rt-PA plus heparin aspirin for acute myocardial infarction?
ACP J Club. 1991 Mar-April;114:34. doi:10.7326/ACPJC-1991-114-2-034
Hsia J, Hamilton WP, Kleiman N, et al. for the Heparin-Aspirin Reperfusion Trial (HART) Investigators. A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. N Engl J Med. 1990;323:1433-7.
To compare the effects of heparin and low-dose aspirin as early adjuncts to recombinant tissue plasminogen activator (rt-PA) in preventing acute coronary artery reocclusion and to investigate their effects on hemorrhagic events and recurrent ischemia.
Randomized trial, lasting 7 days for each patient.
3 university medical centers in the United States.
205 patients under 76 years of age, presenting with acute myocardial infarction, were randomized: 106 to heparin and 99 to aspirin. Patients with other serious disease or with contraindications to thrombolytic therapy were excluded. 86% of patients completed the study protocol.
Intravenous therapy with rt-PA (100 mg over 6 hours) was started a mean of 3.1 hours from onset of symptoms. Oral aspirin, 80 mg daily, was given immediately and for 7 days. An intravenous bolus of heparin, 5000 U, was given immediately, followed by 1000 U/h (adjusted), for 7 days.
Main outcome measures
Angiographic patency of the infarct-related artery after 7 to 24 hours and after 7 days. Angiographic interpretation was blinded to drug assignment. Secondary end points were recurrent ischemia and hemorrhagic events.
Angiography was done 7 to 24 hours after treatment started. Of 100 patients assigned to heparin who had angiography, 82 (82%) had patent infarct-related arteries (95% CI, 76% to 89%) compared with 48 of 93 patients (52%) taking aspirin (CI, 41% to 62%; P < 0.001). Angiography was repeated at 7 days on patients with patent arteries on the initial angiogram, excluding 11 patients on heparin and 6 on aspirin who had had surgery or angioplasty and 14 patients who refused. On day 7, 53 of 60 patients on heparin had infarct-related arteries that remained open compared with 36 of 38 patients taking aspirin (P = 0.17). Ischemic episodes >24 hours after presentation occurred in 8 of 106 patients in the heparin group and in 2 of 99 taking aspirin (P = 0.16). Bleeding events were similar in the two groups (18 patients on heparin [17%] and 15 patients on aspirin [15%]).
Given concomitantly with rt-PA, heparin achieved higher rates of sustained patency of the infarct-related artery than did aspirin during the first 24 hours after myocardial infarction.
Source of funding: Genentech; Pfizer Scholars Award.
Address for article reprint: Dr. J. Hsia, George Washington University, 2150 Pennsylvania Avenue, N.W., Washington, DC 20037.
Two issues in the treatment of acute myocardial infarction are the optimal thrombolytic regimen and the role of adjunctive therapy in maintaining coronary patency. The HART study bears directly on the second and indirectly on the first. The difference between the heparin and aspirin groups in patency of the infarct-related artery 18 hours after therapy (82% vs. 52%) is significant both statistically and clinically. The dose of aspirin used (80 mg) was lower than in other studies, however, and may have been insufficient to halt reocclusion of the infarct-related artery after successful thrombolysis. Follow-up angiography at 7 days was not done in 22 patients assigned to heparin compared with 10 assigned to aspirin, which may have introduced a bias into the observed rates of late reocclusion of the infarct-related artery.
The HART study also bears on the choice of a thrombolytic agent for acute myocardial infarction. The GISSI-2 study (1) showed no difference in mortality between patients randomized to either rt-PA or streptokinase, but in that study subcutaneous heparin was given starting 12 hours after thrombolysis. The HART findings support critics who claim this method of giving heparin may have eliminated any advantage from the higher rate of reperfusion at 90 minutes after rt-PA than after streptokinase. Control patients in HART, however, received a lower dose of aspirin (80 mg vs. 325 mg) and no heparin whatsoever, so the regimens in GISSI-2 and HART were not strictly comparable. The continuing controversy over the optimal thrombolytic regimen will (I hope) be settled by several ongoing and planned randomized trials.
When tissue-plasminogen activator is given for acute myocardial infarction, full-dose heparin should be given concomitantly and continued for at least 24 hours.
Mark A. Hlatky, MD
Stanford University School of Medicine Stanford, California, USA