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European Heart Journal Advance Access originally published online on February 21, 2007
European Heart Journal 2007 28(6):692-698; doi:10.1093/eurheartj/ehl564
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Early decrease in coagulation activity after myocardial infarction is associated with lower risk of new ischaemic events: observations from the ESTEEM trial

Christina Christersson1,3,*, Jonas Oldgren1, Anders Bylock2, Agneta Siegbahn3 and Lars Wallentin4

1 Department of Cardiology and Medical Sciences, Uppsala University Hospital, Uppsala, Swedon
2 AstraZeneca R + D, Mölndal, Sweden
3 Clinical Chemistry, Uppsala University Hospital, Uppsala, Swedon
4 Uppsala Clinical Research Center, Uppsala, Sweden

Received 16 March 2006; revised 29 January 2006; accepted 1 February 2007; online publish-ahead-of-print 21 February 2007.

* Corresponding author. Tel: +46 18 611 90 68; fax: +46 18 50 66 38. E-mail address: christina.christersson{at}akademiska.se


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aim Patients with a recent myocardial infarction have an increased risk of recurrent ischaemic events. In the ESTEEM trial, the oral direct thrombin inhibitor ximelagatran reduced the risk of new ischaemic events when compared with placebo in aspirin treated post myocardial infarction patients. Ximelagatran persistently reduced markers of coagulation activity, i.e. prothrombin fragment 1 + 2 (F1 + 2) and D-dimer levels. The aim of this substudy was to evaluate the levels of these markers and activated thromboplastin time (APTT) in relation to new ischaemic events or bleeding.

Methods and results In the substudy, 518 out of 1883 patients were included and within 14 days after a myocardial infarction randomized to ximelagatran or placebo for 6 months. The clinical endpoints death, myocardial infarction, severe recurrent ischaemia, ischaemic stroke, and bleeding were evaluated. The levels of F1 + 2, D-dimer, and APTT were analysed at randomization and in serial samples during the study. Ximelagatran treatment appeared to have a larger treatment effect in patients with F1 + 2 and D-dimer levels above the median at randomization with a reduction of ischaemic events from 18 to 9% (P = 0.03) for F1 + 2 and from 20 to 9% for D-dimer (P = 0.009). A reduction of D-dimer levels was found in 60% of the patients 1 week after randomization and these patients had less ischaemic events when compared with patients with unchanged or increased levels (P = 0.03) regardless of treatment. F1 + 2 and D-dimer levels were unrelated to bleeding risk. In the ximelagatran group, increased APTT was not related to ischaemic events but associated with a raised risk of bleeding.

Conclusion A reduction of initially high coagulation activity, as measured by the D-dimer level, in patients with recent myocardial infarction identifies patients with a decreased risk of new ischaemic events, regardless whether the reduction occurs spontaneously or is induced by pharmacological means. Patients with higher initial coagulation activity seemed to benefit most from long-term treatment with ximelagatran.

Key Words: Myocardial infarction • Ischaemic event • Coaguulation activity • Direct thrombin inhibitor


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Myocardial infarction is most often caused by a disruption of an atherosclerotic plaque with activation and aggregation of platelets, thrombin, and fibrin generation leading to formation of a thrombus.1 The instability of the endothelium and the activation of platelets and the coagulation system after myocardial infarction expose the patient to high risk of new thrombotic events. Both prothrombin fragment 1 + 2 (F1 + 2), reflecting the thrombin generation, and D-dimer, reflecting fibrin formation and degradation, are elevated in acute myocardial infarction and these markers persist elevated for several months after the acute event.2,3 Elevated levels of F1 + 2 and D-dimer at the acute event or in the follow-up period have been related to a raised risk of new thrombotic events both in the short- and long-term perspective.4–8 An early reduction of F1 + 2 after the acute event has been associated with a reduction of new ischaemic events4,9 although results have not been entirely consistent.10

Single or dual treatment with anti platelet drugs has been shown to reduce both the acute and long-term risk of new ischaemic events after a myocardial infarction.11 Low molecular weight (LMW) heparin reduces the risk of new cardiac events in the acute phase and tends to have beneficial effects also at prolonged treatment in patients with non-ST-elevation myocardial infarction.12–14 Long-term treatment with vitamin K antagonists has also been shown to reduce the risk of new ischaemic events more effectively than the aspirin in post-myocardial infarction patients.15 Still, the sustained activation of platelets and coagulation activity and the raised risk of new ischaemic events indicate a need of improved antithrombotic therapy for long-term prophylaxis.

The appearance of a new oral direct thrombin inhibitor ximelagatran provided a new alternative for long-term oral anticoagulation in these patients. In the ESTEEM study, a phase II study for efficacy and safety of the oral direct thrombin inhibitor ximelagatran after recent myocardial infarction, ximelagatran together with aspirin reduced the risk of new ischaemic events in form of death, new myocardial infarction, severe recurrent ischaemia, and ischaemic stroke from 17.6 to 12.8% when compared with only aspirin treated patients during 6 months treatment.16 Ximelagatran also reduced the thrombin generation and fibrin turnover already after 1 week, in a non-dose dependant manner, and the effect was persistent during the treatment period.17

The aim of the present substudy to the ESTEEM trial was to evaluate if the markers for thrombin generation and fibrin turnover and activated thromboplastin time (APTT) were related to clinical outcome and whether the changes of levels of the markers could indicate risk of new ischaemic events or bleedings.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Patients and treatments
The design, performance, and main results of the ESTEEM trial have been published.16 In brief, the study included 1883 patients admitted to the hospital because of acute myocardial infarction within 14 days after the index event. The diagnosis was confirmed by raised biochemical markers (troponin T, troponin I, creatinine kinase-MB above upper limit, or creatinine kinase above upper limit of normal when the cardiac-specific markers were unavailable), and new ischaemic electrocardiogram changes (ST-segment elevation, ST-segment depression of > 0.05 mV or acute T-wave inversion > 0.1 mV, or both). In addition, at least one of the following risk factors were required: age 65 years or older, diabetes mellitus, previous myocardial infarction, known multi-vessel coronary disease, previous ischaemic stroke, peripheral arterial occlusive disease, symptomatic congestive heart failure, or left ventricular ejection fraction of < 40%, presumed new left bundle branch block, ST-segment depression of 0.1 mV or greater associated with the index event, or history of hypertension. Patients with percutaneous coronary intervention (PCI) in the past 4 months or planned within 60 days, conditions related to increased risk of bleeding, known liver disease, or high concentration of liver enzymes (more than twice the upper limit of normal) were not included in the study. All patients received aspirin; treatment with clopidogrel was not permitted in the study. In the acute phase also, thrombolysis when indicated and heparin or LMW heparin were used as appropriate. At cessation of parenteral anticoagulant treatment or at the latest 14 days after the index event, the patients were randomized to one of four doses of ximelagatran (24, 36, 48, or 60 mg) or placebo bid in a 1:1:1:1:2 fashion during 6 months.16 Assessment visits with collection of clinical information and blood sampling were done after 1 week and then every month during treatment and 2 weeks after cessation of study drug at 6 month or premature discontinuation. The study drug was permanently discontinued in patients who developed a stroke, needed PCI, or coronary artery bypass grafting.

Definition of ischaemic events and bleedings
New ischaemic events in form of death, myocardial infarction, severe recurrent ischaemia, and ischaemic stroke were pre-specified endpoints in the ESTEEM study. New myocardial infarction was diagnosed by at least two of three criteria: raised biochemical markers of myocardial damage defined as creatinine phosphokinase-MB twice the upper limit of normal; symptoms suggestive of myocardial infarction or development of significant Q wave. Severe recurrent ischaemia was defined as severe, prolonged, or repetitive anginal pain at rest despite optimum medical treatment and at least one of the following: new ischaemic electrocardiographic changes (ST elevation ≥ 0.05 mV, ST depression ≥ 0.05 mV, or T wave inversion in at least two adjacent leads); an increase in creatinine phosphokinase-MB not fulfilling the criteria of myocardial infarction, or raised concentration of troponin T or I; or admission leading to unplanned coronary angiography or intervention. Stroke was diagnosed as abrupt onset of focal neurological deficit persisting more than 24 h. All strokes during the study were to be assessed by CT or MRI scan.

Bleeding was classified as minor or major; the later defined as one or more of the following criteria: fatal bleeding; clinical overt bleeding associated with a fall in haemoglobin of at least 20 g/L, or leading to transfusion of two or more units of whole blood or erythrocytes: intracranial, intraspinal, intraocular, pericardial, or atraumatic intra-articular bleeding. A major bleeding was defined as an endpoint in the study leading to cessation of study treatment.

Blood sampling and laboratory methods
Five hundred eighteen of the patients in the ESTEEM study randomized in Sweden (22 centres), Norway (14 centres), and Denmark (11 centres) took part in the present coagulation marker substudy. Venous blood samples were collected in tubes containing citrate. Samples were drawn at randomization, before start of study medication, after 1, 8, and 26 weeks on treatment and 2 weeks after cessation of study drug after 6 months treatment or 2 weeks after premature discontinuation called follow up. After centrifugation, the plasma was frozen in aliquots at – 70°C until analysis.

Both F1 + 2 and D-dimer were analysed with commercial immunoassays (Enzygnost®, Dade Behring, Germany for F1 + 2 and TintElize®D-dimer, Biopool®, Umeå, Sweden) at the Research Coagulation Laboratory, University Hospital, Uppsala, Sweden.

The APTT was analysed by Laboratories Medical Laboratory Automation (MLA) Electra 1400C (Beckman Coulter) with reagent from Dade-Behring at Quest Diagnostics (Middlesex, UK).

Statistical analysis
All ximelagatran treated patients were analysed and presented as one group in the present substudy since there were no significant differences in F1 + 2 and D-dimer levels between the four ximelagatran groups at any time point.17 Medians have been used for description of continuous variables at baseline and proportions have been used to describe categorical variables. The markers for coagulation activity and APTT were not normally distributed and therefore medians were used for description and Wilcoxon two-sample tests were used for between-groups comparisons. Clinical endpoints; death, myocardial infarction, severe recurrent ischaemia, ischaemic stroke, major and minor bleedings were described in frequencies and percentages. According to the pre-specified statistical analysis plan clinical endpoints were compared between the different strata of patients, based on the median level of the coagulation markers at randomization. The change of the coagulation markers after 1 week was dichotomized as reduction or no reduction. The change of the coagulation markers from cessation to follow up was dichotomized as increased or unchanged/decreased. Kaplan–Meier estimates with log-rank test were used to illustrate cumulative frequencies over time. Differences were evaluated with {chi}2 test or Fisher's exact test, when appropriate. The coagulation markers at randomization and change of markers after 1 week were also analysed as continuous variables in relation to the clinical endpoints. The levels were summarized as medians with 25th and 75th percentiles and compared between patients with and without clinical events using Mann–Whitney U test. Cox regression with models including the interaction terms treatment *F1 + 2 at randomization and treatment * D-dimer at randomization were performed. The coagulation markers were in these analyses dichotomized as above and below medians. The interactions between treatments and the change of coagulation markers after 1 week on treatment were also evaluated. The changes were dichotomized as reduction and no reduction in the analyses. The change of APTT in the ximelagatran group after 1 week was divided according to APTT ratio; levels less than two times the level at randomization compared to levels of greater than equal to two times the level at randomization. New ischaemic events and bleedings were compared between the different strata. Kaplan–Meier estimates with log-rank test were used to illustrate cumulative frequencies over time. Differences were evaluated with {chi}2 test or Fisher's exact test, when appropriate. All tests were two-sided. A P-value < 0.05 was considered significant. All analyses were considered to be hypothesis-generating; hence no adjustments for multiplicity were used.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Baseline characteristics
Patients were included 5 (±2) days after their myocardial infarction. Mean age was 71 (±10) years, 31% were females and 57% had a ST-elevation myocardial infarction and 43% a non-ST-myocardial infarction as inclusion criteria (Table 1). There were no significant differences in the baseline characteristics between the ximelagatran and the placebo groups. Treatment with unfractionated heparin or LMW heparin was terminated 48 h before randomization and start of study drug treatment in both the ximelagatran and the placebo groups. The patients were treated with study drug during 133 (±68) days. Thirty nine per cent (203 out of 518) discontinued study treatment prematurely. The main reasons for early discontinuation in the ESTEEM trial were occurrence of cardiovascular endpoints (pre specified in the study protocol), bleedings, or raised concentrations of alanine transaminase. During the study, four out of 518 patients were lost to follow up.


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  		Table 1 Baseline characteristics and medical treatment

 
Blood samples for measurement of the coagulation markers were available in 95% (492 out of the 518) of substudy patients at randomization. The calculation of the change in the coagulation markers after 1 week was based on samples available from 85% (n = 443) of the patients and the calculation of the change from cessation of study drug to follow up was based on 71% (n = 366) of the patients. APTT was analysed in 89% (n = 463) of the patients at randomization and the change of APTT after 1 week was calculated in 77% (n = 397) of the substudy patients.

Ischaemic events
There were 64 ischaemic events in the form of death (n = 3), myocardial infarction (n = 32), severe recurrent ischaemia (n = 25), or ischaemic stroke (n = 4) during treatment. In the ximelagatran group, 11% (n = 36) had an ischaemic event compared to 16% (n = 28) of the patients in the placebo group during the study treatment (P = 0.12). During the 2-week period from cessation of study treatment to follow up there were in total 11 ischaemic events in the ximelagatran group (4%) and 9 in the placebo group (6%) (P = 0.3).

Bleeding events
Minor or major bleedings occurred in 31% (n = 103) of the patients in the ximelagatran group compared to 16% (n = 29) in the placebo group (P < 0.001). The frequency of major bleedings was 2% during the study with no difference between the ximelagatran group and the placebo group. After cessation of study treatment to follow up, there were in total 11 bleedings in the study population.

Thrombin generation and fibrin turnover in relation to ischaemic events
At randomization, there were no significant differences in F1 + 2 and D-dimer levels between the ximelagatran and the placebo groups.17 The levels of F1 + 2 and D-dimer at randomization were not related to clinical outcome in the total substudy cohort (Table 2). Treatment with ximelagatran significantly decreased the risk of new ischaemic events in patients with levels of F1 + 2 and/or D-dimer above the median at randomization (Figure 1). In contrast, there appeared to be little beneficial effects of the direct thrombin inhibitor in patients with lower levels of these coagulation markers. There was no significant interaction between coagulation levels at randomization and study treatment, although for D-dimer there was a tendency to a treatment interaction for patients with levels above (hazard ratio = 0.40) compared to those below the median (hazard ratio = 1.08, P = 0.06).


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  		Table 2 Coagulation markers in patients with and without ischaemic events

 

Figure 1
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  		Figure 1 The proportion of new ischaemic events: death, myocardial infarction, severe recurrent ischaemia, and ischaemic stroke in the ximelagatran group (grey) and placebo group (white) in relation to F1 + 2 and D-dimer below/equal or above the median at randomization. P-value, comparing differences between ximelagatran and placebo groups by {chi}2 tests.

 
After a week, the levels of F1 + 2 were reduced in 63% of the patients in the total substudy cohort. In the ximelagatran treated patients, 76% (n = 221) had decreased F1 + 2 levels after 1 week, compared to 39% (n = 61) in the placebo group (P < 0.001). Patients with reduction vs. no reduction of F1 + 2 tended to have a lower frequency, 10% vs. 14%, of ischaemic events during the period of randomized treatment (Figure 2).


Figure 2
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  		Figure 2 The cumulative frequency of death, myocardial infarction, severe recurrent ischaemia, and ischaemic stroke during treatment in relation to reduction (black line) or no reduction (black dots) of F1 + 2 after 1 week. P-value by log-rank test.

 
Sixty per cent of the total patient population had reduced D-dimer levels after 1 week. D-dimer levels were decreased in 72% (n = 207) of the ximelagatran treated patients compared to 40% (n = 62) in the placebo group (P < 0.001). The group of patients without ischaemic events showed a significantly larger reduction of D-dimer levels than patients with ischaemic events (Table 2). Accordingly, in the group with decreased D-dimer levels, there were significantly less ischaemic events during treatment (9%) compared to the group with unchanged or increased levels (16%) (Figure 3).


Figure 3
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  		Figure 3 The cumulative frequency of death, myocardial infarction, severe recurrent ischaemia, and ischaemic stroke during treatment in relation to reduction (black line) or no reduction (black dots) of D-dimer levels after one week. P-value by log-rank test.

 
Similar results, with an association between a lower ischaemic event rate and decreased coagulation activity, were found when the ximelagatran group was analysed separately. There was, however, no significant interaction (interaction P > 0.5) between changes in coagulation activity and study treatment.

Within the cohort of patients with reduced levels of F1 + 2 after 1 week, the frequency of ischaemic events did not significantly differ regardless whether the patients were in the ximelagatran (10%) or placebo (13%) groups (P = 0.5). Similarly, within patients with reduced D-dimer levels after 1 week, the frequency of ischaemic events was similar in the ximelagatran (8%) and the placebo (11%) groups (P = 0.5).

At cessation of study treatment after 6 months or at premature discontinuation, the median levels for F1 + 2 and D-dimer in the ximelagatran group were still significantly reduced when compared with the placebo group (P < 0.001). However, at follow-up, 2 weeks after cessation of study treatment, the median levels of F1 + 2 and D-dimer had increased in the ximelagatran group and at this time-point there remained no significant difference between the ximelagatran and the placebo groups.

The levels of F1 + 2 or D-dimer at cessation of study treatment were not related to the frequency of ischaemic events from cessation of study treatment to the last follow up visit.

In the total substudy cohort 66% and 69% showed increased F1 + 2 and D-dimer levels, respectively, from cessation to follow-up. These changes in F1 + 2 or D-dimer levels were not related to the occurrence of ischaemic events.

Thrombin generation and fibrin turnover in relation to bleeding events
The frequencies of minor and major bleedings during the treatment were not related to the levels of F1 + 2 or D-dimer at randomization (P = 0.5 and P = 0.4, respectively) or to the change of levels after 1 week. Neither was there any significant difference of the frequency of bleeding events comparing the patients with reduced levels of F1 + 2 after 1 week (29%) with the patients with increased levels of F1 + 2 (24%) (P = 0.2). Similar results were found for D-dimer, with a frequency of bleeding events of 28% in the group with decreased D-dimer levels after 1 week, compared to 26% in the group with unchanged or increased levels (P = 0.6). Neither were levels of F1 + 2 and D-dimer at cessation, nor changes of these levels after cessation of treatment, related to bleeding events.

APTT relations to ischaemic events and bleedings
At randomization, the median level of APTT was 28 s in both the ximelagatran and placebo groups. After 1 week, 98% in the ximelagatran group showed increased APTT levels and 24% of them demonstrated a level of APTT twice or more compared to the level at randomization. The APTT levels were stable during the study treatment period.

In the ximelagatran group, there was no significant difference of ischaemic event rate in the group with an APTT after 1 week < 2 x level at randomization (10%) compared to the group with an APTT after 1 week ≥ 2 x level at randomization (8%) (P = 0.8).

Increased APTT levels after 1 week were found in 85% of the patients with bleedings during study treatment. In the ximelagatran group, the degree of the elevation of APTT after 1 week was significantly related to bleeding events during treatment (Figure 4).


Figure 4
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  		Figure 4 The cumulative frequency minor and major bleeding events in relation to change in APTT values after 1 week. Placebo group (black line), ximelagatran group with APTT < 2 x the level at randomization (black dots), and ximelagatran group with APTT ≥ 2 x the level at randomization (broken line). P-value comparing the two ximelagatran groups by log-rank test.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
Treatment with ximelagatran together with aspirin, compared with aspirin alone, have previously been shown to persistently decrease F1 + 2 and D-dimer levels, reflecting reduced coagulation activity, and furthermore, to reduce the risk of new ischaemic events after a myocardial infarction.16,17 In the present substudy, we found that patients with higher levels of F1 + 2 and D-dimer at randomization benefit from ximelagatran treatment, while patients with lower levels of coagulation activity seemed to have no reduction in ischaemic events when assigned to ximelagatran compared to placebo.

Elevated levels of F1 + 2 and D-dimer on admission have been demonstrated in previous studies of patients with unstable angina or myocardial infarction with a persisting increase over several months.3 Patients with increased levels of F1 + 2 and D-dimer at the acute myocardial infarction or two months afterwards have also been attributed an elevated, both short- and long-term, risk of new cardiac events.4–6 Melagatran, the active compound of the oral direct thrombin inhibitor, ximelagatran, is able to bind and inhibit both circulating and fibrin bound thrombin and thereby effectively reduces thrombin activity and fibrin turnover. This might explain the benefit of this drug on the clinical outcome in the patients with higher coagulation activity at randomization.

A reduction in D-dimer levels after 1 week was significantly related to improved clinical outcome, with a similar trend in relation to reduced F1 + 2 levels, regardless whether the reduction occurred spontaneously, or more commonly, by ximelagatran treatment. Early reduced F1 + 2 levels during treatment with an intravenous direct thrombin inhibitor, unfractionated heparin, or LMW heparin in the acute phase of myocardial infarction have previously been related to decreased risk of new ischaemic events.4,9 Increased D-dimer levels have been identified as a risk marker for future myocardial infarction among apparently healthy men and have also been suggested to reflect the severity of atherothrombotic disease.18–20 Increased levels of D-dimer also predict cardiovascular events and stroke in patients with atrial fibrillation or peripheral artery occlusive disease.21,22 Thus, the benefit of early reduced D-dimer levels in the present study further supports the concept of D-dimer as a useful marker to estimate the risk of new thrombotic events in atherothrombotic disease.

After cessation of subcutaneous LMW heparin and also intravenously administrated direct thrombin inhibitors, there have been clusters of new ischaemic events related to an increase in D-dimer and F1 + 2 levels.23,24 In the present study, we found no increase of ischaemic events after cessation of the oral direct thrombin inhibitor even though the levels of F1 + 2 and D-dimer increased to the same levels as in the only aspirin treated patients. Such an absence of clinical reactivation might be attributed to the fairly long duration of treatment with the oral thrombin inhibitor after the acute event, which might have attenuated the risk of new ischaemic events. Another factor of importance might be the continuation with aspirin also after cessation of ximelagatran. However, a limitation of this observation is the more limited number of patients with available levels of coagulation markers after cessation of study treatment due to premature discontinuation of study drug because of pre specified clinical endpoints or adverse events.

The optimal therapeutic APTT range during treatment with direct thrombin inhibitors is poorly defined, although APTT has been used to monitor the treatment in several clinical trials of intravenous direct thrombin inhibitors.25,26 Higher APTTs were related to increased risk of new ischaemic events during treatment with the direct thrombin inhibitor inogatran.27 In the present study, an increase in APTT was observed almost exclusively in the ximelagatran group and the patients did not appear to have more benefit regarding ischaemic events when APTT increased to above twice the level at randomization. Thus, APTT does not seem to be a suitable marker for the clinical efficacy of ximelagatran and does not reflect ximelagatran effects on thrombin generation and fibrin turnover.17 The rate of bleedings during treatment was related to the increase of APTT as expected from similar experiences during acute phase anticoagulant treatment.28 In contrast, the frequency of bleedings was not related to the changes in the markers for thrombin generation and fibrin turnover.

We conclude that a reduction of initially high coagulation activity, preferably measured by D-dimer levels, in patients with a recent myocardial infarction identifies patients with decreased risk of new ischaemic events, regardless whether the D-dimer reduction occurs spontaneously or is induced by pharmacological means. Patients with sustained high D-dimer levels after the acute phase might benefit from a more intense antithrombotic treatment. However, the usefulness of addition of long-term anticoagulation in patients with low D-dimer levels can be questioned. The oral direct thrombin inhibitor, ximelagatran, effectively reduced coagulation activity, and reduced the risk of new ischaemic events in patients with high initial coagulation activity. Thus, further evaluation of oral anticoagulants as complement to platelet inhibition in post-myocardial infarction patients with increased coagulation activity is warranted.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
Investigators and centres in Sweden, Norway, and Denmark for inclusion of patients and collection of blood samples. Birgitta Fahlström, biomedical analyst, for laboratory assistance. Sylvia Olofsson, biostatistician, for excellent statistical advice. Astrazeneca was the sponsor of the ESTEEM trial and supported the presents study with research grants. Swedish Heart-Lung Foundation and the Uppsala County association against Heart and Lung Diseases for providing financial support.

Conflict of interest: C.C. and J.O. have no conflicts of interest. A.B. is employed at AstraZeneca R + D. A.S. and L.W. have received research grants from AstraZeneca R + D.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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C. Christersson, J. Oldgren, A. Bylock, A. Siegbahn, and L. Wallentin
Early decrease in coagulation activity after myocardial infarction is associated with lower risk of new ischaemic events: observations from the ESTEEM: reply
Eur. Heart J., July 2, 2007; 28(14): 1783 - 1783.
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