ABSTRACT: The main therapeutic goals for patients who have an acute coronary syndrome are to reestablish normal epicardial flow and to increase distal myocardial perfusion. Fibrinolytic treatment with tissue plasminogen activator within 70 minutes of the onset of symptoms dramatically reduces the mortality rate from myocardial infarction. Other fibrinolytic agents include reteplase, which is given as a double bolus, and tenecteplase, which is given as a single bolus. In most hospitals, fibrinolytic therapy is more readily available than percutaneous transluminal coronary angioplasty (PTCA); however, PTCA may be the preferred approach if it is available within an hour and a half. Antiplatelet drugs, such as glycoprotein IIb/IIIa receptor antagonists, are used to improve distal myocardial perfusion. If follow-up coronary angiography is not available to assess whether epicardial blood flow and distal myocardial perfusion have been restored, a 12-lead ECG can provide valuable information. The resolution of ST-segment abnormalities is a marker for improved perfusion.
Currently, more than 1 million persons have an acute myocardial infarction (MI) each year in the United States. Many of these MIs present as out-of-hospital sudden death. The patients who survive long enough to obtain medical care are still at risk, but the earlier that definitive care can be provided, the better the chance of survival.
Over the past 40 to 50 years, significant improvements have been made in acute cardiovascular care. Even as treatment continues to be refined, additional reductions in mortality can be difficult to achieve. However, a 1% decrease in the mortality from cardiovascular disease represents more than 3000 lives saved each year.
In a previous article (CONSULTANT, October 2002, page 1473), I discussed the use of low molecular weight heparin and other cardiac drugs in patients with acute coronary syndromes. Here I focus on fibrinolytic and antiplatelet agents.
The pathophysiology of an acute coronary syndrome begins with an atherosclerotic plaque. The plaque becomes unstable, and a thrombus develops. With radionuclide tracer imaging, the lipid portion of an atherosclerotic plaque can be visualized with the platelet aggregation (white clot) and fibrin-rich thrombus (red clot).
The first step in the pathophysiology of an acute coronary syndrome usually is rupture or cracking of the plaque.1-5 The roughened surface of the plaque activates platelets that aggregate on the plaque, forming the white clot. Next, fibrin deposits on the plaque, forming a red clot, which further traps platelets. Thus, a vicious circle ensues.
Clinically, this process precipitates unstable angina, which may progress or stabilize. The ECG may show evidence of a non-ST-segment elevation (subendocardial) infarction or, depending on the extent of myocardium supplied by the particular coronary artery, persistent elevation of the ST segments may occur.
Epidemiologic data show that there is a circadian pattern to MI, sudden cardiac death, and stroke-3 entities that often involve an unstable atherosclerotic plaque, platelet activation, and thrombus formation.6-8 A seasonal pattern also exists for MI and sudden cardiac death. In the Northern Hemisphere, the incidence of MI is 25% to 30% higher in January, February, and March than in the summer months. This pattern exists even in the southern US states, so this higher incidence is not related to climate.9 Similarly, in the Southern Hemisphere, the incidence of MI is higher in the winter months of that region (June, July, and August). The same seasonal pattern exists for sudden cardiac death and stroke.10
RATIONALE FOR REPERFUSION THERAPY
If the reasons for atherosclerotic plaque rupture or cracking were known, more specific interventions might be possible. However, for now, the treatment of acute coronary thrombotic occlusion is based on our current understanding and is centered on the early administration of thrombolytic therapy. Such therapy is really better termed "fibrinolytic therapy" because these drugs-heparin, tissue plasminogen activator (tPA), and analogs of tPA-attack the fibrin thrombus (red clot). Drugs that attack the platelet or white clot are the glycoprotein (GP) IIb/IIIa receptor antagonists, the so-called superaspirins. These agents play an important role in the treatment of acute coronary syndrome.11
A major objective in treating a patient who has an acute coronary syndrome is to reopen the affected epicardial coronary artery and establish normal epicardial flow. However, an equally important objective is to increase distal myocardial perfusion.
The sooner an occluded or partially occluded coronary artery is reopened after a patient begins having symptoms of myocardial ischemia, the better the prognosis.12 Restoring blood flow in the epicardial vessels decreases mortality, and the earlier that blood flow is restored-especially if this is accomplished within a few hours-the more likely that myocardial damage will be minimized and infarction may be prevented.12
TIMING OF THERAPYThe earlier, the better. The Myocardial Infarction Triage and Intervention (MITI) study demonstrated the benefit of early restoration of blood flow.13,14 The purpose of the study was to determine the long-term effect of tPA given out of hospital (pre-hospital) by emergency medical technicians (EMTs) compared with in-hospital administration of tPA. The primary end points were long-term survival or survival free of readmission to the hospital for angina, MI, congestive heart failure, or revascularization.
This clinical trial did not show a difference between the patients who received tPA pre-hospital or in-hospital. However, the EMTs had transmitted the pre-hospital 12-lead ECG findings to the hospital before the patient's arrival at the emergency department (ED) and had communicated the result of the checklist for fibrinolytic therapy. Thus, the hospital staff was alerted that a candidate who was randomized for in-hospital administration of tPA was en route to the hospital; in this group, the interval between a patient's arrival at the hospital and the administration of tPA was very short. Consequently, the difference between the times of administration of pre-hospital and in-hospital fibrinolytic treatment was extremely small.
However, a reanalysis of the data showed that among patients who were treated with tPA within 70 minutes of the onset of symptoms, the mortality rate was 1.2%, in contrast to 8.7% among those who were treated more than 70 minutes after the onset of symptoms (P = .009).13 Thus, the MITI trial showed that it did not matter whether patients were treated with tPA pre-hospital or in-hospital. What did matter was the time between symptom onset and treatment; the shorter the time, the better the prognosis.
Several studies have shown that the maximal benefit of fibrinolytic therapy is obtained within 6 hours, but some benefit is obtained even when reperfusion is accomplished within 12 hours.15 However, reperfusion after 12 hours-between 12 and 24 hours-has not been shown to improve survival significantly. Moreover, after 12 hours, the likelihood of hemorrhage into the infarcted myocardium increases because the tissue has become necrotic and weakened. Thus, late fibrinolysis may increase the risk of myocardial rupture.
Inadequate therapy. A major problem is that many patients who qualify for fibrinolytic therapy do not receive it. The National Registry of Myocardial Infarction (NRMI) contains data on about 1.5 million patients from about 1600 hospitals. Analysis of this database has shown that patients who are inadequately treated in EDs include those older than 75 years (Box), those who have left bundle branch block, and those who seek medical care several hours after the onset of symptoms.16,17 About a quarter of patients in the NRMI database who were eligible for fibrinolytic therapy did not receive it. Also, many patients who were later found to have had an MI did not have chest discomfort when they sought medical care. These patients have what has been called the staggered-start presentation.
Usually, with the staggered-start presentation, a patient has an initial period of unstable angina. This acute myocardial ischemia is the result of a combination of acute thrombus formation on an atherosclerotic plaque with intermittent spasm of the affected coronary artery. When the spasm occurs, the patient has symptoms, and when the spasm eases, the symptoms abate. Once the degree of myocardial ischemia becomes severe enough, the patient's symptoms are often typical of severe myocardial ischemia: profuse perspiration and crushing, substernal chest pain. At this point, the patient seeks medical treatment.
Even if such a patient says that the discomfort began, for example, 18 hours previously, a carefully obtained history often discloses that the symptoms have been intermittent or staggered. In this setting, the infarction may be less than 12 hours old, and the patient initially had myocardial ischemia of unstable angina. This type of patient may be a candidate for reperfusion therapy. In such a case, the time the symptoms become severe enough to prompt the patient to seek medical help is often considered to be the onset of infarction.
In the ED, a fibrinolytic agent that is administered by bolus rather than by continuous infusion is often preferable for reperfusion therapy because the physician can directly supervise the fibrinolytic agent's administration. Table 1 lists the characteristics of the ideal fibrinolytic agent.18
|Table 1 - Characteristics of the ideal fibrinolytic agent|
|Bolus dosing Fibrin specificity Low incidence of bleeding Low incidence of intracranial hemorrhage Rapid onset of action Prolonged duration of effect Lack of antigenicity Lack of adverse hemodynamic effects Resistance to endogenous substances, such as plasminogen activator inhibitor–1 Low cost-benefit ratio Compatibility with other intravenous drugs|
|Data from Gibson CM. Ann Intern Med. 1999.|
In the United States, 4 fibrinolytic agents currently are available. Arranged in increasing order of fibrin specificity, they are streptokinase, reteplase, tPA, and tenecteplase.
Streptokinase was initially the preferred fibrinolytic agent in the 1980s and early 1990s. It has a relatively prolonged duration of action. However, it is antigenic and is not actually fibrin-specific.
Recombinant tPA is considerably more expensive than streptokinase. However, the trial known as GUSTO-I (Global Utilization of Streptokinase and tPA for Occluded Arteries) demonstrated that tPA has advantages over streptokinase, including lower 30-day mortality.19,20 Therefore, in the mid-1990s, tPA became the dominant fibrinolytic agent. The administration regimen is somewhat complex; it consists of a combination of bolus and infusion and thus requires a fair amount of vigilance.
Reteplase, known as rPA, is a deletion mutein of tPA composed of 355 of the 527 amino acids of tPA; it became popular in the late 1990s. It is given as a double bolus, with the second bolus given 30 minutes after the first. At least theoretically, reteplase has less fibrin specificity than tPA and tenecteplase.
Tenecteplase is a recombinant form of tPA that has more fibrin specificity than tPA. It is given as a single bolus; the dose is based on the patient's weight. Both tenecteplase and reteplase have prolonged half-lives compared with tPA, so each can be given as a bolus without the need for a continuous infusion.
Of these fibrinolytic agents, tPA is the present gold standard. However, findings from the GUSTO-I trial19,20 and the NRMI database indicated that more complex regimens are associated with a higher prevalence of medication errors, including doses that are too high or too low and a rate of administration that is too fast or too slow.21
A multicenter study of reteplase and tPA found that the use of reteplase was associated with a significantly reduced prevalence of medication errors.22 This finding supports the contention that bolus therapy carries a lower risk of medication error. Incorrect dosing of tPA may have contributed to a higher mortality rate in some studies.
Nevertheless, large clinical trials have not found reteplase to be superior to tPA.23 In GUSTO-II, the mortality rates were virtually identical for both medications.
The clinical trial known as Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) clearly demonstrated that tenecteplase and tPA have comparable efficacy.24 However, tenecteplase is much easier to give, because of its single-bolus regimen, and is more fibrin-specific. In ASSENT-2, the incidence of noncerebral hemorrhagic complications was slightly lower with tenecteplase than with tPA, but the incidence of stroke (hemorrhagic and ischemic) was similar.24
RESPONSE TO THERAPY
The question arises as to whether restoring blood flow in an epicardial blood vessel is the most appropriate end point or whether there is another, more clinically significant end point. The system that has been in use to gauge the response to fibrinolytic therapy has been the so-called TIMI (Thrombolysis in Myocardial Infarction) system (Table 2).12,25,26
|Table 2 -TIMI classification of coronary blood flow*|
|TIMI-0: no blood flow|
|TIMI-1: almost completely arrested flow; only a trickle of blood passes through the obstructing plaque|
|TIMI-2: blood flow at a less-than-normal rate; probably, either the distal microvasculature is obstructed because of sludging or myocardial edema is preventing perfusion|
|TIMI-3: normal flow; however, TIMI-3 is not necessarily associated with good microvascular perfusion|
|TIMI, Thrombolysis in Myocardial Infarction. *The TIMI system predicts the risk of death in a particular patient. For instance, if there is TIMI-0 or TIMI-1 flow 60 to 90 minutes after a fibrinolytic agent is given, the probability of death is much higher than if the flow is graded as TIMI-2 or TIMI-3.12|
The TIMI system predicts the risk of death in a particular patient. For instance, if there is TIMI-0 or TIMI-1 flow 60 to 90 minutes after a fibrinolytic agent is administered, the probability of death is much higher than if the flow is graded as TIMI-2 or TIMI-3.12
However, high-resolution contrast echocardiography has revealed that TIMI-3 (normal) flow can occur, in some cases, despite deficient microvascular perfusion of the myocardium distally.27,28 The TIMI frame count has been used to assess this phenomenon.25 The TIMI frame count has revealed that in patients who have MI, it is not only the occluded vessel that has low flow. In about one third of patients, blood flow remains abnormal even after an arterial stent has been placed and there appears to be good filling beyond the stent.26 Also, in about a quarter of patients, flow in the unaffected coronary arteries (the non-infarct-related arteries or non-culprit arteries) is actually slower than in the infarct-related artery.
The conclusion from these observations is that occlusion of one coronary artery is associated with dysfunction in all coronary arteries. This may be a consequence of neurogenic or vasomotor reflexes, or it may be a result of increased resistance in the coronary collateral circulation. Whatever the specific mechanism, occlusion of one coronary artery appears to lead to global dysfunction of myocardial perfusion.26
In addition to the TIMI frame count and traditional TIMI systems, a newer system-known as the blush system-has been shown to predict mortality following MI.29 After contrast material is injected into a coronary artery, material should flow into the capillaries throughout the myocardium and give a ground-glass appearance to the myocardium between the coronary arteries (the "blush"). With a normal blush reaction (TIMI myocardial perfusion [TMP] grade 3), the blush begins to clear during a "washout" phase. A blush that takes longer than normal to clear is TMP grade 2, pooling of the contrast material is TMP grade 1, and no blush (poor myocardial perfusion) is TMP grade 0. The better the blush and the faster it disappears, the better the perfusion of the myocardium and the lower the mortality risk.29
These observations in the coronary catheterization laboratory have been translated into practical bedside information. Studies have shown that the TIMI flow rate, the TIMI frame count, and the TMP grade correlate very well with the rapidity with which ST-segment abnormalities resolve. The resolution of ST abnormalities is not just a marker for reopening of an epicardial vessel, it is also a marker for improved perfusion at the cellular level. The 12-lead ECG provides information about actual perfusion of the myocardium.30
RESTORING DISTAL PERFUSION
Why is reopening of an occluded coronary artery sometimes associated with poor perfusion distally? The current thinking is that fibrinolysis of the clot results in distal embolization of platelets and clot debris into the microvasculature circulation.31 Therefore, to reduce platelet aggregation and adhesion and to improve distal perfusion, antiplatelet drugs are needed.
Aspirin is the most cost-effective emergency cardiovascular drug available. However, the inhibitors of the platelet GP IIb/IIIa receptors appear to be more potent inhibitors of platelet aggregation.32 Drugs such as tirofiban and eptifibatide reversibly bind fibrinogen and von Willebrand factor so that these coagulation factors are not available for binding to the platelet GP IIb/IIIa receptor sites.32 A third agent, abciximab, binds to the intact GP IIb/IIIa receptor sites, thereby making these sites unavailable for binding with fibrinogen and von Willebrand factor and various adhesion molecules.32
Several studies have shown that combining the GP IIb/IIIa receptor inhibitors with either half-dose or full-dose fibrinolytic drugs in some patients who have an acute coronary syndrome produces a synergistic effect.18,33,34 The fibrinolytic drug attacks the red clot and reestablishes blood flow in the epicardial artery, and the GP IIb/IIIa drug attacks the white clot, thereby preventing or reversing platelet aggregation distal to the red clot. Consequently, perfusion in the distal microvascular circulation is improved.18,35,36
Angioplasty is generally a backup procedure to fibrinolytic therapy for treating an acute coronary syndrome because it is not available in most US hospitals. However, in some settings, it may be the primary procedure.
The best studies of angioplasty have been done by a group of hospitals (the Primary Angioplasty in Myocardial Infarction [PAMI] Study Group) that decided to use angioplasty as their preferred primary strategy.37 At these hospitals, the typical time from the arrival at the ED to balloon inflation (door-to-balloon inflation time) is 1 hour or less. Also, at these hospitals, angioplasty has been superior to fibrinolytic therapy in reducing the in-hospital mortality rate and the combination of in-hospital mortality rate and nonfatal reinfarction rate. In addition, the intracranial hemorrhage rate has been almost zero with primary balloon angioplasty.37
The problem with applying these results to the general population is that most hospitals in the United States have neither a cardiac catheterization laboratory nor facilities for immediate angioplasty. Among the 5000 to 6000 hospitals that have EDs, the typical door-to-balloon inflation time is about 2 hours. In contrast, the national door-to-drug (fibrinolytic) time among the hospitals in the NRMI database is about 33 minutes. According to the NRMI database, there is no difference between fibrinolytic therapy administered early and angioplasty performed at 2 hours.38
These data refer to patients who are hemodynamically stable. If the patient is hypotensive and hemodynamically unstable, invasive intervention is the preferred management strategy, including use of angioplasty and a balloon pump if necessary.
The answer as to which is the best strategy in the ED is hospital-dependent. If percutaneous transluminal coronary angioplasty (PTCA), with or without placement of a stent, is available within an hour and a half, then that is probably the better approach, because the patency rate is higher with PTCA than it is with fibrinolytic therapy. In contrast, if the typical time before the coronary artery is reopened in the cardiac catheterization laboratory is 2 hours or more, the better strategy would be to use a fibrinolytic drug and reserve angioplasty as a rescue procedure.18,39
The role of combination therapies was addressed in the Plasminogen-activator Angioplasty Compatibility Trial (PACT).40 Patients who had an acute coronary syndrome received either a reduced bolus of tPA without a continuous infusion or a placebo bolus. Patients then had immediate coronary angiography. If blood flow was restored to TIMI-3, a second bolus of tPA was given, followed by angiography 5 to 7 days later. However, if the blood flow was less than TIMI-3, angioplasty was performed immediately. Both primary PTCA and rescue PTCA restored TIMI-3 blood flow equally well. However, greater convalescent ejection fractions were found in patients whose infarct-related artery was patent following fibrinolysis.40
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