Acute Myocardial Infarction: Comprehensive Guidelines for Patient Evaluation an
Acute Myocardial Infarction: Comprehensive Guidelines for Patient Evaluation and Mortality Reduction
Part II: Thrombolysis, Procedural Revascularization, and Future Strategies
Authors: Gideon Bosker, MD, FACEP, Assistant Clinical Professor, Section of Emergency Medicine, Yale University School of Medicine, New Haven, CT; Associate Clinical Professor, Oregon Health Sciences University. David J. Robinson, MD, MS, Director of Research, Assistant Professor, Department of Emergency Medicine, University of Texas at Houston Medical School, Houston, TX; David A. Jerrard, MD, FACEP, Associate Professor of Surgery Medicine and Clinical Director, Emergency Care Services, Veterans’ Affairs Hospital, Baltimore, MD; Dick C. Kuo, MD, Assistant Professor, Division of Emergency Medicine, University of Maryland Medical Center, Baltimore, MD.
Peer Reviewer: Chuck Emerman, MD, Associate Professor of Emergency Medicine, Case Western Reserve University; Chairman of Emergency Medicine, MetroHealth Medical Center, Cleveland Clinic Foundation, Cleveland, OH.
Emergency management of acute myocardial infarction (AMI) is evolving at an extremely rapid pace. What nearly all mortality-reducing strategies have in common is prompt restoration of blood flow to ischemic myocardium that has been compromised by intracoronary thrombosis. Although the precise relationship between the degree of coronary patency/flow and clinical outcomes may be debated, all experts agree that "time is muscle." Moreover, regardless of whether pharmacological (thrombolysis) or procedural interventions (angioplasty, stent, or coronary artery bypass) are employed, short- and long-term prognosis is optimized when blood flow to injured tissue is restored as quickly as possible.
Although the mandate to restore coronary perfusion is well-accepted, approaches to myocardial salvage vary from one institution to another. For example, in those emergency departments where access to coronary angiography is limited, thrombolytic therapy with such agents as t-PA will be the anchor agent for pharmacologic therapy, which, along with aspirin, may also include a mortality-reducing cocktail of beta-blockers, nitrates, and anticoagulants. In contrast, other institutions may be intervention intensive, in which case the majority of patients with AMI will be catheterized on an emergent basis, and, depending upon the anatomic lesions encountered, angioplasty and/or stent insertion will be the procedures of choice. Complicating approaches to patient management is the emergence of data from recent studies suggesting that some combination of thrombolytic and procedural intervention may be better than either technique alone.
The purpose of Part II of this two-part series on myocardial infarction is to review current strategies for myocardial salvage, with an emphasis on recent advances and controversies in thrombolytic therapy. In addition, new developments in combined pharmacologic and procedural approaches to AMI are discussed. Finally, future strategies for mortality reduction in AMI are highlighted. — The Editor
Thrombolytics: Mortality-Reducing Options
Introduction. Plasmin is the complex that facilitates lysis of a coronary thrombus that precipitates AMI. Thrombolytic therapy enhances the conversion of plasminogen to plasmin, thereby inducing clot lysis. Plasminogen is an inactive proteolytic enzyme that is found in plasma and bound to fibrin in thrombi.1 Tissue plasminogen activator (t-PA) essentially induces clot-specific lysis by cleaving bound plasminogen to the active form, plasmin, which then degrades fibrin to degradation products. These degradation products have antiplatelet and anticoagulant effects and also reduce viscosity. All t-PA variants can be compared regarding risks and benefits (see Table 1), and all have the same contraindications. (See Table 2.) The major limitation of all available plasminogen activators is that they generate active thrombin and stimulate platelet aggregation, which necessitates therapy with antithrombin and antiplatelet drugs in order to maintain arterial patency.
| Table 1. Benefits and Risks of Thrombolytics | |
| Alteplase (t-PA, rt-PA, Activase) | |
| Benefits: | > 10 yrs clinical experience |
| > 1 million patients treated | |
| Fibrin specificity | |
| Weight-dosed regimen | |
| 30 day mortality: | 6.3% (GUSTO I) |
| ICH rate: | 0.7% (GUSTO I) |
| Reteplase (rPA, Retavase) | |
| Benefits: | Double bolus dosing |
| 30 day mortality: | 7.47% (GUSTO III) |
| ICH rate: | 0.91% (GUSTO III) |
| Streptokinase (SK, Streptase) | |
| Benefits: | Less expensive than t-PA |
| 30 day mortality: | 7.3% (GUSTO I) |
| ICH rate: | 0.6% (GUSTO I) |
| PTCA | |
| Benefits: | Fewer bleeding complications than thrombolysis |
| Successful if performed in timely fashion | |
| In-hospital mortality: | 2.6% (PAMI) |
| ICH rate: | 0% (PAMI) |
Streptokinase. Streptokinase (SK) is produced from b-hemolytic Streptococci cultures. Intravenous SK acts on circulating inactive plasminogen to produce the active enzyme plasmin. This, in turn, leads to fibrin lysis and thrombus dissolution, but is not clot-specific.2 Reports of IV and intracoronary SK use were first published in 1958 and 1976, respectively.2,3 It was demonstrated in the early 1980s that SK could recanalize an acutely occluded coronary artery in a living patient.4 European, placebo-controlled megatrials, such as GISSI-1 and ISIS-2, showed that mortality in patients with AMI could be reduced 23% and 30%, respectively, by administering IV SK within six hours of the onset of chest pain.5,6
The current recommended dose of IV SK is 1.5 million units given over 60 minutes. A drawback to SK is its antigenicity. In the GUSTO trial, 5.7% of patients developed allergic reactions and 13% had sustained hypotension. Because of this potential, it is not recommended for use in those with recent Streptococcal throat infection or readministration to those who have had previous use in the prior 12 months. In these individuals, the use of a nonantigenic thrombolytic agent, such as t-PA, is recommended.7
Tissue Plasminogen Activator. The first reported clinical use of t-PA was in 1984.8,9 Tissue plasminogen activator is a naturally occurring enzyme found in vascular endothelial cells. This agent converts plasminogen to plasmin. At low doses, t-PA is characterized as clot-specific because of its propensity to bind to any new thrombus within the coronary artery lumen. Activase was proven to be superior to streptokinase in the GUSTO I trial (1993).10,11 Thirty-day mortality rates for accelerated Activase with IV heparin were 6.3%, compared with 7.3% for streptokinase with heparin—a statistically significant difference. The mortality reduction was sustained at one year and was consistent in all major subgroups; as a result, this 1% mortality difference has become a standard threshold for improvement when new thrombolytics are compared.
The GUSTO III trial (1997) was a 15,000-patient study designed to prove the superiority of Retavase over Activase.12 The trial failed to show superiority of Retavase; 30-day mortality rates were 7.47% and 7.24% for Activase. Ninety-five percent confidence intervals ranged from -1.11 to 0.66, implying that Retavase could be up to 1.11% worse than Activase, or 0.66% better than Activase.
Weight-Adjusted Dosing of Alteplase: Essentials for Maximizing Benefit/Risk Ratio
A recent study examined the frequency of risk factors for intracranial hemorrhage with t-PA in patients treated for AMI.13 The study was performed retrospectively by collecting data on 71,703 AMI patients entered in the National Registry of Myocardial Infarction (NRMI-2) who received treatment with t-PA as the initial reperfusion strategy. The main outcome measure was occurrence of intracranial hemorrhage, confirmed by computed tomography or magnetic resonance imaging.
The study found that 673 patients (0.95%) suffered intracranial hemorrhage (ICH) during hospitalization for acute MI; 625 patients (0.88%) had the event confirmed by CT imaging or MRI. Of these 625 patients, 331 (52.9%) died during the hospitalization. Risk factors significantly associated with the occurrence of ICH were older patients, female gender, black race, systolic blood pressure higher than 140 mmHg, diastolic blood pressure higher than 100 mmHg, history of previous stroke, t-PA dose greater than 1.50 mg/kg, and lower body weight.
It was noted that the occurrence of intracranial hemorrhage in the study was somewhat higher than that observed in the clinical trial setting. For example, the incidence rate of ICH in the GUSTO-I trial was 0.70%, compared with 0.88-0.95% observed in this study of registry patients. The authors suggest that variances were due to differing characteristics in the two patient populations; for example, the NRMI-2 population included a greater percentage of women than did GUSTO-I, the average systolic blood pressure among registry patients was substantially higher than in the GUSTO-I population, and participants in the GUSTO-I trial did not receive doses of t-PA greater than 1.50 mg/kg.
Specific differences in patient management patterns among different thrombolytic trials can be highlighted in order to give emergency physicians a framework for how to maximize benefits of t-PA therapy. For example, in GUSTO I, patients were administered t-PA according to a weight-dosing protocol to which physicians strictly adhered. In the Gurwitz study, 15% of patients received a dose of 1.5 mg/kg—a factor that was found to be associated more commonly with ICH.13 Moreover, a history of stroke was an exclusion criterion for the GUSTO I trial, whereas this analysis reveals that 3% of patients treated with t-PA were found to have a history of stroke, a factor significantly associated with ICH. In addition, the study population differed from that of GUSTO I in that it included a greater percentage of women, a history of diabetes mellitus and hypertension were more common, and median systolic blood pressure was higher (140 mmHg) than in GUSTO I (130 mmHg). Based on this analysis, there is a suggestion that lower body weight patients may benefit from weight-adjusted dosing of thrombolytic therapy in terms of less bleeding complications.
This NRMI-2 study only reinforces the need to weigh the potential benefits of thrombolysis against the potential risks on a patient-by-patient basis. Moreover, it illustrates the importance of individual risk assessment for intracranial hemorrhage in AMI patients being considered for thrombolysis. These findings emphasize the critical importance of weight-adjusted dosing of t-PA, especially in light of the fact that the authors found a strong inverse relationship between body weight and intracranial hemorrhage, and that a t-PA dose greater than 1.50 mg/kg was associated more commonly with ICH than lower doses (< 1.50 mg/kg). From a risk management and quality assurance perspective, it should be emphasized that more than 15% of NRMI-2 study patients received this higher dose of t-PA, which may have contributed to the excessive ICH rate observed in this trial as compared with previous clinical trials.
This retrospective analysis should be considered cautionary and stresses the importance of ensuring that all patients with MI who are treated with t-PA are dosed according to weight and in compliance with the manufacturer’s prescribing information. What is the appropriate, weight-adjusted dose? For patients weighing more than 67 kg, the recommended dose administered is 100 mg as a 15 mg intravenous bolus, followed by 50 mg infused over the next 30 minutes, and then 35 mg infused over the next 60 minutes. For patients weighing less than or equal to 67 kg, the recommended dose is administered as a 15 mg intravenous bolus, followed by 0.75 mg/kg infused over the next 30 minutes not to exceed 50 mg, and then 0.5 mg/kg over the next 60 minutes not to exceed 35 mg. Total dose should not exceed 100 mg.
Reteplase. Reteplase (r-PA) is a non-glycosylated deletion mutant of wild-type t-PA. Reteplase is administered as a double bolus infusion of 10 megaunits (10 MU) 30 minutes apart. In INJECT, r-PA was compared to SK, and demonstrated equivalence but not superiority. Mortality rates at 35 days were 9.0% for r-PA and 9.5% for streptokinase (P = NS). Outcomes data from the large GUSTO-III trial support its efficacy.12 It is important to note that the magnitude of clinical experience is an important determinant in selecting a thrombolytic agent.
Combination Therapy with t-PA and Antiplatelet GP IIB/IIIA Inhibitors: Evolving Cocktails for Mortality Reduction
Optimal outcome in acute treatment of MI is now defined by how the most effective thrombolytic is combined with the best mix of platelet inhibitors and anticoagulants. The goal is to speed restoration of blood flow and keep the artery open, with minimal bleeding complications. According to Eric J. Topol, MD, Cleveland Clinic Foundation, Cleveland, OH, "rapid reperfusion is the standard of care, but patency at 90 minutes is not the whole story. Even the most potent thrombolytic therapies do not restore complete coronary blood flow in all patients."14 He suggested that the new goals of therapy are emerging in the types of regimens used in the recently completed TIMI-14 (the 14th study in the Thrombolysis in Myocardial Infarction trial series) and SPEED trials. Because each of these trials involve a reduced dose of the thrombolytic agent, it is conceivable that the risk of hemorrhagic complications may be reduced.
In each of these trials, abciximab was combined with different reduced doses of thrombolytics. Initial results suggest that the efficacy of this combination may be greatest when abciximab is combined with t-PA.
The abciximab/t-PA combination was evaluated in the first part of the TIMI-14 study, with the best regimen (full dose abciximab plus half dose t-PA) showing TIMI-3 patency (indicating a fully open vessel) at 60 minutes in 73% of patients and at 90 minutes in 77% of patients. These results compare favorably with those seen with full-dose t-PA alone (which gave TIMI-3 flow rates of 43% at 60 minutes and 62% at 90 minutes in this study).
In contrast, results from the second phase of TIMI-14 testing abciximab with r-PA (reteplase, Retavase) demonstrate a TIMI-3 flow rate at 90 minutes of 70% with the arm chosen for further study (full-dose abciximab plus half-dose r-PA given as two 5 mg bolus doses 30 minutes apart). Efficacy more in line with the abciximab/t-PA combination has been seen when the r-PA dose is increased to 10 mg plus 5 mg. The SPEED trial also tested r-PA (5 mg + 5 mg) with abciximab, and TIMI-3 flow rates at 60-90 minutes were 62%.
Percutaneous Coronary Angioplasty. One of the most important debates in emergency medicine is whether pharmacologic therapy (thrombolysis) or mechanical therapy (PTCA) is the preferred strategy for achieving reperfusion with AMI. In this regard, the Primary Angioplasty in Myocardial Infarction (PAMI) Study Group reported a lower combined incidence of reinfarction and death in the hospital in those treated with percutaneous transluminal coronary angioplasty (PTCA) vs. patients treated with thrombolytic therapy.15 Patients who received PTCA also had a lower incidence of intracranial bleeding (0% vs 2%).
However, preliminary results from GUSTO II-b revealed that there was no statistical difference in mortality rates after 30 days. These differences may reflect heterogeneity in door-to-balloon time. In PAMI, 60 minutes was the usual time from door to balloon. In GUSTO II-b, the time was 114 minutes. The Myocardial Infarction Triage and Intervention (MITI) trial reported no difference in mortality, either in hospital or in the long-term.16 Because 14 of the 19 hospitals in this study were community based, it is quite possible that the data didn’t properly reflect the "high-volume expert centers." Outcomes may vary considerably secondary to the expertise of the interventionist. In 1997, it was concluded that in New York, at least, both hospital and cardiologist PTCA volume are inversely related to in-hospital mortality rate and same stay CABG surgery rate. The lowest same-stay CABG surgery rates were achieved with annual cardiologist PTCA volumes of 75 or more and annual hospital PTCA volumes between 600 and 999.17
PTCA is an alternative to thrombolytic therapy only if performed in a timely fashion by individuals skilled in the procedure (those who perform more than 75 PTCA procedures per year) and supported by the experienced personnel in high-volume centers. Current recommendations that favor PTCA over thrombolytic administration include the ability to perform PTCA within 60-90 minutes of AMI. It also is recommended in patients at high risk for intracranial bleeding and in individuals who fail to qualify for thrombolytic therapy. In those situations where PTCA will not be available for more than 60-90 minutes, thrombolytics should be considered the primary mortality-reducing intervention. In the hands of experienced operators, PTCA may provide superior, short-term outcomes and is highly recommended in those patients with cardiogenic shock. It would appear that the success of PTCA is very much dependent on the volume of procedures that is performed by the hospital or operator. Recent data suggest that the lowest mortality rates of patients undergoing PTCA are reported when the center and the cardiologist perform in excess of 400 and 200 cases, respectively, each year.17
Generally speaking, either angioplasty or thrombolytic agents are used for mortality reduction in AMI. However, studies are currently evaluating protocols using a combined approach, in which patients are given a lower dose of a thrombolytic, which is followed immediately by angioplasty. Early results suggest that outcomes may be improved with this combined approach. The rationale is that a lower dose of the thrombolytic agent may prevent bleeding complications associated with a procedural intervention, while at the same time promoting early patency, until the procedure can be performed. Until more definitive comparative data become available, the goal should be to maximize the speed and efficiency of both approaches.
Complications of Thrombolysis
Bleeding is the most common adverse effect associated with thrombolysis.18,19 Most complications occur at vascular access sites and rarely require transfusions. Other sites include gastrointestinal, genitourinary, and intracranial locations. (Contraindications to thrombolytics are listed in Table 2.)20 Intracranial hemorrhage is the most serious complication of thrombolytic therapy; standard ICH rates are listed in Table 1.
| Table 2. Contraindications to Thrombolytic Therapy |
| Contraindications |
| • Active internal bleeding |
| • History of cerebrovascular accident |
| • Recent intracranial or intraspinal surgery to trauma. (See Warnings.) |
| • Intracranial neoplasm, arteriovenous malformation, or aneurysm |
| • Known bleeding diathesis |
| • Severe uncontrolled hypertension |
| Warnings |
| • Recent major surgery (e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels) |
| • Cerebrovascular disease |
| • Recent gastrointestinal or genitourinary bleeding |
| • Recent trauma |
| • Hypertension: systolic BP ³ 180 mmHg and/or diastolic BP ³ 110 mmHG |
| • High likelihood of left heart thrombus (e.g., mitral stenosis with atrial fibrillation) |
| • Acute pericarditis |
| • Subacute bacterial endocarditis |
| • Hemostatic defects including those secondary to severe hepatic or renal disease |
| • Significant hepatic dysfunction |
| • Pregnancy |
| • Diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions |
| • Septic thrombophlebitis or occluded AV cannula at seriously infected site |
| • Advanced age (e.g., older than 75 years) |
| • Patients currently receiving oral anticoagulants (e.g., warfarin sodium) |
| Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its locaton |
Despite the increased incidence of hemorrhagic stroke after thrombolytic therapy, the overall incidence of stroke is similar whether or not thrombolytic therapy is administered. The difference, of course, is that most strokes in AMI patients who have not received thrombolytics are of the nonhemorrhagic variety.19,21 The risk of intracranial hemorrhage with t-PA use is greater in patients older than 65 years, those with hypertension, or weight less than 70 kg. Focal neurologic deficits mandate immediate CT scan. If positive, thrombolytic therapy and heparin should be discontinued.
Adverse effects may occur in patients treated with SK. Hypotension may occur, but it is usually responsive to IV fluids and may not necessitate halting the SK infusion.22 Bronchospasm, urticaria, and serum sickness may occur in up to 20% of patients.23 Since anaphylactic reactions are rare, pretreatment with antihistamines and corticosteroids may not be necessary. Systemic bleeding has been noted to occur slightly more frequently with SK vs. t-PA, but t-PA is associated with a higher incidence of intracranial hemorrhage than SK.24
Punctured vessels that bleed secondarily to thrombolytics usually respond to direct pressure. It may occasionally be necessary to stop the anticoagulant and thrombolytic if bleeding from these vessels continues unabated or worsens. Transfusion may be required. Protamine sulfate, in a dose of 1 mg per 100 units of heparin, may be given to shorten the half-life of heparin. Cryoprecipitate (10-15 bags) may be employed as well if bleeding does not respond. Continuing hemorrhage would require fresh frozen plasma (2-6 units). Platelets may also be administered to gain control of hemorrhage.
Selecting Patients for Thrombolysis
ECG Criteria. Traditionally, ST elevation in limb and chest leads has been an essential criterion for initiating thrombolytic therapy. The AHA/ACC criteria for using thrombolysis are as follows:25
• Class I:
• ST Elevation (greater than 0.1 mV, two or more contiguous leads), time to therapy 12 hours or less, age younger than 75 years.
• Bundle branch block (obscuring ST-segment analysis) and history suggesting acute MI.
• Class IIa:
• ST elevation, age 75 years or older.
• Class IIb:
• ST Elevation, time to therapy greater than 12-24 hours.
• Blood pressure on presentation greater than 180 mmHg systolic and/or greater than 110 mmHg diastolic associated with high-risk MI.
• Class III:
• ST elevation, time to therapy greater than 24 hours, ischemic pain resolved.
• ST-segment depression only.
Hypertension. Historically, acute hypertension was considered a contraindication to thrombolytic use because elevated blood pressure is associated with a higher rate of hemorrhagic CVA. Studies have supported this rationale.26 The risk of ICH is significantly greater when the presenting BP at time of AMI is 180/110 mmHg or greater. The TIMI-2 trial observed that aggressive reduction in blood pressure with beta-blockade therapy decreased the incidence of hemorrhagic CVA in patients with AMI in whom t-PA was administered.20 Those with anterior AMI are most likely to experience hypertension and might benefit from IV beta-blockade. However, paradoxical blood pressure depression is more commonly seen after administration of nitroglycerine and morphine. Elderly patients presenting with AMI and hypertension are at high risk for intracranial hemorrhage (ICH).27 A benefit to risk ratio must be considered when administering thrombolytics in all populations.
CPR. A number of studies have touted the safety of thrombolysis in patients who have received CPR.28,29 A 1991 report was more cautious in its recommendation. The authors suggest a possible increase in major bleeding episodes.30 The benefit to risk ratio must be calculated on an individual basis. More recent recommendations suggest that thrombolytics may be administered if CPR was performed for less than 10 minutes.31 Musculoskeletal trauma such as broken ribs may complicate thrombolytic therapy after prolonged CPR and should be considered a risk factor for continued bleeding.
Patient Age. Despite higher morbidity and mortality as compared to younger patients who receive thrombolytics, the number of lives saved in those older than 75 years of age is greater than those younger than age 75.32 However, many comorbid conditions in this age group can preclude or diminish the attractiveness of thrombolytic use in the elderly. (See Table 2.) Age older than 65 increases the odds of intracranial hemorrhage,33,34 as well as that of nonhemorrhagic stroke. But absolute mortality reductions, nevertheless, favor treatment of the elderly. AHA/ACC guidelines suggest that "thrombolysis benefits the patient irrespective of age."
Treatment Time. A number of studies have shown that mortality rates drop precipitously when thrombolytic agents are given as soon as possible after coronary artery occlusion. The prehospital MITI trial group noted early thrombolytic treatment within 70 minutes reduced mortality to 1.2%, compared to 9% for those patients who waited for more than 70 minutes to begin treatment.35 GISSI-1 demonstrated a mortality reduction of 50% when thrombolytic therapy was given one hour or less after onset of symptoms.36 A meta-analysis of 60,000 patients by the Fibrinolytic Therapy Trialists Collaborative Group reported an increase of 1.6 lives/1000 lost with each hour delay.37
At one time, it was felt that thrombolytics might confer no benefit if given beyond six hours of symptom onset. GISSI-1 revealed no benefit in mortality reduction beyond six hours with SK.38 However, ISIS-2, the LATE trial, and the EMRAS trial5,39 demonstrated mortality benefits if thrombolytics were administered within 12 hours. Only ISIS-2 suggested any benefit beyond this 12-hour window. AHA/ACC guidelines mention that "the greatest benefit occurs when thrombolysis is initiated within six hours of symptom onset, although it exerts definite benefit when begun within 12 hours."25
Thrombolysis vs. PTCA. Survival and LV function are clearly improved with early administration of IV thrombolytics such as t-PA. This likely equates with a greater reduction in AMI-associated mortality. Front-loaded regimens of t-PA provide better patency rates and are now supported as the regimen of choice by most institutions.
Although the debate still persists, experts agree that too few AMI patients receive reperfusion or receive it quickly enough. The time from onset of symptoms to definitive management has not changed in the last seven years.
Studies support PTCA as the most effective therapy in cardiogenic shock and in patients in whom attempts with thrombolysis are not successful. Debate continues as to which modality, primary PTCA or thrombolytics, is the best first-line treatment for other patients AMI. Primary PTCA may be favored over thrombolytics assuming the hospital and interventional cardiologist have adequate experience and PTCA can be initiated within 60 minutes of arrival to the hospital. However, since fewer than 20% of U.S. hospitals have an angioplasty suite or the capability to staff one in rapid fashion, thrombolysis with t-PA remains a primary modality in the majority of hospital EDs.
Managing Complications of AMI
Arrhythmias. ACLS protocols are readily available for the management of arrhythmias encountered in the setting of AMI. Immediate defibrillation is the treatment of choice for V-fib or hemodynamically unstable ventricular tachycardia (VT). Ventricular ectopy is common in the setting of AMI and should not be routinely treated. Lidocaine may be used for the treatment of frequent (5/minute) ventricular premature depolarizations (VPDs), multifocal VPDs, or those that may induce VT or V-fib. Procainamide may be used if lidocaine is ineffective, although hypotension and widening of the QRS complex may be observed.
Accelerated idioventricular rhythm (AIVR) often occurs after thrombolysis has produced coronary reperfusion. This wide complex escape rhythm may occur when the sinus rate falls to less than 60. This rhythm usually requires no specific treatment and lidocaine should be avoided, inasmuch as ventricular suppression may lead to symptomatic bradycardia or asystole. If there is hemodynamic instability or if this rhythm is associated with VF or VT, atropine or overdrive pacing may be used.
Supraventricular rhythms are also encountered. Persistent sinus tachycardia may suggest a poor prognosis. The underlying causes (fever, pain, anxiety, hypovolemia, CHF) should be treated and, if necessary, treatment with judicious amounts of a beta-blocker is indicated. Paroxysmal supraventricular tachycardia (PSVT) is uncommon but should be treated with synchronized cardioversion if the patient is unstable. Stable patients may require standard pharmacologic management as appropriate. Atrial fibrillation and flutter may be treated with IV diltiazem, verapamil, or propranolol, but if the patient is unstable, synchronized cardioversion is the treatment of choice. Atrial fibrillation with a rapid ventricular rate should also be cardioverted. Unstable atrial fibrillation with ventricular rates below 100 may require transvenous pacing before cardioversion to prevent asystole.
Sinus bradycardia is associated with inferior MI and should be treated with atropine if associated with symptoms of decreased cardiac output. Temporary pacing is indicated for any unstable patient that fails to respond to atropine or develops a high grade heart block. Mobitz type II requires pacing regardless of symptoms and third-degree AV block requires emergent transvenous pacing, as these patients may readily progress to asystole.
Pump Failure. Pump failure is usually the result of decreased left ventricular systolic function or decreased compliance of the left ventricle. Acute mitral regurgitation, VSD, or exacerbation of existing valvular disease may also result in pulmonary edema or shock. Mild heart failure may be treated with furosemide but hypovolemia and hypotension should be avoided. Topical or low-dose IV nitrates may be of some benefit by reducing left ventricular filling pressures. ACE inhibitors may be used in patients with heart failure, but hypotension must be avoided. Initially, hypovolemia should be treated with fluids. These patients will have a low pulmonary capillary wedge pressure (PCWP) and a low cardiac index. Patients with volume overload or decreased left ventricular compliance can be treated with diuretics or nitrates. Swan-Ganz catheters are helpful in the management of patients with pump failure to measure CI and PCWP, but are rarely available in the ED. Advanced management in the critical care unit is recommended in patients with pump dysfunction in the setting of AMI.
The mortality of patients with cardiogenic shock is greater than 75%. Cardiogenic shock usually reflects infarction involving more than 50% of left ventricular mass. This may reflect an acute event or cumulative old and new infarctions. Left ventricular dysfunction, typically associated with decreased cardiac output and elevated PCWP, might temporarily benefit from alpha and beta agonists. Intravenous dopamine starting at 0.5-1.0 mcg/kg/min is helpful in cases of severe shock (< 80 mmHg sbp). Doses higher than 10 mcg/kg/min may induce vasoconstriction, which is deleterious to ischemic or infarcting tissue. Dobutamine is most effective when hypertension is secondary to low cardiac output. Dobutamine at 2.5 to 15.0 mcg/kg/min primarily affects b-1 receptors, but also has smaller affects on peripheral b-2 and a-receptors. Dobutamine increases cardiac output, decreases peripheral resistance and increases perfusion. Unsuccessful use of vasopressors may dictate the need for an intra-aortic balloon pump. This may provide temporary left ventricular assistance.
Right Ventricular Infarction (RVI). RVI occurs in approximately 30-50% of posterior-inferior infarctions.40 Hypotension, low PCWP, and intolerance to nitrates characterize decreased right ventricular propulsion. Right-sided precordial leads such as V4R exhibiting ST segment elevation indicate RVI. In RVI, a high right ventricular filling pressure must be supported by administration of fluids to maintain adequate left ventricular filling pressures. Clinically, RVI is usually recognized by evidence of impedance to right ventricular filling (elevated neck pains, quiet lung fields). Rarely, patients with RVI may present with cardiogenic shock reflecting concomitant left ventricular dysfunction. Use of Swan-Ganz monitoring techniques may be required to distinguish left ventricular forward failure or cardiogenic shock from hypovolemia or RVI. Dobutamine may be needed as for inotropic augmentation in selected cases.
Advanced Generation Thrombolytics
Although thrombolytic therapy has greatly advanced the management of AMI, the currently available agents are subject to several limitations. The ideal thrombolytic therapy would offer enhanced fibrin specificity and resistance to plasminogen activator inhibitor-1, resulting in more complete and rapid reperfusion; a prolonged half-life, allowing for single-bolus dosing; limited activation of the fibrinolytic system, reducing the risk of bleeding complications; better compatibility with potent antiplatelet/antithrombin therapies, increasing potency and reducing the risk of reocclusion; a lack of antigenicity, permitting repeat administration; and reasonable cost. Some of these goals may be achieved by newer thrombolytic therapies currently under development. TNK-tPA has been specifically bioengineered to have an extended half-life that allows for single-bolus dosing, enhanced resistance to plasminogen activator inhibitor-1 (PAI-1), and a high degree of fibrin specificity and potency, with minimal systemic anticoagulation activity. In large dose-finding trials, TNK-tPA has been associated with high patency rates and a low incidence of bleeding complications.41-44
In the phase II Thrombolysis in Myocardial Infarction (TIMI) 10B study, patients with AMI presenting within 12 hours of symptom onset (n = 886) were randomized in an open-label design to one of three treatment arms: 30 mg TNK-tPA as a single 5- to 10-second bolus; 50 mg TNK-tPA (replaced with a 40-mg dose early in the trial) as a single 5- to 10-second bolus; or 100 mg t-PA (90-minute infusion, accelerated dosing).27 The efficacy of TNK-tPA was comparable to that of t-PA. No significant difference in 90-minute TIMI grade 3 flow was seen between t-PA and 40 mg or 50 mg TNK-tPA.
A large, international double-dummy, double-blind Phase III mortality trial, called ASSENT II, has been completed. The objective of the trial was to demonstrate equivalence in 30-day mortality between bolus administration of TNK-tPA and accelerated t-PA. In 16,505 eligible, randomized patients, results showed that TNK-tPA is equivalent to accelerated t-PA in reducing 30-day mortality rates. (See Table 3.) Results were presented at the March 1999 American College of Cardiology meeting.
| Table 3. TNK-tPA vs. t-PA | |||
| TNK-tPA | t-PA | ||
| 30-day mortality | 6.17% | 6.15% | |
| ICH | 0.93 | 0.94% | |
| Severe Bleed | 0.83% | 1.05% | |
| Mild and Moderate Bleed | 26.0% | 28.1% | p = 0.002 |
| Units transfused | p = 0.001 |
None (%)
95.8% 94.5%1-2 (%)
2.59% 3.2%> 2 (%)
1.66% 2.2%In addition, TNK-tPA showed a significant reduction in bleeding complications compared with Activase. Investigators at the ACC meeting suggested a possible link between fibrin specificity and safety (i.e., fewer bleeds).
Summary
Aggressive methods to detect and treat AMI are imperative to reduce mortality among the 1.5 million patients with AMI each year. The history and physical exam can be invaluable in aiding diagnosis. The electrocardiogram and serum enzyme markers (CK-MB) continue to be the mainstay in AMI detection, although newer cardiac markers show promise as ancillary aids.
Once diagnosis of AMI is confirmed, management should be aggressive and systematic. Thrombolytic agents such as t-PA (front-loaded) can reduce mortality significantly and should be administered promptly in eligible candidates. Adjunctive agents such as beta blockers, ACE-inhibitors, and aspirin have also been shown to decrease mortality. Mechanical means to open obstructed coronary arteries should be given preferential consideration provided the facility has significant PTCA experience and can perform this procedure in an expedient manner. Next generation thrombolytic agents offer significant hope for improvement in AMI patient care.
References
1. Marder V. Relevance of changes in blood and coagulation parameters during thrombolytic therapy. Am J Med 1987;83:15.
2. Fletcher A, Alkajaerstig N, Smyrniotis F. The treatment of patients suffering from early myocardial infarction with massive and prolonged streptokinase therapy. Trans Assoc Am Phys 1958;71:287.
3. Chazav E, Matteeva L, Mazadev A. Intracoronary administration of fibrinolysis in acute myocardial infarction. Ter Arkh 1976; 48:8.
4. Rentrop P, Blanke H, Karsch K. Selective intracoronary thrombolysis in acute myocardial infarction and unstable angina pectoris. Circulation 1981;63:307.
5. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-360.
6. ISIS-1 (First International Study of Infarct Survival) in Collaborative Group. Randomized trial of intravenous atenolol among 16027 cases of suspected acute myocardial infarction. Lancet 1986;2: 57-66.
7. Dykewicz, M, McGrath K, Davison R. Identification of patients at risks for anaphylaxis due to streptokinase. Arch Intern Med 1986;146:305-307.
8. Vandewerf, Ludbrook P, Bergman S. Coronary thrombolysis with tissue plasminogen activator in patients with evolving myocardial infarction. N Engl J Med 1984;310:609-613.
9. Rao A, Pratt C, Berke A. Hemorrhagic manifestations and changes plasma fibrinolytic system in patients treated with tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11:1.
10. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673-682.
11. The GUSTO Angiographic Investigators. The 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;329:1615-1622.
12. Recent Developments in Coronary Intervention: GUSTO-III and other Highlights from ACC 97. Roberts R, McCabe JB, eds. In: Clinical Challenges in Acute Myocardial Infarction. 1997;7:1-11.
13. Gurwitz JH, Gore JM, et al. Risk for intracranial hemorrhage after tissue plasminogen activator treatment for acute myocardial infarction. Ann Intern Med 1998;129:597-604.
14. Ferguson JJ. Meeting highlights: XlXth Congress of the European Society of Cardiology. Circulation 1997;96:3818-3821.
15. Grines C, Browne K, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993;328:673-679.
16. Every N, Parsons L, Hlatky M, et al. A comparison of thrombolytic therapy with primary coronary angioplasty for acute myocardial infarction. N Engl J Med 1996;335:1253-1262.
17. Hannan E, Racz M, Ryan T, et al. Coronary angioplasty volume-outcome relationships for hospitals and cardiologists. JAMA 1997;277:892-898.
18. Blankenship J, Almquist A. Cardiovascular complications of thrombolytic therapy in patients with a mistaken diagnosis of acute myocardial infarction. J Am Coll Cardiol 1989;14:1579-1582.
19. Eleff S, Borel C, Bell W. Acute management of intracranial hemorrhage in patients receiving thrombolytic therapy case reports. Neurosurgery 1990;26: 867-869.
20. Bovill E, Terrin M, Stump D, et al. Hemorrhagic events during therapy with tissue plasminogen activator, heparin and aspirin for acute myocardial infarction: Results of the TIMI, phase II trial. Ann Intern Med 1991;115:256-265.
21. Maggioni A, Franzosi M, Santoro E, et al. The risk of stroke in patients with acute myocardial infarction after thrombolytic and antithrombotic treatment. N Engl J Med 1992;327:1-6.
22. Bednarczyk E, Sherlock S, Farah M, et al. Anaphylactic reaction to streptokinase with first exposure: Case report and review of the literature. Ann Pharmacother 1989;23:869.
23. Schweitzer D, vander Wall, Bosker H. Serum sickness-like illness as a complication after streptokinase therapy for acute myocardial infarction. Cardiology 1991;78:68-71.
24. GISSI-2. A factorial randomized trial of alteplase versus streptokinase and heparin versus no heparin among 12490 patients with acute myocardial infarction. Lancet 1990;336:65-71.
25. Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: Executive summary. Circulation 1996;94:2341-2350.
26. Anderson J, Karagounis L, Allen A, et al. Older age and elevated blood pressure are risk factor for intracerebral hemorrhage after thrombolysis. Am J Cardiol 1991;68:166-170.
27. The TIMI Study Group. Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction: Results of the thrombolysis in myocardial (TIMI) phase II trial. N Engl J Med 1989;320:618-627.
28. Cross S, Lee H, Rawles J, et al. Safety of thrombolysis in association with cardiopulmonary resuscitation. BMJ 1991;303: 1241-1242.
29. Scholz K. Frequency of complications of cardiopulmonary resuscitation after thrombolysis during acute myocardial infarction. Am J Cardiol 1992;69:724-728.
30. Tenaglia A, Califf R, Candela R, et al. Thrombolytic therapy in patients requiring cardiopulmonary resuscitation. Am J Cardiol 1991;68:15.
31. Habib G. Current status of thrombolysis in acute myocardial infarction. Chest 1995;107:528-534.
32. Krumholz H, Pasternak R, Weinstein M, et al. Cost-effectiveness of thrombolytic therapy with streptokinase in elderly patients with suspected acute myocardial infarction. N Engl J Med 1992;327: 7-13.
33. Simoons ML, Maggioni AP, Knatterud G, et al. Individual risk assessment for intracranial hemorrhage during thrombolytic therapy. Lancet 1993;342:1523-1528.
34. De Jaegere PP, Arnold AA, Balk AH, et al. Intracranial hemorrhage in association with thrombolytic therapy: Incidence and clinical predictive factors. J Am Coll Cardiol 1992;19:289-294.
35. Weaver W, Cerqueira M, Hallstrom A, et al. Prehospital initiated vs. hospital-initiated thrombolytic therapy: The Myocardial Infarction Triage and Intervention Trial. JAMA 1993;270: 1211-1216.
36. Tierney WM, Roth BJ, Psaty B, et al. Predictors of myocardial infarction in emergency room patients. Crit Care Med 1985;13:526-531.
37. Fibrinolytic Therapy Trialists 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;343:311-321.
38. GISSI. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-402.
39. EMERAS Collaborative Group. Randomized trial of late thrombolysis in patients with suspected acute myocardial infarction. Lancet 1993;342:767.
40. Zehender M, Kasper W, Kander E, et al. Right ventricular infarction as an independent predictor of prognosis after acute inferior infarction. N Engl J Med 1993;328:982-988.
41. Cannon CP, McCabe CH, Gibson M, et al. TNK-tissue plasminogen activator in acute myocardial infarction. Circulation 1997;95;351-356.
42. Cannon CP, McCabe CH, Gibson M, et al. TNK-tissue plasminogen activator compared with front-loaded tissue plasminogen activator in acute myocardial infarction: primary results of the TIMI I 10B trial. Circulation 1997;96:1-206.
43. Gibson M, Cannon CP, van de Werf FJ, et al. A randomized prospective comparison of T-PA with TNK using the TIMI frame count: Results of TIMI 10B. Circulation 1997;96(suppl):1-330.
44. Keyt BA, Paoni NF, Refino CJ, et al. A faster-acting and more potent form of tissue plasminogen activator. Proc Natl Acad Sci USA 1994;91:3670-3674.
Recommended Reading
• Bode C, Smalling R, Berg G. 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 infarct. Circulation 1996;94:891-898.
• Jugduff BL, Warnica JW. Intravenous Nitroglycerin therapy to limit myocardial infarct size, expansion, and complications. Effect of timing, dosage, and infarct location. Circulation 1988;78: 906-919.
• Yusuf S, Collins R, MacMahon S, et al. Effect of intravenous nitrates on mortality in acute myocardial infarction: An overview of the randomized trials. Lancet 1988;1:1088-1092.
• HART. A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. Heparin Aspirin Reperfusion Trial. N Engl J Med 1990;323:1433-1437.
• SCATI. Randomized controlled trial of subcutaneous calcium-heparin in acute myocardial infarction. Studio Sella Cacipamina nell Angina enella Trombosi Venticolare nell Infarcto. Lancet 1989;2:182-186.
• SIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: A randomized comparison of streptokinase vs. tissue plasminogen activator vs. anistreplase and of aspirin plus heparin vs. aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet 1992;339:753-770.
• GUSTO investigators: The 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;329:1615-1622.
• Brett J. Late assessment of thrombolytic efficacy with alteplase (rt-Pa) six-24 hours after onset of acute myocardial infarction. Aust N Z J Med 1993;23:745-748.
• Granger C, White H, Bates E. A pooled analysis of coronary artery patency and left ventricular function after intravenous thrombolysis for acute myocardial infarction. Am J Cardiol 1994;74:1220-1226.
• Newhaus K, von Essen R, Tebbe U. Improved thrombolysis in acute myocardial infarction with front-loaded administration of alteplase: Results of the rt-Pa - APSAC patency study (TAPS). J Am Coll Cardiol 1992;19:885-891.
• O’Neill W, Weintraub R, Grines C. et al. A prospective placebo-controlled randomized trial of intravenous streptokinase and angioplasty therapy of acute myocardial infarction. Circulation 1992;86:1710-1717.
• Ridker P, O’Donnell C, Marder V, et al. A response to "holding GUSTO up to the light." Ann Intern Med 1994;120:882-888.
• Maggioni A, Franzosi M, Farina M, et al. Cerebrovascular events after myocardial infarction: Analysis of the GISSI trial. BMJ 1991;302:1428-1431.
• Risenfors M, Zukauskiene I, Albertsson P, et al. Early thrombolytic therapy in suspected acute myocardial infarction-role of electrocardiogram: Results from the TEAHAT Study. J Intern Med 1991;734(Suppl):19-25.
• Cannon CP, McCabe CH, Diver DJ, et al. Comparison of front-loaded recombinant tissue-type plasminogen activator, anistreplase and combination thrombolytic therapy for acute myocardial infarction: results of the Thrombolysis in Myocardial lnfarction (TIMI) 4 trial. J Am Coll Cardiol 1994;24:1602-1610.
CME Physician Questions
1. In the GUSTO-I Trial the 30-day mortality rates for accelerate t-PA with heparin versus streptokinase with heparin, respectively, were:
A. 10.2% and 12.3%.
B. 9.3% and 9.9%.
C. 8.3% and 9.3%.
D. 6.3% and 7.3%.
E. none of the above.
2. Based on a review of patients entered into the NRMI-2 (National Registry of Myocardial Infarction-2) Study, there is a suggestion that:
A. lower body weight patients may benefit from weight-adjusted dosing of thrombolytic agents, in terms of lower fewer bleeding complications.
B. there is no need to consider body weight when dosing thrombolytics.
C. bleeding complications cannot be prevented.
D. all of the above.
E. none of the above.
3. For PTCA to be considered an alternative to thrombolytic therapy, the procedure should be:
A. performed in timely fashion, preferably within 60-90 minutes of arrival.
B. performed by people skilled in the procedure, preferably performing more than 75 PTCA procedures per year.
C. performed in institutions with high volume of procedures with experienced support staff.
D. all of the above.
E. none of the above.
4. PTCA is recommended preferentially especially in the following patients:
A. those at high risk for intracranial bleeding.
B. individuals who fail to qualify for thrombolytic therapy.
C. patients in cardiogenic shock.
D. all of the above.
E. none of the above.
5. Most bleeding complications of thrombolytic therapy:
A. occur in the brain.
B. occur in the GI tract.
C. occur in the GU tract.
D. occur at vascular access sites.
E. none of the above.
6. The most serious complication of thrombolytic therapy with t-PA is:
A. transient hypotension.
B. allergic reactions.
C. intracranial hemorrhage.
D. immune complex disease.
E. none of the above.
15. Thrombolytics should not be used in patients older than age:
A. 60.
B. 65.
C. 70.
D. 75.
E. none of the above.
16. Lidocaine should be avoided in accelerated idioventricular rhythms associated with thrombolysis.
A. True
B. False
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.