TREATMENT OF ACUTE MYOCARD INFARCTION

Treatment

Because myocardial damage progresses rapidly during the early hours, efforts during this critical period must be directed toward reducing myocardial oxygen demand and improving coronary blood supply to diminish the extent of myocardial damage. To be maximally effective, these interventions must be initiated as soon as possible: The reduction in benefit is very time-dependent, and patients who are treated within an hour fare significantly better than those treated later. Thus, prompt reperfusion therapy via primary angioplasty or thrombolytic therapy should be initiated in the absence of contraindications as early as possible in patients with ST elevation acute infarctions. It is now becoming clear that urgent treatment also reduces the morbidity associated with non-Q wave infarctions as well, especially if followed by definitive intervention on the infarct related artery.


A. EMERGENCY CARE AND PROTOCOLS

More than 85% of patients who present with ST elevation within 4 h of the onset of acute infarction have total thrombotic occlusion, thought to be caused by plaque rupture and subsequent development of an intramural coronary thrombus. The timely reestablishment of nutritive perfusion saves lives. This is best done, if possible, by primary angioplasty but if not available in <60 min (door to balloon time), thrombolytic agents should be used. The time window may not be the same for all patients, however. In some patients, collateral perfusion to the infarct zone extends this window; in others, there is only intermittent occlusion and transient recanalization prior to total occlusion, which may modify the time course of the infarction. It cannot be emphasized enough that the earlier treatment occurs the better (Figure 5–4). Although the magnitude of benefit varies for thrombolytic therapy, patients treated within 1 h of the onset of infarction (an impossibility if treatment requires 90 min to initiate) have up to a 50% reduction in mortality rates; those treated in the second hour have only half that benefit, and there is controversy about whether benefit occurs at all after 6 h. For primary angioplasty, this time dependence, especially after the first hour is less, but treatment during the initial 60–90 min is associated with profound benefit. The mortality rate for patients treated within 60–90 min of the onset of infarction in an outpatient trial of thrombolysis was 1%; for patients receiving identical treatment from 90 min to 3 h, the mortality rate was 10%. Emergency departments and hospitals must facilitate the way in which interventions aimed at coronary recanalization are implemented.

To this end, each hospital should have a plan that addresses each step in the identification, triage, and treatment of the patient who is a potential candidate for coronary recanalization.
It is starting to become clear that such a plan should be expanded, albeit with different therapies for patients with non-Q wave events as well. Such plans should include:
1. Activities that can be initiated by paramedics en route to the hospital— Paramedics can record and transmit 12-lead ECGs to the receiving facility; they can screen patients for indications for and contraindications to treatment with thrombolytic agents. In some emergency medical systems, thrombolytic therapy can safely be implemented by paramedics. Although the cost-effectiveness of initiating therapy in the field is unclear, screening by paramedics and the availability of a diagnostic ECG prior to arrival appear desirable.
2. Emergency room procedures— A triage plan should be developed to identify patients with chest discomfort compatible with ischemia and to facilitate rapid ECGs. Electrocardiograph machines should be available in all emergency facilities, with personnel trained to rapidly record 12-lead ECGs available at all times. The ECG must be read expeditiously by a physician. Although ECG screening by computer algorithms may be a reasonable adjunct, all computer systems do not perform equally well. The ultimate responsibility for interpretation of the ECG therefore resides with the physician. Emergency room physicians without a high level of expertise in this area should have readily available expert consultation (whether on-site or via electronic communications) to minimize delays in interpretation. This step should take no more than 5 min.
The first physician who sees the patient with chest discomfort and appropriate ECG changes should have both the responsibility and the authority to initiate treatment. If there is a prospective plan to use primary angioplasty in patients with ST elevation events, this is the therapy of choice. If not or if there is delay, thrombolytic therapy should be given. For patients with non-Q wave events (those with elevated troponins), treatment with antiischemic agents such as nitrates and b-blockers and the use of heparin (LMWH is better) is called for, and if intervention is likely, IIB/IIIA agents should be initiated. Each hospital should develop a protocol to address the following issues:

How many intravenous (IV) lines are necessary? One line must always be available in the event of an emergency and for infusion of medication to facilitate reperfusion (heparin, lytic agents, or IIB/IIIA agents). An additional line may be necessary for other medicines or for a heparin lock through which to draw blood.

How much oxygen should be used routinely? This should be defined; blood gases are relatively contraindicated in this situation, oximetry is preferred.

If primary angioplasty is the therapy of choice, prospectively detailed lines of communication must be established. If thrombolysis is the choice, the facility should know the thrombolytic agent of choice, and the dose for the routine patient. These should be decided by consensus. Instances in which an exception is necessary should be detailed, as should whom to call for consultation. The agent for routine use should, of course, be available in appropriate doses within the emergency department to facilitate rapid administration.

Which medicines should be used adjunctively? Aspirin, heparin, nitroglycerin, b-blockers, and IIB/IIIA agents for the routine patient should be specified in advance—and should be immediately available in the emergency department.

Which contraindications should preclude treatment?

How will patients be moved rapidly from the treatment area to their ultimate destination in an intensive care unit?
B. GENERAL PROCEDURES

1. Intravenous line— An intravenous line should be placed immediately in any patient who is seriously considered to have suffered acute ischemia; this will provide access for the administration of pharmacologic agents should they be necessary and for emergency treatment should the need arise. The IV line should be large (18 gauge or greater); its patency should be maintained with an infusion of 5% dextrose in water, one-half normal saline, or normal saline solution.
2. Oxygen— Oxygen is appropriate for all patients with suspected AMI. Given the current aggressive approach toward anticoagulation and reperfusion in treating coronary heart disease, which often entails the use of potent anticoagulants or thrombolytic agents, blood gas determinations are not appropriate as a routine measure; oximetry is preferred. The empiric use of oxygen, usually via nasal prongs at 2–4 L/min, is recommended for all patients except those who have both normal oxygen saturations by oximetry or some reason to withhold oxygen (eg, a history of CO2 retention). Even patients with severe chronic obstructive pulmonary disease who may be at risk for CO2 retention should receive oxygen if systemic oxygenation is inadequate. Although supported by experimental data, the concern that supraphysiologic doses of oxygen may induce vasoconstriction and adverse effects has never been convincingly documented clinically.
3. Relief of discomfort— Relief of discomfort is a high priority.
a. Sublingual nitroglycerin— Unless contraindicated by hemodynamic abnormalities, sublingual nitroglycerin can be used to try to relieve chest discomfort and reverse ECG changes. A reversal of ECG changes is found most often in patients with patent infarct-related coronary arteries; it suggests that ischemia rather than infarction is present. Nitroglycerin must be given cautiously, however, especially to patients with inferior MI who may have RV infarction and who are prone to hypotension in response to this agent. A small subset of patients without RV infarction will also develop hypotension and an inappropriately slow heart rate after nitroglycerin. This is a vagally mediated phenomenon that has also been reported with morphine sulfate. Atropine (0.5 mg) is the treatment of choice in such cases.
b. Intravenous nitroglycerin— If patients have a beneficial response to sublingual nitroglycerin, it is reasonable to initiate treatment with IV nitroglycerin at a low dose (5–10 µg/min). Although this may relieve some of the chest discomfort in patients with acute infarction, it does not reduce the need for treatment with analgesics. Furthermore, reductions in blood pressure by more than 10% in normotensive patients are likely to be detrimental. Keeping the dose low and not expecting it to provide total relief of discomfort is recommended. This approach reduces the incidence of tolerance to the agent, which occurs in up to 25% of patients. Some physicians also use more potent vasodilators such as sublingual nifedipine to assess whether chest pain can be relieved and ECG changes reversed. Although these agents are effective, there is an associated incidence of marked hypotension that can cause detrimental cardiovascular effects. Calcium channel blockers are not recommended for routine administration.
c. Morphine sulfate— If the patient does not have a prompt response to sublingual nitroglycerin, morphine sulfate is the drug of choice. An IV dose of 2–4 mg and repeated as necessary and tolerated until chest discomfort is relieved is recommended. In addition to relieving pain, morphine sulfate reduces anxiety and the catecholamine secretion that occurs across the myocardial vasculature during acute infarction. As noted earlier, there is a small incidence of hypotension with an inappropriate heart-rate response that responds to atropine. Other analgesic agents used for the treatment of pain include meperidine and pentazocine.
d. Beta-blockers— Beta-blockers are commonly used to treat the chest discomfort associated with AMI in countries outside the United States. They have been shown to be effective, apparently because of both their membrane-stabilizing effects and their beneficial effects on myocardial oxygen supply and demand. Small doses of metoprolol (generally 5 mg), propranolol (1–3 mg IV) or esmolol (a loading dose of 250 mg/kg followed by 25–50 mg/kg/min, up to a maximum dose of 300 mg/kg/min) can be given as long as hemodynamic and electrical stability can be maintained. Although esmolol’s efficacy in this area is not well established, it is rapidly metabolized by esterases in red cells and is the only agent with a brief duration of action. Beta-blockers may also be useful in reducing the extent of infarction and for secondary prevention (see section d. Adjunctive therapy).
e. Angiotensin-converting enzyme inhibitors— Patients with ST elevation infarction seem to benefit from the early initiation of treatment with angiotensin-converting enzyme inhibitors (ACEI) if blood pressure allows. This strategy improves ventricular remodeling acutely but is even more efficacious over the longer term
4. Activity— Bed rest, except for the patients who require the use of a bedside commode, is mandatory during the first 24 h; autonomic instability, hypotension, and arrhythmias are common. It was believed in years past that strict bed rest was appropriate for 7–10 days and that discharge should occur after approximately 2 weeks. It is now clear that it is less stressful and thus more beneficial medically if hemodynamically stable patients are allowed to sit in a chair and use a bedside commode after 24 h. In general, patients without complications remain in an intensive care unit for 2–3 days, during which time their activities are markedly restricted. On transfer out of the intensive care unit, they can gradually begin ambulation, and most patients without complications can be discharged as early as 4 days after infarction.
5. Diet— It generally has been recommended that patients with acute infarction avoid extremes of hot and cold, have no caffeine, and be maintained initially on a liquid diet. The rationale for this approach includes the presence of autonomic instability, concerns that caffeine might exacerbate arrhythmias, and fear that particulate matter could be aspirated in the event of cardiac arrest (which tends to occur early during the evolution of acute infarction). Although none of these concerns have been strictly validated, such restrictions are considered prudent. After the first day, if patients are stable, their diet can be advanced. Education to facilitate good eating habits and a reduction in fat intake can be initiated at that time.
6. Bowel care— Patients, especially those who are older and are put to bed-rest with a reduced oral intake, have a tendency to constipation. Given the autonomic instability indigenous to AMI, the reduction of straining when bowel movements occur is recommended. In general, the use of stool softeners such as docusate sodium in a once-a-day dose of 100 mg is adequate. Some degree of selection is appropriate; some patients are not in need of this treatment, whereas others require more potent treatment.
7. Sedation— If patients are excessively restless and no physical cause can be determined, sedation with small doses of a sedative-hypnotic agent such as diazepam is recommended. During the initial 24 h, the dosage should be the minimum required to relieve anxiety, and patients should be continually reassessed to ensure that what is being treated is anxiety and not an underlying complication of infarction.
8. Electrocardiographic monitoring— All patients with significant likelihood of AMI should be monitored electrocardiographically. Those with chest pain and ECG changes that are highly likely to be due to infarction should be hospitalized in an intensive care unit. Those deemed at less risk still require ECG monitoring in an environment where defibrillation is readily available. It is recommended that patients with uncomplicated acute infarction be monitored until discharge; patients with complications require longer periods of observation.
9. Heparin— Unless there are contraindications to its use or patients are receiving other anticoagulants, all patients should receive subcutaneous heparin, 5000 units every 12 h. This regimen has been shown to reduce the incidence of deep venous thrombi that occurs in as many as 24% of treated patients; it should reduce the frequency of pulmonary emboli as well. Although the studies documenting these effects were done at a time when long periods of bed rest were mandated, they are most likely still correct—at least in principle—and there is little morbidity associated with the relatively modest doses of heparin. Therefore, despite earlier ambulation, the use of subcutaneous heparin twice daily is still recommended. Most patients with ST segment elevation AMI or with non-Q wave AMI benefit from the use of therapeutic doses of heparin. Many still recommend unfractionated heparin to increase the activated partial thromboplastin time (aPTT) to 1½–2½ times. However, it is now clear that LMWH is mC. RECANALIZATION THERAPY

Prompt coronary recanalization clearly reduces infarct size and, in the long term, saves lives. The so-called open artery hypothesis also has additional benefits (see section 2. Implemantation of Reperfusion Strategies). At one time, there was legitimate controversy over whether coronary recanalization induced by mechanical means (angioplasty) was better, with lower mortality and morbidity rates, than that induced by thrombolysis in patients presenting with an ST elevation MI. Comparative studies indicate that the greater degree of coronary patency induced by angioplasty produces less residual ischemia and recurrent infarction. It is clear that patients whose vessels are open, with sluggish flow (TIMI II grade), have a substantially worse prognosis than do those whose vessels are widely patent with a normal (TIMI III grade) flow. Thus, because direct reperfusion of a coronary artery via mechanical means is more apt to induce TIMI grade III flow and, thus, better nutritive perfusion, it results in reduced mortality and morbidity. In general, patency rates with primary percutaneous coronary intervention (PCI) are in the range of 85–90%, whereas with thrombolysis, the rates are roughly 65% and recurrent events are more common. With modern advances, direct stenting appears to be by far the best approach. This is clearly the case for patients who present ³1–1½ h after the onset of symptoms. The results with thrombolysis in early (<90 min) patients probably match the results of PCI. If intervention is delayed for more than 60 min, results are far less positive. Thus, unless PCI can be done immediately, treatment with thrombolytic agents should be initiated.
Similar data concerning the advantages of recanalization therapy are starting to emerge for those with non-Q wave infarction as well although the data are still controversial. However, both the FRISC 2 and Tactics TIMI 18 studies strongly suggest that the aggressive use of newer anticoagulants such as IIB/IIIA agents and LMWH along with urgent recanalization improve prognosis. Additional trials in this important area are ongoing.
1. Subsets of patients—
a. Inferior versus anterior myocardial infarction— The mortality rates associated with anterior ST elevation MI are at least twice those for ST elevation inferior MI, and patients with the former should be treated more aggressively. Specifically, recanalization therapy should be considered appropriate for as long as 12 h in patients with anterior MI. This is particularly true when the ST segment elevation is greater than 2 mm or when more than two anterior precordial leads are involved. Data from patients with inferior infarction suggest that those with marked ST elevation and especially those with ST depression in the right-sided anterior precordial leads (V1–V3) are at greatest risk. Such changes are associated with a larger area at risk for infarction and subsequent morbidity and mortality. In addition, patients with RV involvement benefit substantially from recanalization. Therefore, the site of infarction and the ECG changes must be factored in with the patient’s age, hemodynamic stability, and other signs in determining the time during which treatment is appropriate.
b. Elderly patients— Elderly patients with acute ST elevation MI are at high risk for increased morbidity and mortality with thrombolytic agents. Indeed, some studies suggest that these agents have no benefit in this group. On the other hand, PCI is clearly beneficial. However, if PCI cannot be accomplished, individual decisions concerning the risk (which is substantial, especially in regard to intracranial bleeding) and the potential benefits must be balanced. Given the high (20–30%) mortality rate from ST elevation MI in the elderly, some increased risk may be reasonable.
c. Hypertension— Many studies of thrombolysis have been extremely cautious about enrolling patients with concurrent hypertension. In some studies, the presence of hypertension has been a demonstrable risk factor for bleeding; in others, this has not been the case. Although even patients with severe hypertension have been treated with beneficial results and no complications in some studies, definitive data are absent in this area. One important consideration is the ease with which blood pressure can be controlled. Transient hypertension that resolves quickly when pain is treated is less worrisome than that which requires treatment with vasodilators. The use of less aggressive dosing regimens and gentler anticoagulation may help to avoid morbidity when treating hypertensive patients. Again, PCI avoids many of these problems.
d. Prior cerebral vascular accidents— Initially, all patients with a history of cerebral vascular accidents were handled cautiously and were considered to have contraindications to the use of thrombolytic agents. It is now clear that this criterion is too rigid, and only cerebral vascular accidents that have occurred within the past 2 months and those associated with intracranial bleeding should be considered absolute contraindications.
2. Implementation of reperfusion strategies— Once the decision is made to treat a patient, treatment should be initiated promptly and the patient transferred to an intensive care unit. (Contraindications to the use of thrombolytic agents are contained in Table 5–2).

a. Urgent percutaneous coronary intervention— Recent data suggest that stenting with the use of clopidogrel for at least 4 weeks is the preferred modality of therapy. Although in one study, stenting appeared to present a possible initial early hazard, this was not observed in a subsequent study, and the frequency of subsequent ischemia and restenosis is clearly improved. The adjunctive use of LMWH is problematic because the only data concerning its use in this setting are preliminary. However, for enoxaparin, an initial IV dose of 30 mg appears optimal or dalteparin in a dose of 120 IU/kg subcutaneously.
b. Plasminogen activators— Plasmin, the key ingredient in the fibrinolytic system, degrades fibrin, fibrinogen, prothrombin, and a variety of other factors in the clotting and complement systems. This effect inhibits clot formation and can lead to bleeding. Patients with AMI and ST segment elevation have little evidence of spontaneous or intrinsic fibrinolysis, despite the intense thrombotic stimulus present. This may be due in part to increased levels of circulating PAI 1 in plasma or PAI-1 that is elaborated locally from platelets. The pharmacologic administration of plasminogen activators (Table 5–3) to such patients seems reasonable. Plasminogen activators can be administered intravenously or directly into the coronary artery. Although more rapid patency occurs with local administration, and lower doses can be used, given the need for early treatment, plasminogen activators are generally administered intravenously.

In addition to invoking fibrinolysis and inhibiting clotting by degrading clotting factors, all activators enhance clot formation. These effects seem greater with nonspecific activators such as streptokinase and urokinase and could partly explain why fibrin-specific activators such as t-PA open arteries more rapidly.
The enhancement of coagulation by plasminogen activators suggests an important role for the concomitant use of antithrombotic agents.
(1) Streptokinase— Streptokinase is derived from streptococcal bacteria and activates plasminogen indirectly, forming an activator complex with a slightly longer half-life than streptokinase alone (23 min versus 18 min after a bolus). Because it activates both circulating plasminogen and plasminogen bound to fibrin, both local and systemic effects occur; that is, circulating fibrinogen degrades substantially (fibrinogenolysis as well as fibrinolysis occurs).
Because antibodies to the streptococci exist in many patients, allergic reactions can occur; anaphylaxis is rare, however, and the use of steroids to avoid allergic reactions is no longer recommended. When streptokinase is administered intravenously, a large dose is necessary to overcome antibody resistance. Because a dose of 250,000 units will suffice in 90% of patients, the recommended dose of 1.5 million units over a 1-h period is generally more than adequate to overcome resistance. Patients who are known to have had a severe streptococcal infection or to have been treated with streptokinase within the preceding 5 or 6 months (or longer) should not receive the agent.
Rapid administration of streptokinase, even at the recommended dose, can cause a substantial reduction in blood pressure. Although this might be considered a potential benefit of the agent, it may also be detrimental. The rate of the infusion should therefore be reduced in response to significant hypotension, and the blood pressure should be monitored closely. Because streptokinase is more procoagulant than other thrombolytic agents, it should not be surprising that patients benefit to a greater extent from the concomitant use of potent antithrombins such as hirudin. However, in combination with IIB/IIIA agents, streptokinase seems to be associated with markedly increased bleeding rates.
(2) Urokinase— Urokinase is a direct activator of plasminogen. It has a shorter half-life than streptokinase (14 ± 6 min) and is not antigenic. Its effects on both circulating and bound-to-fibrin plasminogen are similar to those from streptokinase. It is therefore difficult to understand why IV doses of urokinase (2.0 million units as bolus or 3 million over 90 min) seem to induce coronary artery patency more rapidly than does streptokinase. There is substantial synergism between urokinase and t-PA.
(3) Tissue plasminogen activator— The initial human t-PA was made by recombinant DNA technology. The half-life in plasma was short (4 min) as a bolus but longer (46 min) with prolonged infusions. Despite the short half-life lytic activity persisted for many hours after clearance of the activator. Although t-Pas are considered “fibrin-specific,” no activator is totally fibrin-specific, and fibrin specificity is lost at higher doses. At clinical doses, however, less fibrinogen degradation took place than with nonspecific activators. Tissue plasminogen activator clearly opened coronary arteries more rapidly than nonspecific activators and this is likely why its use improved mortality rates. Bleeding was not less and there was a slight increase in the number of intracranial bleeds which was in part due to the need for dosage adjustment for lighter-weight patients.
The original regimen for the use of t-PA was 100 mg over 3 h: 10 mg as a bolus, followed by 50 mg over the first hour and 40 mg over the next 2 h. Patients who weighed less than 65 kg received 1.25 mg/kg over 3 h with 10% of the total dose given as a bolus. An alternative front-loaded regimen was found to be more effective and included an initial bolus of 15 mg, followed by 50 mg over 30 min and 35 mg over the next 60 min. Doses higher than 100 mg are associated with a higher incidence of intracranial bleeding.
(4) Reteplase— Over time a variety of t-PA variant molecules have been developed. This mutant, called reteplase, lacks several of the structural areas of the parent molecule (the finger domain, kringle 1, and the epidermal growth factor domain). It is less fibrin-specific (causes more systemic degradation of fibrinogen) than the parent molecule, and has a longer half-life. Accordingly, it is used as a double bolus of 10 units initially followed by a second bolus 30 min later. Initial studies suggested that such a regimen used with unfractionated heparin opened more coronary arteries faster than did t-PA. This led to a large trial (GUSTO III) that compared the activators and found no difference. If anything, the minor trends that were present, favored the parent molecule. Nonetheless, many have elected to use reteplase because of the convenience of the double bolus administration.
(5) Tenecteplase— Tenecteplase is also a mutant form of t-PA. It has substitutions in the kringle 1 and protease domains to increase its half-life, increase its fibrin specificity, and reduce its sensitivity to its native inhibitor (PAI-1). These effects were substantiated in clinical trials and initially it appeared that the agent might be substantially superior to the parent molecule. However, in a direct comparison trial (Assent 2), using a 40-mg dose of tenecteplase, no differences in patient outcomes were observed with the possible exception of the group treated more than 4 h after the onset of symptoms. Nonetheless, because of the convenience of a single bolus dose, this agent is generally being used in preference to the parent molecule.
c. Combined thrombolysis and percutaneous coronary intervention— This combination approach has substantial promise. The early experience with coronary interventions after thrombolysis suggested substantial morbidity. Recent data using a half dose of thrombolytic agent (PACT) and studies using IIB/IIIA agents have suggested that now rapid serial thrombolysis and PCI can be accomplished without detriment and may in the long run permit the benefits of both modalities to be combined. This may be an important strategy for those patients living in areas where transport times or logistics make timely PCI impossible. Trials are ongoing to further test these strategies.
d. Adjunctive therapy—
(1) Aspirin— The ISIS II study showed that the combination of aspirin and streptokinase produced a greater reduction in mortality rates than did streptokinase or aspirin alone. Aspirin alone, however, in a dose of 162.5 mg, reduced mortality from acute infarction to almost the same extent as did streptokinase alone. These impressive data have led to the use of aspirin in all patients with AMI. Such a posture is supported by strong experimental evidence that aspirin inhibits platelet aggregation and facilitates fibrinolysis. In general, chewable aspirin in a dose of 162.5–325 mg is recommended initially because its effects on platelets occur within 20 min.
(2) Heparin— Intravenous heparin, used with plasminogen activators, improves the rapidity with which patency is induced; it is essential for maintaining coronary patency, especially with t-PA type agents. Its use is less necessary after treatment with streptokinase, probably because of the anticoagulant effects of fibrinogen depletion and degradation products.
The standard dose of unfractionated heparin is usually a bolus of 5000 units, followed by a 1000-unit-per-hour infusion until the partial thromboplastin time (PTT) can be used to titrate a dose between 1.5 and 2 times the normal range. It has become clear that optimal titration of unfractionated heparin is problematic and that if the activated PTT is either too high or too low, some benefit is lost. For this reason, the use of LMWH is recommended. With the exception of patients with renal failure, a dose of 1 mg/kg for enoxaparin and 120 unit/kg for dalteparin provides for consistent reduction in anti-Xa levels and thus consistent anticoagulation. This is probably the reason that recent studies suggest it is more effective for the treatment of patients with AMI. In addition, because LMWH inhibits Xa activity predominantly, there is some suggestion that discontinuing it may be less problematic than is the case for unfractionated heparin, which has fewer effects on Xa and more direct effects (when combined with antithrombin 3) on thrombin itself. The ability to use the agent intravenously in the catheterization laboratory has not been a problem in regions where this strategy has been embraced.
(3) Beta-blockers— If given early, IV b-blockers have been shown to lower the risk of reinfarction in low-risk patients treated with thrombolytic agents. This provides a rationale for their use (metoprolol, 5 mg IV every 5 min for 3 doses, followed by 25–50 mg every 12 h orally; or propranolol, 0.1 mg/kg initially (IV), followed by 20–40 mg every 6 h) in patients receiving thrombolytic therapy. It is presumed but has not been proven that similar benefits accrue to patients treated with primary PCI. Contraindications to the use of b-blockers include rales more than one-third of the way up the posterior lung fields, systolic blood pressure of less than 100 mm Hg, a heart rate of less than 60 bpm, conduction disturbances, a history of chronic obstructive pulmonary disease or asthma, or a history of an adverse responses to b-blockers. Tachycardia should not be considered the result of increased adrenergic tone and should be treated with b-blockers until all possible physiologic causes can be excluded. This is particularly important with diabetic patients, in whom autonomic neuropathy can at times cause tachycardia. Once treatment with b-blockers has been initiated, there will be some reason to discontinue the drug during the first 2–3 days for 20–30% of patients. This may be due to the evolution of infarction with the development of heart failure or to unanticipated complications of the drug (Table 5–4).

Table 5–4. Standard intravenous doses of commonly used agents in patients with acute myocardial infarction.

In general, b-blockers appear to induce most benefit in patients who reduce their degree of ST segment elevation in response to treatment. This is thought to be the marker of a patent infarct-related vessel and probably permits the agent to reach the infarct zone.
(4) Nitroglycerin— Sublingual nitroglycerin is usually administered immediately to patients with suspected AMI to assess resolution of ST elevation and relief of pain (discussed earlier). Intravenous nitroglycerin has been shown to reduce infarct size in patients not receiving reperfusion and to improve survival in patients with infarction and CHF. Its use during thrombolysis was presumed to induce similar benefit; however, the ISIS 4 trial failed to show any effect on subsequent morbidity and mortality. Therefore, the routine use of IV nitroglycerin is not recommended.
(5) Intravenous magnesium— Several small studies have documented a reduction in mortality rates after administration of IV magnesium (1–2 g over 1 h, followed by 8 g over 24 h) to patients presenting during the initial 24 h of acute infarction. ISIS 4, however, failed to demonstrate any benefit in morbidity or mortality with the routine use of IV magnesium. Therefore, because IV magnesium induces mild hypotension and bradycardia, its use cannot be recommended unless serum magnesium levels are shown to be low or other indications, such as torsade de pointes, are present.
(6) Calcium channel blockers— Dihydropyridine calcium channel blockers have shown to be detrimental in patients with AMI, probably because of a small but important incidence of severe hypotension. The data are inadequate to assess the risk or benefit of other calcium channel blockers. Although it is hoped that IV preparations may avoid adverse effects, allowing achievement of some of the benefits seen in experimental models, the use of calcium channel blockers cannot be recommended at this time.
(7) Lidocaine— Lidocaine was initially administered to patients receiving thrombolytic agents because of concern that coronary recanalization might exacerbate arrhythmias; However, recanalization reduces the incidence of such arrhythmias. In addition, recent analyses suggest the routine use of lidocaine may actually increase mortality rates. Accordingly, the use of prophylactic lidocaine is not recommended. The agent should be used if ventricular tachycardia (VT) or ventricular fibrillation (VF) occurs.
(8) IIB/IIIA agents— These agents bind to the platelet fibrinogen receptor and prevent platelet aggregation and activation. The initial agent in this group was abciximab, which is a chimeric antibody fragment to the receptor. Now both small peptide and nonpeptide competitive inhibitors of the receptor are available. These agents markedly inhibit hemostasis by both inhibiting hemostatic plug formation and reducing subsequent coagulation. They have not as yet been shown to be of benefit in patients with ST elevation AMI but are clearly efficacious in patients with non-Q wave events, especially if they undergo PCI. This is a group with an adverse long-term prognosis without intervention.
e. Complications— The most serious complication of treatment with thrombolytic agents is bleeding, particularly intracranial hemorrhage. Reduction in this dreaded complication is one of the very substantial benefits of catheter-based interventions. The mechanism of bleeding with thrombolytic agents is unclear but has been related to the efficacy of the agent, the concomitant use of antithrombotic agents such as heparin and aspirin, and the degree of hemostatic perturbation induced by the plasminogen activators. In most studies, the incidence of stroke and intracerebral bleeding has been slightly higher with t-PA type activators. This may be in keeping with the greater efficacy and rapidity of their effects. Although most bleeding occurs early during treatment, some can occur 24–48 h later, and vigilance even after the first few hours is important.
Bleeding may be of several types. Intracranial bleeding is by far the most dangerous because it is often fatal. For most activators, the incidence of intracranial hemorrhage is less than 1%; it may be as high as 2–3% in elderly patients. Risk factors for intracranial bleeding include a history of cerebral vascular disease, hypertension, and age. These factors must be taken into account when determining whether a thrombolytic agent has an appropriate benefit-to-risk relationship. Changes in mental status require an immediate evaluation—clinical and computed tomography or magnetic resonance imaging. If bleeding is strongly suspected, heparin should be discontinued or reversed with protamine.
There also is a substantial incidence of nonhemorrhagic, probably thrombotic, stroke that may be partly due to dissolution of thrombus within the heart, followed by migration. The exact mechanisms of this phenomenon are unclear. In some studies, the excess of strokes with t-PA has been found to be related to this phenomenon and in others it has been due to an apparent increase in intracranial bleeding.
Bleeding outside the brain can occur in any organ bed and should be prevented whenever possible. The puncture of noncompressible arterial or venous vessels is relatively contraindicated in all cardiovascular patients: those with unstable angina one day may be candidates for thrombolytic treatment on the next. Blood gas determinations should therefore be avoided if possible and oximeters used instead in cardiovascular patients. It should be understood that central lines placed in cardiovascular patients pose a substantial risk should there be a subsequent need for a lytic agent. Foley catheters and endotracheal (especially nasotracheal) intubation can also predispose to significant hemorrhage. Bleeding should be watched for assiduously. If severe bleeding occurs while heparin is in use, it should be antagonized with protamine. In general, this and supportive measures are all that can be done. In some studies, there appears to be a slightly higher incidence of extracranial bleeding with nonspecific activators than with t-PA; this finding has not been consistent. In an occasional patient, who begins to bleed shortly after receiving the plasminogen activator, epsilon amino caproic acid, which changes the activation of plasminogen, may be useful. Otherwise, discontinuation of the drug and conservative local measures are all that can done. If volume repletion is necessary, red blood cells are preferred to whole blood, and cryoprecipitate is preferred to fresh frozen plasma because they do not replenish plasminogen.
Allergic reactions related to the use of streptokinase are unusual but should be identified when they occur. Mild reactions such as urticaria can be treated with antihistamines; more severe reactions such as broncho-spasm may require glucocorticoids or epinephrine.
Bleeding after primary PCI whether for ST elevation of non-Q wave AMI can also be substantial, particularly if IIB/IIIA agents are administered. The use of newer closure devices are touted by some but close observation is the key to minimizing bleeding from the catheter site. On occasion, platelet transfusions may be necessary.
3. Subsequent early management— Aggressive monitoring can help determine which patients have coronary recanalization in response to treatment and which do not. Conventional ECG monitoring for ST segments and arrhythmias and consideration of the presence or absence of chest pain are not particularly reliable for this purpose. In fact, increasing degrees of ST segment elevation during the first hour after treatment appear to be a sign of incipient recanalization.
Emergency cardiac catheterization and angioplasty are not indicated for the routine patient who has been successfully thrombolysed. However, patients with non-Q wave AMI who have been stabilized pharmacologically and who are candidates for intervention should have it performed promptly. Patients who suffer continuing or persistent chest discomfort, who have recurrent segment change, or who have difficult-to-treat hypotension and heart failure should be considered for cardiac catheterization.
D. OTHER INTERVENTIONS

A variety of other interventions have been suggested throughout the years. These include the use of glucose, insulin, potassium, and hyaluronidase. Intraaortic balloon pumps have also been suggested, especially in patients with anterior infarction who might be deemed at risk for the development of severe heart failure. In general, none of these are recommended as routine measures. Perhaps the most promising of these is in the area of tight glucose control in diabetes. The DIGAMI study suggested an impressive benefit in early and late mortality and morbidity. With the availability of accurate glucose monitoring for point of care use, implementation of a strategy using rapid adjustments of IV insulin guided by hourly glucose measurements is likely to emerge as an important additional strategy.