Effectiveness of Streptokinase in Acute Myocardial Infarction - Research Paper Example

?Pharmacology Effectiveness of streptokinase in Acute Miocardial Infarction Acute myocardial infarction can be treated using streptokinase.Streptokinase is derived from Streptococci. This Enzyme is a protein that binds to the plasmingoen and induces the thrombolysis. The studies have found that the administration of streptokinase within 6 hours of acute myocardial infarction can reduce the mortality rate. As the time increases, the mortality rate increases and the effect f streptokinase is present in the body upto 48 hours. The administration of aspirin and heparin before the treatment will increase the survival rate. Introduction: Acute myocardial infraction is the breakdown of the heart muscles due to the lack of oxygen supply. The shortage in oxygen supply is caused by the collection of lipids at the heart muscles. This creates a block in the blood vessels resulting in ischemia and if left untreated it results in infraction of the myocardial cells. The risk factors of acute myocardial infarction (AMI) are cardiovascular disease, tobacco smoking, older age, kidney diseases, blood pressure, excessive alcohol consumption and obesity. Streptokinase is one of the first thrombolytic agent to be used for the treatment of Acute myocardial infarction. Streptokinase was discovered in the year 1933 by Dr. William Smith Tillett. The use of Streptokinase for the treatment of acute myocardial infarction started in the year 1947 when Sol Sherry identified the potential of streptokinase. (Sikri and Bardia, 2007).The clinical trials using streptokinase started thereafter. They concluded that streptokinase can be used to treat hemothorax, purulent and sanguineous pleural exudations, fibrinous and tuberculosis meningitis. (Sikri and Bardia, 2007).The difficulties in purifying the protein streptokinase led to the delay in the intravenous use. The intravenous use of streptokinase was started in the year 1952. This proved to be a promising approach. Streptokinase was the protein identified from the bacteria beta- hemolytic streptococci. It contains a single chain of 414 amino acids with molecular weight of 47 – 50 KDa. (Becker, 1997). This protein does not have any intrinsic activity. It acts as the non fibrin specific activator of endogenous plasminogen. Streptokinase binds to the circulating plasminogen and forms a complex. This complex activates the plasminogen through a three step mechanism. If fibrin is present, then the streptokinase – plasmin complex forming capacity gets increased and thus lyses the clots. (Becker, 1997). After infusion of the clot, the streptokinase spreads through the plasma. There are two phases of streptokinase clearance. The half life of first phase streptokinase is 11-17 minutes and that of the second phase is 85 minutes. The current recommended dose level of streptokinase is 1.5 million units for 30- 60 minutes. (Becker, 1997). The main drawback of streptokinase is that it is antigenic. The administration of streptokinase produces antibodies in the blood. The antibodies formed may neutralize the drug. (Becker, 1997). Development: After the discovery of Streptokinase in the year 1933, the mechanisms of action of streptokinase in humans were determined. In 1959, Ruegsegger discovered the intracoronary clots. Many clinical trials were conducted at this time. There was a small risk of allergy. Many investigators considered this to be the plausible option for the treatment of acute myocardial infraction. In the year 1985 many small trials were conducted to standardize the protocol for streptokinase but no trial produced positive result. Finally they concluded that when the drug was administered for 1.5 to 3 hours, they were able to receive reperfusion rate of 90%. (Sikri and Bardia, 2007). GISSI Trial: Gruppo Italiano per la Sperimentazione della Streptochinasi nell'Infarto Miocardico ( GISSI) trial was conducted as the large scale trial. 11806 patients were enrolled in the study for a period of 17 months in 176 coronary heart care centre. New patients were recruited at a rate of 700 per month. (Sikri and Bardia, 2007).The patients were given streptokinase within 12 hours from the onset of the first symptom (i. e) pain in the chest. It was concluded that if streptokinase was administered quicker after the onset of the trial, the survival chance was very high (that is greater than 90%). The risk rates were found to be in the range of 74%, 80%, 85% for the patients who were given streptokinase in the 3rd hour, 6th hour and 9th hour respectively. Beyond that the risk rate was greater than 100%. The side effects in using streptokinase were very minimal. (Sikri and Bardia, 2007). The GISSI trial was followed by many trials that further dropped light on the use of streptokinase. Most of the trials concluded that streptokinase usage within 9 hours of the onset of the first symptom reduced the risks greatly than other drugs such as tissue plasminogen activator ( tPA) and other anticoagulants. (Sikri and Bardia, 2007). Other multicenter trials: Many multicenter trials were also conducted after GISSI trial. Some of them are GISSI-2, GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries), ISIS-3 (Third International Study of Infarct Survival Collaborative Group) etc,. of these ISIS-3 trial compared the efficacy of tPA and streptokinase. (Sikri and Bardia, 2007). tPA was found to reduce the mortality rates when compared to streptokinase. GUSTO trial found to show no difference in the results between the usage of streptokinase and tPA. (Sikri and Bardia, 2007). Similarly the high and short dose streptokinase use for the treatment of acute myocardial infarction was studied in the year 1986. The patients with age less than 70 were considered for this study. The patients were administered one million units of streptokinase after 4 hours of onset of acute myocardial infarction for a time of 30 to 60 minutes. The ST segment was greater than 4 mm at the interior or exterior leads. The ST segment was resolved in a mean time of 95 minutes. (Maclennan et al., 1986). The resolution of ST segment was the positive sign for the reperfusion of the myocardial infarction. Hydrocortisone (250 mg) was given to all the patients to reduce the allergy symptoms before the treatment. (Maclennan et al., 1986). After 24 hours, Heparin was administered at a dose concentration of 40,000 IU. Apart from the intravenous infusion, nine million units were given through 100 ml of physiological saline. The activated partial thromboplastin time was checked at two hours time interval. The ECG was taken at the end of streptokinase infusion for all the patients. It was concluded that early infusion of streptokinase for acute myocardial infarction was a very promising and safe method. They also concluded from this study that along with streptokinase we must also administer other adjuvant treatment agents for better and complete cure. Anisoylated plasminogen- streptokinase complex and Tissue plasminogen activator can be used along with streptokinase for good results. (Maclennan et al., 1986). It was also observed that only selected patients must be given high dose of streptokinase. Streptokinase vs alteplase: In acute myocardial infarction, thrombolysis is done using either streptokinase or front – loaded alteplase regimens. There is on guarantee that reperfusion is 100%. There are chances for the failure of the regimens too. To overcome this in addition to the regimens the use of Tissue plasminogen activator was recomnnended in this study. The difference between prothrombolysis and thrombolysis can be reduced by the use of Tissue plasminogen activator. kallikrein–contact-phase system was found to be activated only after the administration of streptokinase and this results in the activation of plasmin. (Maclennan et al., 1986). Thus kallikrein–contact-phase system is found to be the most important part. The activation of kallikrein–contact-phase system can be done by using complement cascades too. The present studt thus focused on kallikrein–contact-phase system and also on the thrombin generation by the plasmin mediated activation system. A random study was conducted with streptokinase administered within one hour of acute myocardial infarction of 1.5 million units and recombinant tissue plasminogen activator in the front loaded and weight adjusted regimen. (Maclennan et al., 1986). The synthesis of TAT complexes, the markers of the thrombin generation was found to be higher in all the patients in the therapy. It was concluded from this study that streptokinase administration has induced the kallikrein–contact-phase system more efficiently than the tissue plasminogen administration. (Hoffmeister et al., 1998). Thrombolytic therapy effect was observed in the patients after one day. Similarly the D-dimer level was found to be high even after two days. The fibrinogen levels which were found elevated got reduced to as low as 59 mg/dl after the therapy. The fibrinogen level increased only after 48 hours of treatment. The conclusion was streptokinase is more efficient and it has longer lasting effect. (Hoffmeister et al., 1998). Some studies were conducted to check the failure rate of streptokinase. A study conducted by Lee et al. in the year 2008 was a similar study that identified the thrombolytic failure using electrocardiogram. The association of streptokinase with other independent variables and outcome parameters were also studied. The thrombolysis failed in 59% of the patients due to five major parameters. They are anterior location of the myocardial infarct, longer door to needle time, diabetes mellitus, hypetension and white blood cell count. Recurrent acute coronary syndrome followed by death after one year was also found in this study. Hence it was suggested that the patients with the above five parameters must undergo other earlier reperfusion strategy and then follow streptokinase treatment. (Lee et al., 2008). Timeline and Efficacy level: Intracoronary fibrinolytic therapy can be used to reduce the ischemic myocardium and early restoration of the left ventricular function. Mortality benefit using thrombolysis IV was identified in this study and presented in the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. For the patients treated within 6 hours of the myocardial infraction, the mortality reduction rate was very good. The mortality rate was found to increase after 7 -12 hours, even higher after 24 hours. (Menon et al., 2004). Previously the concentration was on improving the efficacy and potency of streptokinase. Later the focus was made on finding the adjunctive therapies. GP IIb/IIIa inhibitors and LMWH therapies were tested. They proved to be a fusion of fibrinolysis and percutaneous intervention. The most important complication was bleeding. Menon et al., 2004).They also found that the use of heparin in the throughout the study as the best measure. The Heparin was used at a low concentration in the previous studies. The utilization of the bolus fibrolytic treatment before the rapid treatment of acute myocardial infarction will result in the faster recovery. It was concluded after the analysis of many clinical trials that tested the efficacy of streptokinase, the treatment results were based on many factors such as age, infarct location etc. This is still under approval. In this conference the merits and demerits of many trails were discussed including the GISSI-1, GISSI -2 and ISIS trails. Menon et al., 2004).In some trials aspirin was used along with streptokinase for increasing the efficacy of the treatment. alteplase, reteplase, or tenecteplase were used for the treatment of acute myocardial infarction as a three hour trial. (Menon et al., 2004). Alteplase versus streptokinase efficacy was tested in a separate trial. The mortality rate was less in the alteplase usage but the complications thereafter were very severe such as cardiogenic shock, congestive heart failure, and ventricular arrhythmia. (Menon et al., 2004). Effect on Neutrophil function: The administration of thrombolytic therapy is the most common method for the treatment of acute myocardial infarction nowadays. The effect of this treatment on the neutrophil number was studied in a separate trial. (Menon et al., 2004). The thrombolytic agents and the byproducts of fibrinolysis have the potential to affect the neutrophil’s function. (Susan et al., 1995).This may increase the myocardial damage thereafter. After the administration of the streptokinase, the circulating degradation products and white cells were found at high concentration than the normal patients. The neutrophils adherence to endothelium and homotypic neutrophil interactions had no difference before and after treatment. Thus there was no sequential change in the circulating neutrophil adhesion and CD II b expression or L-selectin concentration in the patients with AMI following the thrombolytic therapy. (Susan et al., 1995). Complications and suggestions: Similar to the fibrinolysis test, the after treatment measures were also studied by some scientists. The survival and complications after the streptokinase treatment for acute myocardial infarction was studied by Hishamuddin, Azmi and Jackson in the year 1993. This was a retrospective analysis study. Malays, Chinese and Indians were studied. The age of the patients ranged from 31 – 67 years. The patients with less than 6 hours of myocardial infarct with ECG showing ST elevation of greater than 2 mm was used for this study. The complications that occurred in this study were hypotension, reperfusion arrhythmias, gum bleeding and masculopapular rash. Cardiogenic shock was also identified in this study as after complication. The patients with disorders such as hypertension, bleeding, anticoagulation therapy, stroke streptococcal infection were not included in the study. (Hishamuddin, Azmi and Jackson, 1993).The survival rate was 91% after four weeks of the treatment. Thus it was found that the intravenous administration of streptokinase for the early myocardial infarction was the best method and for acute myocardial infarction, the survival rate was 91% and there was no guarantee for complete cure. This survival rate was the same as compared to the other trials. (Hishamuddin, Azmi and Jackson, 1993). Conclusion: Thus many studies have proved that streptokinase usage within 6 hours of acute myocardial infarct can reduce the mortality rate. The usage of streptokinase along with other thrombolytic agents will increase the survival rate and the efficiency of treatment. References: Becker, R. C. (1997). Text book of coronary and thrombolysis. Springer. Camille, A. P., Curt, D. F., Ellen, S.O., Bruce, M.P., Lewis, K., Neil, R. P. and Teri, M. (2006). Characteristics and Baseline Clinical Predictors of Future Fatal Versus Nonfatal Coronary Heart Disease Events in Older Adults. American heart association – circulation 113: 2173- 2185. Hishamuddin, H. M., Azmi, N. N and Jackson, N. (1993). Acute Myocardial Infarction survival rate and complications after streptokinase therapy in Hospital Universiti Sains Malaysia, Kelantan – A comparative study, Singapore medical Journal 34: 316 – 318. Hoffmeister, H. M., Sebastian, S., Kastner, C., Beyer, M.E., Helber, U., Kazmaier, S., Wendel, H. P., Heller, W and Seipel, L. (1998). Thrombolytic Therapy in Acute Myocardial Infarction : Comparison of Procoagulant Effects of Streptokinase and Alteplase Regimens With Focus on the Kallikrein System and Plasmin. American Heart Association – Circulation 98: 2527- 2533. Lee, Y. Y., Tee, M. H., Zurkurnai, Y., Than, W., Sapawi, M and Suhairi, I. (2008). Thrombolytic failure with streptokinase in acute myocardial infarction using electrocardiogram criteria. Singapore Medical Journal 49 (4): 304. Maclennan, B. A., Mcmaster, A., Webb, S. W., Khan,M. M and Adgey, A. A. J. (1986). High dose intravenous streptokinase in acute myocardial infarction short and long term prognosis. British Heart Journal 55: 231-9. Menon, V., Harrington, R. A., Hochman, J. S., Cannon, C. P., Goodman, S. D., Wilcox, R. G., Schunemann, H. J and Ohman, E. M. (2004). Thrombolysis and adjunctive therapy in acute myocardial infarction. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy., Chest, 23 (6): 549- 575. Sikri, N and Bardia, A. (2007). A History of Streptokinase Use in Acute Myocardial Infarction. Texas Heart Institute 34 (3): 318–327. Susan, A. A., Froese, S. P., Kirsch, R. E., Shephard, E. G., Robson, S C., Green, B. K. W and Commerford, P. J. (1995). Treatment of acute myocardial infarction with streptokinase does not appear to modulate circulating neutrophil function, Clinical Cardiology 18 (8): 459–463. Read More