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Indian Journal of Medical Sciences, Vol. 59, No. 5, May, 2005, pp. 200-207 Original Article Indigenous recombinant streptokinase Vs natural streptokinase in acute myocardial infarction patients: Phase III multicentric randomized double blind trial Diwedi SK, Hiremath JS, Kerkar PG, Reddy KrishnaN, Manjunath CN, Ramesh SS, Prabhavati S, Dhobe M, Singh Kavita, Bhusari P, Rao Raman Clinical Research Division, Shantha Biotechnics Ltd., Hyderabad Code Number: ms05029 ABSTRACT Background : Streptokinase is the most widely used thrombolytic agent and can now be made using recombinant DNA technology. The present trial was initiated to assess an indigenous recombinant streptokinase (Shankinase, r-SK).Aim: To compare the efficacy and safety of indigenous recombinant streptokinase (Shankinase, r-SK) and natural streptokinase (Streptase, n-SK). Settings and Design: Double blind, randomized, non-inferiority, multicentric, parallel study. Materials and Methods: Patients of AMI < 6 hours of chest pain and 2 mm ST elevation in 2 contiguous chest leads V1- V6 or 1 mm in limb leads were randomized to receive 1.5 miu of either r-SK or n-SK. CK Peaking and decrease of > 50% ST segment were used to assess reperfusion. Statistical analysis: Difference in the groups was assessed by chi-square or paired t test as required. Probability value <0.05 was considered significant with 95% confidence interval. Results: Overall 150 patients were recruited (96 r-SK group and 54 in n-SK group) and demographic and clinical profile of the groups was comparable. Reperfusion was seen in 68.2% (58) and 69.4% (34) patients in r-SK and n-SK groups respectively. Commonly seen adverse events were fever in 7 (8.5%), hypotension in 3 (3.6%), nausea in 2 (2.4%) patients. Minor bleeding were seen in 4 (4.8%) of patients. Conclusion: Indigenous recombinant Streptokinase (r-SK) is as efficacious as natural streptokinase (n-SK) in establishing reperfusion as assessed by non-invasive parameters with comparable side effect profile.. Keywords: Streptokinase, Recombinant streptokinase, Myocardial infarction, Thrombolysis INTRODUCTION Over the last few years intravenous thrombolysis has become the standard therapeutic approach for patients with acute myocardial infarction (AMI). Intervention with thrombolytic agents in acute myocardial infarction is an effective means of limiting myocardial damage. The reduction in short and long-term mortality rates caused by thrombolytics has been demonstrated in several large-scale clinical trials.[1],[2],[3] Despite a slight difference in mortality found in the GUSTO trial, favoring tissue plasminogen activator (t-PA) when given as an accelerated infusion, the effects of natural streptokinase (n-SK) on the outcome of the patients with AMI has been similar to other thrombolytic agents and it remains the agent of choice in India as it is cheaper.[4],[5],[6] Though the greatest benefit occurs when streptokinase infusion is initiated early after onset of symptoms, late benefit has also been observed in patients treated even after 24 hrs of onset of symptoms.[1],[7]| Presently all available streptokinase for use in India, are naturally derived and expensive, while Shankinase is the first indigenously manufactured streptokinase obtained by means of recombinant-DNA technology. The recombinant-DNA process entails the culturing of E. coli carrying appropriate plasmid DNAs encoding for recombinant natural-type streptokinase followed by cell-lysis, refolding of streptokinase to their biologically active states, and their isolation at approximately 98% purity by chromatographic means. | This study was conducted at 6 centers, with the objective of comparing the effects of recombinant (r-SK) and natural (n-SK) streptokinase on coronary reperfusion in patients with acute myocardial infarction (AMI) and also the side effects. MATERIALS AND METHODS The present comparative, double blind, randomized, multicentric, parallel study between natural and recombinant Streptokinase was carried out in six hospitals across the country between January and June 2003. The medical division of Shantha Biotechnics, Hyderabad was responsible for coordinating and monitoring the study. An independent data monitoring safety board monitored all the events and serious adverse events regularly throughout the trial. The ethics committee at each hospital, and the Drug Controller General of India approved the protocol. Block randomization was done by using computer generated codes using the SAS software version 8.2 (SAS Institute Inc, Cary, NC, US). Between January 2003 to June 2003, 150 were patients recruited in the study while 96 received recombinant 54 patients were administered natural streptokinase. As per protocol 85 out of 96 and 49 out of 54 patients were eligible for evaluation for efficacy while as per intention to treat all 150 were evaluated for safety. The organizational chart of the recruitment of the patients is represented in [Figure - 1]. There was no significant difference in the demographic and clinical profile of patients in both the groups [Table - 1]. Mean symptom-treatment interval was 3.6±2.5 hrs and 3.8±2.1 hrs for Shankinase and Streptase respectively. Reperfusion CK peaking less than or at 12 hours was seen in 83.5% (71) and 89.8% (44) patients in r-SK and n-SK groups respectively. The kinetics of CK peaking at different intervals in both the groups is represented in [Figure - 2]. ST segment resolution ≥50% was observed in 81.2% (69) and 79.6% (39) patients in r-SK and n-SK group respectively. Pain resolution in 94.1% (80) and 93.9% (46) of patients in r-SK and n-SK group respectively. Reperfusion as assessed by the combination of CK peaking and ST resolution ≥ 50 was seen in 68.2% (58) and 69.4% (34) in r-SK and n-SK groups respectively. When assessed by all three parameters reperfusion rates where 69.0% (59) and 65.3% (32) in r-SK and n-SK respectively ( P =N.S.) [Table - 2]. Overall 47 serum samples were tested (27 from r-SK and 20 from n-SK group) for Anti-streptococcal antibodies. As is evident from the [Table - 3] presence of anti-streptococcal antibodies did not interfere with the reperfusion, in either of the groups. The occurrence of reperfusion arrhythmias was observed in 25% of patients in both the groups. The most commonly seen arrhythmias were accelerated idoventricular rhythm (AIVR) (38.8%), ventricular premature beats (38.8%) and ventricular tachycardia (22.2%). Adverse Events No significant differences were observed in the adverse event profile between the two groups although hypotension and fever were relatively common [Table - 4]. Hypotension in all the patients responded to inotropes and saline infusion after transient cessation of therapy. Fever of moderate grade and was accompanied by rigors in three patients in r-SK group. All patients were given antipyretics and responded to therapy. Nausea and vomiting which was seen in 2 and 3 cases respectively in the two groups was controlled by administration of antiemetics. Overall eight bleeding episodes were reported of which only one was major bleeding in the n-SK group, the remaining 7 were minor events 4 and 3 events in the r-SK and n-SK groups respectively. One patient who had a major gastrointestinal bleeding needed blood transfusion he also had Thrombocytopenia, which subsided on stoppage of heparin. Of these four events in the r-SK group two patients had bleeding at the site of venipuncture, which later healed without any need for medication, one patient had gastrointestinal bleeding, who was managed conservatively, while another patient had an episode of gum bleed followed by haemoptysis, which did not recur. Of the three events reported from the n-SK group two were cases of minor oozing at the site of vein puncture, which resolved without medication, one patient had gastrointestinal bleeding without hemodynamic compromise and was managed conservatively. DISCUSSION Reperfusion in the present study which was the primary end point was asseseed using a combination of enzyme (Creatine Kinase) peaking and ST segment resolution was observed in 68.2% (58) in the r-SK and in 69.4% (34) patients in n-SK group whereas, rates reported in literature by the present criteria vary from 59 to 82%.[1],[4],[5],[6],[9] A randomized comparative study was carried out in over 200 patients where a reperfusion rate of 67.1 and 70.7 was observed with recombinant and natural streptokinase respectively.[10] A similar rate of 70.6% was reported from previous Indian studies with natural streptokinase.[8]Safety profile assessment which was the secondary end point in the present study was similar in both the r-SK and n-SK group. These events seen were similar to those reported by other studies. Incidence of bleeding was 4.2% (4) in the r-SK group while it was 5.4% (3) in the n-SK group, which are similar to the rates reported in literature vary between 0.5 to 15.2%.[1],[5],[11],[13] No anaphylactic reactions were seen in the r-SK group whereas one was reported from the n-SK group. Adverse effects of thrombolytic therapy commonly include hypotension 4.5-15%, fever 5%, rigors, nausea and vomiting 46% and bleeding (0.5-15.2%). The mortality rates were low for both the groups {3.1% (3) and 5.5% (3)}, however the present small study did not have the statistical power to show the difference in the two comparable treatment groups. Post thrombolysis, cardiogenic shock was observed in 1 (1.2%) and 2 (3.6%) in the recombinant and natural streptokinase groups respectively whereas reinfarction was seen in 2 (2.4% and 3.6%) patients respectively in both the groups which is much less than in other studies. The present study has its limitations as the sample size is small and the markers used for assessing reperfusion were non-invasive instead of the gold standard that is angiography, although the non-invasive methods have been validated against angiography and are proven surrogate markers of reperfusion. Since this trial was a randomised controlled trial the instigators were of the opinion that the conditions to see the efficacy and safety need some factors to be controlled including patients not more that 65yers of age and without any co-orbid conditions that might influence the outcome. A larger study with patecny assessed by angiography and without influencing factors of age or others would give a precise assessment of reperfusion. Streptokinase is the most widely used thrombolytic agent particularly in India while others like tPA are expensive. Reviews comparing other thrombolytic agents have shown that streptokinase to be as good as that of tPA or rPA in terms of both efficacy and safety.[14],[15] Recombinant streptokinase has the advantage of not containing streptolysin and streptodornase unlike streptococci-derived natural streptokinase which might make it safer, and will be cheap which is very relevant to our country′s population. This technology can be further used to make more modifications in the present agents to make them more safe and efficacious. REFERENCES
Copyright 2005 - Indian Journal of Medical Sciences The following images related to this document are available:Photo images[ms05029t4.jpg] [ms05029t2.jpg] [ms05029t3.jpg] [ms05029t1.jpg] [ms05029f2.jpg] [ms05029f1.jpg] |
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