European Heart Journal (1992) 13,818-823
Efficacy and safety of APSAC in the treatment of acute myocardial infarction A. MACHRAOUI*, D. JAGER*, J. BARMEYER* AND J. ARMBRECHT|
"Department of Cardiology and Angiology, Internal Medicine Clinic, University ofBochum and^Smith Kline Beecham Pharmaceuticals, Munich, Germany KEY WORDS: Myocardial infarction, thrombolysis, APSAC, mortality. A prospective, open, multicentre post-marketing surveillance on the efficacy and safety of intravenous APSAC in the treatment of acute myocardial infarction was performed in 2436 patients. Reperfusion suggested by non-invasive parameters was achieved in 77-3% of patients. In-hospital mortality was low (7-1%). After exclusion from analysis of patients > 70 years of age and those reported to be in cardiogenic shock, mortality rate was 2-9%. More importantly, noninvasive evidence for successful thrombolysis resulted in a significantly lower mortality (3-3%) compared with patients without evidence of successful reperfusion (17-2%). The incidence ofserious adverse events was low (132 in 2436 patients, 8/2436 = 0-3% fatal). The data from this post-marketing surveillance conducted under every-day clinical conditions confirm the efficacy and safety of APSAC as a thrombolytic agent in acute myocardial infarction, as demonstrated previously in controlled clinical trials.
Introduction In most cases, myocardial infarction is caused by formation of an intracoronary thrombus. A previous study assessing this issue invasively, reported an incidence of 87% of temporary coronary occlusion due to thrombi or spasm in acute myocardial infarction'11. The introduction of thrombolysis in the treatment of acute myocardial infarction has resulted in a significant reduction of mortality associated with myocardial infarction. Several thrombolytic agents have been examined in the past113': streptokinase'4-*1, urokinase171 pro-urokinase18'9', APSAC (anisoylated plasminogen streptokinase activator complex'1(M61) and rt-PA (recombinant tissue plasminogen activator1'7""1). There are several potential advantages of APSAC over currently used thrombolytic agents: APSAC has a long plasma half-life (1-5 h) due to the fact that its biologically active part has to be gradually activated by deacylation. Thus, it can be conveniently administered in a single intravenous injection over 2-5 min and continues to exert its thrombolytic properties for a prolonged period of time. Furthermore, APSAC is immediately active in plasma, unlike streptokinase which has to combine with circulating endogenous plasminogen before thrombolysis occurs. Accordingly, earlier studies using APSAC have demonstrated high patency rates (73-88%"2-15-20'2'1) and a significant reduction of mortality after myocardial infarction (-50-5% after 30 days and -42-7% after 1 year1"1). This post-marketing surveillance was performed in order to assess the effect of the thrombolytic drug APSAC on myocardial reperfusion and mortality after myocardial infarction in a large number of patients under routine Submitted for publication on 8 April 1991, and in revised form 22 August 1991. Correspondence: PD Dr A. Machraoui, Berufsgenossenschaftliche Krankenanstaltcn Bergmannshcil. Gilsingstr 14, 4630 Bochum, Germany. 0195-668X/92/060818 + 06 $03.00/0
Downloaded from https://academic.oup.com/eurheartj/article-abstract/13/6/818/555300 by University of Adelaide user on 09 May 2018
clinical conditions. In addition, the frequency of adverse events was reported. Methods A prospective multicentre post-marketing surveillance was performed in 248 German hospitals. Patients were recruited for this study between May 1987 and April 1990. Patients of all ages experiencing chest pain with a duration of more than 30 min, unresponsive to nitrate or calcium-antagonist therapy, meeting ECG criteria of an acute myocardial infarction (i.e. ST elevation of at least 0-1 mV in one or more standard leads or at least 0-2 m V in one or more precordial leads) were enrolled in the study. Exclusion criteria were the contraindications of APSAC therapy current in West Germany during the study period (haemorrhagic diathesis, gastrointestinal, urogenital bleedings, catheterization of great vessels or extracorporeal resuscitation up to 8 days prior to the event, surgery in the last 10 days, severe untreated hypertension, acute pancreatitis, previous streptococcal infections, peripartal state or recent abortion, and thrombolytic therapy with APSAC or streptokinase during the last 5 months, and cerebral bleeding or injury or neurosurgery within the last 30 days). The decision about the inclusion of a patient older than 70 years was left to the discretion of the treating physician, since the APSAC prescribing information at the time of the study contained a warning to treat patients over the age of 70 years with caution. However, in patients below the age of 70 years there was no selection other than the inclusion and exclusion criteria outlined in this chapter. After confirmation of a patient's eligibility for the postmarketing surveillance, 30 units of APSAC (Eminase) in 5 ml of water for injection were injected intravenously over 5 min. Corticosteroids were not routinely administered prior to thrombolysis; their protective value has • 1992 The European Society of Cardiology
Efficacy of A PSA C in AMI
819
Table 1 Patient characteristics
Age (years) 70 Unknown
Male
(%)
Female
(%)
Total
(%)
492 1351 149 9
24-6 67-5 7-4 0-4
68 297 86 0
151 65-9 191 0
560 1648 235 9
22-8 67-2 9-6 0-4
2452 lnfarct localization Anterior infarction Inferior infarction Ant. + inf. infarction Unknown Previous infarction Cardiogenic shock Heart failure
950 1027 13 11
47-5 51-3 0-6 0-5
250 197 1 3
55-4 43-7 0-2 07
1200 1224 14 14
4S-9 49-9 0-6 0-6
324 222
16-2 11! 14 2
64 69
14 2 15-3 22-6
388 291
15-8 11-9 15-7
284
102
recently been disputed'22'. Additional medical therapy, including anticoagulation, was left to the discretion of the treating physicians. The efficacy of thrombolysis was assessed using noninvasive parameters: (1) Evidence for the occurrence of reperfusion was assumed in the presence of at least two of the following non-invasive parameters: reversal of ST elevations on the ECG within 2 h, occurrence of peak CK within 14 h, reperfusion arrhythmias and the disappearance of chest pain. (2) Reocclusion (i.e. reinfarction) was assumed to have occurred when a second ST elevation on the ECG or a later rise in CK serum levels were documented. Silent reocclusions of course stay undetected using these non-invasive parameters. All relevant clinical as well as laboratory and ECG data, including adverse events and the above-mentioned non-invasive efficacy parameters, were entered in a prospectively designed questionnaire for each patient in order to permit subsequent verification of the clinical diagnoses. Results are presented in absolute numbers and percentages; significance testing was performed with the Chi-square test. Results
2452 patients, whose characteristics are summarized in Table 1, were enrolled in this post-marketing surveillance. Sixteen patients died before completion of thrombolytic therapy, so that reperfusion was assessed only in 2436 patients (1989 male, 447 female). According to the treating physicians the reasons for these fatalities were unrelated to thrombolysis; however, no necropsies were performed. All 2452 patients were included in the calculation of overall mortality. Age averaged 57 years (range 21-86) for males and was slightly higher in female patients (62 years, range 28-88). There were 1200 (48-9%) anterior, 1224 inferior (49-9%) and 14 combined anterior and inferior infarctions (0-6%). In 14 cases (0-6%) no statements about the localization of the infarction could be obtained.
386
EFFICACY OF THROMBOLYSIS
Evidence of reperfusion was reported in 1883 out of 2436 patients (77-3%). 88-6% of the patients underwent thrombolytic therapy within 4 h after the onset of symptoms, 8-2% between 4 and 6 h, 2% after more than 6 h, and in 1-2% no information about the exact time of therapy was documented. The fraction of patients with evidence of successful reperfusion tended to be higher when thrombolytic therapy was initiated early after the onset of symptoms (78-7%4h, Table 2) and it was similar in all infarcted areas. For further clinical details of the patient population (previous infarctions, cardiogenic shock or consequent heart failure) refer to Table 2. In-hospital reinfarction occurred in 210/1883 (11-2%) patients, in 32 (1-7%) before and in 178 patients (9-5%) after 24 h following suspected reperfusion. All cases of reinfarction within the first 24 h occurred in patients in whom thrombolysis had been initiated up to a maximum of 300 min after the onset of symptoms. Reinfarction after 24 h occurred independently of the time period between the onset of symptoms and thrombolysis (Table 3). MORTALITY
Overall in-hospital mortality was 7 1 % (173/2452). Mortality was higher in women than in men (12-9% vs 5-7%, P< 0-001). Certain patterns of risk factors were also associated with an increase in in-hospital mortality: previous myocardial infarction (17-3%), cardiogenic shock as defined by the attending physicians (33-3%) and myocardial failure (22-8%). Furthermore, mortality increased with age (14-9% in patients aged > 70 years vs 6-3% in patients ^70 years, P< 0001, Table 4). After excluding patients of > 70 years of age and those with cardiogenic shock from analysis overall mortality was 2-9% Mortality was 3-3% (62/1883) in the patients revealing evidence of reperfusion and 17-2% (95/553) in the patient
Downloaded from https://academic.oup.com/eurheartj/article-abstract/13/6/818/555300 by University of Adelaide user on 09 May 2018
820 A. Machraouiet al.
Table 2
Reperfusion (based on clinical symptoms, ECC and CK) Men
Women
Total
N
%
N
%
N
%
1560/1989
78-4
323/447
72-3
1883/2436
77-3
712/942 830/1023 11/13 7/11
75 6 811 84-6 63 6
180/248 140/196 1/1 2/2
72 6 71-4 1000 1000
892/1190 970/1219 12/14 9/13
75-0 79-6 85-7 69-2
Start ol thrombolysis after onset of symptoms (min) 0-60 61-120 121-180 181-240 241-300 301-360 >360 No information
217/257 520/655 453/576 217/270 82/118 31/47 24/43 16/23
84-4 79-4 78-6 80-4 69-5 660 55-8 69-6
33/48 110/139 93/136 56/77 15-23 7/12 4/6 5/6
68-8 79 1 68-4 72-7 65-2 58-3 66-7 83-3
250/305 630/794 546/712 273/347 97/141 38/59 28/49 21/29
820 79-3 76-7 78-7 68-8 644 57-1 72-4
Previous inf. Heart failure Cardiogenic shock
238/324 191/277 151/219
73-5 690 68-9
45/62 59/102 34/66
72-6 57-8
283/386 250/379 185/285
73-3 660 64-9
Total Anterior myocardial inf. Inferior myocardial inf. Ant. + inf. myocardial inf. Unknown
Table 3
515
Reocclusion (based on clinical symptoms, ECG and CK) Men N
Total
Women %
N
Reocclusion < 2 4 h Anterior myocardial inf. Inferior myocardial inf. Anterior + inferior inf. Unknown Total
15/712 12/830 0/11 0/7 27/1560
21 1-4 0 0 1-7
2/180 3/140
Reocclusion > 2 4 h Anterior myocardial inf. Posterior myocardial inf. Anterior + posterior inf. Unknown Total
75/712 67/830 0/11 2/7 144/1560
10-5 81 0 28-6 9-2
N
%
1-9
5/323
0 0 1-5
17/892 15/970 0/12 0/9 32/1883
20/180 14/140 0/1 0/2 34/323
11-1 100 0 0 10 5
95/892 81/970 0/12 2/9 178/1883
10-7 8-4 0 22-2 9-5
0/1 0/2
11
%
2-1
15
0 0 1-7
group where thrombolytic therapy appeared to have failed to result in infarct vessel reperfusion (P< 0-001, Table 4, Fig. 1). In men the difference in mortality was 2-9% (46/1560) vs 13-3% (57/429, P70 Stable haemodynamics + age ^ 7 0
Rep
%
No rep Overall
'
Rep
No rep Men
'
Rep
17-3
22-8 33-3 44-4 2-9
No rep
Women
Figure I Mortality rates for patients undergoing thrombolysis with (Rep) and without evidence for reperfusion (No Rep). Data given for the whole patient population and for each gender. Mortality is significantly lower in patients revealing evidence of reperfusion in all subgroups.
needed. This was the objective of this post-marketing surveillance of APSAC in acute myocardial infarction. At present, thrombolytic therapy appears to be the only effective means of restoring ventricular function and thus reducing mortality from acute myocardial infarction. Several controlled studies employing different thrombolytic agents have shown that patency of the infarct-related coronary arteries can be achieved in a significantly higher number of cases, together with an improvement in ventricular function'12' and a- decrease in mortality12'310"'.
821
Controlled studies using APSAC reported angiographically proven patency rates of the infarct-related vessels of 55-88% and a reperfusion rate of 64% 90min after the initiation of therapy"516-20-231. Using non-invasive parameters for the assessment of the efficacy of-thrombolysis following myocardial infarction, the distinction between vessel patency and reperfusion (after initial documentation of occlusion) is not possible. For this reason we have coined the expression 'evidence for reperfusion' stating that clinical, laboratory and ECG parameters indicated a substantial improvement in myocardial perfusion compared with the patient status at hospital admission. The actual vessel patency or reperfusion after prior vessel occlusion can only be determined with certainty angiographically. For that reason comparison of the thrombolysis efficacy parameters used in this postmarketing surveillance other than mortality with earlier invasive studies is difficult. However, the majority of hospitals confronted with patients with acute myocardial infarction do not have the facilities for coronary angiography so that the use of non-invasively determined 'surrogate measures' of coronary perfusion, as performed in this post-marketing surveillance, reflects every day clinical practice. The percentage of patients revealing evidence of reperfusion (77%) in this post-marketing surveillance study was similar to results obtained in earlier controlled trials. The patient fractions with evidence of reperfusion in male and female patients and in different infarct sites were also in agreement with previous results. Patency rates reported for other thrombolytic agents were in the range of 5373% for streptokinase"5-23"251, 61-89% for rt-PA'26-28' and 60-66% for urokinasel26-2". It must be noted, however, that comparison between reperfusion rates and patency rates after a certain period post-thrombolysis determined invasively is also difficult because patency rates in infarct patients are generally somewhat higher than reperfusion rates due to the fact that in a certain subgroup of patients'with acute myocardial infarction no complete coronary vessel occlusion can be documented in the first place. The incidence of inhospital reinfarction in this study was relatively low with a value of 11-2%. In-hospital mortality was higher than data reported from two previous controlled trials assessing mortality after administration of APSAC in acute myocardial infarction (56 and 6-4%y10"'. However, if patients above the age of 70 years were excluded from analysis, as in the two aforementioned studies, a comparable in-hospital mortality rate was found in this present trial (6-2%). Further exclusion from analysis of patients reported to be in cardiogenic shock at the time of admission, as in previous studies, leads to an even lower in-hospital mortality rate of 2-9%.-In contrast to earlier trials, mortality was not only determined for all the patients undergoing thrombolytic therapy but mortality rates were also compared between patients with and without evidence of reperfusion. As expected, mortality was significantly lower in patients with evidence of reperfusion. Overall,
Downloaded from https://academic.oup.com/eurheartj/article-abstract/13/6/818/555300 by University of Adelaide user on 09 May 2018
822
A. Machraouiela\.
Table 5 Adverse events (independent of causality. 659 adverse events occurred in 490/2452 patients (20%). Several adverse events could be documented in one patient) Overall adverse events
Serious adverse events
N
%
N
%
Haemorrhage Local Cerebral Haematuria Others
130 100 7 9 14
5-30 408 0-29 0-37 0-57
19 11 0 3
0-77 0-45 0-20 0 012
Arrhythmias Bradyarrhythmia Ventricular fibrillation Others Hypotension
174 77 25 72 123
7-10 3-14 102 2-94 502
45 19 8 18 27
1-84 0-77 0 33 0-73 110
Allergic reactions General Anaphylactic shock Local or assumed allergic reactions
39 35 4 152
1 59 1-43 016 6 20
11 8 3 16
0-45 0-33 012 0-65
3 38
012 1-55
0 14
0 0-57
Blood biochemistry abnormality Others
Table 6
5
Haemorrhage and mortality rales Mortality rates Total
Fatal N
Cerebral bleedings Gastrointestinal bleedings Lung bleedings
7 12 2
5/2452 2/2452 1/2452
0-20 008 004
Total
21
8/2452
0-33
there was a reduction in mortality from 17-2% without, to 3-3% in patients with, the above mentioned evidence of reperfusion (/*< 0-001). Thus, overall mortality was reduced by 81% in patients showing evidence of reperfusion. This was true for both genders (2-9 vs 13-3% in men P
Efficacy and safety of APSAC in the treatment of acute myocardial infarction A. MACHRAOUI*, D. JAGER*, J. BARMEYER* AND J. ARMBRECHT|
"Department of Cardiology and Angiology, Internal Medicine Clinic, University ofBochum and^Smith Kline Beecham Pharmaceuticals, Munich, Germany KEY WORDS: Myocardial infarction, thrombolysis, APSAC, mortality. A prospective, open, multicentre post-marketing surveillance on the efficacy and safety of intravenous APSAC in the treatment of acute myocardial infarction was performed in 2436 patients. Reperfusion suggested by non-invasive parameters was achieved in 77-3% of patients. In-hospital mortality was low (7-1%). After exclusion from analysis of patients > 70 years of age and those reported to be in cardiogenic shock, mortality rate was 2-9%. More importantly, noninvasive evidence for successful thrombolysis resulted in a significantly lower mortality (3-3%) compared with patients without evidence of successful reperfusion (17-2%). The incidence ofserious adverse events was low (132 in 2436 patients, 8/2436 = 0-3% fatal). The data from this post-marketing surveillance conducted under every-day clinical conditions confirm the efficacy and safety of APSAC as a thrombolytic agent in acute myocardial infarction, as demonstrated previously in controlled clinical trials.
Introduction In most cases, myocardial infarction is caused by formation of an intracoronary thrombus. A previous study assessing this issue invasively, reported an incidence of 87% of temporary coronary occlusion due to thrombi or spasm in acute myocardial infarction'11. The introduction of thrombolysis in the treatment of acute myocardial infarction has resulted in a significant reduction of mortality associated with myocardial infarction. Several thrombolytic agents have been examined in the past113': streptokinase'4-*1, urokinase171 pro-urokinase18'9', APSAC (anisoylated plasminogen streptokinase activator complex'1(M61) and rt-PA (recombinant tissue plasminogen activator1'7""1). There are several potential advantages of APSAC over currently used thrombolytic agents: APSAC has a long plasma half-life (1-5 h) due to the fact that its biologically active part has to be gradually activated by deacylation. Thus, it can be conveniently administered in a single intravenous injection over 2-5 min and continues to exert its thrombolytic properties for a prolonged period of time. Furthermore, APSAC is immediately active in plasma, unlike streptokinase which has to combine with circulating endogenous plasminogen before thrombolysis occurs. Accordingly, earlier studies using APSAC have demonstrated high patency rates (73-88%"2-15-20'2'1) and a significant reduction of mortality after myocardial infarction (-50-5% after 30 days and -42-7% after 1 year1"1). This post-marketing surveillance was performed in order to assess the effect of the thrombolytic drug APSAC on myocardial reperfusion and mortality after myocardial infarction in a large number of patients under routine Submitted for publication on 8 April 1991, and in revised form 22 August 1991. Correspondence: PD Dr A. Machraoui, Berufsgenossenschaftliche Krankenanstaltcn Bergmannshcil. Gilsingstr 14, 4630 Bochum, Germany. 0195-668X/92/060818 + 06 $03.00/0
Downloaded from https://academic.oup.com/eurheartj/article-abstract/13/6/818/555300 by University of Adelaide user on 09 May 2018
clinical conditions. In addition, the frequency of adverse events was reported. Methods A prospective multicentre post-marketing surveillance was performed in 248 German hospitals. Patients were recruited for this study between May 1987 and April 1990. Patients of all ages experiencing chest pain with a duration of more than 30 min, unresponsive to nitrate or calcium-antagonist therapy, meeting ECG criteria of an acute myocardial infarction (i.e. ST elevation of at least 0-1 mV in one or more standard leads or at least 0-2 m V in one or more precordial leads) were enrolled in the study. Exclusion criteria were the contraindications of APSAC therapy current in West Germany during the study period (haemorrhagic diathesis, gastrointestinal, urogenital bleedings, catheterization of great vessels or extracorporeal resuscitation up to 8 days prior to the event, surgery in the last 10 days, severe untreated hypertension, acute pancreatitis, previous streptococcal infections, peripartal state or recent abortion, and thrombolytic therapy with APSAC or streptokinase during the last 5 months, and cerebral bleeding or injury or neurosurgery within the last 30 days). The decision about the inclusion of a patient older than 70 years was left to the discretion of the treating physician, since the APSAC prescribing information at the time of the study contained a warning to treat patients over the age of 70 years with caution. However, in patients below the age of 70 years there was no selection other than the inclusion and exclusion criteria outlined in this chapter. After confirmation of a patient's eligibility for the postmarketing surveillance, 30 units of APSAC (Eminase) in 5 ml of water for injection were injected intravenously over 5 min. Corticosteroids were not routinely administered prior to thrombolysis; their protective value has • 1992 The European Society of Cardiology
Efficacy of A PSA C in AMI
819
Table 1 Patient characteristics
Age (years) 70 Unknown
Male
(%)
Female
(%)
Total
(%)
492 1351 149 9
24-6 67-5 7-4 0-4
68 297 86 0
151 65-9 191 0
560 1648 235 9
22-8 67-2 9-6 0-4
2452 lnfarct localization Anterior infarction Inferior infarction Ant. + inf. infarction Unknown Previous infarction Cardiogenic shock Heart failure
950 1027 13 11
47-5 51-3 0-6 0-5
250 197 1 3
55-4 43-7 0-2 07
1200 1224 14 14
4S-9 49-9 0-6 0-6
324 222
16-2 11! 14 2
64 69
14 2 15-3 22-6
388 291
15-8 11-9 15-7
284
102
recently been disputed'22'. Additional medical therapy, including anticoagulation, was left to the discretion of the treating physicians. The efficacy of thrombolysis was assessed using noninvasive parameters: (1) Evidence for the occurrence of reperfusion was assumed in the presence of at least two of the following non-invasive parameters: reversal of ST elevations on the ECG within 2 h, occurrence of peak CK within 14 h, reperfusion arrhythmias and the disappearance of chest pain. (2) Reocclusion (i.e. reinfarction) was assumed to have occurred when a second ST elevation on the ECG or a later rise in CK serum levels were documented. Silent reocclusions of course stay undetected using these non-invasive parameters. All relevant clinical as well as laboratory and ECG data, including adverse events and the above-mentioned non-invasive efficacy parameters, were entered in a prospectively designed questionnaire for each patient in order to permit subsequent verification of the clinical diagnoses. Results are presented in absolute numbers and percentages; significance testing was performed with the Chi-square test. Results
2452 patients, whose characteristics are summarized in Table 1, were enrolled in this post-marketing surveillance. Sixteen patients died before completion of thrombolytic therapy, so that reperfusion was assessed only in 2436 patients (1989 male, 447 female). According to the treating physicians the reasons for these fatalities were unrelated to thrombolysis; however, no necropsies were performed. All 2452 patients were included in the calculation of overall mortality. Age averaged 57 years (range 21-86) for males and was slightly higher in female patients (62 years, range 28-88). There were 1200 (48-9%) anterior, 1224 inferior (49-9%) and 14 combined anterior and inferior infarctions (0-6%). In 14 cases (0-6%) no statements about the localization of the infarction could be obtained.
386
EFFICACY OF THROMBOLYSIS
Evidence of reperfusion was reported in 1883 out of 2436 patients (77-3%). 88-6% of the patients underwent thrombolytic therapy within 4 h after the onset of symptoms, 8-2% between 4 and 6 h, 2% after more than 6 h, and in 1-2% no information about the exact time of therapy was documented. The fraction of patients with evidence of successful reperfusion tended to be higher when thrombolytic therapy was initiated early after the onset of symptoms (78-7%4h, Table 2) and it was similar in all infarcted areas. For further clinical details of the patient population (previous infarctions, cardiogenic shock or consequent heart failure) refer to Table 2. In-hospital reinfarction occurred in 210/1883 (11-2%) patients, in 32 (1-7%) before and in 178 patients (9-5%) after 24 h following suspected reperfusion. All cases of reinfarction within the first 24 h occurred in patients in whom thrombolysis had been initiated up to a maximum of 300 min after the onset of symptoms. Reinfarction after 24 h occurred independently of the time period between the onset of symptoms and thrombolysis (Table 3). MORTALITY
Overall in-hospital mortality was 7 1 % (173/2452). Mortality was higher in women than in men (12-9% vs 5-7%, P< 0-001). Certain patterns of risk factors were also associated with an increase in in-hospital mortality: previous myocardial infarction (17-3%), cardiogenic shock as defined by the attending physicians (33-3%) and myocardial failure (22-8%). Furthermore, mortality increased with age (14-9% in patients aged > 70 years vs 6-3% in patients ^70 years, P< 0001, Table 4). After excluding patients of > 70 years of age and those with cardiogenic shock from analysis overall mortality was 2-9% Mortality was 3-3% (62/1883) in the patients revealing evidence of reperfusion and 17-2% (95/553) in the patient
Downloaded from https://academic.oup.com/eurheartj/article-abstract/13/6/818/555300 by University of Adelaide user on 09 May 2018
820 A. Machraouiet al.
Table 2
Reperfusion (based on clinical symptoms, ECC and CK) Men
Women
Total
N
%
N
%
N
%
1560/1989
78-4
323/447
72-3
1883/2436
77-3
712/942 830/1023 11/13 7/11
75 6 811 84-6 63 6
180/248 140/196 1/1 2/2
72 6 71-4 1000 1000
892/1190 970/1219 12/14 9/13
75-0 79-6 85-7 69-2
Start ol thrombolysis after onset of symptoms (min) 0-60 61-120 121-180 181-240 241-300 301-360 >360 No information
217/257 520/655 453/576 217/270 82/118 31/47 24/43 16/23
84-4 79-4 78-6 80-4 69-5 660 55-8 69-6
33/48 110/139 93/136 56/77 15-23 7/12 4/6 5/6
68-8 79 1 68-4 72-7 65-2 58-3 66-7 83-3
250/305 630/794 546/712 273/347 97/141 38/59 28/49 21/29
820 79-3 76-7 78-7 68-8 644 57-1 72-4
Previous inf. Heart failure Cardiogenic shock
238/324 191/277 151/219
73-5 690 68-9
45/62 59/102 34/66
72-6 57-8
283/386 250/379 185/285
73-3 660 64-9
Total Anterior myocardial inf. Inferior myocardial inf. Ant. + inf. myocardial inf. Unknown
Table 3
515
Reocclusion (based on clinical symptoms, ECG and CK) Men N
Total
Women %
N
Reocclusion < 2 4 h Anterior myocardial inf. Inferior myocardial inf. Anterior + inferior inf. Unknown Total
15/712 12/830 0/11 0/7 27/1560
21 1-4 0 0 1-7
2/180 3/140
Reocclusion > 2 4 h Anterior myocardial inf. Posterior myocardial inf. Anterior + posterior inf. Unknown Total
75/712 67/830 0/11 2/7 144/1560
10-5 81 0 28-6 9-2
N
%
1-9
5/323
0 0 1-5
17/892 15/970 0/12 0/9 32/1883
20/180 14/140 0/1 0/2 34/323
11-1 100 0 0 10 5
95/892 81/970 0/12 2/9 178/1883
10-7 8-4 0 22-2 9-5
0/1 0/2
11
%
2-1
15
0 0 1-7
group where thrombolytic therapy appeared to have failed to result in infarct vessel reperfusion (P< 0-001, Table 4, Fig. 1). In men the difference in mortality was 2-9% (46/1560) vs 13-3% (57/429, P70 Stable haemodynamics + age ^ 7 0
Rep
%
No rep Overall
'
Rep
No rep Men
'
Rep
17-3
22-8 33-3 44-4 2-9
No rep
Women
Figure I Mortality rates for patients undergoing thrombolysis with (Rep) and without evidence for reperfusion (No Rep). Data given for the whole patient population and for each gender. Mortality is significantly lower in patients revealing evidence of reperfusion in all subgroups.
needed. This was the objective of this post-marketing surveillance of APSAC in acute myocardial infarction. At present, thrombolytic therapy appears to be the only effective means of restoring ventricular function and thus reducing mortality from acute myocardial infarction. Several controlled studies employing different thrombolytic agents have shown that patency of the infarct-related coronary arteries can be achieved in a significantly higher number of cases, together with an improvement in ventricular function'12' and a- decrease in mortality12'310"'.
821
Controlled studies using APSAC reported angiographically proven patency rates of the infarct-related vessels of 55-88% and a reperfusion rate of 64% 90min after the initiation of therapy"516-20-231. Using non-invasive parameters for the assessment of the efficacy of-thrombolysis following myocardial infarction, the distinction between vessel patency and reperfusion (after initial documentation of occlusion) is not possible. For this reason we have coined the expression 'evidence for reperfusion' stating that clinical, laboratory and ECG parameters indicated a substantial improvement in myocardial perfusion compared with the patient status at hospital admission. The actual vessel patency or reperfusion after prior vessel occlusion can only be determined with certainty angiographically. For that reason comparison of the thrombolysis efficacy parameters used in this postmarketing surveillance other than mortality with earlier invasive studies is difficult. However, the majority of hospitals confronted with patients with acute myocardial infarction do not have the facilities for coronary angiography so that the use of non-invasively determined 'surrogate measures' of coronary perfusion, as performed in this post-marketing surveillance, reflects every day clinical practice. The percentage of patients revealing evidence of reperfusion (77%) in this post-marketing surveillance study was similar to results obtained in earlier controlled trials. The patient fractions with evidence of reperfusion in male and female patients and in different infarct sites were also in agreement with previous results. Patency rates reported for other thrombolytic agents were in the range of 5373% for streptokinase"5-23"251, 61-89% for rt-PA'26-28' and 60-66% for urokinasel26-2". It must be noted, however, that comparison between reperfusion rates and patency rates after a certain period post-thrombolysis determined invasively is also difficult because patency rates in infarct patients are generally somewhat higher than reperfusion rates due to the fact that in a certain subgroup of patients'with acute myocardial infarction no complete coronary vessel occlusion can be documented in the first place. The incidence of inhospital reinfarction in this study was relatively low with a value of 11-2%. In-hospital mortality was higher than data reported from two previous controlled trials assessing mortality after administration of APSAC in acute myocardial infarction (56 and 6-4%y10"'. However, if patients above the age of 70 years were excluded from analysis, as in the two aforementioned studies, a comparable in-hospital mortality rate was found in this present trial (6-2%). Further exclusion from analysis of patients reported to be in cardiogenic shock at the time of admission, as in previous studies, leads to an even lower in-hospital mortality rate of 2-9%.-In contrast to earlier trials, mortality was not only determined for all the patients undergoing thrombolytic therapy but mortality rates were also compared between patients with and without evidence of reperfusion. As expected, mortality was significantly lower in patients with evidence of reperfusion. Overall,
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A. Machraouiela\.
Table 5 Adverse events (independent of causality. 659 adverse events occurred in 490/2452 patients (20%). Several adverse events could be documented in one patient) Overall adverse events
Serious adverse events
N
%
N
%
Haemorrhage Local Cerebral Haematuria Others
130 100 7 9 14
5-30 408 0-29 0-37 0-57
19 11 0 3
0-77 0-45 0-20 0 012
Arrhythmias Bradyarrhythmia Ventricular fibrillation Others Hypotension
174 77 25 72 123
7-10 3-14 102 2-94 502
45 19 8 18 27
1-84 0-77 0 33 0-73 110
Allergic reactions General Anaphylactic shock Local or assumed allergic reactions
39 35 4 152
1 59 1-43 016 6 20
11 8 3 16
0-45 0-33 012 0-65
3 38
012 1-55
0 14
0 0-57
Blood biochemistry abnormality Others
Table 6
5
Haemorrhage and mortality rales Mortality rates Total
Fatal N
Cerebral bleedings Gastrointestinal bleedings Lung bleedings
7 12 2
5/2452 2/2452 1/2452
0-20 008 004
Total
21
8/2452
0-33
there was a reduction in mortality from 17-2% without, to 3-3% in patients with, the above mentioned evidence of reperfusion (/*< 0-001). Thus, overall mortality was reduced by 81% in patients showing evidence of reperfusion. This was true for both genders (2-9 vs 13-3% in men P
