European Journal (2003) 24,897–908

Low molecular weight (dalteparin) compared to unfractionated heparin as an adjunct

to rt-PA () for improvement of coronary Downloaded from https://academic.oup.com/eurheartj/article/24/10/897/473619 by guest on 02 October 2021 artery patency in acute — 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, 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

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

KEYWORDS Background Current thrombolytic–antithrombotic regimens in acute myocardial ; infarction (AMI) are limited by incomplete early coronary reperfusion and by reocclusion Coronary disease; and reinfarction. We compared the effects of low molecular weight heparin (LMWH) Heparin; versus unfractionated heparin (UFH) as an adjunct to recombinant tissue-plasminogen Myocardial infarction; activator (alteplase) on coronary artery patency and clinical outcomes in AMI. Methods Patients with AMI treated with alteplase (nϭ439) were randomised to either subcutaneous dalteparin (120 IU/kg every 12 h) for 4–7 days or intravenous infusion of UFH for 48 h. 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 (pϭ0.016). The predefined primary end-point, TIMI grade 3 flow, did not reach statistical significance (dalteparin 69.3% versus heparin 62.5%; pϭ0.163). However, TIMI 0-1 flow (13.4 versus 24.4%; pϭ0.006) and its combination with intraluminal (27.9 versus 42.0%; pϭ0.003) were less common in the dalteparin group. During the period of ran- domised treatment there were less myocardial reinfarctions in the dalteparin group

* Corresponding author. Tel.: +46-18-611-43-93; fax: +46-18-50-66-38 E-mail address: [email protected] (L. Wallentin).

0195-668X/03/$ - see front matter © 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved. doi:10.1016/S0195-668X(03)00006-X 898 L. Wallentin et al.

(pϭ0.010) but after cessation of dalteparin there were more reinfarctions resulting in no difference in or MI at 30 days. There were no significant differences in major bleeding or 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. © 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.

Introduction blinded evaluation of the primary end-point and an independent safety review board. The inclusion Downloaded from https://academic.oup.com/eurheartj/article/24/10/897/473619 by guest on 02 October 2021 Thrombolytic treatment of ST-elevation acute myo- criteria were symptoms of AMI within 6 h of onset cardial infarction (AMI) is associated with early and with ST-segment elevation P0.1 mV in two or reperfusion of occluded arteries, smaller infarct more limb leads, or P0.2 mV in two or more con- size, better left ventricular function, and improved tiguous precordial leads or a presumed new left 1,2 short and long-term survival. However, even with bundle-branch block (LBBB) on the presenting the current regimens of thrombolysis that include electrocardiogram. The exclusion criteria were age , 48 h intravenous unfractionated heparin below 18 years, hypertension, use of any glyco- (UFH) and, in selected patients, coronary revascu- protein IIb/IIIa antagonists within 24 h, recent larization, there is at least a 15% incidence of death or trauma, history of stroke or transient or reinfarction after 3 months. Thus, current ischaemic attack or dementia or any known struc- thrombolytic and antithrombotic therapies con- tural damage of the central nervous system, cur- tinue to have limitations of incomplete early rent therapeutic oral anticoagulation, renal 3–5 recanalisation, reocclusion and reinfarction in a dysfunction, pregnancy or parturition within the 6,7 substantial proportion of patients. previous 30 days, participation in another investi- An alternative strategy to improve the long-term gative study in the past 30 days, previous enrolment outcome after treatment with recombinant tissue- in this study or any other condition that the inves- plasminogen activator (rt-PA) based thrombolytic tigator felt would place the patient at increased agents might be to prolong and simplify the heparin treatment by the use of low molecular weight heparin (LMWH). In unstable coronary artery syn- dromes LMWH results in approximately a 50% reduc- tion 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 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 48 h of UFH, as an adjunct to alteplase, on predischarge coronary blood flow and on longer-term clinical events and safety in patients with AMI.

Material and methods

Trial design (Fig. 1)

The trial was a binational, multicentre, randomised (1:1), parallel group, open study using a central Fig. 1 ASSENT PLUS trial design chart. Dalteparin and rt-PA in acute MI 899 risk if the investigational therapy was initiated or Coronary angiography and inability to follow protocol and comply with follow-up requirements. Coronary angiography was to be performed between 4 (minimum period 96 h) and 7 days in Randomised treatment all patients without contraindications. Coronary angiography was performed using the conventional The randomisation was performed on admission, projections. The stenotic or occluding lesions were stratified by centre and assigned by to be imaged in at least two orthogonal projections. boxes in consecutive order blinded to the investi- The final evaluations of all angiograms were per- gator prior to assignment (Fig. 1). Alteplase formed in a core laboratory based on a consensus (Actilyse®/Activase®) and dalteparin (Fragmin®) between two experienced radiologists unaware of were supplied to the centres by the sponsors, while the randomised treatment. The following variables Downloaded from https://academic.oup.com/eurheartj/article/24/10/897/473619 by guest on 02 October 2021 patients randomised to UFH received the standard were evaluated: infarct related artery based on hospital supply of UFH. The randomised treatment relation between the lesion and the ECG changes,15 was started immediately after initiation of acceler- antegrade flow grading according to the throm- ated 90 min infusion of #100 mg of alteplase. bolysis in myocardial infarction (TIMI) study group Dalteparin was given at a dose of 120 anti-Xa IU/kg criteria16 and intraluminal thrombus based on body weight subcutaneously every 12 h with one reproducible demonstration of a contrast deficit quarter of the initial dose—30 anti-Xa IU/kg body surrounded by contrast material in the infarct weight (maximal dose 2500 anti-Xa IU)—as an intra- related artery. The occurrence and degree of venous bolus. The dalteparin treatment was con- stenosis was determined by visual estimates in all tinued for at least 96 h and the last dose was to be coronary arteries. Corrected TIMI frame count17 given in the evening before the coronary angiogra- was calculated. Revascularization was performed phy. UFH was started with an intravenous bolus of at the discretion of the treating physician. UFH was 4000 or 5000 IU and was followed by an infusion of used as the at procedures 800 or 1000 IU/h at body weights of # or >67 kg, in both groups. respectively. The infusion rate was adjusted to a target APTT level of 50–75 s and continued for 48 h. Clinical events Concomitant therapy The following clinical events were recorded All patients were treated with 150–325 mg aspirin while the patients were in hospital: death, stroke immediately at entry and thereafter once daily. (ischaemic or haemorrhagic), other major bleeding The use of abciximab (ReoPro®) or other glycopro- (defined as a decrease in haemoglobin of >20 g/l tein IIb/IIIa antagonists was discouraged during the in association with symptoms or >40 g/l regardless first 24 h after randomisation. The use of other of symptoms, any intraocular, intraspinal, intra- was at the discretion of the treating cranial or retroperitoneal bleeding and bleeding physician. leading to death), other adverse events, recurrent MI and revascularization. Vital status, stroke, Laboratory investigations major/minor bleeding, non-fatal cardiac events, other adverse events and any revascularization Twelve-lead ECGs were performed before ran- procedure were also established at 30 days. domisation, after 24–36 h, at hospital discharge Recurrent MI during the initial 18 h after the and if symptoms suggestive of recurrent myocardial start of study drug was defined by recurrent signs ischaemia occurred. Serial blood samples for and symptoms of ischaemia at rest accompanied by measurement of levels of biochemical markers (CK, new or recurrent ST segment elevation of ≥0.1 mV CK-MB or troponin) were obtained on admission, in at least two contiguous leads lasting at least before coronary angiography, 10–20 h after any 30 min. After 18 h, recurrent MI was defined by the revascularization procedure and at recurrent presence of new Q waves or new LBBB or elevation symptoms suggestive of myocardial ischaemia. In a of biochemical markers, i.e. reelevation of CK-MB substudy of 26 patients treated with dalteparin, to above the upper limit of normal and increased by plasma samples for core laboratory analyses of ≥25% over the previously elevated level. Recurrent anti-Xa levels (Rotachrom, Lmw HeparinO`) were MI after revascularization was defined by the pres- obtained at randomisation and after 90 min, 3, 4, 8, ence of new Q waves in two or more contiguous 48 and 52 h. APTT levels were obtained regularly in leads or at angioplasty (+/− stenting) by CK-MB >2 all patients treated with UFH. times the upper limit or at coronary artery by-pass 900 L. Wallentin et al. surgery by CK-MB >5 times the upper limit of normal. Autopsy was the preferred method for determin- ing 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 adjudi- cated the cause of all , as well as occur- rence of cardiac and other adverse events, major bleeding and stroke. Downloaded from https://academic.oup.com/eurheartj/article/24/10/897/473619 by guest on 02 October 2021 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.

Statistics

The objective was to compare the effects of treat- Fig. 2 Distribution of patients. ment with dalteparin or UFH, as an adjunct to alteplase, on TIMI flow rates in the culprit coronary corrections for multiplicity. Boehringer-Ingelheim arteries evaluated by coronary angiography during (Sweden) together with Pharmacia Corporation initial hospital stay after 4 days but no later than (Sweden) performed data management and moni- 14 days after randomisation. The primary end-point toring. The statistical analyses were performed was TIMI 3 flow. Other predefined assessments of independently by the Pharmacia Corporation and the treatment effects were occurrence of TIMI 0-1 the coordinating investigator. flow, thrombus in the culprit coronary artery, the combination of TIMI 0-1 flow or thrombus and also Results the corrected TIMI frame count. The secondary endpoints were clinical events including death, MI, Patients and randomised treatment revascularization and several safety end-points including non-cerebral bleeding, intracranial Between March 1999 and April 2000, 439 patients haemorrhage and stroke. A sample size of 170 were recruited in 18 Swedish and four North patients was required to give 80% power at a two- American centres out of which 434 received any sided significance level of 5%, to detect a change in study treatment (dalteparin group, nϭ221; UFH TIMI grade 3 flow from 50 to 65%. A sample size of group, nϭ213) (Fig. 2). The patients were 70% 200 patients per treatment group was planned and, males, with an average age of 65 years, 32% had during the trial, further extended to compensate hypertension, 34% were current smokers and 12% for an actual withdrawal rate higher than expected had diabetes mellitus. Most patients (88%) were in mostly due to the performance or timing of the Killip class I, 54% had an inferior, 44% had an scheduled angiography. The evaluation of the anterior and 2% non-specified location of the primary end-point of coronary blood flow was infarction. The delay between onset of symptoms confined to those patients who underwent the and start of treatment was less than 2 h in 33% and scheduled coronary angiogram within the pre- 2–4 h in 49% of the patients (Table 1). There were defined time interval and while still in-hospital for no significant differences in baseline characteris- the index event. The analyses of clinical and safety tics or clinical findings between the randomised end-points included all patients who received any groups. study treatment. Chi-square tests (or Fisher's Exact test if appropriate) were used for analysis of the Coronary blood flow primary and secondary endpoints. Non-parametric Mann–Whitney U-test was used to compare cor- In 56 patients (dalteparin, nϭ19; UFH, nϭ37) the rected TIMI frame counts. The tests were to be scheduled coronary angiography was either not per- two-sided with an alpha level of 0.05 without formed because of the patient's clinical condition Dalteparin and rt-PA in acute MI 901

Table 1 Baseline characteristics Dalteparin (N=221) Heparin (N=213) Gender: male n (%) 158 (71.5%) 148 (69.5%) Age (years): mean±SD 64.1±10.6 65.0±10.9 Body weight (kg): mean±SD 79.2±14.2 78.7±13.7 Height (cm): mean±SD 172.8±8.4 171.8±8.9 Body mass index: mean±SD 26.5±3.6 26.8±3.8 Previous MI n (%) 28 (12.7) 35 (16.4) Previous CABG n (%) 3 (1.4) 9 (4.2) Previous PTCA n (%) 7 (3.2) 11 (5.2) Hypertension n (%) 63 (28.5) 76 (35.7) Diabetes n (%) 29 (13.1) 23 (10.8) Current smoker n (%) 76 (35.3) 67 (32.1) Downloaded from https://academic.oup.com/eurheartj/article/24/10/897/473619 by guest on 02 October 2021 Never smoked n (%) 77 (35.8) 83 (39.7) Systolic b.p. (mmHg): mean±SD 138.1±21.9 138.4 ±23.4 Diastolic b.p. (mmHg): mean±SD 83.2±14.0 83.1 ±16.4 Heart rate: mean±SD 71.4±15.1 72.5±18.7 Killip class I n (%) 193 (88.1%) 187 (87.8%) Infarct location: anterior n (%) 99 (44.8) 92 (43.2) Infarct location: inferior n (%) 116 (52.5) 117 (54.9) Treatment delay (0–2 h) 83 (37.7) 63 (29.9) Treatment delay (>2–4 h) 98 (44.5) 111 (52.6)

Table 2 Evaluation of coronary blood flow in culprit coronary artery (TIMI Grade 0-3) at coronary angiography during initial hospital stay Dalteparin (n=202) Heparin (n=176) Odds ratio (95% CI), p TIMI flow=0 24 (11.9%) 38 (21.6%) Linear-by-linear association, p=0.016 TIMI flow=1 3 (1.5%) 5 (2.8%) TIMI flow=2 35 (17.3%) 23 (13.1%) TIMI flow=3 140 (69.3%) 110 (62.5%) TIMI flow=3 140 (69.3%) 110 (62.5%) 1.11 (0.96–1.28), p=0.163 TIMI flow=0-1 27 (13.4%) 43 (24.4%) 0.55 (0.35–0.85), p=0.006 Visual thrombus 38 (18.9%) 48 (27.3%) 0.69 (0.48–1.01), p=0.053 TIMI flow 0-1 or thrombus 56 (27.9%) 74 (42.0%) 0.66 (0.50–0.87), p=0.003 Evaluation of any association between the TIMI flow rates and the randomised treatment was performed by Chi square test using linear-by-linear association. Comparison of proportions of patients with each coronary flow characteristic between the randomised groups was then performed by Chi square tests.

or, in a few patients, non-evaluable for technical dalteparin than the UFH group (13.4 versus 24.4%; reasons (Fig. 2). The median time from randomis- pϭ0.006) indicating significantly less occlusions or ation to the scheduled coronary angiography was poor flow in the dalteparin than the UFH group. 6 days in both groups with 23 and 26% on day 5, 34 Furthermore, the occurrence of intraluminal and 39% on day 6, 24 and 23% on day 7, 12 and 7% on thrombi tended to be less common (18.9 versus day 8 and 7 and 12% outside this time range in the 27.3%; pϭ0.053) in the dalteparin than the UFH dalteparin and UFH groups, respectively. Taking all group. Accordingly the occurrence of the combined four categories of TIMI flow grades into considera- end-point, TIMI 0-1 flow or intraluminal thrombus, tion there was a significant difference in TIMI flow was less frequent (27.9 versus 42.0%; pϭ0.003) in with a better flow in the dalteparin group than in the dalteparin than in the UFH group (Table 2). the UFH group (pϭ0.016) (Table 2). Comparing the Among the patients with TIMI 3 flow there was, randomised groups in accordance with the pre- however, no difference in TIMI frame count. The defined primary end-point of solely TIMI grade 3 evaluation of the coronary blood flow in relation to flow, the difference did not reach statistical sig- the time after thrombolysis showed similar flow on nificance (pϭ0.163). However, TIMI flow 0-1 was days 4–5 and thereafter a continuous deterioration present in significantly fewer patients in the of coronary blood flow in the UFH 48 h group and a 902 L. Wallentin et al. Downloaded from https://academic.oup.com/eurheartj/article/24/10/897/473619 by guest on 02 October 2021

Fig. 3 Poor (TMI 0–1) coronary blood flow in the culprit coronary artery in relation to time of coronary angiography and randomised treatment. continuous improvement in the dalteparin group (Fig. 3). Table 3 Evaluation of extent of coronary artery disease and culprit coronary artery stenosis at coronary angiography The extent of coronary artery disease was com- during initial hospital stays parable between the two treatment groups: 27% Dalteparin (N=201) Heparin (N=176) had three-vessel or left main disease, 31% had two-vessel disease, 37% had one-vessel disease and Extent of CAD n (%) <50% stenosis 13 (6.5%) 8 (4.5%) 5% had no significant coronary lesions. In both 1-VDa 70 (34.8%) 65 (36.9%) groups 85% of patients had more than 70% stenosis 2-VD 64 (31.8%) 56 (31.8%) or occlusion of the culprit artery (Table 3). 3-VD or LMD 54 (26.9%) 47 (26.7%) Still direct coronary angioplasty in association with Degree of stenosis in the culprit artery n (%) the coronary angiography was only performed in 21 No stenosis 14 (7.0%) 12 (6.9%) and 24% of the respective dalteparin and UFH Less than 50% 4 (2.0%) 2 (1.1%) groups. 50–70% 14 (7.0%) 10 (5.7%) >70≤100% 147 (73.1%) 113 (64.6%) 100% 22 (10.9%) 38 (21.7%) Clinical outcome a 1-VD=significant ≥50% stenosis in one major coronary During the initial 7 days there was a trend of a lower artery, 2-VD=significant ≥50% stenosis in two major coronary rate of death and MI (pϭ0.059) and a significantly artery, 3-VD or LMD=significant ≥50% stenosis in the three ϭ major coronary arteries or the main stem of the left coronary lower rate of myocardial reinfarction alone (p artery. 0.010) 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 out of the 12 patients with early reinfarction had dalteparin cessation were observed predominantly undergone an angioplasty procedure at the time of in patients with 2-3 vessel disease (8.6 versus 1.2% the scheduled predischarge coronary angiogram. at 0-1 vessel disease; pϭ0.027) and with a 50–99% This rate was similar to the 29% rate of predis- stenosis remaining in the culprit coronary artery charge in the total patient population (6.9 versus 0% at no significant stenosis or total (Table 4). However, at the 30 days follow-up occlusion; pϭ0.13) (Table 5). Despite the frequent around 53% of all patients had undergone coronary occurrence of severe coronary lesions only three revascularization. Dalteparin and rt-PA in acute MI 903

Table 4 Clinical events at days 7 and 30 in relation to randomised treatment Day 7 Day 30 Dalteparin (N=221) Heparin (N=212) Dalteparin (N=220) Heparin (N=210) Death 5 (2.3%) 8 (3.8%) 9 (4.1%) 11 (5.2%) MI 3 (1.4%) 11 (5.4%) 14 (6.5%) 14 (7.0%) Death or MI 8 (3.6%) 17 (8.1%) 20 (9.1%) 22 (10.6%) Revascularization 61 (29.2%) 72 (37.5%) 105 (50.7%) 106 (55.8%)

and 65% after 48 h (nϭ151). The anti-factor Xa Downloaded from https://academic.oup.com/eurheartj/article/24/10/897/473619 by guest on 02 October 2021 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±0.16 IU/ml after 90 min. The level remained constant until after 3–4 h (0.55±0.16 IU/ml) and became somewhat lower after 8 h (0.40±0.15 IU/ml). During con- tinuous treatment, the dalteparin regimen lead to a trough of 0.44±0.16 IU/ml and peak of 0.67±0.16 IU/ml as evaluated at 48 and 52 h, respectively, after the starting of treatment.

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 intra- cranial 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 in the dalteparin group.

Discussion 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. Coronary perfusion The present study was performed at a time and in Compliance and coagulation inhibition centres with limited resources for urgent or rescue PCI, which allowed the performance of late cor- Compliance with treatment was good: 88% in the onary and avoidance of early UFH group and 91% of patients in the dalteparin revascularization procedures. The results suggest group obtained at least 24 h of treatment, 62% in that 4–7 days of treatment with subcutaneous the UHF group received at least 48 h and 61% in dalteparin improves coronary patency and per- dalteparin received at least 96 h of randomised fusion as evaluated at the end of the treatment treatment. The APTT level in the heparin group period. The between group difference in pre- was within or below target range in 28 and 20%, defined primary endpoint, TIMI grade 3 blood flow, respectively, after 6 h (nϭ180), 43 and 42% after did not reach statistical significance. Although 12 h (nϭ170), 29 and 64% after 24 h (nϭ168) and 32 hampered by limitations of statistical comparisons 904 L. Wallentin et al.

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 Myocardial reinfarction (n=11) No myocardial reinfarction (n=187) Culprit artery stenosis No or <50% 0 17 (9.1%) 50–70% 1 (9.1%) 13 (7.0%) 70–99% 10 (90.9%) 136 (72.7%) 100% 0 21 (11.2%) Extent of CAD 0 to <50% stenosis 0 13 (6.9%) 1-VD 1 (9.1%) 69 (36.7%)

2-VD 4 (36.4%) 59 (31.4%) Downloaded from https://academic.oup.com/eurheartj/article/24/10/897/473619 by guest on 02 October 2021 3-VD or LMD 6 (54.5%) 47 (25.0%) Culprit artery flow TIMI flow=0 0 23 (12.1%) TIMI flow=l 0 2 (1.1%) TIMI flow=2 2 (18.2%) 33 (17.5%) TIMI flow=3 9 (81.8%) 131 (69.3%)

Table 6 Incidence of adverse events, death, bleedings and stroke On treatment After treatment until day 30 Dalteparina (N=224) Heparina (N=210) Dalteparin (N=220) Heparin (N=204) Adverse events Drug-related AE 37 (16.5%) 34 (16.2%) 14 (6.4%) 9 (4.5%) Serious AE 25 (11.2%) 36 (17.1%) 39 (17.9%) 27 (13.5%) Death 4 (1.7%) 6 (2.8%) 5 (2.2%) 5 (2.4%) Bleeding Any bleeding 40 (17.9%) 35 (16.7%) 25 (11.6%) 23 (11.9%) Major bleeding 8 (3.6%) 11 (5.2%) 8 (3.7%) 9 (4.6%) Cerebral bleeding 1 (0.5%) 4 (1.9%)b 1 (0.5%) 0 Minor bleeding 34 (15.2%) 28 (13.3%) 20 (9.3%) 14 (7.2%) Stroke Any stroke 4 (1.8%) 4 (1.9%) 2 (0.9%) 1 (0.5%) Haemorrhagic stroke 1 (0.4%) 4 (1.9%) 1 (0.5%) 0 Ischaemic stroke 3 (1.3%) 0 1 (0.5%) 1 (0.5%)

a All patients also received rt-PA (alteplase). b Two of the bleedings were fatal.

without correction for multiplicity, there were con- prolongation of the anticoagulant treatment was sistent and statistically significant benefits con- the main reason for the improvement in coronary cerning several other important indicators of blood flow. coronary blood flow in favour of the dalteparin The angiography results were supported by the group. Thus, there were significantly fewer corresponding lower rates of MI during the patients with very poor coronary blood flow, i.e. dalteparin treatment period. These findings are TIMI flow 0-1, in the dalteparin compared to the consistent with recent similarly designed coronary UFH group and significantly fewer with TIMI flow angiography trials,18,19 which also showed indica- 0-1 or intraluminal coronary thrombi. The cor- tions of improved perfusion and less reocclusions rected TIMI frame count also indicated a signifi- when comparing enoxaparin or pentasaccharide cantly better patency in the dalteparin group. with heparin in rt-PA treated AMI patients treated When evaluating the patients in relation to time of with alteplase. Support for improved patency with angiography there was no difference in TIMI flow at LMWH in AMI also can be derived from studies day 4–5 while there was a substantial difference in comparing dalteparin14 or enoxaparin20 to placebo TIMI 0-1 flow at day 7. These findings indicate that in streptokinase treated AMI patients. The results Dalteparin and rt-PA in acute MI 905 from the present and previous trials suggest that Reactivation-rebound 4–7 days of LMWH, compared to 48 h of UFH, will improve coronary patency and perfusion and During treatment with alteplase, as well as after reduce the risk of early occlusion and reinfarction other thrombolytic drugs, there is an activation of 12,26–28 in patients with AMI. coagulation and platelets. Both during and Whether or not similar results could be obtained early after the 90 min tPA infusion there is often with prolongation of the UFH infusion for 4–7 days repeated episodes of reperfusion–reocclusion, that and until coronary angiography is still an open can be prevented by simultaneous treatment with 14,21,22 issue.21,22 However, the LMWH heparin regimen UFH or LMWH. Also after cessation of the with twice daily subcutaneous injections rather 24–48 h standard heparin infusion there are early 29,30 than intravenous infusion and no requirement for reactivation events. The design of the present laboratory monitoring would, in most cases, be trial was therefore a comparison of two treatment Downloaded from https://academic.oup.com/eurheartj/article/24/10/897/473619 by guest on 02 October 2021 considered a more convenient and acceptable strategies—one with prolonged and one with short approach, both from the patient and staff perspec- anti-coagulation treatment in order to avoid both tive. A possible alternative might be to use oral early and late reocclusions. The duration of treat- , which also seem to reduce the risk ment was selected in order to allow protection of reocclusion after thrombolysis.23 during further risk stratification or while awaiting coronary angiography and revascularization. There- fore the study does not allow any direct comparison Reinfarction of the efficacy of the two drugs. Compared to the UFH strategy in the current trial, the low rate of The 30-day mortality was low and similar to levels reinfarction between days 2 and 7 suggests that reported in recent trials of thrombolysis in AMI longer-term treatment with dalteparin can prevent 24 using almost identical inclusion criteria. The 30- those early reinfarctions. However, in the present day reinfarction rate of 6–7% was also similar to trial later reactivation events were observed after 6,7 previous reports. During treatment the reinfarc- cessation of the dalteparin treatment. These obser- tion rates in the dalteparin group were considerably vations are in accordance with experiences of lower than in the UFH group. However, the initial dalteparin treatment also in streptokinase treated gain during this period was diminished because of a patients in the BIOMACSII trial14 as well as in unsta- cluster of reinfarctions within a few days after ble coronary artery disease.8 The same proportion cessation of dalteparin treatment suggesting reac- of reactivation events has not been reported in tivation of the thrombotic process. The perform- trials with other LMWHs.10,11,18 These differences ance of coronary angiography in all patients before might depend on differences in treatment design, cessation of dalteparin treatment provided a e.g. rate of early revascularization or a variable unique opportunity to elucidate some of the rea- duration or dose of anticoagulation treatment after sons for the early reinfarctions. The results suggest cessation of the randomised treatment. Another that the reactivation events tended to occur in possibility is that the different anticoagulant patients with 2-3 vessel or left main disease and properties of LMWHs, e.g. different anti-Xa/anti-IIa with significant stenosis remaining in the culprit ratios, might be associated with different risks of coronary artery. In the present trial only 25–30% of rebound activation of the coagulation system. patients underwent angioplasty in direct associ- These findings emphasise the importance of ation with the scheduled coronary angiography evaluation of clinical events both while on- although 85% had severe stenosis or total occlusion treatment as well as longer-term outcome in of the culprit artery and 58% had multivessel dis- trials of anticoagulants and platelet inhibitors as ease. In settings with a more aggressive approach adjuncts to thrombolytic agents in ST-elevation MI. to revascularization of severe lesions detected on post-infarct coronary angiography, the reactivation Dosing regimen events might be less prominent. The present results indicate that severe stenosis remaining in the The dalteparin dose—120 anti-Xa IU/kg subcu- culprit coronary artery, and multivessel disease, taneous every 12 h—used as an adjuvant to may be risk factors for early reinfarction even at alteplase was the same as that used in acute-phase TIMI flow grade 2-3. These results also raise the treatment of patients with unstable coronary possibility that treatment with LMWH dalteparin artery disease.8,9,25 In order to obtain an adequate might be useful as a ‘bridge-to-revascularization’ anti-Xa level immediately after the start of treat- after thrombolysis of AMI as well as in unstable ment one quarter of the first dose was given as coronary artery disease.25 an intravenous bolus. The results of the present 906 L. Wallentin et al. pharmacokinetic substudy indicated that this regi- treatment and/or early invasive coronary pro- men leads to a stable anti-Xa level within 90 min of cedures deserve further evaluation in large-scale the first dose. Thus, a therapeutic level of the trials. Such a regimen might be very useful as an anticoagulant was reached to counteract the acti- alternative in settings when the direct PCI34 is not vation of platelets and coagulation induced after immediately available. cessation of the thrombolytic treatment.12,26,27,28 Acknowledgements Safety This work was supported by grants from Pharmacia Corporation and Boehringer-Ingelheim. Despite the longer treatment (4–7 days) with dalteparin compared to the 48 h with UFH, there Appendix A Downloaded from https://academic.oup.com/eurheartj/article/24/10/897/473619 by guest on 02 October 2021 was no increase in the risk of bleeding. As expected there were few major bleeding events and also few Steering committee intracranial haemorrhages—numerically less in the Lars Wallentin (Coordinating investigator and dalteparin than the heparin arm. The low bleeding Chairman, Uppsala, Sweden), John H. Alexander rates are similar to those reported for previous (Duke Clinical Research Institute, Durham, USA), trials involving approximately 4500 patients with Lott Bergstrand (Danderyd's Hospital, Stockholm), unstable coronary artery disease exposed to at 8,9,25 Rhonda Collins-Facile (Pharmacia Corp., Sweden), least 4–7 days of dalteparin treatment. These Mikael Dellborg (Sahlgrenska Universitetssjukhuset results are reassuring that safety will be acceptable O¨stra, Gothenburg, Sweden), Carin Fellenius in the further evaluation of the exchange of appro- (Pharmacia Corp., Sweden), Christopher B. Granger priately dosed LMWHs as an alternative to UFH as an (Duke Clinical Research Institute, Durham, North adjunct to thrombolytic treatment. Carolina, USA), Barbro Ha˚kansson (Boehringer- Ingelheim, Sweden), Bertil Lindahl (Uppsala, Clinical implications Sweden), Lars-Eric Lins (Boehringer-Ingelheim, Sweden), Tage Nilsson (Karolinska Hospital, Dalteparin for 3–7 days in place of UFH infusion for Stockholm), Kenneth Pehrsson (Karolinska Hospital, 48 h, as an adjunct to alteplase in the treatment of Stockholm), Eva Pihl (Falun), Ma˚rten Rosenqvist AMI, appears safe and seems to improve coronary (Pharmacia Corp., Sweden), Gun Setterberg patency and reduce the risk of early reocclusion (Pharmacia Corp., Sweden), Agneta Siegbahn and reinfarction. However, after thrombolytic (Uppsala, Sweden), and Eva Swahn (Linko¨ping, treatment the majority of patients with AMI still Sweden). have a significant stenosis or occlusion of the culprit artery and multivessel coronary artery Principal investigator and research nurse at the disease. In these patients there is an increased risk participating centres of reocclusion and reinfarction early after cessation G. Ahlberg, E. Pihl (Falun, Sweden), P. Ahlstro¨m, of dalteparin treatment. In accordance with the S.-B. Jensen (Motala, Sweden), S. Bandh, A. Fro¨jdh, present results, the recently presented large-scale L. Dova˚s (Va˚stera˚s, Sweden), M. Dellborg, A.-M. ASSENT331 trial demonstrated that the LMWH Svensson, H. Svensson (Sahlgrenska Universitetss- enoxaparin as an adjunct to TNK-tPA was safe and jukhuset O¨stra, Gothenburg, Sweden), M. Eriksson, reduced the composite of 30 day mortality and in M. So¨dersten (St. Go¨rans Sjukhus, Stockholm, hospital myocardial infarction (MI). However, con- Sweden), O. Hansen, E. Steensgaard (Malmo¨, cerning the risk of post-discharge ischaemic events Sweden), A. Hansson, J. Soffman, G. Dahl (Lund, after cessation of the enoxaparin treatment, forth- Sweden), M. Hartford, H. A˚kesson, M. So¨derblom coming reports need to be awaited. Furthermore (Sahlgrenska Universitetssjukhuset, Gothenburg, two recent trials have demonstrated beneficial Sweden), J. Hulting, G. Wede´en (So¨dersjukhuset, effects of prolonged post-discharge treatment with Stockholm, Sweden), J.-E. Karlsson, B. Thulin, C. oral anticoagulation in addition to aspirin after Eriksson (Jo¨nko¨ping, Sweden), B. Lindahl, G. A˚lsjo¨, AMI.32,33 Therefore, the present results suggest C. Henriksson (Uppsala, Sweden), H. Nilsson, M. that treatment with the LMWH dalteparin might be Snickars (Fagersta, Sweden), K. Pehrsson, C. Hage useful as a bridge to longer-term oral anticoagula- (Karolinska Sjukhuset, Stockholm, Sweden), E. tion or to early revascularization after thrombolysis Swahn, E. Logander (Linko¨ping, Sweden), L. in ST-elevation MI. Thus, the combination of LMWH Svennberg, E. Sjo¨lund (Ga¨vle, Sweden), S. So¨der- and tPA agents and the appropriate selection of berg, C. Sundholm, M. Johansson (Umea˚, Sweden), patients and timing of continued anticoagulant H. Tygesen, A.-C. Tygesen (Bora˚s, Sweden), C. Dalteparin and rt-PA in acute MI 907

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