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Clin. Cardiol. 23, 635–636 (2000)

Editor's Note

Thrombolytic Therapy for Acute Myocardial Infarction: What Dose Should Be Used?

Key words: myocardial infarction, thrombolysis, obesity

I have never really worried about the dose of tissue plasminogen activator (t-PA) or streptokinase when treating the usual slightly overweight patient with an acute ST-segment elevation myocardial infarction (MI).

I always worried about giving too high a dose of thrombolytic drug to the underweight patient--for example, the 100-pound elderly lady. It seems to me that this patient might require less thrombolytic therapy than the 200-pound male. It is my impression that most physicians use a "standard" dosing schedule in most patients. What follows are the standard dosing regimens as published in the literature. Recommended doses are based upon patient weight, but the dose should not exceed 100 mg because of the concern about excess bleeding.

The Accelerated Infusion Regimen

As presented in the prescribing information, the incidence of intracerebral bleeding in patients with acute MI treated with t-PA is 0.4% using 100 mg for 3 h, 0.7% using ¾ to 100 mg accelerated program, 1.3% using 150 mg, and 0.4% using 1–1.4 mg/kg. This regimen consists of using a 15 mg IV bolus followed by 50 mg infused over 30 min followed by 35 mg infused over the next 60 min. This is recommended for persons in the range of 70 kg or greater. For patients weighing less than 70 kg, a 15 mg IV bolus is given, followed by 0.75 mg/kg infused over the next 30 min not to exceed 50 mg and then 0.5 mg/kg over the next 60 min not to exceed 35 mg.

The Three-Hour Infusion Regimen

In this regimen, 100 mg is administered as 60 mg in the first hour (6–10 mg is administered as a bolus), 20 mg over the second hour, and 20 mg over the third hour. For smaller patients, that is, <70 kg, a dose of 1.25 mg/kg administered over 3 h should be used.

All of the above are well known to physicians treating patients with acute MI, and there is plenty of literature published on this subject.

The reason for this editorial is not to refute or agree with those recommendations but to share with the readers a clinical situation in an obese patient presenting with an acute ST-segment-elevation MI. This patient weighed 450 pounds. He arrived in our emergency department soon after the onset of his chest pain. His physician decided that urgent angioplasty was inappropriate and perhaps dangerous in this individual because of his weight. Thrombolytic therapy was initiated and I was asked what dose should be used in this 450-pound patient. My recommendation was to use the accelerated regimen with 100 mg t-PA. I contacted Genentech, Inc., to see if they had any information about the use of thrombolytic therapy in grossly obese patients having an acute MI.

To summarize quickly, Genentech did not recommend exceeding the approved maximum dose regardless of patient weight because of the increased risk of intracranial bleeding.

Several have written about the weight-adjusted dosing of t-PA in both low and heavy body weight patients in an effort to minimize complications of therapy and to maximize the efficacy of that therapy.1 However, only a few publications of higher dosing regimens are reported in the literature.

Two t-PA dosing regimens were employed in the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) trial, both using a total of 150 mg.2 The initial regimen provided a fixed first-hour dose of 60 mg followed by 20 mg/h for 2 h, then 100 mg/h for 5 h. The second regimen used a weight-adjusted dose of 1 mg/kg (90 mg maximum) over the first hour with the remainder of the 150-mg dose infused over 5 h. The weight-adjusted dose resulted in greater patency at 90 min, less bleeding, and a lower rate of reocclusion. Because the first-hour dose of t-PA was limited to 90 mg, the effect of larger doses in patients weighing >90 kg (using a 1 mg/kg first-hour dose) is unknown.

There have been reports that t-PA-treated patients weighing <60 kg were noted to have an increased incidence of stroke compared with patients weighing >60 kg who received the same dose of t-PA (100 mg over 3 h).3

In a comparison of two doses, 1.0 mg/kg and 1.5 mg/kg, reported by Gibelin et al.,4 50 patients were treated with 1 mg/kg over 90 min (10 mg bolus) and 50 patients received 1.5 mg/kg over 3 h (20 mg bolus). The higher dose was found to be more effective. No significant differences in complications were reported for femoral hematomas or transfusions. No cerebrovascular accidents occurred.

Smalling and colleagues reported on the efficacy of two weight-adjusted doses in the High dose Intravenous Thrombolysis in Myocardial Infarction (HITMI) trial.5 Patients were randomized to receive doses of 1.25 mg/kg over 3 h or 2.0 mg/kg over 3 h. Bleeding complications were similar in the two groups; however, two patients who received 2 mg/kg developed intracerebral hemorrhage.

Neuhaus et al.6 suggested that efficacy of an accelerated regimen of t-PA as assessed by 90-min coronary angiography was not affected by patient weight, but the highest weight was listed as >85 kg. There were no data reported in grossly obese patients.

Gurwitz et al.,7 analyzed data from the National Registry of Myocardial Infarction 2 (NRMI-2) database. They identified a t-PA dose of >1.5 mg/kg as one of the risk factors for the development of intracranial hemorrhage. An inverse relationship between body weight and intracranial hemorrhage was also observed. The authors conclude that appropriate weight-dosing of t-PA may reduce the risk of developing an intracranial hemorrhage, but they give no advice on what dose should be used in the grossly overweight patient.

Summary

Most of the concern about dosing of t-PA as presented in the literature is related to the lower weight groups and the increased incidence of bleeding in this patient population. Not much is known or written about what doses of t-PA should be used in the grossly obese patient with an MI.

In the patient described briefly at the beginning of this editorial, the usual accelerated dose regimen was used. Although the patient's symptoms resolved quickly, ST-segment elevation never returned to baseline. Creatine kinase-MB and troponin I rose and fell slowly. He had an uneventful course in the hospital but my impression is that he did not reperfuse his myocardium. Unfortunately, because of his weight, we were unable to evaluate this patient with either coronary angiography or echocardiography.

As I think more about this case, I am of the opinion that the patient was underdosed with 100 mg of t-PA. If I had it to do over again, I would use a higher dose of t-PA. I would be interested to hear how others would have treated the patient.

C. Richard Conti, M.D., M.A.C.C.
Editor-in-Chief

Reference

  1. Califf RM, Topol EJ, George BS, Boswick JM, Abbottsmith C, Sigmon KN, Candela R, Masek R, Kereiakes D, O'Neill WW, Stack RS, Stump D, and the Thrombolysis and Angioplasty in Myocardial Infarction Study Group: Hemorrhagic complications associated with the use of intravenous tissue plasminogen activator in the treatment of acute myocardial infarction. Am J Med 1988;85:353–359
  2. Topol EJ, George BS, Kereiakes DJ, Candela RJ, Abbottsmith CW, Stump DC, Boswick JM, Stack RS, Califf RM: Comparison of two dose regimens of intravenous tissue plasminogen activator for acute myocardial infarction. Am J Cardiol 1988;61:723–728
  3. Topol EJ, Agnelli G: Strategies for administration of tissue plasminogen activator. Mol Biol Med 1991;8:219–234
  4. Gibelin P, Tiger F, Moles V, Bossan S, Blanc P, Baudouy M, Morand P: Influence of the rt-PA dose (1 mg/kg versus 1.5 mg/kg) and duration of administration on the patency of the coronary artery responsible for infarction in 100 patients. Eur Heart J 1990;11(suppl):315
  5. Smalling RW, Schumacher R, Morris D, Harder K, Fuentes F, Valentine RP, Battey LL Jr, Merhige M, Pitts DE, Lieberman HA, Nishikawa A, Adyanthaya A, Hopkins A, Grossbard E: Improved infarct-related arterial patency after high dose, weight-adjusted, rapid infusion of tissue-type plasminogen activator in myocardial infarction: Results of a multicenter randomized trial of two dosage regimens. J Am Coll Cardiol 1990;15:915–921
  6. Neuhaus KL, von Essen R, Tebbe U, Vogt A, Roth M, Riess M, Niederer W, Forycki F, Wirtzfeld A, Maeurer W, Limbourg P, Merx W, Haerten K: Improved thrombolysis in acute myocardial infarction with front-loaded administration of alterplase: Results of the rtPA-APSAC patency study (TAPS). J Am Coll Cardiol 1992;19:885–891
  7. Gurwitz JH, Gore JM, Goldberg RJ, Barron HV, Breen T, Rundle AC, Sloan MA, French W, Rogers WJ: Risk for intracranial hemorrhage after tissue plasminogen activator treatment for acute myocardial infarction. Ann Int Med 1998;129:597–604

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