health care budget if applied to all patients, a large-scale study of patients in rural areas who receive thrombolytic therapy must be undertaken to determine the patients who need subsequent intervention and the patients who can be treated medically, at least initially. Clinical Criteria for Vessel Patency. In this study, the major clinical criterion for determination of coronary artery reperfusion was an early peak in creatine kinase values. Several other investigators have found a close correlation between early creatine kinase peaks and coronary vessel recanalization. Ong et al [5] used an arbitrary time of 12 hours from the first abnormal value of the MB creatine kinase fraction to the peak value to separate patients with acute myocardial infarction who had early spontaneous coronary recanalization from those who had presumed fixed occlusion. Using this criterion, patients with an early peak of creatine kinase activity had spontaneous improvement in left ventricular function, whereas patients with a delayed creatine kinase peak had no improvement. Ganz et al [6] used a value of 13 hours from the abrupt rise in the MB fraction to the peak value to identify those patients with successful coronary reperfusion after streptokinase administration. Schwarz et al [7] found the peak creatine kinase activity to occur at an average of 15.7 hours after onset of chest pain in 10 patients with proved coronary artery recanalization after intracoronary streptokinase, whereas the peak creatine kinase activity occurred at an average of 23.6 hours after chest pain in patients without recanalization. Alderman et al [8] showed that an interval from initiation of thrombolytic therapy to peak creatine kinase activity of 15 hours or less separated patients with proved (by angiography) recanalization from those without recanalization with a sensitivity of 95 percent and a specificity of 88 percent. Blanke et al [9] found that the mean interval from onset of symptoms to peak creatine kinase activity was 13.5 hours for patients with angiographically proved coronary reperfusion after streptokinase, whereas the mean time from symptoms to peak creatine kinase activity was 22.9 hours in those patients without reperfusion. Using our criterion for clinical evidence of reperfusion (peak creatine kinase activity 16 hours or less after symptom onset), the mean time to peak creatine kinase activity was 10.7 f 5.4 hours for patients with successful reperfusion and 20.9 f 8.1 hours for patients without recanalization. Given the variability in the way various investigators have looked at time to peak creatine kinase activity (whether from symptom onset, infusion onset, or first abnormal creatine kinase value) in patients with proved recanalization, our data are very comparable. This similarity suggests to us the value of this simple and readily available method of determining coronary artery 1997
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THROMBOLYTIC
THERAPY
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ET AL
recanalization in rural centers where definitive evidence of recanalization may not be available. Decrease in the patients’ perception of chest pain and resolution of ischemic electrocardiographic changes were not always reliable predictors of vessel recanalization. The subjective nature of these parameters and the difficulty in rural settings of obtaining complete data in these categories may have contributed to this unreliability. The use of an early creatine kinase peak may be useful in selecting subsequent management for patients who have had thrombolytic therapy for acute myocardial infarction. In particular, those patients whose creatine kinase activity peaked late should be considered to have had completed infarcts and hence would benefit little from intervention on the infarct-related vessel, unless there was later evidence of reversible ischemia in the same vascular bed. Cardiac catheterization might be recommended for those patients with an early peak of creatine kinase activity, particularly if recurrent ischemic episodes ensue after completion of thrombolytic therapy. Spontaneous Late Recanalization. Discordance between clinical criteria for coronary artery recanalization and the findings at late angiography (Table IV) indicates a high rate of spontaneous recanalization. Previous angiographic studies are consistent with this process. DeWood et al [lo] reported an 87 percent prevalence of total coronary artery occlusion in patients who underwent catheterization in the first four hours of myocardial infarction, whereas between 12 and 24 hours after myocardial infarction only 65 percent of patients had total coronary artery occlusion. Bertrand et al [21] showed that, at an average of 16 days after acute myocardial infarction, only 53 percent of patients had a completely occluded infarctrelated artery. Betriu et al [22] reported a 45 percent prevalence of complete coronary artery obstruction among 259 survivors of acute myocardial infarction who underwent catheterization 30 days after onset of symptoms. Our patients in group II (Table IV) had a 50 percent prevalence of patent infarct-related vessels at late angi-
ography, even though clinical criteria for coronary reperfusion were not met early after thrombolytic therapy. These data suggest an increasing prevalence of spontaneous coronary artery recanalization occurring well past any potential for myocardial salvage. The data also indicate that the presence of a patent infarct-related coronary artery at catheterization does not necessarily prove that thrombolytic therapy has been successful in salvaging ischemic myocardium. The decision to revascularize a coronary artery should be based upon evidence of early reperfusion by clinical criteria (e.g., an early peak of creatine kinase activity) or upon evidence of reversible ischemia in that vascular bed. We have shown that physicians in rural hospitals without prior experience with thrombolytic therapy for acute myocardial infarction can safely provide prompt treatment and achieve acceptable rates of coronary artery reperfusion. In addition, our data would suggest that reocclusion of an infarct-related vessel occurs in a minority of patients. Furthermore, we believe that successful early reperfusion can be detected reliably by analysis of the timing of the creatine kinase activity peak relative to the onset of symptoms. Since this information is readily available in rural centers, prudent choices for subsequent coronary angiography and eventual myocardial revascularization could be made by rural-based physicians. Given the inordinate manpower and monetary costs of acute angiographic intervention proposed for patients receiving thrombolytic therapy [23], a trial of more conservative management of patients receiving thrombolytic therapy for acute myocardial infarction is warranted. In particular, a trend toward treatment of acute myocardial infarction only in tertiary care centers may be unacceptable to some patients, referring physicians, and health care insurers. ACKNOWLEDGMENT We wish to express our appreciation to Ms. Karen Haase for preparation of the manuscript.
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4.
Koren G, Weiss AT, Hasin Y, et al: Prevention of myocardial damage in acute myocardial ischemia by early treatment with intravenous streptokinase. N Engl J Med 1985; 313: 1384-1389. Mathey DG, Sheehan FH, Schafer J, Dodge HT: Time from onset of symptoms to thrombolytic therapy: a major determinant of myocardial salvage in patients with acute transmural infarction. J Am Coll Cardiol 1985; 6: 518-525. Simoons ML, Serruys PW, van den Brand M, et al: Early thrombolysis in acute myocardial infarction: limitation of infarct size and improved survival. J Am Coll Cardiol 1986; 7: 717-728.
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Bergmann SR, Lerch RA, Fox KAA, et al: Temporal dependence of beneficial effects of coronary thrombolysis characterized by positron tomography. Am J Med 1982; 73: 573-581. Ong L, Reiser P, Coromilas J, Scherr L, Morrison J: Left ventricular function and rapid release of creatine kinase MB in acute myocardial infarction. N Engl J Med 1983; 309: 1-6. Ganz W, Geft I, Shah PK. et al: Intravenous streptokinase in evolving acute myocardial infarction. Am J Cardiol 1984; 53: 1209-1216. Schwarz F, Schuler G, Katus H, et al: lntracoronary thrombolysis in acute myocardial infarction: correlations among
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(TIMI) trial. N Engl J Med 1985; 312: 932-936. Morris AL, Nernberg V, Roos NP, Henteleff P, Roos L: Acute myocardial infarction; survey of urban and rural hospital mortality. Am Heart J 1983; 105: 44-53. Stross JK, Willis PW, Reynolds EW, et al: Effectiveness of coronary care units in small community hospitals. Ann Intern Med 1976; 85: 709-713. Blanke H, Schicha H, Cohen M, et al: Long-term follow-up after intracoronary streptokinase therapy for acute myocardial infarction. Am Heart J 1985; 110: 736-741. 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. O’Neill W, Timmis GC, Bourdillon PD, et al: A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty for acute myocardial infarction. N Engl J Med 1986; 314: 812-818. Bertrand ME, Lefebvre JM, Laisne CL, Rousseau MF, Carre AG, Lekieffre JP: Coronary arteriography in acute transmural myocardial infarction. Am Heart J 1979; 97: 61-69. Betriu A, Castaner A, Sanz GA, et al: Angiographic findings 1 month after myocardial infarction: a prospective study of 259 survivors. Circulation 1982; 65: 1099-l 105. Top01 EJ, Fung AY, Kline E, et al: Safety of helicopter transport and out-of-hospital intravenous fibrinolytic therapy in patients with evolving myocardial infarction. Cathet Cardiovasc Diagn 1986; 12: 151-15.5.
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