Author + information
- Received March 24, 1999
- Revision received October 20, 1999
- Accepted November 15, 1999
- Published online March 1, 2000.
- Aylee Liem, MD∗,
- Felix Zijlstra, MD∗,* (, )
- Jan Paul Ottervanger, MD∗,
- Jan C.A Hoorntje, MD∗,
- Harry Suryapranata, MD, FACC∗,
- Menko-Jan de Boer, MD∗ and
- Freek W.A Verheugt, MD, FACC†
- ↵*Reprint requests and correspondence: Dr. Felix Zijlstra, Department of Cardiology, Hospital De Weezenlanden, Groot Wezenland 20, 8011 JW Zwolle, the Netherlands.
In the Heparin in Early Patency (HEAP) pilot study a beneficial effect of high-dose heparin on early patency in acute myocardial infarction (MI) was observed in a matched-control study.
High dose bolus intravenous injection of heparin may achieve lysis of coronary thrombi and could enhance early patency of the infarct related vessel in patients with MI scheduled for primary angioplasty.
Before primary angioplasty, 584 patients with MI entered an open randomized trial of high dose (300 IU/kg) or low dose (0 or 5,000 IU) heparin. Of the 584 patients, 299 were randomized to high dose and 285 patients to low dose heparin.
Thrombolysis In Myocardial Infarction (TIMI) flow grade 2 or 3 was observed before primary angioplasty in 65 patients (22%) in the high dose group and 60 patients (21%) in the low dose heparin group (p > 0.1), whereas TIMI flow grade 3 was observed in 38 (13%) and 24 patients (9%), respectively (p = 0.11). There were no differences in the clinical end points between the two groups. There were no hemorraghic strokes, while 10% of the patients in the high dose group required blood transfusion versus 6% in the low dose/no heparin group (p = 0.07). No subsets of patients showed beneficial effects of high dose heparin, such as patients with longer delay between heparin administration and diagnostic angiogram or patients with short delay between symptom onset and admission.
There is no benefit of high dose bolus heparin on early patency compared with no or low dose heparin.
Early coronary reperfusion is the primary goal of the initial treatment for patients with acute myocardial infarction (MI). Primary angioplasty is a highly effective reperfusion therapy in patients with MI, resulting in more complete and sustained patency rate of the infarct related artery than in patients treated with thrombolytic therapy (1). Primary angioplasty, however, is associated with an increased delay between admission and start of treatment, in particular when patients are admitted to community hospitals and are transferred to an angioplasty center. Adjunctive therapy given in the delay before angioplasty, without compromising the angioplasty result, would be desirable. Adjunctive therapy may induce reperfusion, and this may limit myocardial injury before primary angioplasty is performed. In thrombolytic therapy with alteplase, higher early angiographic patency was shown when intravenous heparin was given as an adjunct therapy (2). Heparin gives a dose dependent reduction in the deposition of platelets and fibrin and in the incidence of macroscopic thrombosis in pigs (3). In the Heparin in Early Patency (HEAP) pilot study, a high intravenous dose of heparin (300 IU/kg) was given together with aspirin, to study the effect on early patency (4). In this matched control study, in 51% of patients Thrombolysis In Myocardial Infarction (TIMI) flow grade 2 or 3 was observed, whereas in control patients TIMI flow grade 2 or 3 was seen in only 18% (p < 0.001). These findings needed to be evaluated in a randomized controlled trial.
The protocol was approved by our institutional review board. Patients with MI presenting within 6 h after symptom onset, or those presenting within 24 h if they had evidence of ongoing ischemia, were included in this trial. The age limit was 75 years. Electrocardiographic criteria were ST segment elevation of ≥2 mm in two or more contiguous leads. Patients with contraindications to heparin (active bleeding, history of stroke <3 months, recent major surgery) or with MI after recent angioplasty were excluded. After informed consent, patients were randomized. A heparin bolus was administered according to the outcome of randomization. The standard therapy consisted of aspirin (500 mg intravenously or 300 mg orally) and intravenous nitroglycerine. Patients were recruited at the emergency department of our angioplasty center or referred from hospitals without angioplasty facilities for primary angioplasty. Transferred patients were referred from 11 community hospitals in the region, which are localized at travel distances ranging from two to 40 miles. The heparin bolus was administered at the referral hospital prior to transportation to our angioplasty center. Patients admitted directly to the angioplasty center were brought immediately to the coronary care unit where the heparin bolus was administered. The heparin dose for the group of patients randomized to high dose either at the referral centers or the angioplasty center was 300 IU/kg body weight, administered as a single intravenous bolus. Referred patients randomized to the control group received 5,000 IU heparin bolus before transportation, while control patients admitted directly to the angioplasty center received no heparin before catheterization. No thrombolytics or glycoprotein IIb/IIIa blockers were given. The patients were transferred as soon as possible to the catheterization laboratory, and coronary angiography was performed according to standard procedures. Preprimary angioplasty patency was scored according to TIMI flow grade by two cardiologists blinded to the treatment allocation. Primary angioplasty was performed on indication, and before this procedure, a bolus heparin with a dosage of 5,000 IU was given. Primary angioplasty was considered successful if the residual stenosis of the infarct related artery was less than 50% and TIMI flow grade 3 was present after the procedure. Heparin infusion was given after the procedure for 24 to 48 h in a dose titrated to achieve an activated partial thromboplastin time between two and three times the normal value (5). Patients were not treated with primary angioplasty if extensive coronary artery disease was found or there was involvement of the left main coronary artery that made urgent coronary bypass surgery necessary. If no infarct related artery could be identified and no reperfusion therapy was indicated, conservative treatment followed. Standard therapy consisted of aspirin (80 mg daily), beta-adrenergic blocking agents, if tolerated, and angiotensin-converting enzyme blockers and cholesterol-lowering drugs on indication. Patients randomized to high dose heparin at the referral hospital and at the angioplasty center were compared with patients who received 5,000 IU heparin at the referral hospital and patients who received no heparin at the angioplasty center.
Demographic data and risk factor data were recorded at baseline. The primary end point was the patency of the infarct related artery at diagnostic angiography. All angiograms were reviewed by two cardiologists, blinded for treatment allocation and clinical data. At discharge, left ventricular ejection fraction (LVEF) was measured with a radionuclide technique as previously described (5). All major cardiovascular events during hospital admission were documented. Major bleeding was defined as blood loss, requiring blood transfusion. Enzymatic infarct size was determined by measurements of lactate dehydrogenase as reference enzyme (LDHQ72). Cumulative enzyme release was calculated from serial measurements up to 72 h after symptom onset. From these measurements, an area under the curve was calculated, from at least five measurements. Further details of this method have been described before (5–7).
A sample size of 592 patients, with 296 patients in each treatment group was planned. A trial of this size has a 80% power at an alpha level of 0.05 to show an increase from the reported spontaneous reperfusion rate (TIMI flow grade 2 or 3) of 18% to a reperfusion rate of at least 28% in the high dose heparin group (4). Continuous data are summarized as medians with 25th and 75th percentiles unless otherwise stipulated. Selected baseline characteristics and clinical outcome were compared between treatment groups by the chi-square test or Fisher’s exact test for discrete variables and by the Student ttest for continuous variables.
A total of 584 patients were included, of whom 299 were randomized to high dose, and 285 patients to low dose/no heparin. With regard to baseline characteristics as well as outcome variables, there were no differences between the low dose heparin and the no heparin patients, and, therefore, they are described together. The baseline characteristics of the two groups were comparable and are summarized in Table 1. In none of the patients was abciximab administered. Of the 584 patients, 161 (28%) patients were transferred from other hospitals and received intravenous heparin in the referral hospital before transportation to our institution (Fig. 1). In these transferred patients, 87 patients were randomized to the high dose intravenous heparin (mean bolus 25, 690 IU), and 74 patients were randomized to a low dose of 5,000 IU. The majority of patients (n = 423) were admitted directly to our center; 211 received a high dose bolus and 212 patients were randomized to no heparin. During admission, 8 patients in the high dose group died, and 12 patients in the low dose group died (p > 0.1). No patient died during transportation or during coronary angiography and angioplasty. All deaths were of cardiac causes. Recurrent MI occurred in both groups in 1% of patients during the initial hospital stay.
Preprimary angioplasty patency rate (table 2)
In 65 patients (22%) in the high dose group versus 60 patients (21%) in the low dose group, TIMI flow grade 2 or 3 was observed (p > 0.1); TIMI flow grade 3 was observed in 38 (13%) vs. 24 (8%) (p = 0.11). In the group of patients with ischemic time <200 min, there was a small trend in favor of the high dose heparin group; 11% had TIMI flow grade 3 versus 6% in the low dose heparin group (p = 0.09).
Outcome of primary angioplasty
In the high dose group, 278 (93%) patients underwent primary angioplasty; success was achieved in 91% (TIMI flow grade 3 after angioplasty and a residual stenosis <50%). In 10 patients (3%) coronary artery bypass surgery was indicated, and 11 patients with an open infarct related artery (4%) were treated conservatively after diagnostic angiography. In the low dose group, 266 patients (93%) underwent primary angioplasty with a success rate of 88%. Coronary artery bypass surgery was indicated in seven patients (3%), and 12 patients (4%) were treated conservatively. Stent placement was performed in an equal number of patients in both trial groups. In patients with high dose heparin, stenting was performed in 95 patients (32%) and in 93 patients (32%) in the low dose/no heparin group.
Left ventricular ejection fraction and enzymatic infarct size
The mean LVEF (at day 4) was measured in 67% of patients and was 45% (SD 11%) in both groups. Mean enzymatic infarct size (LDHQ72) was 1,201 U (SD 1,091 U) in the high dose group and 1,285 U (SD 1,082 U) in the low dose group (p > 0.1). Measurements were available in 65% in the high dose group and 70% in the low dose group. Infarct size could not be calculated for patients in whom insufficient blood samples could be taken, e.g., patients who died shortly after admission or patients who were transferred back to the referral center soon after treatment.
No hemorraghic strokes were observed with high dose heparin. A nonhemorraghic stroke occurred on day 4 after primary angioplasty in a single patient (body weight 94 kg) who had been treated with a bolus of 30,000 IU heparin. No significant differences were found between the groups in the number of patients requiring blood transfusions (Table 3).
High dose heparin administration is safe, without excess of bleeding complications but is not associated with a higher rate of patency before primary angioplasty. The mechanism of potential patency with high dose heparin is still unclear. In a porcine model increasing dosages of heparin appeared to decrease macroscopic thrombus (3). High dose heparin also achieves lysis of experimental carotid artery thrombi (8). Still, in the clinical setting of patients with acute MI, regimes of high dose heparin have not been studied. In almost 7,000 patients ≥65 years old who were not treated with reperfusion therapy, the role of conventional dose intravenous heparin was investigated in an observational study (9). Heparin therapy was not associated with an improved 30-day mortality rate, despite its common use in this population.
Heparin and thrombolysis
In the European Cooperative Study Group trial, the use of intravenous heparin as an adjunct to alteplase demonstrated a higher rate of patency in the heparin group (2). Mortality was the same in both groups. In the Global Use of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) trial, patients receiving streptokinase were randomized to receive either delayed subcutaneous heparin or intravenous heparin (10,11). No differences in clinical end points were found. A meta-analysis of six randomized trials conducted with different thrombolytic drugs did not show benefit of heparin after thrombolytic therapy (12).
Heparin and primary angioplasty
The HEAP pilot study investigated the role of heparin without adjunctive treatment of thrombolysis (4). In that study, the early patency rate of the infarct related arteries was 51% versus 18% in a matched control group. Although these findings were promising, the results needed to be verified by a randomized study. In this randomized HEAP trial, no significant difference between the high dose and low dose heparin group could be demonstrated, and the rate of patent arteries is far lower than the reported level of patency achieved by thrombolytic therapy (13). It is also lower than the rate observed in the HEAP pilot study, which may suggest that the patient group in the pilot study was a very selected population. In addition, the results of the randomized trial do not suggest any benefit in clinical outcomes such as survival, primary angioplasty procedural success, enzymatic infarct size or LVEF.
For logistic reasons (heparin bolus in transfer patients was given in the referral hospital) treatment allocation was not blinded. We do not expect that this resulted in a bias since the review of the preprimary angioplasty angiograms was blinded for treatment allocation. The knowledge of outcome of randomization probably did not influence the decision to give blood transfusion, as the indication of blood transfusion is based on the level of hemoglobin.
There is no benefit of high dose intravenous heparin on patency before primary angioplasty. To compensate for door-to-balloon time, delay in patients scheduled for primary angioplasty, other adjunctive therapies have to be evaluated, together with efforts to improve patient logistics in order to shorten time to reperfusion.
- Heparin in Early Patency
- lactate dehydrogenase
- left ventricular ejection fraction
- myocardial infarction
- Thrombolysis In Myocardial Infarction
- Received March 24, 1999.
- Revision received October 20, 1999.
- Accepted November 15, 1999.
- American College of Cardiology
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