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Anti-streptokinase titers and response to streptokinase treatment in Pakistani patients
International Journal of Cardiology 82 (2002) 247–251 www.elsevier.com / locate / ijcard
Anti-streptokinase titers and response to streptokinase treatment in Pakistani patients a b, a b Khawar A. Kazmi , M. Perwaiz Iqbal *, Abdul Rahbar , Naseema Mehboobali b
a Department of Medicine, The Aga Khan University, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan Department of Biological and Biomedical Sciences, The Aga Khan University, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan
Received 5 February 2001; received in revised form 8 October 2001; accepted 21 November 2001
Abstract In order to investigate whether anti-streptokinase (anti-SK) antibody titers have any effect on response to standard dose (1.5 million units) streptokinase (SK) therapy in patients with acute myocardial infarction, anti-SK titers in plasma were determined in 97 such patients. These patients were classified as ‘responders’ or ‘non-responders’ on the basis of a criteria which involved resolution of chest pain in less than 90 min after the start of thrombolysis, greater than 50% reduction of ST segment elevation in two contiguous leads showing maximum elevations in a 12-lead tracing, reperfusion arrythmias and slope of increase in creatine kinase over a 90-min period after initiation of thrombolysis. Anti-SK antibody levels in plasma were determined in these patients as well as in 50 normal healthy subjects by dissolution of clot method. Mean6S.D. anti-SK levels among responders, non-responders and normal healthy subjects were found to be 0.2160.12, 0.2560.22 and 0.2160.15 million units, respectively. A comparison of these mean values by one-way ANOVA revealed no statistical difference (P50.68). However, when compared with the reported values for a Western population, these values were found to be significantly higher (P,0.03). Whereas, compared to the reported values for an Indian population, these were significantly lower (P,0.0001). 42% of patients appeared to have responded to SK treatment, while 21% were found to be non-responders. There was no association between response to SK and anti-SK titers in these patients suggesting that the standard dose of SK (1.5 million units) may be quite appropriate for the Pakistani population requiring SK treatment for the first time. 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Anti-streptokinase antibody; Streptokinase; Thrombolysis; Responders; Non-responders; Myocardial infarction
1. Introduction Streptokinase (SK) is the most commonly used thrombolytic agent in the management of acute myocardial infarction (AMI). However, its efficacy could be limited due to the presence of neutralizing antibodies because of previous streptococcal infec*Corresponding author. Tel.: 192-21-493-0051x4461; fax: 192-21493-4294. E-mail address: [email protected] (M. Perwaiz Iqbal).
tions [1]. Thus, determination of pre-treatment antistreptokinase levels in patients could be of value in predicating the thrombolytic outcome with standard doses of SK. This becomes even more important in patients living in tropical areas where streptococcal infections are quite common. The present study was undertaken to investigate anti-SK antibody levels in a population of Pakistani patients requiring SK treatment for their AMI and to study if there is any association between anti-SK levels and response to SK treatment.
0167-5273 / 02 / $ – see front matter 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 02 )00004-9
K. A. Kazmi et al. / International Journal of Cardiology 82 (2002) 247 – 251
248
2. Patients and methods
marker, creatine kinase activity as described by Zabel et al. [3]. Briefly, the criteria used are as follows:
Ninety-seven consecutive patients with AMI requiring thrombolytic therapy with SK were included in this study. All these patients were admitted to the coronary care unit of The Aga Khan University Hospital between June 1998 and December 1999. The study was approved by the Ethical Committee of The Aga Khan University. Demographic and clinical characteristics of the patients have been given in Table 1. Diagnosis of the patients was on the basis of clinical history, electrocardiogram (ECG) report and biochemical data. The patients had no recent history of streptococcal infection. Patients who had previous treatment with SK were also excluded from the main study. All those patients with typical chest pain $30 min duration, unresponsive to nitrates and with ECG, ST segment elevation of $0.1 mV in at least two limb leads or $0.2 mV in at least two contiguous chest leads were eligible for thrombolytic therapy.
2.1. Thrombolytic therapy with SK SK in a dose of 1.5 million units was administered intravenously over a period of 60 min and the patients were assessed for clinical response to SK over a period of 90 min.
2.2. Clinical assessment of patients for response to streptokinase treatment Response to SK treatment was assessed using the criteria used by Kircher et al. [2] along with serum Table 1 Demographic and clinical characteristics of patients with acute myocardial infarction Variable
Value (mean6S.D.)
Age (years) Sex Male Female Interval (h) between onset of symptoms and thrombolysis Prior history of MI Weight (kg) Haematocrit MI location Anterior Inferior and / or posterior Others
57.6611.6
Frequency (%)
76 (78%) 21 (22%) 461.5 30 (30%) 69.3611.5 40.665.3 43 (44%) 52 (54%) 2 (2%)
1. Resolution of chest pain in less than 90 min after the start of thrombolysis. 2. Greater than 50% reduction of ST segment elevation in the two contiguous leads showing maximal elevations in a 12-lead ECG tracing. 3. Reperfusion arrythmia, defined as arrythmia noted during a 90-min period after SK treatment. The arrythmias, which were considered suggestive of reperfusion, included accelerated idioventricular or junctional rhythm, paroxysmal sinus bradycardia (less than 50 beats per min), second or third degree atrioventricular block, ventricular tachycardia and ventricular fibrillation. 4. Creatine kinase (CK) activity: Blood samples collected before the initiation of thrombolysis and after 90 min of treatment were analyzed for CK activity. Slope of increase over a 90-min period after thrombolysis was calculated as: Slope5T902T0 / 1.5 h where T90 is the value of CK in international units per liter at 90 min and T0 is the value of CK before thrombolysis. The ratio T90 / T0 was also calculated. A slope .60 U l 21 h 21 and the value of T90 / T0 greater than 1.9 were considered a positive parameter for the response. All those patients who fulfilled at least three components of the above-mentioned criteria were considered as ‘responders’ to therapy, while those who were positive for two markers for reperfusion were classified as ‘probable responders’. Patients who were negative for three or all four markers for reperfusion were considered ‘non-responders’.
2.3. Blood collection Ten milliliters blood was collected from the patients immediately before thrombolytic therapy. A 5-ml aliquot was transferred to a tube containing 3.8% sodium citrate as anticoagulant in a ratio of 1:10. Plasma was immediately removed from it by centrifugation at 15003g for 15 min and stored frozen at 260 8C until the time of analysis of anti-SK antibody levels. The other 5-ml aliquot was allowed to clot and serum was removed for CK activity. After
K. A. Kazmi et al. / International Journal of Cardiology 82 (2002) 247 – 251
90 min, another 5 ml blood was collected from the patient and the serum was analyzed for CK activity.
2.4. Controls for anti-streptokinase levels Fifty healthy subjects (39 males and 11 females; mean6S.D. age 56.766.9 years; mean6S.D. weight 66.8613.6 kg; mean6S.D. haematocrit 3765.3) who had been matched for age, sex and socio-economic class of the patients were selected randomly to serve as controls. Their blood was obtained as described above, plasma removed and analyzed for anti-SK antibody level.
2.5. Determination of anti-streptokinase antibody levels Anti-SK antibody levels were determined in the plasma of patients and controls by the method used by Jalihal and Morris [4]. Briefly, SK (Sigma, USA) was diluted with normal physiological saline to obtain dilutions from 100 to 10 000 U / ml; 0.01 ml of each dilution of SK was added to 0.1 ml of patient’s plasma. To this mixture was then added 0.01 ml of freshly prepared bovine thrombin (Sigma, USA, 100 U / ml), which caused the formation of plasma clots in all the tubes. These were then immediately placed in a water bath at 37 8C for 10 min and observed for dissolution of clot in particular tubes. The lowest concentration of SK that caused the clot to lyse within 10 min was noted and the final anti-SK titer in the tube was calculated from this concentration using the following formula: SK neutralization titer (U / ml) Dilution of SK at which dissolution of clot occurs 5 ]]]]]]]]]]]]]]] 10 (dilution factor) Plasma volume of patient (ml) 5 wt (kg) 3 haematocrit ratio 3 75 Total plasma SK neutralization capacity 5 SK neutralization titer 3 plasma volume
2.6. Statistical analysis Comparison of mean values of anti-SK antibody levels in patients and controls was carried out by one-way ANOVA. A value of P,0.05 was considered significant.
249
3. Results and discussion Table 2 shows the mean6S.D. anti-SK antibody levels in patients with AMI and control subjects. The highest anti-SK antibody level in patients was 1.0 million units and the lowest 0.04 million units with a mean value of 0.24 million units. We also classified patients according to their response to SK. The mean anti-SK level among responders was found to be 0.2160.12 million units, while among non-responders the titer was 0.2560.22 million units. Among the normal healthy control subjects, the mean6S.D. anti-SK level was found to be 0.2160.15 million units. Comparison of all mean values by one-way ANOVA revealed no statistical difference among the mean values of control group and patients groups (F-statistic50.17; P-value50.68). Since the anti-SK antibody levels are not different among responders and non-responders, this shows that there appears to be no association between the anti-SK antibody titer and response to standard dose SK treatment. These results are in agreement with those reported by Gaylani et al. [5] who have also shown that there is no difference in the anti-SK antibody levels between reperfused and non-reperfused patients. Similar findings have also been reported by Fears et al. [6] who have shown that antistreptokinase immunoglobulin G is not a significant determinant of the efficacy response to SK. Even in patients from areas, which are endemic for streptococcal infections and in whom anti-SK antibody levels are very high, these antibodies do not appear to interfere with reperfusion [7]. Regarding reperfusion rates in this study, 42% of our patients responded to SK-therapy, 37% were ‘probable responders’ and 21% appeared to have no Table 2 Pretreatment anti-streptokinase antibody levels in patients with acute myocardial infarction and in normal healthy subjects (controls) Group
No. (n)
Anti-SK levels (million units)
Range
P-value a
Patients (total) Patients showing response to SK Patients showing no response to SK Normal healthy subjects (control)
97 41
0.2460.18 0.2160.12
0.0461.00 0.0460.69
NS NS
20
0.2560.22
0.0460.95
NS
50
0.2160.15
0.0660.88
NS
a Mean values were compared using one-way ANOVA (F-statistic5 0.17; P-value50.676); NS, not significant.
K. A. Kazmi et al. / International Journal of Cardiology 82 (2002) 247 – 251
250
response. These results conform well to those reported by Shaila et al. [7] who have shown complete reperfusion in 48% of their patients, probable reperfusion in 28% of the patients and no reperfusion in 28% of them. In another study, Hogg et al. [8] have shown 53% reperfusion at 90 min from the start of therapy with SK. Anti-SK levels in Pakistani normal healthy subjects and patients appear significantly higher (P,0.03) than the levels in a Western population. For example, in a study by Jahilal and Morris [4], the titers for a UK-based population have been reported to be 0.1660.01 million units. However, when the levels in our population were compared with those reported (0.3760.2 million units) for an Indian population [9], these were found to be significantly lower (P, 0.0001). The high titers in Indian population could be due to more streptococcal infections in southern India where that study was performed. The high anti-SK antibody titers in our population compared to titers in the population in UK may have been due to relatively more common streptococcal infections in our part of the world. Table 3 shows the cumulative percentage of patients with their corresponding anti-SK titers. It appears that 0.5 million units of SK will be required to neutralize anti-SK antibodies in 90% of patients, and the remaining 1 million units will, perhaps, be sufficient for thrombolysis. In order to find out how the anti-SK antibody levels in our patient population compare with those found in patients who have had streptokinase treatment in the past, we monitored the anti-SK levels in
eight such patients. Table 4 shows the individual values as well as a mean value of 1.3960.81 million units at a mean period of 14.661.9 months post SK treatment. This titer was nearly seven times higher than the normal anti-SK antibody levels found in our patient population and was in the range of 0.67–2.21 million units. Any one of such patients requiring further thrombolytic therapy, would place the physician in a dilemma whether to give that patient higher than the standard dose of SK with all the associated risks involved or to opt for tissue plasminogen activator which is extremely expensive and not readily available in this part of the world. It is also not clear what level of anti-SK antibodies will compromise the reperfusion ability of SK. A longterm follow-up study would be required to find out the time by which anti-SK antibody levels drop to normal levels in patients who have had thrombolytic treatment with SK as well as the clinical implications of higher antibody levels on re-administration of SK. One of the limitations of this study is that reperfusion was not diagnosed on the basis of angiography which remains the gold standard for determining reperfusion. However, it is costly, invasive and not readily available in most third world countries. A number of studies have shown that non-invasive markers when used in combination can reliably predict reperfusion [2,10,11]. Thus, in this study we have used a combination of three clinical markers and one biochemical marker, serum CK to assess the response to SK and as mentioned above the apparent response rates are comparable to those reported by other investigators.
Table 3 Cumulative percentage of patients with their corresponding anti-streptokinase antibody titer
Table 4 Anti-streptokinase antibody levels in patients with acute myocardial infarction post thrombolytic treatment with streptokinase
Titer
Frequency (f)
Relative frequency ( f/n)
Patient no.
Time after SK treatment (months)
Anti-SK levels (million units)
0–0.1 0.11–0.2 0.21–0.3 0.31–0.4 0.41–0.5 0.51–0.6 0.61–0.7 0.71–0.8 0.81–0.9 0.91–1.0
7 46 30 1 3 3 4 – 1 2
0.072 0.474 0.310 0.010 0.031 0.031 0.041 – 0.010 0.021
–
1 2 3 4 5 6 7 8
18 13 13 14 16 14 16 13
2.64 0.68 0.67 2.05 0.82 2.21 1.4 0.67
97.9 100
Mean6S.D.
14.6361.9
1.3960.81
Cumulative frequency (%) 7.2 54.6 85.6 86.6 89.7 92.8 96.9
K. A. Kazmi et al. / International Journal of Cardiology 82 (2002) 247 – 251
4. Conclusions Lack of association between response to SK and anti-SK antibody titer in our patient population and the fact that the response rates in them to SK treatment are comparable to those reported in the literature suggest that the present standard dose of SK (1.5 million units) may be quite appropriate for Pakistani population requiring SK treatment for the first time.
Acknowledgements We gratefully acknowledge the valuable suggestions by Professor M. Anwar Waqar. We also thank Dr Mohsin Yaqub for his help in obtaining samples from patients who had had SK treatment about a year ago.
References [1] Buchalter MB, Suntharalingam G, Jennings I et al. Streptokinase resistance: When might streptokinase administration be ineffective. Br Heart J 1992;68:449–53.
251
[2] Kircher BJ, Topol EJ, O’Neill WW, Pitt B. Prediction of infarct coronary artery recanalization after intravenous thrombolytic therapy. Am J Cardiol 1987;59:513–5. [3] Zabel M, Hohnloser SH, Koster W, Prinz M, Kasper W, Just H. Analysis of creatine kinase, CK-MB, myoglobin, and troponin T time–activity curves for early assessment of coronary artery reperfusion after intravenous thrombolysis. Circulation 1993;87:1542–50. [4] Jalihal S, Morris GK. Antistreptokinase titers after intravenous streptokinase. Lancet 1990;335:184–5. [5] Gaylani NE, Davies S, Tovey J, Kinnarid T, Duly E, Buchaller MB. Systemic lytic state is not a predictor of coronary reperfusion in acute myocardial infarction. Int J Cardiol 1996;57:45–50. [6] Fears R, Hearn J, Standring R, Anderson JL, Marder VJ. Lack of influence of pretreatment antistreptokinase antibody on efficacy in a multicenter patency comparison of intravenous streptokinase and antistreplase in acute myocardial infarction. Am Heart J 1992;124:305–14. [7] Shaila G, Chandrashekhar YS, Kumar N, Ganguly NK, Anand IS. Antistreptokinase antibodies before and after streptokinase therapy in patients with acute myocardial infarction from areas endemic for streptococcal infection and influence on reperfusion rates. Am J Cardiol 1994;74:187–9. [8] Hogg KJ, Gemmill JD, Burns JMA et al. Angiographic patency study of antistreplase versus streptokinase in acute myocardial infarction. Lancet 1990;335:254–8. [9] Alexander T, Krishnaswami S, Khanduri U. Anti-streptokinase levels in Indian patients. Int J Cardiol 1991;32:361–4. [10] Laperche T, Steg PG, Dehoux M et al. A study of biochemical markers of reperfusion early after thrombolysis for acute myocardial infarction. Circulation 1995;92:2079–86. [11] Hohnloser SH, Zabel M, Kasper W, Meinertz T, Just H. Assessment of coronary artery patency after thrombolytic therapy: Accurate prediction utilizing the combined analysis of three noninvasive markers. J Am Coll Cardiol 1991;18:44–9.
Anti-streptokinase titers and response to streptokinase treatment in Pakistani patients a b, a b Khawar A. Kazmi , M. Perwaiz Iqbal *, Abdul Rahbar , Naseema Mehboobali b
a Department of Medicine, The Aga Khan University, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan Department of Biological and Biomedical Sciences, The Aga Khan University, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan
Received 5 February 2001; received in revised form 8 October 2001; accepted 21 November 2001
Abstract In order to investigate whether anti-streptokinase (anti-SK) antibody titers have any effect on response to standard dose (1.5 million units) streptokinase (SK) therapy in patients with acute myocardial infarction, anti-SK titers in plasma were determined in 97 such patients. These patients were classified as ‘responders’ or ‘non-responders’ on the basis of a criteria which involved resolution of chest pain in less than 90 min after the start of thrombolysis, greater than 50% reduction of ST segment elevation in two contiguous leads showing maximum elevations in a 12-lead tracing, reperfusion arrythmias and slope of increase in creatine kinase over a 90-min period after initiation of thrombolysis. Anti-SK antibody levels in plasma were determined in these patients as well as in 50 normal healthy subjects by dissolution of clot method. Mean6S.D. anti-SK levels among responders, non-responders and normal healthy subjects were found to be 0.2160.12, 0.2560.22 and 0.2160.15 million units, respectively. A comparison of these mean values by one-way ANOVA revealed no statistical difference (P50.68). However, when compared with the reported values for a Western population, these values were found to be significantly higher (P,0.03). Whereas, compared to the reported values for an Indian population, these were significantly lower (P,0.0001). 42% of patients appeared to have responded to SK treatment, while 21% were found to be non-responders. There was no association between response to SK and anti-SK titers in these patients suggesting that the standard dose of SK (1.5 million units) may be quite appropriate for the Pakistani population requiring SK treatment for the first time. 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Anti-streptokinase antibody; Streptokinase; Thrombolysis; Responders; Non-responders; Myocardial infarction
1. Introduction Streptokinase (SK) is the most commonly used thrombolytic agent in the management of acute myocardial infarction (AMI). However, its efficacy could be limited due to the presence of neutralizing antibodies because of previous streptococcal infec*Corresponding author. Tel.: 192-21-493-0051x4461; fax: 192-21493-4294. E-mail address: [email protected] (M. Perwaiz Iqbal).
tions [1]. Thus, determination of pre-treatment antistreptokinase levels in patients could be of value in predicating the thrombolytic outcome with standard doses of SK. This becomes even more important in patients living in tropical areas where streptococcal infections are quite common. The present study was undertaken to investigate anti-SK antibody levels in a population of Pakistani patients requiring SK treatment for their AMI and to study if there is any association between anti-SK levels and response to SK treatment.
0167-5273 / 02 / $ – see front matter 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 02 )00004-9
K. A. Kazmi et al. / International Journal of Cardiology 82 (2002) 247 – 251
248
2. Patients and methods
marker, creatine kinase activity as described by Zabel et al. [3]. Briefly, the criteria used are as follows:
Ninety-seven consecutive patients with AMI requiring thrombolytic therapy with SK were included in this study. All these patients were admitted to the coronary care unit of The Aga Khan University Hospital between June 1998 and December 1999. The study was approved by the Ethical Committee of The Aga Khan University. Demographic and clinical characteristics of the patients have been given in Table 1. Diagnosis of the patients was on the basis of clinical history, electrocardiogram (ECG) report and biochemical data. The patients had no recent history of streptococcal infection. Patients who had previous treatment with SK were also excluded from the main study. All those patients with typical chest pain $30 min duration, unresponsive to nitrates and with ECG, ST segment elevation of $0.1 mV in at least two limb leads or $0.2 mV in at least two contiguous chest leads were eligible for thrombolytic therapy.
2.1. Thrombolytic therapy with SK SK in a dose of 1.5 million units was administered intravenously over a period of 60 min and the patients were assessed for clinical response to SK over a period of 90 min.
2.2. Clinical assessment of patients for response to streptokinase treatment Response to SK treatment was assessed using the criteria used by Kircher et al. [2] along with serum Table 1 Demographic and clinical characteristics of patients with acute myocardial infarction Variable
Value (mean6S.D.)
Age (years) Sex Male Female Interval (h) between onset of symptoms and thrombolysis Prior history of MI Weight (kg) Haematocrit MI location Anterior Inferior and / or posterior Others
57.6611.6
Frequency (%)
76 (78%) 21 (22%) 461.5 30 (30%) 69.3611.5 40.665.3 43 (44%) 52 (54%) 2 (2%)
1. Resolution of chest pain in less than 90 min after the start of thrombolysis. 2. Greater than 50% reduction of ST segment elevation in the two contiguous leads showing maximal elevations in a 12-lead ECG tracing. 3. Reperfusion arrythmia, defined as arrythmia noted during a 90-min period after SK treatment. The arrythmias, which were considered suggestive of reperfusion, included accelerated idioventricular or junctional rhythm, paroxysmal sinus bradycardia (less than 50 beats per min), second or third degree atrioventricular block, ventricular tachycardia and ventricular fibrillation. 4. Creatine kinase (CK) activity: Blood samples collected before the initiation of thrombolysis and after 90 min of treatment were analyzed for CK activity. Slope of increase over a 90-min period after thrombolysis was calculated as: Slope5T902T0 / 1.5 h where T90 is the value of CK in international units per liter at 90 min and T0 is the value of CK before thrombolysis. The ratio T90 / T0 was also calculated. A slope .60 U l 21 h 21 and the value of T90 / T0 greater than 1.9 were considered a positive parameter for the response. All those patients who fulfilled at least three components of the above-mentioned criteria were considered as ‘responders’ to therapy, while those who were positive for two markers for reperfusion were classified as ‘probable responders’. Patients who were negative for three or all four markers for reperfusion were considered ‘non-responders’.
2.3. Blood collection Ten milliliters blood was collected from the patients immediately before thrombolytic therapy. A 5-ml aliquot was transferred to a tube containing 3.8% sodium citrate as anticoagulant in a ratio of 1:10. Plasma was immediately removed from it by centrifugation at 15003g for 15 min and stored frozen at 260 8C until the time of analysis of anti-SK antibody levels. The other 5-ml aliquot was allowed to clot and serum was removed for CK activity. After
K. A. Kazmi et al. / International Journal of Cardiology 82 (2002) 247 – 251
90 min, another 5 ml blood was collected from the patient and the serum was analyzed for CK activity.
2.4. Controls for anti-streptokinase levels Fifty healthy subjects (39 males and 11 females; mean6S.D. age 56.766.9 years; mean6S.D. weight 66.8613.6 kg; mean6S.D. haematocrit 3765.3) who had been matched for age, sex and socio-economic class of the patients were selected randomly to serve as controls. Their blood was obtained as described above, plasma removed and analyzed for anti-SK antibody level.
2.5. Determination of anti-streptokinase antibody levels Anti-SK antibody levels were determined in the plasma of patients and controls by the method used by Jalihal and Morris [4]. Briefly, SK (Sigma, USA) was diluted with normal physiological saline to obtain dilutions from 100 to 10 000 U / ml; 0.01 ml of each dilution of SK was added to 0.1 ml of patient’s plasma. To this mixture was then added 0.01 ml of freshly prepared bovine thrombin (Sigma, USA, 100 U / ml), which caused the formation of plasma clots in all the tubes. These were then immediately placed in a water bath at 37 8C for 10 min and observed for dissolution of clot in particular tubes. The lowest concentration of SK that caused the clot to lyse within 10 min was noted and the final anti-SK titer in the tube was calculated from this concentration using the following formula: SK neutralization titer (U / ml) Dilution of SK at which dissolution of clot occurs 5 ]]]]]]]]]]]]]]] 10 (dilution factor) Plasma volume of patient (ml) 5 wt (kg) 3 haematocrit ratio 3 75 Total plasma SK neutralization capacity 5 SK neutralization titer 3 plasma volume
2.6. Statistical analysis Comparison of mean values of anti-SK antibody levels in patients and controls was carried out by one-way ANOVA. A value of P,0.05 was considered significant.
249
3. Results and discussion Table 2 shows the mean6S.D. anti-SK antibody levels in patients with AMI and control subjects. The highest anti-SK antibody level in patients was 1.0 million units and the lowest 0.04 million units with a mean value of 0.24 million units. We also classified patients according to their response to SK. The mean anti-SK level among responders was found to be 0.2160.12 million units, while among non-responders the titer was 0.2560.22 million units. Among the normal healthy control subjects, the mean6S.D. anti-SK level was found to be 0.2160.15 million units. Comparison of all mean values by one-way ANOVA revealed no statistical difference among the mean values of control group and patients groups (F-statistic50.17; P-value50.68). Since the anti-SK antibody levels are not different among responders and non-responders, this shows that there appears to be no association between the anti-SK antibody titer and response to standard dose SK treatment. These results are in agreement with those reported by Gaylani et al. [5] who have also shown that there is no difference in the anti-SK antibody levels between reperfused and non-reperfused patients. Similar findings have also been reported by Fears et al. [6] who have shown that antistreptokinase immunoglobulin G is not a significant determinant of the efficacy response to SK. Even in patients from areas, which are endemic for streptococcal infections and in whom anti-SK antibody levels are very high, these antibodies do not appear to interfere with reperfusion [7]. Regarding reperfusion rates in this study, 42% of our patients responded to SK-therapy, 37% were ‘probable responders’ and 21% appeared to have no Table 2 Pretreatment anti-streptokinase antibody levels in patients with acute myocardial infarction and in normal healthy subjects (controls) Group
No. (n)
Anti-SK levels (million units)
Range
P-value a
Patients (total) Patients showing response to SK Patients showing no response to SK Normal healthy subjects (control)
97 41
0.2460.18 0.2160.12
0.0461.00 0.0460.69
NS NS
20
0.2560.22
0.0460.95
NS
50
0.2160.15
0.0660.88
NS
a Mean values were compared using one-way ANOVA (F-statistic5 0.17; P-value50.676); NS, not significant.
K. A. Kazmi et al. / International Journal of Cardiology 82 (2002) 247 – 251
250
response. These results conform well to those reported by Shaila et al. [7] who have shown complete reperfusion in 48% of their patients, probable reperfusion in 28% of the patients and no reperfusion in 28% of them. In another study, Hogg et al. [8] have shown 53% reperfusion at 90 min from the start of therapy with SK. Anti-SK levels in Pakistani normal healthy subjects and patients appear significantly higher (P,0.03) than the levels in a Western population. For example, in a study by Jahilal and Morris [4], the titers for a UK-based population have been reported to be 0.1660.01 million units. However, when the levels in our population were compared with those reported (0.3760.2 million units) for an Indian population [9], these were found to be significantly lower (P, 0.0001). The high titers in Indian population could be due to more streptococcal infections in southern India where that study was performed. The high anti-SK antibody titers in our population compared to titers in the population in UK may have been due to relatively more common streptococcal infections in our part of the world. Table 3 shows the cumulative percentage of patients with their corresponding anti-SK titers. It appears that 0.5 million units of SK will be required to neutralize anti-SK antibodies in 90% of patients, and the remaining 1 million units will, perhaps, be sufficient for thrombolysis. In order to find out how the anti-SK antibody levels in our patient population compare with those found in patients who have had streptokinase treatment in the past, we monitored the anti-SK levels in
eight such patients. Table 4 shows the individual values as well as a mean value of 1.3960.81 million units at a mean period of 14.661.9 months post SK treatment. This titer was nearly seven times higher than the normal anti-SK antibody levels found in our patient population and was in the range of 0.67–2.21 million units. Any one of such patients requiring further thrombolytic therapy, would place the physician in a dilemma whether to give that patient higher than the standard dose of SK with all the associated risks involved or to opt for tissue plasminogen activator which is extremely expensive and not readily available in this part of the world. It is also not clear what level of anti-SK antibodies will compromise the reperfusion ability of SK. A longterm follow-up study would be required to find out the time by which anti-SK antibody levels drop to normal levels in patients who have had thrombolytic treatment with SK as well as the clinical implications of higher antibody levels on re-administration of SK. One of the limitations of this study is that reperfusion was not diagnosed on the basis of angiography which remains the gold standard for determining reperfusion. However, it is costly, invasive and not readily available in most third world countries. A number of studies have shown that non-invasive markers when used in combination can reliably predict reperfusion [2,10,11]. Thus, in this study we have used a combination of three clinical markers and one biochemical marker, serum CK to assess the response to SK and as mentioned above the apparent response rates are comparable to those reported by other investigators.
Table 3 Cumulative percentage of patients with their corresponding anti-streptokinase antibody titer
Table 4 Anti-streptokinase antibody levels in patients with acute myocardial infarction post thrombolytic treatment with streptokinase
Titer
Frequency (f)
Relative frequency ( f/n)
Patient no.
Time after SK treatment (months)
Anti-SK levels (million units)
0–0.1 0.11–0.2 0.21–0.3 0.31–0.4 0.41–0.5 0.51–0.6 0.61–0.7 0.71–0.8 0.81–0.9 0.91–1.0
7 46 30 1 3 3 4 – 1 2
0.072 0.474 0.310 0.010 0.031 0.031 0.041 – 0.010 0.021
–
1 2 3 4 5 6 7 8
18 13 13 14 16 14 16 13
2.64 0.68 0.67 2.05 0.82 2.21 1.4 0.67
97.9 100
Mean6S.D.
14.6361.9
1.3960.81
Cumulative frequency (%) 7.2 54.6 85.6 86.6 89.7 92.8 96.9
K. A. Kazmi et al. / International Journal of Cardiology 82 (2002) 247 – 251
4. Conclusions Lack of association between response to SK and anti-SK antibody titer in our patient population and the fact that the response rates in them to SK treatment are comparable to those reported in the literature suggest that the present standard dose of SK (1.5 million units) may be quite appropriate for Pakistani population requiring SK treatment for the first time.
Acknowledgements We gratefully acknowledge the valuable suggestions by Professor M. Anwar Waqar. We also thank Dr Mohsin Yaqub for his help in obtaining samples from patients who had had SK treatment about a year ago.
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