Thrombolytics

Introduction

      Thrombolytics offer a dramatic improvement in the treatment of myocardial infarction. Administration of thrombolytics in the emergency department, either by the emergency department physician or by the patient’s private physician, is now the standard of care for acute myocardial infarction.
      Thrombolytics should be administered by the first physician to make the diagnosis of myocardial infarction. Every physician who sees chest pain patients should learn the indications and contraindications to thrombolytic therapy, and should be prepared to order thrombolytics when appropriate. To wait for a cardiology consultation is no longer accepted practice. Back to Index.


What are Thrombolytics?

      Thrombolytics act on plasminogen, converting it into the active enzyme plasmin. Plasmin then “snips up” fibrin in the blood clot. As the clot breaks apart, blood flow is restored to the myocardium served by the thrombosed coronary artery.
      Thrombolytics can only effectively “dissolve” an intracoronary thrombus if they are used rapidly after the onset of thrombosis. After a few hours, the clot undergoes a hardening process, which makes it resistant to breakdown by plasmin. Thus, delays in administering thrombolytics can reduce their effectiveness.
      By opening up the thrombosed coronary artery, thrombolytics speed healing of the infarcted myocardium. “Borderline” areas of ischemic cardiac tissue may be saved. Long-term cardiac function is improved. Both short-term and long-term risk of death is reduced. Back to Index.


How do Thrombolytics Differ?

      There are five thrombolytics currently used in the U.S. for myocardial infarction: streptokinase (Steptase, Hoechst-Roussel), alteplase (Activase, Genentech), anistreplase (Eminase, SmithKline Beecham), reteplase (Retavase, Boehringer Mannheim), and tenecteplase (TNKase, Genentech). For therapeutic purposes, these products should be regarded as identical in effectiveness, and identical in safety.
      All thrombolytics yield the same success rate, with reperfusion of the ischemic myocardium occurring in about 75 percent of patients. The “accelerated” tPA protocol (used in the GUSTO study) gives earlier reperfusion, but no difference in the final reperfusion rate.
      The rate of reocclusion of the (formerly) thrombosed coronary artery is also similar for all thrombolytics, around 20 percent. The rate of reocclusion is reduced by giving aspirin. With tPA, the rate of reocclusion is further decreased with the use of heparin (the data is less clear for streptokinase and anistreplase).
      The various thrombolytic agents also yield approximately the same rate, and type, of bleeding complications. About 5 percent of patients will have some problem with bleeding. Just over 1 percent of patients (one out of five who bleed) will have a serious episode of bleeding.
      The most feared hemorrhagic complication is intracranial hemorrhage, which occurs with a rate of 0.5 percent to 1 percent. Because of this risk, thrombolytics are contraindicated in patients with a history of stroke, brain tumor or AV malformation, or recent CNS surgery. However, some experts feel a history of stroke is only a contraindication if the stroke is recent — within the past two months. The rate of intracranial bleeding is higher with the “accelerated” tPA strategy.
      Thrombolytics differ in site of action. tPA acts on plasmin only at the site of the clot; streptokinase acts on plasmin systemically; while anistreplase acts on both circulating and clot-bound plasmin. However, this doesn’t make any clinical difference, either in success rate or in complication rate. Tenecteplase is more fibrin-specific than tPA and has some resistance to plasminogen inhibitors, but again, this hasn't been shown to affect clinical outcomes.
     Thrombolytics differ in serum half-life, but effects at the clot are similar. For example, tPA has a serum half-life of five minutes, but effects at the clot persist for hours. Anistreplase has a serum half-life of around two hours, while that of streptokinase is 20 minutes. The half-life of reteplase is 18 minutes; that of tenecteplase, 20 minutes.
      The major CLINICAL difference between products is possible allergic reactions. Patients allergic to streptokinase may react to streptokinase or anistreplase. About 5 percent of patients given streptokinase will have some sort of allergic reaction. The rate of anaphyllaxis is 0.1 percent (one per thousand patients).
      The potential for allergy with streptokinase does NOT affect overall mortality or morbidity. However, some physicians prefer not to give either streptokinase or anistreplase to patients who have had streptokinase previously, because of risk of severe allergic reaction. Back to Index.


Which Thrombolytic to Use?

      If there is a history of severe allergic reaction to anistreplase or streptokinase, you should give one of the plasminogen activators: alteplase, tenecteplase, or reteplase. For other situations, however, the choice of “best” thrombolytic is a hotly debated question. Each physician must decide: Do I believe the outcomes to be similar enough that I'll go with cheapstreptokinase? Or do I believe that earlier patency with alteplase or reteplase gives a substantial advantage?
      The GUSTO study yielded one unequivocal result: it showed that giving heparin with tPA improves outcome. And like the studies before it, GUSTO showed that tPA has an increased risk of hemorrhagic stroke compared to streptokinase. Unique to the GUSTO study was the finding that tPA is superior for large anterior infarctions when given very early after onset of symptoms. But many experts have questioned the GUSTO study results. The study was not “blinded” for either patient or physician. Knowledge of the thrombolytic used may have altered treatment strategies. Mortality was better for tPA in the U.S., while NO difference was found between streptokinase and tPA in other countries.
      TPA probably IS “better” than streptokinase. But with several large “pre-GUSTO” studies showing no difference between tPA and streptokinase, the clinical difference must be small. You can justify continuing to use streptokinase.
      Reteplase offers "convenience in dosing" when compared to alteplase. Early data indicate that it may give earlier arterial patency than either tPA or streptokinase, but it has not been compared directly to alteplase for overall mortality and incidence of stroke. Back to Index.


Indications and Administration

      First, the drug must be reconstituted. Tenecteplase and reteplase are ready in about one minute. For streptokinase or tPA, the typical time from physician order to administration is 12 to 15 minutes. In some hospitals, the delay can be 45 to 60 minutes for pharmacy preparation.
      Complexity of administration differs. Tenecteplase is given as a 5-second IV bolus. Anistreplase can be given as a single IV push over two minutes. Reteplase is given as two bolus injections 30 minutes apart. Streptokinase and tPA must be given by infusion pump, requiring additional setup time. Streptokinase is given as a single infusion over 60 minutes. Under the accelerated 90 minute protocol, tPA is given as a small initial bolus, then at varying rates over 90 minutes.
      Thrombolytics may be used for other situations, such as clotted dialysis fistula, pulmonary embolism, or DVT when appropriate. To order thrombolytics for myocardial infarction, you need only satisfy four conditions: (1) typical chest pain, (2) typical ST segment changes, (3) absense of contraindications, and (4) expected benefits are greater than the risk.
      Although some hospitals have required a cardiology consultation before administering thrombolytics, the standard of care is RAPID administration of thrombolytics as soon as the indications are established. The physician who routinely encounters the MI patient, whether internist, emergency physician, or rural family practice physician, can and should be qualified to determine indications and contraindications for thrombolytic therapy, and should order them when indicated.

Criteria for Thrombolytic Therapy
      A. Typical Chest Pain
           Over 15 minutes
           Less than six hours
           Not responsive to nitroglycerin
      B. Typical ECG Changes
           ST segment elevation in two or more contiguous leads
           of over 1 mm in limb leads or 2 mm in chest leads
      C. Absence of major contraindications
      D. Expected benefit greater than risk if “relative”
           contraindications are present

      Thrombolytics can be started in the emergency room, in the field by paramedics, or even in the doctor’s office. To wait for CCU admission or cardiology consultation decreases myocardial salvage.
      If a patient presents with typical history suggesting MI but the initial ECG is non-diagnostic, the ECG should be repeated at intervals during the first four to six hours. ECG changes of infarction may appear, warranting use of thrombolytics.
      One situation in which the patient has documented myocardial infarction, but should never be given thrombolytics is aortic dissection. The infarction is due to physical compromise of the coronary artery openings near the aortic valve, rather than thrombosis. Thrombolytics would likely prove rapidly fatal. (About 75 percent of victims of dissection will have an abnormal ECG, which may show signs of regional infarction.)
      Streptokinase, tPA, reteplase, and anistreplase must be reconstituted. Anistreplase and reteplase are ready in about one minute. For streptokinase or tPA, the typical time from physician order to administration is 12 to 15 minutes. In some hospitals, the delay can be 45 to 60 minutes for pharmacy preparation.
      Complexity of administration differs. Anistreplase can be given as a single IV push over two minutes. Reteplase is given as two bolus injections 30 minutes apart. Streptokinase and tPA must be given by infusion pump, requiring additional setup time. Streptokinase is given as a single infusion over 60 minutes. Under the accelerated 90 minute protocol, tPA is given as a small initial bolus, then at varying rates over 90 minutes. Back to Index.


Monitoring the Thrombolytic Patient

      Take frequent vital signs and monitor with ECG all patients to whom you give thrombolytics. The patient should be admitted to a monitored hospital bed, with oxygen and IV.
      Reperfusion often occurs about one hour after thrombolytics are started. The patient should be monitored for signs of reperfusion. Serial CPKs and serial ECGs should be obtained. Factors that may indicate reperfusion are:

      *Resolution of the chest pain is 80 percent accurate
      *Resolution of ST segment elevation is 75 percent accurate
      *Early “premature” peaking of CK is 50 percent accurate
      *Arrhythmia (PVCs or brief V-tach) often occurs as
        blood reaches ischemic myocardium

      Pain relief and ST segment normalization together are highly accurate at predicting reperfusion. PVCs and runs of V-tach often occur as the ischemic myocardium is reperfused, and (while not “evidence” that reperfusion has occurred) may serve as a marker of the time of reperfusion.
      As blood reaches ischemic tissue, CK is washed out, causing a dramatic peaking of CK earlier than would be expected. CK normally elevates four to six hours following infarction, with a peak at 24 hours. When reperfusion occurs, however, CK elevates in minutes, and peaks within a few hours. Some centers will draw CK levels every 15 minutes to monitor for evidence of reperfusion, but most will simply follow clinical status and serial ECGs.
      Even in patients with no signs of reperfusion, nearly 50 percent will have cleared the thrombus. Back to Index.


Other Factors in Therapy

      Beta blockers are often given to decrease myocardial oxygen consumption, and to reduce the incidence and severity of reperfusion arrhythmia. Beta blockers reduce arrhythmias, although they haven’t been clearly shown to improve acute- phase mortality. Beta blockade is part of most thrombolytic treatment protocols.
      Low-dose aspirin has been shown to decrease risk of rethrombosis. Give every MI patient 160 mg of chewable aspirin immediately, unless contraindicated. Use aspirin even if thrombolysis is not planned.
      Heparin may be given to prevent reformation of the thrombus. Heparin is clearly helpful with tPA. The role and proper dosage of heparin have not been clearly established for streptokinase and anistreplase.
      “Acute phase” cardiac catheterization is controversial. The MI patient can certainly be given thrombolytics in the small hospital with no “cath lab.” Immediate coronary angioplasty should be considered for patients with large infarctions who fail to reperfuse. Angioplasty is also indicated for patients with contraindications to thrombolytics or those with cardiogenic shock. Back to Index.


Streptokinase

      Streptokinase (SK) is an enzyme derived from group C beta-hemolytic streptococcus. SK is inexpensive to produce. It was the first thrombolytic available.
      SK rapidly complexes with circulating plasminogen. The complex then converts other molecules of plasminogen into plasmin. This “activator complex” has a serum half-life of 20 minutes. SK converts plasminogen into plasmin throughout the circulation.
      Following SK administration, levels of fibrinogen are decreased and fibrin degradation products are increased for about 24 hours. The patient remains somewhat “anticoagulated” even without heparin.
      Because streptokinase causes some type of allergic reaction in about 5 percent of patients, most physicians prefer to pretreat the patient with diphenhydramine (Benadryl), either 25 mg IV or 50 mg PO.
      Give SK by constant IV infusion. The dose for myocardial infarction is 1-1.5 million units, with 1.5 million being most common. The infusion is given over a 60 minute period.
      Give one baby aspirin (160 mg). Aspirin is repeated daily.
      Heparin may lower the risk of reocclusion of the coronary artery, but it hasn’t been proven clearly beneficial with streptokinase. A common dose is 750-1000 units per hour by IV infusion, starting after completion of the SK infusion.
      SK therapy may be combined with beta blockers, either IV or PO. Intravenous use of atenolol (Tenormin) is most common. Back to Index.


Alteplase

      Alteplase or tPA (Activase, Genentech) is a product of genetic engineering. The human gene for the tissue plasminogen activator enzyme is inserted into microorganisms and “turned on.” The organism becomes a factory for the human enzyme.
      Alteplase is expensive. Cost per dose is about 8 to 10 times that of streptokinase. Alteplase has a serum half-life of only five minutes; however, its effects at the clot persist for over an hour. tPA binds to fibrin at the site of a thrombus. tPA activates only clot-bound plasminogen, while SK and anistreplase activate plasminogen throughout the circulation. While this might theoretically be a “safety advantage,” it isn’t clinically significant.
      Alteplase must be reconstituted. Begin with a bolus of 15 mg, then infuse 0.75 mg per kg (maximum 50 mg) over 30 minutes. Next infuse 0.5 mg per kg (maximum 35 mg) over 60 minutes. Total doses larger than 100 mg should not be used because of an increased risk of intracranial hemorrhage.
      Give one baby aspirin (160 mg). The aspirin is repeated daily.
      Heparin should be added to lower the rate of reocclusion. The most common protocol calls for a bolus of 5000 units, followed by 750-1000 mg per hour by IV infusion.
      As with anistreplase and SK, beta blockers may be given for arrhythmia control. Back to Index.


Reteplase

      Reteplase (Retavase, Boehringer Mannheim) is made by genetic engineering. The gene for a fragment of tPA was inserted into E. Coli. The protein is extracted from the bacteria and processed to convert it into active thrombolytic. The half-life of reteplase is 18 minutes.
      Reteplase is expensive. The cost is comparable to alteplase.
      Reteplase is reconstituted before injection. It is usually given as a 10 unit bolus, followed by a repeat 10 unit bolus in 30 minutes.
      Give one baby aspirin (160 mg). The aspirin is repeated daily.
      Heparin should be added to lower the rate of reocclusion. The most common protocol calls for a bolus of 5000 units, followed by 750-1000 mg per hour by IV infusion.
      As with anistreplase and SK, beta blockers may be given for arrhythmia control. Back to Index.


Anistreplase

      Anistreplase (Eminase, SmithKline Beecham) is the third thrombolytic developed. Anistreplase is the activated complex of streptokinase with human plasminogen, with the catalytic site of the enzyme complex temporarily blocked by an anisoyl group.
      In the circulation, anistreplase undergoes spontaneous deacylation to form the active complex of plasminogen- streptokinase. This conversion occurs with a half-life of two hours. The active complex has a half-life of 90 minutes, the longest of any thrombolytic. Anistreplase activates both circulating and clot-bound plasminogen, but is most active within the thrombus.
      Because anistreplase contains complexed streptokinase, the rate and nature of allergic reactions will likely be similar to SK. Anistreplase should not be used in a patient with a previous severe allergic reaction to SK.
      Give anistreplase by simple intravenous injection (IV push) over two to five minutes. Aspirin, 160 mg (1 baby aspirin), is given orally and repeated daily.
      Heparin may be added. The most common dose is 750-1000 mg by infusion, starting four hours after injection of anistreplase. Heparin has not been shown to be clearly beneficial when used with anistreplase.
      As with alteplase and SK, beta blockers may be given. Back to Index.


Tenecteplase:

     Tenecteplase (TNKase, Genentech) is made by genetic engineering. To create tenecteplase, the human gene for tPA was modified so that different amino acids occur at three locations. This gives tenecteplase a longer half-life, and relative resistance to plasminogen activator inhibitor.
     The gene is inserted into hamster ovary cells, which produce the plasminogen activator.
     Tenecteplase is somewhat more fibrin-specific than either native tPA or reteplase. The half-life of tenecteplase is 20 minutes, about four times that of tPA.
     Tenecteplase is expensive. The cost is comparable to alteplase.
     Tenecteplase is reconstituted before injection. It is given as a single IV bolus over 5 seconds. The dose is based on weight.
            < 60 kg      30 mg    6 ml
            60-70 kg   35 mg    7 ml
            70-80 kg   40 mg    8 ml
            80-90 kg   45 mg    9 ml
            > 90 kg      50 mg   10 ml
     Give one baby aspirin (160 mg). The aspirin is repeated daily. Heparin should be added to lower the rate of reocclusion. The most common protocol calls for a bolus of 5000 units, followed by 750-1000 mg per hour by IV infusion.
     As with alteplase, beta blockers may be given for arrhythmia control. Back to Index.


Contraindications to Thrombolytics

Absolute Contraindications to Fibrinolytic Therapy

Relative Contraindications to thrombolytic therapy

Back to Index.


What About “Relative” Contraindications?

      The “use after weighing risk versus benefit” cautions were listed previously for all thrombolytics. You must compare “expected benefit” to “risk should bleeding occur.” Although there is some variation in the exact “relative contraindications” listed among the thrombolytics, you should consider all these drugs to have the same risks EXCEPT that streptokinase and anistreplase have a small risk of serious allergic reaction.
      You must estimate the expected disability and risk of early death that would result from the untreated myocardial infarction. Avoiding this morbidity and risk of death is your “expected benefit.” A large anterior or anterolateral infarction creates great risk of death within the next 5 years, and high likelihood of heart failure or other complications. On the other hand, a small inferior infarct has a much better prognosis.
      Evaluate your “bleeding risk,” and compare it to the risk of withholding thrombolytics. If the danger due to giving thrombolytics outweighs the expected benefits, do not give the thrombolytic.

Example 1: A diabetic with vision in only one eye, who has had retinal hemorrhages and laser treatments in the past, has a small inferior MI. This is a high risk-to-benefit ratio. The patient participates in the decision, but thrombolytics are withheld.

Example 2: A healthy 78 year-old person has a large anterior MI. This is low risk for great potential benefit. With informed consent, thrombolytics are given.

      Whenever a “relative contraindication” exists, the physician should obtain “informed consent.” Many emergency departments have “thrombolytic consent” sheets that the patient signs, similar to operative consent forms. Any relative contraindications should be listed on the sheet before submitting it to the patient for signature.
      None of the thrombolytics specify the cutoff between “severe, uncontrolled hypertension” (a contraindication) and “hypertension (systolic >>180 and/or diastolic >>110)” (a relative caution). Recommendations vary. A reasonable cutoff for severe, uncontrolled hypertension is:

      * Blood pressure can’t be reduced below 200/130 or
      * Active end organ effects, such as:
           Hypertensive retinopathy
           Encephalopathy

Back to Index.


Sample Clinical Policy and Procedure
Department of Emergency Medicine

Diagnosis: Acute myocardial infarction or R/O MI

History Standard:
1. Description of the chest pain with a minimum of the location, duration, quality, and associated symptoms.
2. Presence or absence of patient risk factors for atherosclerosis.
3. Document any historical contraindications to thrombolytic therapy.
4. Past cardiac history, if any.
5. Historical positives and negatives for other causes of chest pain if the diagnosis is R/O MI.
5. Drug allergies.
6. Current medications.

Physical Exam Standard:
1. Complete vital signs, must include blood pressure in both arms.
2. ENT exam must include venous distention.
3. Chest exam — positive and negative findings on auscultation. Should include rales as a pertinent negative.
4. Cardiac exam — presence or absence of gallops, murmurs, or rubs. Rubs must be stated as a pertinent negative if fibrinolytic therapy will be used.
5. Abdominal exam — presence or absence of tenderness or increased liver size.
6. Extremities exam — presence or absence of edema, pedal pulses.

Monitoring Standard:
1. All patients will have continuous ECG monitoring.
2. Monitoring will include a nurse at the bedside, or telegraphic monitoring.
3. Patients who must leave the department for special studies will be accompanied by nurse and ECG monitor (until MI is ruled out).

Laboratory Standard:
1. A full “cardiac packet” of CBC, 18-channel survey, PT & PTT, and baseline CK will be ordered on every patient. These tests will be drawn before administration of thrombolytics. Any abnormalities shall be addressed in the chart.
2. A chest x-ray will be performed on every patient, and the physician’s interpretation documented.
3. An ECG will be performed on every patient, and the physician’s interpretation will be included in the chart.
4. If blood gases are drawn on a patient in whom thrombolytics are contemplated, the reason will be documented on the chart.
5. If blood gases are drawn, the emergency physician’s interpretation will be documented.

Therapeutic Standard:
1. Oxygen will be given to all patients in appropriate doses. In patients with respiratory difficulty, oxygen therapy will be monitored by blood gas analysis.
2. An IV of D5W or NS will be established in every patient.
3. Nitroglycerin (SL tab or spray, paste, or IV) will be used unless there is hypotension or allergy.
4. Morphine sulphate will be given if nitroglycerin does not relieve chest pain, unless contraindicated by hypotension or allergy.
5. Lidocaine or other anti-dysrrhythmic agent will be used if the patient manifests significant new arrhythmia ( >> 6 PVCs/min, multifocal PVCs, 3-beat V-tach, etc).
6. Fibrinolytic therapy will be started in the emergency room within one hour of arrival (if no contraindications or cautionary conditions exist) for those with documented indications (see Supplement A).
7. If fibrinolytic therapy is not given in the emergency room, the reason shall be stated in the chart.
8. Any other therapies or interventions will have documentation to include the reason for intervention, response to therapy, and re-exam of pertinent areas.

Transport and Transfer Standard:
1. All acute myocardial infarctions will be admitted to ICU, to a physician with ICU privileges.
2. The patient will be continuously monitored by ECG and nursing en route to ICU.
3. Patients with acute myocardial infarction will not be transferred to another hospital unless for medical reasons. Medical indications for transfer will be documented in the chart.

Myocardial Infarction Clinical Policy
Supplement A

Indications for Fibrinolytic Therapy:
1. Myocardial infarction diagnosed by ST segment elevation in two or more contiguous leads, and
2. Chest pain suggestive of cardiac origin of less than six hours and greater than 15 minutes duration, not relieved by nitroglycerin, and
3. Absence of any absolute contraindications, and
4. If “relative” contraindications are present, the expected benefits of therapy outweigh the risks.

Absolute Contraindications to Fibrinolytic Therapy

1. Active internal bleeding
2. CNS neoplasm, AV malformation, or aneurysm. CNS procedure or CVA within two months.
3. Severe uncontrolled hypertension (over 200/130 or complicated by retinovascular disease or encephalopathy)
4. Known bleeding diathesis
5. MI due to aortic dissection
6. Allergy to either streptokinase or anistreplase, if streptokinase or anistreplase will be used

Relative Contraindications to thrombolytic therapy:
1. Age over 75
2. Cerebrovascular disease
3. Pregnancy or early postpartum
4. Recent major surgery (less than 10 days), noncompressable vessel puncture, or organ biopsy
5. Recent trauma, including CPR of over 2 minutes duration
6. Recent GI bleeding or active ulcer disease (less than 10 days)
7. Acute pericarditis or subacute bacterial endocarditis
8. Septic thrombophlebitis
9. High likelihood of left heart thrombus (eg. mitral stenosis with atrial fibrillation)
10. Known coagulation defects, including anticoagulant therapy
11. Significant liver dysfunction
12. Conditions associated with bleeding risks, such as diabetic retinopathy.
13. Menstruation
14. Terminal cancer or other end-stage disease
15. Recent streptococcal infection, if streptokinase or anistreplase will be used

Clinical Policy for Myocardial Infarction
Supplement B

Suggested Protocol for Fibrinolytic Therapy

1. Diagnose myocardial infarction, determine indications for thrombolytic therapy (see Supplement A)
2. Screen patient for contraindications to thrombolytics
3. Evaluate relative contraindications
4. Draw lab: CBC, chemical screen, CK, PT, PTT
5. Place a second IV or heparin lock
6. Aspirin, 160 mg chewable
7. Administer thrombolytic according to protocol:
    A. Streptokinase:
         1. Consider pre-medication: Benadryl 25 mg IV
         2. 1.5 million units streptokinase in 250 cc NS
         3. Infuse over 60 minutes
         4. Consider heparin, 750-1000 units/hr after infusion is complete)
    B. tPA:
         1. 15 mg bolus tPA
         2. Infuse 0.75 mg/kg (maximum 50 mg) over 30 minutes
         3. Infuse 0.5 mg/kg (maximum 35 mg) over 60 minutes
         4. Heparin 5000 units IV bolus after tPA bolus
         5. Heparin 1000 units per hour
    C. Reteplase:
         1. 10 unit bolus
         2. 10 unit bolus after 30 minutes
         3. Heparin 5000 units IV bolus with first bolus
         4. Heparin 1000 units per hour
    D. Anistreplase:
         1. Give 30 units anistreplase IV push over 2 minutes
         2. Consider heparin 1000 units/hr, starting 4 hours after anistreplase
    E. Tenecteplase:
         1. Give IV bolus based on weight
                  < 60 kg     30 mg    6 ml
                  60-70 kg   35 mg    7 ml
                  70-80 kg   40 mg    8 ml
                  80-90 kg   45 mg    9 ml
                  > 90 kg     50 mg   10 ml
         2. Heparin 5000 units IV bolus with first bolus
         3. Heparin 1000 units per hour

8. Give beta-blocker, example atenolol 5 mg Q 5 minutes for 3 doses
9. Frequent monitoring of blood pressure (Q 10 min)
10. Serial CK determinations (hourly x 3, then Q 3 hours x 24 hours)
11. Repeat ECG at 30, 60, 90, and 120 minutes
12. Note presence or absence chest pain, ST elevation, dysrhythmias

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