(Supplement)-Thrombolytic therapy for acute myocardial infarction
By Edgar R. Gonzalez, PharmD, FASHP, FASCP
Associate Professor of Pharmacy and Medicine
Medical College of Virginia, Richmond
Introduction
Coronary artery disease, the leading cause of death in the United States, affects approximately 12 million Americans. The medico-economic impact of cardiovascular disease is astronomical; estimated direct and indirect costs for cardiovascular disease and stroke will exceed $250 billion a year, with $111.5 billion of these dollars spent on hospital costs and nursing home services.
Despite a 54% decrease in age-adjusted mortality between 1963 and 1990, 50% of deaths in Americans older than 65 are due to coronary artery disease. Each year 1.25 million Americans suffer an acute myocardial infarction (AMI), causing 500,000 deaths annually. Experts estimate that AMI occurs about once for every 160 persons.
Approximately 50% of patients with AMI die within the first few hours due to electrical instability leading to ventricular fibrillation. Mortality among AMI survivors ranges from 10% to 15% in the first year and is 3% or 4% per year thereafter. Patients with anterior wall infarction, left ventricular dysfunction, and complex ventricular ectopy have the highest one-year mortality rate after AMI (20%). AMI patients without these risk factors have a 3% one-year mortality rate.
The primary goal of therapy for AMI is to reduce mortality. Management of AMI is designed to relieve pain and anxiety, to recognize and control life-threatening arrhythmias, to limit infarct size, and to prevent complications.
Thrombolytic therapy is central in the treatment of AMI for these reasons:
• 85% to 90% of transmural infarctions are caused by a coronary thrombus.
• Thrombolytic agents can effectively lyse coronary thrombi.
• Myocardium can be salvaged if thrombolytics are initiated within six hours of symptom onset.
• AMI-related morbidity and mortality are reduced when thrombolytics are administered no later than six to 12 hours after symptom onset.
Effective management of AMI can save both lives and health care dollars. Because lasting ischemia means more myocardial damage, clinicians must learn to recognize and treat patients with AMI promptly to reduce the duration of electrical instability.
Prompt attention to symptoms of myocardial ischemia is mandatory; ventricular fibrillation is 15 times more likely to occur during the first hour after symptom onset than during the next 12 hours. Successful myocardial salvage is most likely during the first three hours after symptom onset. Any unnecessary delays in treatment place the patient at risk for life-threatening complications and increase the long-term mortality rate.
Open-artery principle
The basic pathophysiologic process leading to an AMI is rupture of an atherosclerotic plaque and the acute formation of a thrombus in a coronary artery. Infarction occurs after prolonged ischemia (i.e. 30 minutes or more), irreversibly damaging the myocardium.
The basic tenet of the open-artery principle is "time saved is muscle saved." The earlier a thrombus-obstructed coronary artery can be opened and kept open, the smaller the infarct, the better the healing of damaged muscle and the lower the probability of post-infarction complications. By reducing the infarct-at-risk zone and salvaging more myocardium, early reperfusion reduces short-term AMI-related morbidity and preserves left-ventricular function.
The current standards of care in AMI center on recognizing symptoms more quickly, initiating emergency cardiac care more quickly, and administering an appropriate thrombolytic agent within 30 minutes of presentation to the treatment facility. Animal studies first demonstrated how early reperfusion limited infarct size. Angiographic studies show that speed is critical in opening the occluded coronary vessel. Treatment in the first hour after symptom onset is an ideal goal for patients with ST-segment elevation AMI because it helps achieve maximum myocardial salvage.
After the first two hours, the incremental benefit of thrombolytic treatment is less, although some benefit can be derived up to at least 12 hours after symptom onset.
Data from the national Myocardial Infarction Triage and Intervention (MITI) trial at the Univer-sity of Washington in Seattle show a 1% mortality rate when thrombolytics are initiated within 70 minutes vs. a 10% mortality rate when they are initiated after 70 minutes. In the MITI trial, an "abortive effect on the AMI" was observed in approximately 40% of patients. This observation suggests that very early thrombolysis (within one hour) dissolves the clots more rapidly: The clot's architecture has not yet become fully organized. Therefore, rapid thrombolysis (within 30 to 60 minutes of symptom onset) may prevent further damage.
Controlled randomized clinical trials confirm that the earlier the thrombolytic agent is given, the greater the benefit. Pooled data from mortality studies suggest that a one-hour reduction between symptom onset and thrombolysis produces a 17% reduction in mortality.
Data from a similar trial, the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial at Baylor College of Medicine in Houston also show important differences between clot-selective and non-clot-selective agents with respect to the open-artery principle. Angiographic studies comparing streptokinase with recombinant tissue plasminogen activator (t-PA) showed that t-PA opens the occluded artery faster.
Data from the GUSTO-1 angiographic trial provide the link between a higher percentage of early vessel patency and significantly better survival by demonstrating that t-PA is superior to streptokinase when administered within the first four hours of symptom onset. Angiographic patency rates at 90 minutes were significantly lower with streptokinase with subcutaneous heparin (54%) and with intravenous heparin (60%) compared with accelerated t-PA.
Clinical pharmacology of thrombolytic agents
Thrombolytic agents activate the conversion of both soluble and surface-bound plasminogen to plasmin. Thrombolysis occurs when plasminogen is converted to plasmin, which subsequently digests fibrin and dissolves the clot. Although timely administration of thrombolytic therapy can decrease the extent of myocardial damage, unresolved concerns regarding therapy in AMI include:
• lack of sufficient thrombolysis in approximately 25% of patients;
• reocclusion in 6% to 16% of patients;
• intracranial hemorrhage in about 0.5% of patients.
Therefore, it is valuable to understand the clinical pharmacology of the commonly used thrombolytic agents.
Streptokinase
Streptokinase (Kabikinase), a protein elaborated by B-hemolytic streptococci, forms a complex with plasminogen that acts to convert additional circulating plasminogen to plasmin. Activation is rapid, and plasmin formation occurs promptly after streptokinase administration. Additional beneficial effects of streptokinase include reductions in plasma viscosity and systemic vascular resistance.
IV streptokinase is administered at a dose of 1.5 million units (MU) over 30 to 60 minutes. After streptokinase, patients receive full-dose IV heparin for 24 to 72 hours. Hydrocortisone 100 mg and diphenhydramine 25 mg may be given intravenously before treatment, although no data prove that these agents decrease the risk of allergic reactions to streptokinase.
Anisoylated plasminogen streptokinase activator complex
Anisoylated plasminogen streptokinase activator complex (APSAC, Eminase) is a direct plasminogen activator complex formed between streptokinase and human plasminogen that is acylated with a p-anisoyl derivative at its enzyme center. This renders the activator inactive, but the acylation of the catalytic site of the plasminogen molecule is reversible over time.
The streptokinase-plasminogen complex of APSAC dissociates at a slower rate than the deacylation rate, ensuring that plasminogen controls the fibrinolytic activity of streptokinase. The deacylation half-life is about 105 minutes in human plasma or whole blood in vitro, and the plasma clearance half-life of fibrinolytic activity is 90 to 112 minutes in patients with AMI. The extended half-life of APSAC allows it to be administered as a single IV injection over four to five minutes.
The main advantage of APSAC over alternative thrombolytic drugs is in ease of IV administration in patients with AMI. The recommended dose is 30 units (U) injected IV over four to five minutes in patients with AMI of less than six hours' duration. Like streptokinase, APSAC reduces plasma velocity and systemic vascular resistance.
Recombinant tissue-type plasminogen activator
Recombinant tissue-type plasminogen activator (t-PA, Activase) produces clot-sensitive thrombolysis by activating fibrin-bound plasminogen; t-PA's activity is dose-dependent.
Although t-PA is generally well-tolerated, hematoma and prolonged bleeding at the injection site are the most commonly reported adverse effects; their frequency as well as the incidence of stroke is similar to that observed with streptokinase. Unlike streptokinase and APSAC, t-PA is not antigenic. However, t-PA is 10- to 20-fold more expensive than streptokinase.
The dose of t-PA for patients over 65 kg is 100 mg over three hours. A 6 to 10 mg bolus is given over two minutes; the remainder of the 60 mg initial dose is infused over 58 minutes. The remaining 40 mg of the 100 mg total dose is administered at a rate of 20 mg/hour. For patients weighing less than 65 kg, the dose of t-PA is 85 mg. The initial 10 mg bolus is followed by 40 mg infused over 58 minutes; then 20 mg is given over hour two and 15 mg is given over hour three. Heparin in a 5,000 U bolus is administered concurrently with the initiation of thrombolytic therapy, and then 1,000 U/hour are administered to maintain the activated partial thromboplastin time at two times above the control value for at least 24 hours.
Various dosing regimens for t-PA have been explored to increase patency and reduce the risk of bleeding. Recent studies suggest that an accelerated (front-loaded) 90-minute infusion of t-PA produces more rapid reperfusion without any change in safety.
Two hundred eighty-one patients with AMI were randomized to receive 100 mg of t-PA over three hours (i.e., a 10 mg bolus followed by 50 mg for one hour, then 20 mg/hour for two hours) or 100 mg of t-PA over 90 minutes (a 15 mg bolus followed by 50 mg over 30 minutes, then 35 mg over 60 minutes). The 60-minute patency rate was significantly higher (p < 0.03) with front-loaded t-PA. Both groups had similar rates of recurrent ischemia, reinfarction, angiographic reocclusion, stroke, major bleeding complications, and death. These findings suggest the speed of reperfusion is linked to the rate of administration of t-PA.
Reteplase
Reteplase (r-PA Retevase) is a nonglycosylated deletion mutant of t-PA that is produced by expression of an appropriately constructed plasmid in E. coli. The fully functional, nonglycosylated protein becomes available after an in vitro refolding process.
Reteplase consists of the kringle-2 domain and protease domain of t-PA, but it lacks the kringle-1 domain, the finger domain, and the epidermal growth factor (EGF) domain. The absence of attached carbohydrate moieties on reteplase decreases its clearance time at a rate of 250 to 450 mL/min and extends its half-life (13 to 16 minutes vs. five to six minutes for t-PA). The absence of the fibrin-specific finger region and the EGF domain on reteplase affects renal blood flow and fibrin specificity and affinity. In summary, these structural modifications result in less high-affinity fibrin binding, a longer half-life, and greater in-vivo thrombolytic potency compared with t-PA.
Reteplase is metabolized in the kidneys, liver, and blood; t-PA is primarily cleared by the liver. The effects of renal failure on the pharmacokinetic properties of reteplase in rats demonstrated a significant (p < 0.001) linear correlation (r = 0.713) between the decrease in insulin clearance and the decrease in reteplase clearance. It has been determined that reteplase clearance was impaired in renal dysfunction.
Reteplase offers potential advantages over t-PA. Reteplase produces more rapid and more complete reperfusion than t-PA. The long half-life of reteplase compared with t-PA permits the use of dual-bolus administration without a continuous infusion. The recommended dose of reteplase is two 10 U IV boluses given 30 minutes apart. This convenient regimen allows for ease of administration compared with the more complex bolus followed by infusion regimens of t-PA, especially in a busy emergency department or a hectic pre-hospital setting.
Streptokinase and APSAC are nonfibrin-selective thrombolytic agents; t-PA and reteplase are fibrin-selective agents. All these agents activate plasma plasminogen. Fibrin selectivity is relatively dose-dependent, and all agents activate circulating plasminogen to different degrees (streptokinase > APSAC > reteplase = tPA).
The activation of circulating plasminogen generates a systemic lytic response, characterized by the conversion of fibrin to fibrin degradation products (FDPs), thereby dissolving the thrombus. The generation of FDPs is of clinical significance because of their inherent anticoagulant properties, which prevent subacute vessel reclosure. Table 1 (above) compares the half-lives, doses, systemic lytic effects, reperfusion and reocclusion rates, advantages, and disadvantages of these agents.
Efficacy and safety of thrombolytic agents
No discussion of AMI and thrombolytic therapy is complete without comparing the efficacy and safety of the available agents. The four endpoints currently used to evaluate efficacy are:
• reperfusion rate;
• patency rate;
• left ventricular function;
• survival.
Because pre-thrombolytic and post-thrombolytic angiographic studies are needed to assess reperfusion rates, this endpoint is not clinically feasible. The assessment of patency rates requires only a post-treatment angiogram.
Although 20% of patients will have spontaneous reperfusion, patency rates allow efficacy between thrombolytic regimens to be compared. The GUSTO trial, using front-loaded t-PA regimens, demonstrated an improved patency rate of 81%.
Clinical trials show that treatment with streptokinase, APSAC, or t-PA improves left ventricular function compared with placebo. Studies also show that thrombolytic therapy reduces AMI-related mortality compared with placebo. Streptokinase reduces in-hospital mortality by 3.7% to 10% and one-year mortality by 13.9%. APSAC reduces one-year mortality by 11.1%; t-PA produces a 3% to 7.2% reduction in pre- hospital mortality and a 5.9% to 7.3% reduction in one-year mortality.
The International Joint Efficacy Comparison of Thrombolytics (INJECT) trial compared the 35-day mortality rates after treatment with reteplase (10 U + 10 U in a bolus regimen) or streptokinase (1.5 MU over 60 minutes) in AMI patients. This study was undertaken to demonstrate that the mortality rate for patients given reteplase was at least equivalent to that for patients given streptokinase. The mortality rates did not differ significantly between the reteplase group (9.02%) and the streptokinase group (9.53%).
The GUSTO trial was designed to determine the importance of IV and subcutaneous heparin after administration of streptokinase and of t-PA. More than 40,000 patients were randomized to one of four treatment groups:
• streptokinase plus IV heparin;
• streptokinase plus SC heparin;
• t-PA plus streptokinase;
• front-loaded t-PA with IV heparin.
The 30-day mortality rates for the four treatment groups (see Table 2, p. 140) translate to the survival of one additional AMI patient following treatment with t-PA when compared with treatment with streptokinase for every 100 AMI patients treated with thrombolytics.
A review of available clinical evidence suggests that certain patients appear to benefit most from t-PA. In patients with anterior wall myocardial infarction, t-PA yielded a lower mortality rate (8.6%) when compared with streptokinase (10.5%). This is a difference of two lives saved per 100. Likewise, patients younger than 75 may receive more benefit from t-PA than from streptokinase. The mortality rates for t-PA vs. streptokinase inpatients under 75 were 4.4% and 5.5%, respectively.
In contrast, neither age > 75 years nor the presence of inferior wall myocardial infarction affected the relative efficacy of the thrombolytics. Finally, in patients treated within two to four hours after the onset of symptoms, mortality rates appear to be lower with t-PA (5.5%) when compared with streptokinase (6.7%).
Safety and cost considerations often are used to differentiate between streptokinase and t-PA. Since thrombolytic agents cannot distinguish between pathologic clots (i.e., those that cause necrosis) and benign clots (i.e., those that are essential for hemostasis, there is always the risk of bleeding following either an overdose of thrombolytics or a drug interaction.
Finally, because the cost per dose of t-PA is substantially higher than for streptokinase, a disease management approach may provide a reasonable way to permit patients to receive whichever thrombolytic agent is most favorable for them, based on their age, elapsed time from symptom onset, location of AMI, or risk factor for stroke.
It is also important to look beyond the cost of the specific thrombolytic agent when assessing the real cost of treating the AMI patient. A subanalysis of the MITI project compared in-hospital mortality, long-term mortality, and resource utilization among 3,145 patients; 1,050 patients were treated with acute angioplasty, and 2,095 received thrombolytic therapy.
After a three-year follow-up period, the study showed no differences in acute mortality or long-term mortality rates between treatment groups. However, after three years, the mean total cumulative inpatient costs were more than $3,000 higher for patients treated with angioplasty than those initially treated with thrombolytic therapy. As expected, the primary cost drivers were repeat angiograms and repeat angioplastics, leading to the summation that thrombolytic therapy may produce better short-term benefits when compared with angioplasty in AMI patients.
Delays in thrombolytic therapy
Not all patients suspected of having AMI receive thrombolytic therapy. This is unfortunate because mortality is substantially higher among those patients who do not (18%) compared with those who do (2.5%). However, more patients are receiving thrombolytic therapy.
In 1988, estimates from community-based hospitals showed that only 5% of patients with AMI received thrombolytic therapy. In 1990, it was estimated that 10% of patients with AMI were being treated with thrombolytic therapy, and by 1993, the number grew to 39%. Clinical trials show a 30% to 40% reduction rate in acute mortality in patients with AMI who meet criteria and have no contraindications to thrombolytic therapy.
Although patients may be excluded from treatment because of contraindications to therapy, for an equivocal electrocardiogram (ECG), or for other reasons (see Table 3, p. 141), the primary reason for not receiving the therapy is too long a delay between symptom onset and arrival at a treatment facility. Factors responsible for delay in the care of AMI patients can be grouped into three categories:
• patient bystander factors;
• pre-hospital factors;
• hospital factors.
Patient bystander factors
The patient component of total delay is two-thirds of the total time from symptom onset to initiation of reperfusion therapy. Patients typically delay seeking treatment a median of four hours from the time of symptom onset because these reasons:
• They don't know the risk factors for heart disease.
• They attribute their symptoms to other causes.
• They do not perceive the severity of their symptoms.
• They are elderly.
• They are women, who may not realize they're at risk because the disease affects men more often.
In general, younger patients, those with hypotension or cardiogenic shock, and those with no previous cardiac history are more likely to seek medical assistance in the first hour after an AMI. Unfortu-nately, it is difficult to convince patients to seek care more quickly. Prospective studies that evaluated whether patient response was affected by public education campaigns on the symptoms of AMI produced conflicting results.
Pre-hospital factors
Despite the widespread availability of emergency medical services (EMS) systems in most communities, only 50% of patients with AMI activate the EMS system. Patients who transport themselves to hospitals come at least two hours later than those who call 911. The door-to-treatment time tends to be longer for patients who do not arrive by ambulance. The use of pre-hospital ECGs can reduce the door-to-treatment time once the patient arrives in the emergency department (ED).
Hospital-related factors
The ED is a major focal point for influencing the timing of thrombolytic therapy because it is the hospital entry point for AMI patients who are candidates for thrombolytic therapy. However, long and avoidable delays after a patient reaches the hospital appear common.
A study to identify and measure four process points through which the AMI patient passes until thrombolytic treatment is administered found a mean interval of time from symptom onset to administration of the thrombolytic of 177 minutes. The in-hospital component of nearly one hour consisted of:
• ECG time — time from arrival in the ED to recording the 12-lead ECG (six minutes);
• decide time — the time from the initial 12-lead ECG to the decision to administer thrombolytic therapy (20 minutes);
• process time — time from the decision to actual administration (20 minutes);
• door-to-needle time — time from arrival to infusion of the agent (50 minutes).
Shorter in-hospital delays correlated with the following factors:
• treatment in an urban hospital;
• treatment in an academic medical center;
• high caseloads (i.e. > 16 cases/six months);
• stocking the agents in the ED;
• treatment by ED physicians;
• selecting an agent administered by bolus injection to avoid continuous infusion.
Table 4 (see p. 141) compares the four time variables across thrombolytic regimens, linking process times and overall door-to-needle times to the use of a simple bolus delivery compared with a complex bolus plus infusion regimen. Multiple barriers and impediments to timely care can occur in the ED during each interval. Identifying the causes for delays in evaluation and treatment and adopting interventions to minimize these delays will improve overall care of AMI patients.
Expediting thrombolytic therapy
Studies show that pharmacy department participation in thrombolytic therapy can be both negative and positive. Thrombolytic agents should be stocked in the ED and the coronary care unit to avoid considerable delays in administration. Pharmacists should help develop critical pathways and treatment guidelines for thrombolytic therapy in AMI.
Once these disease management initiatives are in place, pharmacists can conduct drug use evaluations to facilitate the availability of thrombolytic agents and appropriate adjunct therapies to meet individual patient needs. Pharmacists also can collect patient outcome data and prescriber compliance information that can be used to make formulary decisions. Information obtained from these evaluations also can be used to implement procedural changes and educational efforts that can significantly reduce hospital delays.
Summary
Thrombolytic treatment initiated within 60 to 90 minutes of symptom onset can reduce both the size and extent of myocardial infarction and mortality. As clinical trials continue to assess the best therapeutic approach for AMI, the pharmacist can play a key role as a health care team member by seeking ways to ensure that door-to-needle time is reduced from the current 45 to 75 minutes to less than 30 minutes. Implementation of critical pathways for chest pain management and drug use evaluation provide significant opportunities to highlight the value of pharmaceutical care in the selection and administration of thrombolytic therapy for AMI.
[For more information about this therapy or the cited trials, contact Edgar R.Gonzalez, PharmD, FASHP, FASCP, Medical College of Virginia, P.O. Box 980533, Richmond, VA 23298. Telephone: (804) 828-8331.]
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