Low molecular weight heparin (dalteparin) compared to unfractionated heparin as an adjunct to rt-PA (alteplase) for improvement of coronary artery patency in acute myocardial infarction—the ASSENT Plus study

Lars Wallentina,*, Lott Bergstrandb, Mikael Dellborgc, Carin Felleniusd, Christopher B Grangere, Bertil Lindahlf, Lars-Eric Linsg, Tage Nilssonh, Kenneth Pehrssoni, Agneta Siegbahnj and Eva Swahnk for the ASSENT PLUS Investigators

a Department of Medical Sciences, Cardiology, University Hospital, S-751 85 Uppsala, Sweden
b Department of Radiology, Danderyd's Hospital, Stockholm, Sweden
c Department of Cardiology, Sahlgrenska Hospital, Gothenburg, Sweden
d Pharmacia Corp., Stockholm, Sweden
e Duke Clinical Research Institute, Durham, NC, USA
f Department of Medical Sciences, Cardiology, University Hospital, S-751 85 Uppsala, Sweden
g Boehringer-Ingelheim, Stockholm, Sweden
h Department of Thoracic Radiology, Karolinska Hospital, Stockholm, Sweden
i Department of Cardiology, Karolinska Hospital, Stockholm, Sweden
j Department of Clinical Chemistry, Uppsala, Sweden
k Department of Cardiology, University Hospital, Linkoping, Sweden

* Corresponding author. Tel.: +46-18-611-43-93; fax: +46-18-50-66-38
E-mail address: lars.wallentin{at}thorax.uas.lul.se

Received 9 October 2002; revised 10 December 2002; accepted 10 December 2002


    Abstract
 Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Background Current thrombolytic–antithrombotic regimens in acute myocardialinfarction (AMI) are limited by incomplete early coronary reperfusion and by reocclusion and reinfarction. We compared the effects of low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) as an adjunct to recombinant tissue-plasminogen activator (alteplase) on coronary artery patency and clinical outcomes in AMI.

Methods Patients with AMI treated with alteplase were randomised to either subcutaneous dalteparin (120IU/kg every 12h) for 4–7 days or intravenous infusion of UFH for 48h. Coronary angiography was performed between day 4 and hospital discharge. Clinical events and safety were evaluated until day 30.

Results Overall there were higher thrombolysis in myocardial infarction (TIMI) flows in the infarct related coronary artery in the dalteparin group . The predefined primary end-point, TIMI grade 3 flow, did not reach statistical significance (dalteparin 69.3% versus heparin 62.5%; ). However, TIMI 0-1 flow (13.4 versus 24.4%; ) and its combination with intraluminal thrombus (27.9 versus 42.0%;) were less common in the dalteparin group. During the period of randomised treatment there were less myocardial reinfarctions in the dalteparin group

but after cessation of dalteparin there were more reinfarctions resulting in no difference in death or MI at 30 days. There were no significant differences in major bleeding or stroke after 30 days.

Conclusions In alteplase treated AMI adjunctive dalteparin for 4–7 days seems to reduce the risk of early coronary artery occlusion and reinfarction. However, early after cessation of treatment there is a raised risk of events, which might eliminate any long-term gains.

Key Words: Angiography • Coronary disease • Heparin • Myocardial infarction • Thrombolysis


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Thrombolytic treatment of ST-elevation acute myocardial infarction (AMI) is associated with early reperfusion of occluded arteries, smaller infarct size, better left ventricular function, and improved short and long-term survival.1,2 However, even with the current regimens of thrombolysis that include aspirin, 48h intravenous unfractionated heparin (UFH) and, in selected patients, coronary revascularization, there is at least a 15% incidence of death or reinfarction after 3 months. Thus, current thrombolytic and antithrombotic therapies continue to have limitations of incomplete early recanalisation,3–5 reocclusion and reinfarction in a substantial proportion of patients.6,7

An alternative strategy to improve the long-term outcome after treatment with recombinant tissue-plasminogen activator (rt-PA) based thrombolytic agents might be to prolong and simplify the heparin treatment by the use of low molecular weight heparin (LMWH). In unstable coronary artery syndromes LMWH results in approximately a 50% reduction in death or MI and reduces the rate of recurrent angina compared to placebo8 and is at least as effective as intravenous UFH.9–11 These patients have the same pathophysiology for reinfarction as patients after thrombolysis, i.e. a thrombotic and stenotic lesion with an increased risk of coronary artery occlusion. Previous trials have shown that treatment of patients with AMI with a combination of the LMWH dalteparin and streptokinase reduced mural thrombi and post-reperfusion ischaemic episodes and tended to improve coronary blood flow.12–14 The present trial evaluated the effects of 4–7 days of dalteparin compared to 48h of UFH, as an adjunct to alteplase, on predischarge coronary blood flow and on longer-term clinical events and safety in patients with AMI.


    2. Material and methods
 Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
2.1. Trial design (Fig. 1)
The trial was a binational, multicentre, randomised (1:1), parallel group, open study using a central blinded evaluation of the primary end-point and an independent safety review board. The inclusion criteria were symptoms of AMI within 6h of onset and with ST-segment elevation >=0.1mV in two or more limb leads, or >=0.2mV in two or more contiguous precordial leads or a presumed new left bundle-branch block (LBBB) on the presenting electrocardiogram. The exclusion criteria were age below 18 years, hypertension, use of any glycoprotein IIb/IIIa antagonists within 24h, recent surgery or trauma, history of stroke or transient ischaemic attack or dementia or any known structural damage of the central nervous system, current therapeutic oral anticoagulation, renal dysfunction, pregnancy or parturition within the previous 30 days, participation in another investigative study in the past 30 days, previous enrolment in this study or any other condition that the investigator felt would place the patient at increased risk if the investigational therapy was initiated or inability to follow protocol and comply with follow-up requirements.



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Fig. 1 ASSENT PLUS trial design chart.

 
2.2. Randomised treatment
The randomisation was performed on admission, stratified by centre and assigned by medication boxes in consecutive order blinded to the investigator prior to assignment (Fig. 1). Alteplase (Actilyse®/Activase®) and dalteparin (Fragmin®) were supplied to the centres by the sponsors, while patients randomised to UFH received the standard hospital supply of UFH. The randomised treatment was started immediately after initiation of accelerated 90min infusion of <=100mg of alteplase. Dalteparin was given at a dose of 120 anti-Xa IU/kg body weight subcutaneously every 12h with one quarter of the initial dose—30 anti-Xa IU/kg body weight (maximal dose 2500 anti-Xa IU)—as an intravenous bolus. The dalteparin treatment was continued for at least 96h and the last dose was to be given in the evening before the coronary angiography. UFH was started with an intravenous bolus of 4000 or 5000IU and was followed by an infusion of 800 or 1000IU/h at body weights of <= or >67kg, respectively. The infusion rate was adjusted to a target APTT level of 50–75s and continued for 48h.

2.3. Concomitant therapy
All patients were treated with 150–325mg aspirin immediately at entry and thereafter once daily. The use of abciximab (ReoPro®) or other glycoprotein IIb/IIIa antagonists was discouraged during the first 24h after randomisation. The use of other medications was at the discretion of the treating physician.

2.4. Laboratory investigations
Twelve-lead ECGs were performed before randomisation, after 24–36h, at hospital discharge and if symptoms suggestive of recurrent myocardial ischaemia occurred. Serial blood samples for measurement of levels of biochemical markers (CK, CK-MB or troponin) were obtained on admission, before coronary angiography, 10–20h after any revascularization procedure and at recurrent symptoms suggestive of myocardial ischaemia. In a substudy of 26 patients treated with dalteparin, plasma samples for core laboratory analyses of anti-Xa levels (Rotachrom, Lmw HeparinÒ) were obtained at randomisation and after 90min, 3, 4, 8, 48 and 52h. APTT levels were obtained regularly in all patients treated with UFH.

2.5. Coronary angiography and revascularization
Coronary angiography was to be performed between 4 (minimum period 96h) and 7 days in all patients without contraindications. Coronary angiography was performed using the conventional projections. The stenotic or occluding lesions were to be imaged in at least two orthogonal projections. The final evaluations of all angiograms were performed in a core laboratory based on a consensus between two experienced radiologists unaware of the randomised treatment. The following variables were evaluated: infarct related artery based on relation between the lesion and the ECG changes,15 antegrade flow grading according to the thrombolysis in myocardial infarction (TIMI) study group criteria16 and intraluminal thrombus based on reproducible demonstration of a contrast deficit surrounded by contrast material in the infarct related artery. The occurrence and degree ofstenosis was determined by visual estimates in all coronary arteries. Corrected TIMI frame count17 was calculated. Revascularization was performed at the discretion of the treating physician. UFH was used as the anticoagulant at angioplasty procedures in both groups.

2.6. Clinical events
The following clinical events were recorded while the patients were in hospital: death, stroke (ischaemic or haemorrhagic), other major bleeding (defined as a decrease in haemoglobin of >20g/lin association with symptoms or >40g/l regardless of symptoms, any intraocular, intraspinal, intracranial or retroperitoneal bleeding and bleeding leading to death), other adverse events, recurrent MI and revascularization. Vital status, stroke, major/minor bleeding, non-fatal cardiac events, other adverse events and any revascularization procedure were also established at 30 days.

Recurrent MI during the initial 18h after the start of study drug was defined by recurrent signs and symptoms of ischaemia at rest accompanied by new or recurrent ST segment elevation of ≥0.1mV in at least two contiguous leads lasting at least 30min. After 18h, recurrent MI was defined by the presence of new Q waves or new LBBB or elevation of biochemical markers, i.e. reelevation of CK-MB to above the upper limit of normal and increased by ≥25% over the previously elevated level. Recurrent MI after revascularization was defined by the presence of new Q waves in two or more contiguous leads or at angioplasty (+/– stenting) by CK-MB >2 times the upper limit or at coronary artery by-pass surgery by CK-MB >5 times the upper limit of normal.

Autopsy was the preferred method for determining cause of death. The cause of stroke was to be established by computed tomographic scanning, magnetic resonance imaging, or autopsy. An Independent Data Monitoring Committee adjudicated the cause of all deaths, as well as occurrence of cardiac and other adverse events, major bleeding and stroke.

2.7. Informed consent
Written informed consent was obtained from all patients. The trial was approved by all Independent Ethics Committees and performed in conformance with the principles of the Declaration of Helsinki.

2.8. Statistics
The objective was to compare the effects of treatment with dalteparin or UFH, as an adjunct to alteplase, on TIMI flow rates in the culprit coronary arteries evaluated by coronary angiography during initial hospital stay after 4 days but no later than 14 days after randomisation. The primary end-point was TIMI 3 flow. Other predefined assessments of the treatment effects were occurrence of TIMI 0-1 flow, thrombus in the culprit coronary artery, the combination of TIMI 0-1 flow or thrombus and also the corrected TIMI frame count. The secondary endpoints were clinical events including death, MI, revascularization and several safety end-points including non-cerebral bleeding, intracranial haemorrhage and stroke. A sample size of 170patients was required to give 80% power at a two-sided significance level of 5%, to detect a change in TIMI grade 3 flow from 50 to 65%. A sample size of 200 patients per treatment group was planned and, during the trial, further extended to compensate for an actual withdrawal rate higher than expected mostly due to the performance or timing of the scheduled angiography. The evaluation of the primary end-point of coronary blood flow was confined to those patients who underwent the scheduled coronary angiogram within the predefined time interval and while still in-hospital for the index event. The analyses of clinical and safety end-points included all patients who received any study treatment. Chi-square tests (or Fisher's Exact test if appropriate) were used for analysis of the primary and secondary endpoints. Non-parametric Mann–Whitney U-test was used to compare corrected TIMI frame counts. The tests were to be two-sided with an alpha level of 0.05 withoutcorrections for multiplicity. Boehringer-Ingelheim (Sweden) together with Pharmacia Corporation (Sweden) performed data management and monitoring. The statistical analyses were performedindependently by the Pharmacia Corporation and the coordinating investigator.


    3. Results
 Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
3.1. Patients and randomised treatment
Between March 1999 and April 2000, 439 patients were recruited in 18 Swedish and four North American centres out of which 434 received any study treatment (dalteparin group, ; UFH group, ) (Fig. 2). The patients were 70% males, with an average age of 65 years, 32% had hypertension, 34% were current smokers and 12% had diabetes mellitus. Most patients (88%) were in Killip class I, 54% had an inferior, 44% had an anterior and 2% non-specified location of theinfarction. The delay between onset of symptoms and start of treatment was less than 2h in 33% and 2–4h in 49% of the patients (Table 1). There were no significant differences in baseline characteristics or clinical findings between the randomised groups.



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Fig. 2 Distribution of patients.

 

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Table 1 Baseline characteristics

 
3.2. Coronary blood flow
In 56 patients (dalteparin, ; UFH, ) the scheduled coronary angiography was either not performed because of the patient's clinical condition or, in a few patients, non-evaluable for technical reasons (Fig. 2). The median time from randomisation to the scheduled coronary angiography was 6 days in both groups with 23 and 26% on day 5, 34 and 39% on day 6, 24 and 23% on day 7, 12 and 7% on day 8 and 7 and 12% outside this time range in the dalteparin and UFH groups, respectively. Taking all four categories of TIMI flow grades into consideration there was a significant difference in TIMI flow with a better flow in the dalteparin group than in the UFH group (Table 2). Comparing the randomised groups in accordance with the predefined primary end-point of solely TIMI grade 3 flow, the difference did not reach statistical significance . However, TIMI flow 0-1 was present in significantly fewer patients in the dalteparin than the UFH group (13.4 versus 24.4%; ) indicating significantly less occlusions or poor flow in the dalteparin than the UFH group. Furthermore, the occurrence of intraluminal thrombi tended to be less common (18.9 versus 27.3%; ) in the dalteparin than the UFH group. Accordingly the occurrence of the combined end-point, TIMI 0-1 flow or intraluminal thrombus, was less frequent (27.9 versus 42.0%; ) in the dalteparin than in the UFH group (Table 2). Among the patients with TIMI 3 flow there was, however, no difference in TIMI frame count. The evaluation of the coronary blood flow in relation to the time after thrombolysis showed similar flow on days 4–5 and thereafter a continuous deterioration of coronary blood flow in the UFH 48h group and a continuous improvement in the dalteparin group (Fig. 3).


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Table 2 Evaluation of coronary blood flow in culprit coronary artery (TIMI Grade 0-3) at coronary angiography during initial hospital stay

 


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Fig. 3 Poor (TMI 0–1) coronary blood flow in the culprit coronary artery in relation to time of coronary angiography and randomised treatment.

 
The extent of coronary artery disease was comparable between the two treatment groups: 27% had three-vessel or left main disease, 31% had two-vessel disease, 37% had one-vessel disease and 5% had no significant coronary lesions. In both groups 85% of patients had more than 70% stenosis or occlusion of the culprit artery (Table 3). Still direct coronary angioplasty in association with the coronary angiography was only performed in 21 and 24% of the respective dalteparin and UFH groups.


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Table 3 Evaluation of extent of coronary artery disease and culprit coronary artery stenosis at coronary angiography during initial hospital stays

 
3.3. Clinical outcome
During the initial 7 days there was a trend of a lower rate of death and MI and a significantly lower rate of myocardial reinfarction alone in the dalteparin compared to the UFH group. However, early after cessation of the dalteparin treatment there was an increased rate of reinfarction in the dalteparin group leading to similar rates of death or MI at 30 days (Table 4, Fig. 4a, b). These reinfarctions occurring after dalteparin cessation were observed predominantly in patients with 2-3 vessel disease (8.6 versus 1.2% at 0-1 vessel disease; ) and with a 50–99% stenosis remaining in the culprit coronary artery (6.9 versus 0% at no significant stenosis or total occlusion; ) (Table 5). Despite the frequent occurrence of severe coronary lesions only three out of the 12 patients with early reinfarction had undergone an angioplasty procedure at the time of the scheduled predischarge coronary angiogram. This rate was similar to the 29% rate of predischarge angioplasties in the total patient population (Table 4). However, at the 30 days follow-up around 53% of all patients had undergone coronary revascularization.


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Table 4 Clinical events at days 7 and 30 in relation to randomised treatment

 


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Fig. 4 (a) Cumulative probability of MI until day 30 in relation to randomised treatment. (b) Cumulative probability of death or MI until day 30.

 

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Table 5 Evaluation of extent of coronary artery disease and culprit artery stenosis and blood flow at coronary angiography days 4–7 in dalteparin treated hospital survivors with or without myocardial reinfarction after day 7

 
3.4. Compliance and coagulation inhibition
Compliance with treatment was good: 88% in the UFH group and 91% of patients in the dalteparin group obtained at least 24h of treatment, 62% in the UHF group received at least 48h and 61% in dalteparin received at least 96h of randomised treatment. The APTT level in the heparin group was within or below target range in 28 and 20%, respectively, after 6h , 43 and 42% after 12h , 29 and 64% after 24h and 32 and 65% after 48h . The anti-factor Xa levels, as evaluated in 26 consecutive patients in the dalteparin group at four centres, had reached a stable level with a mean of 0.56±0.16IU/ml after 90min. The level remained constant until after 3–4h (0.55±0.16IU/ml) and became somewhat lower after 8h (0.40±0.15IU/ml). During continuous treatment, the dalteparin regimen lead to a trough of 0.44±0.16IU/ml and peak of 0.67±0.16IU/ml as evaluated at 48 and 52h, respectively, after the starting of treatment.

3.5. Safety
There were no notable differences in adverse events between the two groups (Table 6). Twenty of 434 (4.6%) patients had died by day 30, evenly distributed at 10 each in the dalteparin and UFH groups. The reason for death was related to cardiac disease, with the exception of two fatal intracranial haemorrhages in the UFH group. Major bleeding was uncommon in both treatment arms. There were two intracranial haemorrhages in the dalteparin group (one while on therapy) and four during UFH treatment. The total incidence of stroke was similar in both treatment arms, although there was a lower number of haemorrhagic strokes in the dalteparin group.


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Table 6 Incidence of adverse events, death, bleedings and stroke

 

    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
4.1. Coronary perfusion
The present study was performed at a time and in centres with limited resources for urgent or rescue PCI, which allowed the performance of late coronary angiographies and avoidance of early revascularization procedures. The results suggest that 4–7 days of treatment with subcutaneous dalteparin improves coronary patency and perfusion as evaluated at the end of the treatment period. The between group difference in predefined primary endpoint, TIMI grade 3 blood flow, did not reach statistical significance. Although hampered by limitations of statistical comparisons without correction for multiplicity, there were consistent and statistically significant benefits concerning several other important indicators of coronary blood flow in favour of the dalteparin group. Thus, there were significantly fewer patients with very poor coronary blood flow, i.e. TIMI flow 0-1, in the dalteparin compared to the UFH group and significantly fewer with TIMI flow 0-1 or intraluminal coronary thrombi. The corrected TIMI frame count also indicated a significantly better patency in the dalteparin group. When evaluating the patients in relation to time of angiography there was no difference in TIMI flow atday 4–5 while there was a substantial difference in TIMI 0-1 flow at day 7. These findings indicate that prolongation of the anticoagulant treatment was the main reason for the improvement in coronary blood flow.

The angiography results were supported by the corresponding lower rates of MI during the dalteparin treatment period. These findings are consistent with recent similarly designed coronary angiography trials,18,19 which also showed indications of improved perfusion and less reocclusions when comparing enoxaparin or pentasaccharide with heparin in rt-PA treated AMI patients treated with alteplase. Support for improved patency with LMWH in AMI also can be derived from studiescomparing dalteparin14 or enoxaparin20 to placebo in streptokinase treated AMI patients. The results from the present and previous trials suggest that 4–7 days of LMWH, compared to 48h of UFH, will improve coronary patency and perfusion and reduce the risk of early occlusion and reinfarction in patients with AMI.

Whether or not similar results could be obtained with prolongation of the UFH infusion for 4–7 days and until coronary angiography is still an open issue.21,22 However, the LMWH heparin regimen with twice daily subcutaneous injections rather than intravenous infusion and no requirement for laboratory monitoring would, in most cases, be considered a more convenient and acceptable approach, both from the patient and staff perspective. A possible alternative might be to use oral anticoagulants, which also seem to reduce the risk of reocclusion after thrombolysis.23

4.2. Reinfarction
The 30-day mortality was low and similar to levels reported in recent trials of thrombolysis in AMI using almost identical inclusion criteria.24 The 30-day reinfarction rate of 6–7% was also similar to previous reports.6,7 During treatment the reinfarction rates in the dalteparin group were considerably lower than in the UFH group. However, the initial gain during this period was diminished because of a cluster of reinfarctions within a few days after cessation of dalteparin treatment suggesting reactivation of the thrombotic process. The performance of coronary angiography in all patients before cessation of dalteparin treatment provided a unique opportunity to elucidate some of the reasons for the early reinfarctions. The results suggest that the reactivation events tended to occur in patients with 2-3 vessel or left main disease and with significant stenosis remaining in the culprit coronary artery. In the present trial only 25–30% of patients underwent angioplasty in direct association with the scheduled coronary angiographyalthough 85% had severe stenosis or total occlusion of the culprit artery and 58% had multivessel disease. In settings with a more aggressive approach to revascularization of severe lesions detected on post-infarct coronary angiography, the reactivation events might be less prominent. The present results indicate that severe stenosis remaining in the culprit coronary artery, and multivessel disease, may be risk factors for early reinfarction even at TIMI flow grade 2-3. These results also raise the possibility that treatment with LMWH dalteparin might be useful as a ‘bridge-to-revascularization’ after thrombolysis of AMI as well as in unstable coronary artery disease.25

4.3. Reactivation-rebound
During treatment with alteplase, as well as after other thrombolytic drugs, there is an activation of coagulation and platelets.12,26–28 Both during and early after the 90min tPA infusion there is often repeated episodes of reperfusion–reocclusion, that can be prevented by simultaneous treatment with UFH or LMWH.14,21,22 Also after cessation of the 24–48h standard heparin infusion there are early reactivation events.29,30 The design of the present trial was therefore a comparison of two treatment strategies—one with prolonged and one with short anti-coagulation treatment in order to avoid both early and late reocclusions. The duration of treatment was selected in order to allow protection during further risk stratification or while awaiting coronary angiography and revascularization. Therefore the study does not allow any direct comparison of the efficacy of the two drugs. Compared to the UFH strategy in the current trial, the low rate of reinfarction between days 2 and 7 suggests that longer-term treatment with dalteparin can prevent those early reinfarctions. However, in the present trial later reactivation events were observed after cessation of the dalteparin treatment. These observations are in accordance with experiences of dalteparin treatment also in streptokinase treated patients in the BIOMACSII trial14 as well as in unstable coronary artery disease.8 The same proportion of reactivation events has not been reported in trials with other LMWHs.10,11,18 These differences might depend on differences in treatment design, e.g. rate of early revascularization or a variable duration or dose of anticoagulation treatment after cessation of the randomised treatment. Another possibility is that the different anticoagulantproperties of LMWHs, e.g. different anti-Xa/anti-IIa ratios, might be associated with different risks of rebound activation of the coagulation system. These findings emphasise the importance ofevaluation of clinical events both while on-treatment as well as longer-term outcome in trials of anticoagulants and platelet inhibitors as adjuncts to thrombolytic agents in ST-elevation MI.

4.4. Dosing regimen
The dalteparin dose—120 anti-Xa IU/kg subcutaneous every 12h—used as an adjuvant to alteplase was the same as that used in acute-phase treatment of patients with unstable coronary artery disease.8,9,25 In order to obtain an adequate anti-Xa level immediately after the start of treatment one quarter of the first dose was given asan intravenous bolus. The results of the present pharmacokinetic substudy indicated that this regimen leads to a stable anti-Xa level within 90min of the first dose. Thus, a therapeutic level of the anticoagulant was reached to counteract the activation of platelets and coagulation induced after cessation of the thrombolytic treatment.12,26,27,28

4.5. Safety
Despite the longer treatment (4–7 days) with dalteparin compared to the 48h with UFH, there was no increase in the risk of bleeding. As expected there were few major bleeding events and also few intracranial haemorrhages—numerically less in the dalteparin than the heparin arm. The low bleeding rates are similar to those reported for previous trials involving approximately 4500 patients with unstable coronary artery disease exposed to at least 4–7 days of dalteparin treatment.8,9,25 These results are reassuring that safety will be acceptable in the further evaluation of the exchange of appropriately dosed LMWHs as an alternative to UFH as an adjunct to thrombolytic treatment.

4.6. Clinical implications
Dalteparin for 3–7 days in place of UFH infusion for 48h, as an adjunct to alteplase in the treatment of AMI, appears safe and seems to improve coronary patency and reduce the risk of early reocclusion and reinfarction. However, after thrombolytic treatment the majority of patients with AMI still have a significant stenosis or occlusion of the culprit artery and multivessel coronary arterydisease. In these patients there is an increased risk of reocclusion and reinfarction early after cessation of dalteparin treatment. In accordance with the present results, the recently presented large-scale ASSENT331 trial demonstrated that the LMWH enoxaparin as an adjunct to TNK-tPA was safe and reduced the composite of 30 day mortality and in hospital myocardial infarction (MI). However, concerning the risk of post-discharge ischaemic events after cessation of the enoxaparin treatment, forthcoming reports need to be awaited. Furthermore two recent trials have demonstrated beneficial effects of prolonged post-discharge treatment with oral anticoagulation in addition to aspirin after AMI.32,33 Therefore, the present results suggest that treatment with the LMWH dalteparin might be useful as a bridge to longer-term oral anticoagulation or to early revascularization after thrombolysis in ST-elevation MI. Thus, the combination of LMWH and tPA agents and the appropriate selection of patients and timing of continued anticoagulant treatment and/or early invasive coronary procedures deserve further evaluation in large-scale trials. Such a regimen might be very useful as an alternative in settings when the direct PCI34 is not immediately available.


    Appendix A
 Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
A.1: Steering committee
Lars Wallentin (Coordinating investigator and Chairman, Uppsala, Sweden), John H. Alexander (Duke Clinical Research Institute, Durham, USA), Lott Bergstrand (Danderyd's Hospital, Stockholm), Rhonda Collins-Facile (Pharmacia Corp., Sweden), Mikael Dellborg (Sahlgrenska Universitetssjukhuset Östra, Gothenburg, Sweden), Carin Fellenius (Pharmacia Corp., Sweden), Christopher B. Granger (Duke Clinical Research Institute, Durham, North Carolina, USA), Barbro Hkansson (Boehringer-Ingelheim, Sweden), Bertil Lindahl (Uppsala,Sweden), Lars-Eric Lins (Boehringer-Ingelheim, Sweden), Tage Nilsson (Karolinska Hospital, Stockholm), Kenneth Pehrsson (Karolinska Hospital, Stockholm), Eva Pihl (Falun), Mrten Rosenqvist (Pharmacia Corp., Sweden), Gun Setterberg (Pharmacia Corp., Sweden), Agneta Siegbahn (Uppsala, Sweden), and Eva Swahn (Linköping, Sweden).

A.2: Principal investigator and research nurse at the participating centres
G. Ahlberg, E. Pihl (Falun, Sweden), P. Ahlström, S.-B. Jensen (Motala, Sweden), S. Bandh, A. Fröjdh, L. Dovs (Vsters, Sweden), M. Dellborg, A.-M. Svensson, H. Svensson (Sahlgrenska Universitetssjukhuset Östra, Gothenburg, Sweden), M. Eriksson, M. Södersten (St. Görans Sjukhus, Stockholm, Sweden), O. Hansen, E. Steensgaard (Malmö,Sweden), A. Hansson, J. Soffman, G. Dahl (Lund, Sweden), M. Hartford, H. kesson, M. Söderblom (Sahlgrenska Universitetssjukhuset, Gothenburg, Sweden), J. Hulting, G. Wedéen (Södersjukhuset, Stockholm, Sweden), J.-E. Karlsson, B. Thulin, C. Eriksson (Jönköping, Sweden), B. Lindahl, G. lsjö, C. Henriksson (Uppsala, Sweden), H. Nilsson, M. Snickars (Fagersta, Sweden), K. Pehrsson, C. Hage (Karolinska Sjukhuset, Stockholm, Sweden), E. Swahn, E. Logander (Linköping, Sweden), L. Svennberg, E. Sjölund (Gävle, Sweden), S. Söderberg, C. Sundholm, M. Johansson (Ume, Sweden), H. Tygesen, A.-C. Tygesen (Bors, Sweden), C.björn, K. Pollack (Karlstad, Sweden), N. Lakkis (Ben Taub General Hospital, Houston, Texas, USA), D. O'Dea (Hudson Valley Heart Center, Poughkeepsie, New York, USA), T. Pow (Cedarwood Medical Center, St. Joseph, Michigan, USA), L. Lancaster (Pima Heart Institute, Tucson, Arizona, USA).

A.3: Core laboratory for evaluation of coronary angiography
Karolinska Hospital, Stockholm, Sweden (Tage Nilsson, Lott Bergstrand).

A.4; Core Laboratory for coagulation markers
Department of Coagulation, Clinical Chemistry Laboratory, Uppsala University Hospital, Sweden (Agneta Siegbahn, Birgitta Fahlström).

A.5: Independent data and safety monitoring
The IDMC reviewed all serious adverse events (SAE), especially all deaths and serious bleedings, any major bleeding and the overall trends of adverse events. Also the incidence of recurrent MI and revascularization was reviewed. The Independent Data Monitoring Committee (IDMC) members were: Stig Persson (Malmö, Sweden) and Scott Berkowitz (Duke Clinical Research Institute, Durham, USA). Independent neurologist to evaluate CT-scans was Toivo Matilainen (Malmö, Sweden).

A.6: Clinical study supply management
Supply of dalteparin (Fragmin) from Pharmacia Corp. (Sweden), alteplase Activase®for the Swedish centres from Boehringer-Ingelheim (Sweden) and alteplase Activase®for the UScentres from Genentech (US).


    Acknowledgments
 
This work was supported by grants from Pharmacia Corporation and Boehringer-Ingelheim.


    References
 Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 Appendix A
 References
 

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