Reperfusion therapy for ST-segment elevation myocardial infarction: a review of the available treatment options in Kuwait

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1 Reperfusion therapy for ST-segment elevation myocardial infarction: a review of the available treatment options in Kuwait Mohammad Zubaid 1, Wafa A. Rashed 2, Mustafa Ridha 3 CME Acute myocardial infarction is currently classified into two broad categories of ST-segment elevation (STEMI) and non-st-segment elevation (NSTEMI) myocardial infarction, based on electrocardiographic features at the time of presentation. This classification serves as an important factor determining the type of treatment a patient receives. Reperfusion therapy is currently the standard treatment for STEMI. There are two forms of reperfusion therapy, pharmacologic and mechanical. There is strong evidence that, when carried out in a timely fashion and in appropriate circumstances, mechanical reperfusion provides lower mortality and morbidity events compared to pharmacologic reperfusion. In this article we will review the pros and cons of each of the two reperfusion therapies and comment on the treatment options available to physicians in Kuwait. Key words: Acute myocardial infarction, fibrinolytic therapy, primary angioplasty Bulletin of KIMS 2002;1:69-75 Bulletin of KIMS carries some articles specifically designated as CME. They provide the opportunity for the reader to obtain credit points in the CME Program of KIMS. Reperfusion therapy for STsegment elevation myocardial infarction: a review of the available treatment options in Kuwait is one in this category. Studying the article, answering the questions related to it on page 75, and sending a copy of the Answer Sheet (page 80) to the CME Center of KIMS makes the reader eligible for 1 CME credit in Category 1. To claim credit, the reader has to have obtained registration in the CME Program of KIMS, the answer sheet should be received by the CME Center before 31 st August 2003, and all questions should have been attempted. Readers who satisfy the above requirements would receive a certificate from the CME Center indicating the credit data. 1Department of Medicine, Faculty of Medicine, Kuwait University; 2 Department of Medicine, Mubarak Al- Kabeer Hospital and 3 Department of Medicine, Al-Adan Hospital, Ministry of Health. Correspondence: Dr. Mohammad Zubaid, Head, Division of Cardiology, Mubarak Al-Kabeer Hospital. Department of Medicine, Faculty of Medicine, Kuwait University. P.O. Box 24923, Safat 13110, Kuwait. Fax: ; zubaid@hsc.kuniv.edu.kw A 38-year-old male presented to hospital at 08:30 complaining of sudden onset of severe crushing retrosternal chest pain. The pain was typical ischemic cardiac in nature and had started at 07:30 after eating his breakfast. His risk factors included smoking and hypercholesterolemia. Initial physical examination revealed stable vital signs. The ECG showed 3 mm ST-segment elevation in leads II, III and avf. The diagnosis was acute STsegment elevation inferior wall myocardial infarction. The issues that will be discussed here are: 1. Is reperfusion therapy indicated for this man? 2. What form of reperfusion therapy would benefit him most? The classification and treatment of myocardial infarction (MI) has undergone tremendous evolution over the past 2 decades. 1 Current classification of MI identifies two distinct entities, namely ST-segment elevation MI and non-st-segment elevation MI. They correspond to what used to be termed Q-wave MI and non-q-wave MI, respectively. They differ significantly in their immediate and long term management. For the purpose of this discussion we will focus on the immediate treatment of ST-segment elevation MI. In principle, two options for reperfusion therapy are available, pharmacological reperfusion therapy and emergency primary percutaneous coronary intervention (PCI). Each of those two therapies offers benefits but the choice among them is complex and still evolving. Adjunctive therapy is used with each of these strategies (aspirin, heparin, glycoprotein IIb/IIIa antagonist, etc). These adjunctive therapies will not be discussed in this article. 69

2 Pharmacological reperfusion treatment Prospective randomized trials with various fibrinolytic agents have shown a clear mortality reduction compared to placebo. 2 Fibrinolytic agents are divided into two classes, non-fibrin-specific agents and fibrin-specific agents. These agents, either directly or indirectly, convert plasminogen to its active form, plasmin. Plasmin is the major protease of the fibrinolytic system that can digest fibrin. NON-FIBRIN-SPECIFIC AGENTS Streptokinase (SK) is the prototype of this class and is the most common agent used globally. It is a single-chain protein produced by β-hemolytic streptococci. It does not enzymatically activate plasminogen but forms a complex with it. This complex then converts uncomplexed plasminogen molecules to plasmin, which initiates fibrinolysis. 3 It is used as an infusion over 60 minutes in doses of 1.5 million units. As anti-sk titer rises rapidly within few days, repeated administration is impractical except very early after initial administration. 4 FIBRIN-SPECIFIC AGENTS The prototype of this class is rt-pa (alteplase). It is produced by recombinant DNA technology. It is a fibrin-specific plasminogen activator that has high affinity for plasminogen in the presence of fibrin. It converts fibrin-bound plasminogen to the active protease, plasmin. The latter digests fibrin clot. 3 The recommended dose of rt-pa is 100 mg administered front loaded, according to the GUSTO trial protocol, as 15 mg intravenous bolus followed by a weight adjusted regimen of 0.75 mg/kg over 30 minutes (not to exceed 50 mg) and then 0.5 mg/kg over 60 minutes (not to exceed 35 mg). 5 In this study, rt-pa was found to be superior to SK for both early and one year mortality. The angiographic substudy of GUSTO demonstrated the importance of establishing early coronary patency. Survival was significantly higher when the infarct-related artery had normal perfusion at 90 minutes from time of thrombolytic drug administration, regardless of the type of agent used. 6 Of the two agents rt-pa was associated with higher 90 minute infarct-related patency rate. Should one, therefore, always use the more expensive agent rt-pa? In the GUSTO trial, the overall absolute 30-day mortality benefit of rt-pa over SK was 0.9%, which was statistically significant. However, analysis of the data shows that there was no difference in mortality, between the two agents, in patients who suffered small MIs. Therefore, in many centers, it is customary to reserve rt-pa for large MIs and use SK for small MIs (e.g. isolated inferior or high lateral MI) in order to save money. MUTANTS AND VARIANTS OF rt-pa Several variants of rt-pa have recently been developed and are gaining wide spread use in clinical practice. They are created by processes that involve altering the amino acid sequence of rt-pa by deletion or substitution. The two agents most extensively studied and approved are r-pa (reteplase) and TNK-tPA (tenecteplase). It is important to know about those two agents, as they will be replacing rt- PA in clinical use in the near future and have become available in Kuwait. Their main advantage over rt-pa is their use as a bolus instead of infusion. In the RAPID II trial, when reteplase was administered as a double bolus of 10 million units 30 minutes apart, it yielded a higher 90- minute reperfusion rates than front-loaded rt- PA (59.9% versus 45.2%, p=0.01). 7 In the GUSTO III trial no difference was demonstrated between these agents in 30-day mortality, hemorrhagic stroke, bleeding complications, and the combined end point of death and stroke. 8 A 1-year follow up in GUSTO III has confirmed similar mortality outcomes in the two treatment arms of this trial. 9 The other significant rt-pa variant is tenecteplase. In several studies, tenecteplase yielded comparable 90-minute patency rates to front-loaded rt-pa, as well as clear doseresponse relationship of weight-adjusted tenecteplase for both coronary patency and intracranial and systemic hemorrhage. 10,11 The ASSENT-2 compared tenecteplase with rt-pa in patients with acute MI. 12 Weight-adjusted tenecteplase was compared with front-loaded rt-pa and revealed identical 30-day (6.18% for tenecteplase; 6.15% for rt- PA) and 1-year mortalities. Tenecteplase is administered as a weight-adjusted single bolus of mg. 70

3 Table 1. Fibrinolytic therapy use Indications Ischemic symptoms 12 hours ST-Segment elevation >1 mm in 2 contiguous leads Bundle-branch block, presumed to be new Absence of contraindications Absolute contraindications Active bleeding or bleeding diathesis Prior intracranial hemorrhage/hemorrhagic stroke or brain tumor Aortic dissection Relative contraindications Severe uncontrolled hypertension (>180/110 mm Hg) Oral anticoagulation and INR >1.5 Major recent trauma/surgery Pregnancy Recent retinal laser therapy Noncompressible recent vascular punctures nificant benefit is achieved if fibrinolysis is administered within 12 hours of symptom onset. It is estimated that about 30 lives are saved per 1000 patients treated within 0 to 6 hours and 20 lives per 1000 are saved if patients receive it between 7 and 12 hours. 2 The FTT overview has shown a decline of benefit of 1.6 lives per 1000 patients treated per 1- hour delay. In addition, there is now ample evidence to support a particular benefit when treatment is administered within the first minutes of symptom onset the golden hour. 13 Even at this day and age, and despite the strong evidence supporting the life-saving potential of fibrinolysis and reperfusion in general, two problems remain a key challenge, namely underutilization and delay in administering this therapy. This underutilization has been underscored in a large European survey, a United States national registry and a more recent 14-country registry (GRACE Registry). 14,15,16 Of those eligible for fibrinolysis and reperfusion, 37% in the European survey, 24% in the US registry, and 30% in the GRACE registry did not receive it. Luckily, this has not been the case in Kuwait. A retro- Table 1 lists the indications and contraindications for fibrinolytic therapy in patients with presumed acute MI. An overview of about patients from the Fibrinolytic Therapy Trialists (FTT) suggested that sigspective, single hospital (Mubarak Al- Kabeer), 3-year ( ) registry showed that only 6.6% of those eligible for fibrinolysis did not receive it. 17 Preliminary analysis of a prospective, country-wide, 6-month registry is showing the same promising pattern in Kuwait (unpublished data). The other fibrinolysis-related problem, that needs to be seriously addressed, is the delay in administering this life-saving therapy. Practice guidelines recommend a door to needle time of 30 minutes in order to maximize the benefit of fibrinolysis to the individual patient. 1 The main causes of the delay are patient-related and physician/system-related. Education campaigns aimed at the public might result in patients presenting earlier to the emergency department. Meanwhile, physicians looking after MI patients need to change their attitude and system in order to deal with the MI patient more expeditiously. Currently, all fibrinolysis is being administered to patients in the coronary care unit. This by itself is one of the important factors for delay. With the availability of new bolus fibrinolytic agents, we have introduced a new procedural protocol that will enable us to administer fibrinolysis, in the emergency department, shortly after patient presentation. It will be interesting to compare the door to needle time and its effect on mortality/morbidity, in our institution, before and after the introduction of this new protocol. Several large scale trials have recently presented us with alternative pharmacological reperfusion therapy in the form of reduced (half dose) lytic therapy in conjunction with a platelet glycoprotein IIb/IIIa antagonist. 18,19 Although such combination therapy seems to increase the speed and quality of myocardial reperfusion and reduce the incidence of inhospital recurrent ischemia, it had not been shown to reduce mortality and is associated with increased bleeding complications, especially in the elderly. Primary PCI treatment The non-pharmacologic alternative for the treatment of acute ST-segment elevation MI is emergency PCI without thrombolytic therapy. This modality has been shown to be superior to thrombolytic therapy in terms of restoration of normal epicardial blood flow (95% 71

4 versus 60%) and event free survival. A metaanalysis of several trials showed a reduction in 30-day mortality from 6.5% to 4.4%, and a reduction in stroke from 2% to 0.7%, compared with thrombolytic therapy. 20 Another advantage of successful primary PCI is the feasibility and safety of discharging the patient as early as 3 days post MI, with the potential for substantial cost saving. 21 Therefore, the recently updated ACC/AHA guidelines provides a class I recommendation for primary PTCA as an alternative to thrombolytic therapy in patients with acute MI and ST-segment elevation or new, or presumed new, left bundle branch block who can undergo angioplasty of the infarct-related artery within 12 hours of onset of symptoms or beyond 12 hours if symptoms persist, if performed in a timely fashion (balloon inflation within 90±30 minutes of admission) and supported by experienced personnel in an appropriate laboratory environment. 1 MERITS OF PRIMARY PCI VERSUS FIBRINOLYSIS This is one of the hottest debates in Cardiology. The advantages and disadvantages of each modality are listed in Table The difficulty in deciding which therapy is more superior arises from the fact that there are only a small number of randomized comparisons of the two therapies, the practice in large study centers cannot be generalized to the smaller community hospitals, where the bulk of the cases are, and that both modalities of treatment are undergoing rapid changes. Having said that, the evidence suggests that if it can be done in a timely fashion by experienced operators, it would be more beneficial than fibrinolysis. 20 Emergency primary PCI is safe and comparable, if not superior, to fibrinolysis even when patients present to local hospitals that lack catheterization facility, as is the case in the whole of Kuwait. On the basis of three recently conducted trials, the 60 to 90 minute additional treatment delay relating to patient transfer to a catheterization facility does not adversely affect the benefit gained from primary PCI. 23,24,25 Certainly in certain subsets of patients, e.g. those in cardiogenic shock and those with contraindications, primary PCI is the first choice of therapy. 26 Therefore, in Kuwait, the decision between local fibrinolytic therapy and transfer to Table 2. Comparison of emergency Primary PCI and fibrinolysis * Advantages Primary PCI Superior early patency Reduced residual stenosis, recurrent ischemia, and reinfarction Less intracranial hemorrhage Lower early mortality Superior in cardiogenic shock When fibrinolysis is contraindicated Disadvantages Operator experience is critical Limited access Longer time to treatment *Adapted from reference 22 with minor changes. Fibrinolysis Widely available with broad access Little dependence on operator experience Can be given promptly and on site Simple to administer in bolus form Systemic bleeding Intracranial hemorrhage Chest Diseases Hospital for emergency primary PCI depends on distance (e.g. Al-Sabah Hospital has an advantage), patient condition, local infrastructure, ability to ensure no time delay, and physician preference. A very critical factor also is the infrastructure at Chest Diseases Hospital in terms of operator availability, bed availability, and most importantly steady and continuous availability of crucial supply of stents and glycoprotein IIb/ IIIa inhibitors. Treatment recommendations for our patient Due to the unique structure of Chest Diseases Hospital as a referral centre, without an emergency room and emergency admissions of acute MI patients, we are not practicing primary PCI strategy for the treatment of acute MI. Therefore, this patient would receive fibrinolytic therapy. Since he is presenting with limited inferior MI (small), SK is an acceptable agent. The preferred agent for an anterior MI would be rt-pa or one of its newer variants, reteplase or tenecteplase. In fact, this patient presented to Chest Diseases Hospital's outpatient department an hour after symptom onset, in the morning working hours. He was admitted to the catheterization laboratory very quickly and underwent successful emergency primary PCI (Figures 1 and 2). The time from presentation to hospital 72

5 Figure 1. The occluded right coronary artery before emergency primary PCI. Figure 2. The right coronary artery after recanalization by means of balloon angioplasty and stent insertion to balloon inflation was about 45 minutes. The ST-segment elevation resolved, with disappearance of chest pain, within 5 minutes of opening the occluded right coronary artery. References 1. Ryan TJ, Antman EM, Brooks NH, et al update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: Executive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation 1999;100: Fibrinolytic Therapy Trialists (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet 1994;343: Handin RI, Loscalzo J. Hemostasis, Thrombosis, Fibrinolysis, and Cardiovascular Disease. In: Braunwald E, editor. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: W. B. Saunders; p White HD, Cross DB, Williams BF, et al. Safety and efficacy of repeat thrombolytic treatment after acute myocardial infarction. Br Heart J 1990;64: GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329: GUSTO Angiographic Investigators. The comparative effects of tissue plasminogen activator, streptokinase, or both on coronary artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993;329: Bode C, Smalling RW, Berg G, et al. Randomized comparison of coronary thrombolysis achieved with double bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction: the RAPID II Investigators. Circulation 1996;94: GUSTO III Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997;337: Topol E, Ohman EM, Armstrong PW, et al. Survival outcomes one year after reperfusion therapy with either alteplase or reteplase for AMI: results from GUSTO III trial. Circulation 2000;102: Cannon CP, Gibson CM, McCabe CH, et al. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial: Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators. Circulation 1998;98: Van de Werf F, Cannon CP, Luyten A, et al. Safety assessment of single-bolus administration of TNK tissue plasminogen activator in acute myocardial infarction: the ASSENT-1 trial: the ASSENT-1 Investigators. A Heart J 1999;137:

6 12. ASSENT-2 Investigators. Single-bolus tenecteplase compared with front- loaded alteplase in acute myocardial infarction: The ASSENT-2 bouble blind randomized trial. Lancet 1999;354: Boersma E, Mass ACP, Deckers JW, et al. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet 1996;348: European Secondary Prevention Group. Translation of clinical trials into practice: a European population based study of the use of thrombolysis for acute myocardial infarction. Lancet 1996;347: Barron HV, Bowlby LT, Breen T, Rogers WJ, Canto JG, Zhang Y, Tiefenbrunn AJ, Weaver WD. Use of reperfusion therapy for acute myocardial infarction in the United States: data from the National Registry of Myocardial Infarction2. Circulation 1998;97: Eagle KA, Goodman SG, Avezum A, et al. Practice variations and missed opportunities for reperfusion in ST-segment-elevation myocardial infarction: Findings from the Global Registry of Acute Coronary Events (GRACE). Lancet. 2002;359: Zubaid M, Rashed WA. Thrombolytic therapy in acute myocardial infarction: Practice pattern at an Arab Middle Eastern centre. Acta Cardiol. 2001;56: The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomized trial in acute myocardial infarction. Lancet. 2001;358: The GUSTO V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and glycoprotein IIb/IIIa inhibition: the GUSTO V randomized trial. Lancet. 2001;357: Weaver WD, Simes RJ, Betriu A, et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy of acute myocardial infarction: a quantitative review. JAMA. 1997;278: Grines CL, Marsalese DL, Brodie B, et al. Safety and cost-effectiveness of early discharge after primary angioplasty in low risk patients with acute myocardial infarction. J Am Coll Cardiol. 1998;31: Armstrong PW, Collen D. Fibrinolysis for acute myocardial infarction. Current status and new horizons for pharmacological reperfusion, part 2. Circulation. 2001;103: Grines CL, Westerhausen DR, Grines LL, et al. A randomized trial of transfer for primary angioplasty versus on-site thrombolysis in patients with high-risk myocardial infarction: The air primary angioplasty in myocardial infarction study. J Am Coll Cardiol. 2002;39: Widimsky P, Groch L, Zelizko M, et al. Multicentre randomized trial comparing transport to primary angioplasty vs immediate thrombolysis vs combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory. The Prague study. Eur Heart J. 2000;21: Andersen HR. The DANAMI-2 Study. Proceedings of the Late Breaking Clinical Trials Sessions of the American College of Cardiology; 2002 March 20; Atlanta, GA, USA. 26. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. N Engl J Med. 1999;341:

7 CME Questions BULLETIN OF THE KUWAIT INSTITUTE FOR MEDICAL SPECIALIZATION 2002;1:69-75 After you have completed reading the above article, take the test given below. Circle T (True) or F (False) in the answer sheet (page 80) to show the correct answer to each question. Questions 11 to 20 are related to the content in this article. 11. Treatment of MI differs significantly between ST-segment elevation MI and non-st-segment elevation MI. 12. The fibrinolytic agents SK and rt-pa are similar in their mechanism of action. 13. In the GUSTO trial there was a higher benefit of SK compared to rt-pa in the treatment of acute ST-segment elevation MI. 14. There is convincing evidence that the new variants of rt-pa are more effective than rt-pa itself. 15. For a small myocardial infarction SK and rt-pa are equal in their efficacy. 16. Reteplase is administered as a double bolus 30 minutes apart in the treatment of acute MI. 17. Under-utilization of reperfusion therapy is a common problem reported in the world literature. 18. Combination of reperfusion therapy and platelet glycoprotein IIb/IIIa antagonist reduces the mortality and morbidity of acute MI. 19. In metaanalysis, primary PCI was shown to be less effective than reperfusion therapy. 20. Currently primary PCI is the established mode of therapy of acute MI in Kuwait. 75