Br Heart J 1992;68:167-70 167 Monitoring of streptokinase resistance titre in acute myocardial infarction patients up to 30 months after giving streptokinase or anistreplase and related studies to measure specific antistreptokinase IgG R Fears, H Ferres, E Glasgow, R Standring, K J Hogg, J D Gemmill, J M A Burns, A P Rae, F G Dunn, W S Hillis Abstract Varying concentrations of antibodies to strep- Objective-To examine the induction tokinase (SK) may be present in patients with of antistreptokinase antibodies after acute myocardial infarction (AMI) as a result giving streptokinase or anistreplase to of previous streptococcal infections."2 The patients with acute myocardial infarc- induction of anti-streptokinase (anti-SK) tion. antibodies after the administration of SK or Design-Patients were randomly anistreplase (Eminase, APSAC) is, therefore, allocated to receive either 15 x 10' IU, an anamnestic response. Previous studies on streptokinase or 30U anistreplase in a SK have measured the antibody response with double blind study. Blood samples were a surrogate endpoint, the functional SK resis- collected immediately before treatment tance titre, which also reflects the influence of and subsequently at intervals up to 30 inhibitors such as a2 antiplasmin and varia- months; plasma samples were assayed tions in other plasma proteins such as fibrin- for streptokinase resistance titre (func- ogen and plasminogen."35 These studies have tional assay) and streptokinase binding shown that a peak value was reached by two by IgG (microradioimmunoassay). weeks after dosing with SK and returned Setting-Cardiology department in a towards pretreatment values by six months. general hospital. The development of neutralising antibodies Patients-128 consecutive eligible may influence the efficacy and risk of an patients. Samples were collected for up adverse reaction to SK or anistreplase on to one year according to a prospective readministration for a subsequent myocardial design: a subsection of 47 patients was infarction, and in the context of the increasing selected for intensive study over the first use of thrombolytic therapy this might 14 days. After one year, all available become an increasingly relevant clinical patients (67) were sampled on one fur- problem. It is therefore important to define the ther occasion. times of induction and decline in a population Results-Antibody responses to strep- large enough to reflect the range of individual tokinase and anistreplase were similar. variations in neutralising antibody concentra- Streptokinase resistance titres exceeded tion. It was the purpose of the present work to pretreatment concentrations five days compare changes in SK resistance titre in after dosing, and values peaked at 14 response to the standard doses of SK and 12 months of SmithKline Beecham days. By after dosing, 92% anistreplase in patients with AMI. The results Pharmaceuticals, resistance titres (n = 84) had returned to from this functional assay were compared Great Burgh, Epsom, within the pretreatment range. Anti- with those from a novel method of assaying Surrey streptokinase concentrations also one class in terms of R Fears IgG antibody (IgG) antigen H Ferres exceeded baseline concentrations within binding.6 E Glasgow five days and peaked at 14 days. Half of R Standring the individual values had returned to University within the pretreatment range by 12 Department of months (n = 84) and 89% 30 months Medicine and by Patients and methods = Therapeutics, Stobhill (n 18). PATIENTS General Hospital, Conclusion-Although we cannot be One Glasgow sure of the clinical significance, because hundred and twenty eight consecutive K J Hogg of the increased likelihood of resistance eligible patients (101 men, 27 women age range J D Gemmill 31-70) were recruited between April 1987 and J M A Burns due to antistreptokinase antibody, strep- 1989. Inclusion and A P Rae tokinase and anistreplase may not be January exclusion criteria F G Dunn if more five and adjunct treatments have been described W S Hillis effective administered than previously.7 Patients were randomised in days after an earlier dose of streptokin- Correspondence to: double blind, double dummy fashion to receive Dr R Fears, SmithKline ase or anistreplase, particularly between either 1-5 x 106IU SK infused Beecham Pharmaceuticals, five days and 12 months, and increased intravenously Great Burgh, Yew Tree over one hour or 30 U anistreplase injected Bottom Road, Epsom, antistreptokinase antibody may increase intravenously overfiveminutes. Initial patency, Surrey KT18 5XQ the risk of allergic-type reactions. Accepted for publication rates of reocclusion, and adverse events are 13 January 1992 (Br Heart J 1992;68: 167-70) described elsewhere.7 168 Fears, Ferres, Glasgow, Standring, Hogg, Gemmill, Burns, Rae, Dunn, Hillis Evaluation ofvariations in streptokinase resistance titre after dosing with streptokinase or anistreplase Period offollow up (months with range) Analysis 3 6 12 (11-15) 18 (16-20) 24 (21-27) 30 (28-31) Median evaluation as fold increase over 20 (39)t 15 (38) 4 (60) 5 (22) 2 (20) 2 (18) individual pretreatment value (n) Values (%) returning to: Within pretreatment range 51 72 92 100 100 100 Within 95th percentile pretreatment range 31 44 76 86 77 88 For all patients (n) (45)t (50) (84) (22) (26) (18) Theoretical neutralisation of streptokinase (IU) (combininggroupmedian)* 1-2 x 106 12 x 106 6 x 105 3 x 105 3 x 105 3 x 105 *Theoretical neutralisation by pretreatment median value = 1 5 x IO' (assuming a standard plasma volume of 31). tNumbers of patients in the two types of analysis differ because median evaluation could only be calculated for those patients for whom pre and post treatment pairs of samples were available. At any one sampling time these pairs of samples are fewer than the total number of patients sampled. Blood samples were collected from patients are normally distributed, and the conclusions before dosing and serially at intervals for up to are similar to those derived from a considera- one year in a prospectively designed study. A tion of median values. The SK resistance and subsection of 47 patients was selected for antiSK IgG results were analysed by the intensive study over the first 14 days although Mann-Whitney U test. not all samples were received from each patient. Figures 1 and 3 show data from this cohort. The remaining figures and tables show Results available data for all patients. After one year all SK RESISTANCE TITRE available patients (67) were sampled on one Early serial changes (one to 14 days) were further occasion and these patients were studied in detail in a subgroup of 47 patients. grouped according to the classification de- The response was similar whether patients scribed in the table. were treated with SK or anistreplase, and baseline (pretreatment) values were consis- LABORATORY ASSESSMENTS tently exceeded by five days after dosing (fig 1). The SK resistance titre and antiSK IgG con- Figure 2 shows results for all patients, centrations were measured in individual monitored up to 30 months. Measurements up plasma samples as described previously.6 Cal- to 12 months are serial analyses in the same culations of the theoretical neutralisation of a patients (although a maximum ofonly 84 out of second dose of SK were performed by multi- a possible 115 samples were collected in the plying the SK resistance titre by the average prospectively designed study). By contrast, plasma volume of 3 litres. each patient was only sampled once over the period 12-30 months; that is, different patients STATISTICAL ANALYSIS appear in the groups collated at 18, 24, and 30 The SK resistance titres and anti-SK IgG months and therefore groups are smaller at concentrations, as analysed by either the Wilk- these times. Sampling times for the points Shapiro or the Kolmogorov-Smirnov test, within the period 12-30 months represent were not normally distributed and so cannot be ranges: the total ranges are specified in the table. represented as arithmetic means. Values for Changes in SK resistance titre were similar SK resistance titres and for comparison IgG for SK and anistreplase throughout the period are shown as median values with ranges. The of follow up (fig 2). Baseline (pretreatment) IgG values have also been analysed as values however were significantly higher in the geometric means as the log transformed values group of patients assigned to treatment with anistreplase (50 v 20 IU/ml, p < 0 05). Peak titres were reached two weeks after Figure 1 Initial changes in SK resistance titre. 'a Values are shown as E median and range for en -~10000 patients who received SK Q (open bars) or anistreplase m (stippled bars). Patient numbers are indicated (n). 0 CL Das 0 :, (D Oh 7 14 1 2 3 6 12 18 24 30 1n in - n v-cv cn o a coo am c a) r- ONc Days Months C4 _-_N- -C C C_d4- 4 N _ _ Oh 1 2 3 4 5 6 7 14 Sampling time Days Figure 2 Changes in SK resistance titre up to 30 Sampling time months. See legend tofig 1 for details. Monitoring ofstreptokinase resistance titre in acute myocardial infarction patients 169 Figure 3 Initial changes in anti-SK IgG. See early fall in IgG (fig 3) is not accompanied by a legend tofig 1 for details. E similar decline in SK resistance titre (fig 1). n Figure 4 showed results for all patients Q monitored to a up 30 months: changes in anti- SK IgG were similar for SK and anistreplase 01 throughout the period of follow up. It is ._ noteworthy that baseline values are not higher in the patients assigned to anistreplase, unlike cn the situation with SK resistance titre (fig 2). -0 01 In agreement with the changes in SK resis- cn tance titre, peak values of anti-SK IgG were attained 14 days after dosing (150 fold rise in median).