Multiple Center Investigation of the Limit of Infarction - MILIS


Hyaluronidase, propranolol, and placebo for limiting myocardial infarct size.


To evaluate the effects of hyaluronidase, propranolol and placebo on myocardial infarct (MI) size.

Study Design

Study Design:

Patients Screened: 9,450
Patients Enrolled: 851
Mean Follow Up: 36 months
Mean Patient Age: 58
Female: 30
Mean Ejection Fraction: 46%

Patient Populations:

Less than 76 years old
At least 30 minutes of pain typical of myocardial ischemia
ECG changes suggestive of acute ischemia or evolving infarction


>18 hours elapsed between onset of symptoms and randomization
Cardiogenic shock
Concurrent serious illness
Need for artificial pacemaker
Major surgery or myocardial infarction within previous 2 weeks
Current therapy with beta blockade or nitrates unable to be discontinued for 72 hours
Participation in conflicting protocols
Unable to return for follow-up

Primary Endpoints:

Infarct size, estimated from changes in CK-MB levels

Secondary Endpoints:

Incidence of myocardial infarction
Other measures of infarct size
Ventricular function

Drug/Procedures Used:

Patients were randomised to hyaluronidase, propranolol, or placebo, or, if propranolol was contraindicated, to hyaluronidase or placebo. Hyaluronidase: 500 U/kg given every six hours for 48 hours.

Principal Findings:

A total of 851 patients were randomly assigned to hyaluronidase or placebo therapy with a mean of 9.4 +/- 0.1 hours after the onset of pain. There were no significant differences between the hyaluronidase- and placebo-treated patients in incidence of AMI (86 vs 88%). There were also no differences in infarct size as determined by creatinine kinase MB enzymes , change in total R wave, or pyrophosphate scintigrams. There was no significant difference between hyaluronidase and placebo groups in cumulative proportion surviving 4 years (0.70 +/- 0.03 vs 0.68 +/- 0.03).

The propranolol limb of the MILIS study comprised 269 patients, who were randomized to acute intravenous and subsequent oral therapy with propranolol (n = 134) or placebo (n = 135). Therapy was started at an average time of 8.5 hours after onset of symptoms. There was no significant difference in mortality between the 2 groups during an average of 36 months' follow-up.


These findings indicate there is no overall benefit from administration of hyaluronidase more than 9 hours after the onset of AMI. Although propranolol can be administered safely to patients with acute myocardial infarction who are selected on the basis of simple clinical criteria, there is no evidence of reduction of infarct size when beta blockade is begun 8.5 hours after the onset of symptoms. These results are comparable to the MIAMI study, and further emphasize the need to administer beta-blockade early in the course of acute myocardial infarction.


1. Am J Cardiol 1986;57:1236-43. Final results (hyaluronidase)
2. Am J Cardiol 1986;57:38F-42F. Propranolol results

Keywords: Hyaluronoglucosaminidase, Myocardial Infarction, Follow-Up Studies, Digoxin, Propranolol, Pain, Electrocardiography, Creatinine, Diphosphates

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