Abstract
The field of thrombocardiology, dealing with the delicate balance between thrombotic complications and bleeding, is thought to be increasingly important in modern cardiology. Dramatic thromboembolic complications, such as myocardial infarction and stroke, have stimulated the development of a series of active drugs with inherent predisposition to serious bleeding. The EuroThrombosis Summit 2009 (8–10 October 2009, Oslo, Norway) provided an impressive update from leading authorities and researchers in the field. With the focus on basic mechanisms of thrombosis and bleeding, new antithrombotic drugs on the arena and ‘in the pipeline’, both for acute coronary syndromes and their long-term prophylaxis, were discussed in relation to efficacy and safety. The thrombotic mechanisms in atrial fibrillation mainly responsible for the threatening complication of stroke were also highlighted.
The 3rd EuroThrombosis Summit was held on 8–10 October 2009 in Oslo, Norway. Altogether, 54 original lectures were presented, some in two parallel sessions in collaboration with the Working Group for Acute Cardiac Care. Approximately 160 delegates, including leading experts in the field participated. In this report, we will highlight some of the important topics presented.
Freek Verheugt (Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands) gave a historical survey on anticoagulants in coronary heart disease, stressing the crucial role of thrombin generation for the dramatic acute thrombotic complications in atherosclerotic coronary heart disease giving rise to myocardial infarction (MI). He documented the importance of thrombin, with convincing results from randomized clinical trials with traditional vitamin K antagonists such as warfarin, also stressing the need for close therapeutic control with INR values between 2.5 and 3.0 when given alone. In addition, realizing the importance of platelets in the thrombogenic process, he documented the optimal antithrombotic effect of the combination of aspirin with warfarin, in this case with INR values of 2.0–2.5 Citation[1].
The importance of thrombin generation locally in the left ventricle in large anterior wall infarctions was discussed further by Svein Solheim (Oslo University Hospital, Ullevål, Oslo, Norway) in his lecture on mural thrombosis in the era of dual antiplatelet therapy after percutaneous coronary interventions (PCIs). He documented a 15% incidence of this complication in a series of 100 patients undergoing detailed echocardiographic examinations in the first days/weeks after PCI for anterior wall infarctions. All patients were then treated with heparin and warfarin in addition to their dual antiplatelet treatment for at least 3 months; only one patient experienced a cerebral stroke.
A special session on “New anticoagulants in CAD” focused on Factor Xa and Factor IIa (thrombin) inhibitors, both in the acute phase of coronary artery disease and in the long-term secondary prevention of relapses. Kurt Huber (Wilhelminenhospital, Vienna, Austria) focused on the indirect inhibitor of Factor Xa, fondaparinux, as being especially suitable in acute situations, where less bleeding than with traditional low-molecular-weight heparin had been documented. In the long-term secondary prophylaxis, Erik Grove (Aarhus University Hospital Skejby, Aarhus, Denmark) pointed out the promising results with the oral direct Factor Xa inhibitor rivaroxaban, where Phase III studies are currenly underway in patients with atrial fibrillation, as well as in patients who have suffered acute coronary syndromes. Concerning Factor IIa inhibitors, Jan Eritsland (Oslo University Hospital, Ullevål, Oslo, Norway) focused on bivalirudin in the acute setting where evidence exists for equal effect and reduced bleeding when compared with a combination of low-molecular-weight heparin and GP IIb/IIIa inhibitor Citation[2]. Finally, Verheugt focused on the very promising recent results with the direct thrombin inhibitor dabigatran in patients with atrial fibrillation, where noninferiority versus warfarin was parallelled with a reduced number of intracerebral bleedings Citation[3]. Results from a large Phase II study with this drug in patients with coronary heart disease will be presented in the near future. This drug will most likely represent a suitable alternative to warfarin in atherothrombotic disease states with a broader ‘therapeutic window’ and no need for control testing. Thus, with this alternative, thrombin generation can probably be kept under long-term control in the arterial vasculature.
Moving to the update on antiplatelet drugs, Karsten Schrør (Heinrich-Heine-Universitat Dusseldorf, Dusseldorf, Germany) gave an overview on platelet physiology with clinical relevance. The present status to improve antiplatelet treatment focused on overcoming the reduced responsiveness to prodrugs such as clopidogrel and prasugrel, where dependence on cytochrome P (CYP)450–drug interactions is a great challenge. Lars Wallentin (Uppsala Clinical Research Center, Uppsala, Sweden) gave details on the Phase III results with ticagrelor, a direct and reversible inhibitor of the P2Y12 ADP receptor. Impressive long-term results on atherothrombotic events were obtained in patients with coronary heart disease as compared with clopidogrel; however, this was at the cost of more bleeding episodes Citation[4]. Robert Storey (University of Sheffield, Sheffield, UK) introduced promising results with a new principle of platelet inhibition, namely an inhibitor of the thrombin receptor protease-activated receptor-1. With this principle, it might be possible to inhibit atherothrombosis without affecting the predominant physiological hemostatic effect of platelets, and thus reduce bleeding episodes. Phase III studies with this priniciple are now underway.
In a special symposium on new developments in dual antiplatelet therapy, the improved metabolic characteristics of prasugrel as compared with clopidogrel were emphasized by Steen Dalby-Kristensen (Aarhus University Hospital Skejby, Aarhus, Denmark), and the use of this drug was recommended in acute coronary syndromes where a rapid and predictable effect was of importance Citation[5]. Kurt Huber gave special attention to the inter-individual variability in response to antiplatelet drugs, again underlining the more predictable metabolism of prasugrel as compared with clopidogrel in relation to the CYP system.
Finally, Franz-Josef Neumann (Heart Center Bad Krozingen, Bad Krozingen, Germany) also recommended prasugrel, as it is already on the market and is ‘ready for use’ in cardiology.
The mechanisms for ‘nonresponsiveness to antiplatelet therapy’, probably better described as ‘residual platelet reactivity’ during antiplatelet treatment, were targeted in a special session where Marco Cattaneo (University of Milan, Milan, Italy) gave an overview of the field. In his opinion, the serum levels of thromboxane B2 was the best measure of compliance and the effect of aspirin, although slightly influenced by ongoing inflammation Citation[6]. Alf-Åge Pettersen (Oslo University Hospital, Ullevål, Oslo, Norway), conducting a large prospective, randomized trial on 1000 patients with coronary heart disease, evaluated a broad range of platelet functional tests against clinical end points after 2 years, and presented the first results on nonresponsiveness to aspirin Citation[7]. The discussion focused on the lack of agreement on cut-off points for ‘nonresponsiveness’ with the different tests. The need for standardization of test procedures and relation to clinical end points was highlighted.
Erik Grove presented interesting results on immature platelets still containing RNA. They were large, active, contained more COX2 than mature platelets, and were present in higher amounts in smokers and diabetics.
Franz-Josef Neumann presented an update on the hot topic of late stent thrombosis (LST; 30–365 days) and very late stent thrombosis (VLST; >365 days). He concluded that LST seems to occur in approximately 2% of cases, and probably only approximately a third of that with bare metal stents. The similar prevalence of VLST is approximately 0.6% per year, and probably not dependent on continued dual antiplatelet treatment. In addition, he pointed out that continued dual antiplatelet treatment beyond 6 months after stent implantation was not evidence-based today, this being in contrast to the most recent guidelines.
A special session was dedicated to the mechanisms of atherothrombosis in diabetics. Thomas Wascher (University of Vienna, Vienna, Austria) focused on the role of hyperglycemia-induced reactive oxygen species in mitochondria and the role of free fatty acids in addition to advanced glycation end products. Niko Marx (University of Ulm, Ulm, Germany) shed light on the possible pathogenetic role of the insulin C-peptide in atherogenesis. Eva Cecilie Knudsen (Oslo University Hospital, Ullevål, Oslo, Norway) presented results indicating that very early testing with an oral glucose tolerance test after an acute MI (<16 h) does not provide valid information on the long-term prediction of glucose intolerance, probably due to the influence of stress phenomena on the test in the acute phase of large MIs Citation[8]. Thomas Weiss (Oslo University Hospital,Ullevål, Oslo Norway; Wilhelminenhospital, Vienna, Austria) finally suggested that in patients with metabolic syndrome, a proinflammatory score for the measure of mRNA values in adipose tissue, the APPIA score, was predictive for cardiovascular end points.
Regarding prehospital thrombolytic therapy in patients with ST segment elevation MI, Frans Van de Werf (University Hospitals Leuven, Leuven, Belgium) presented an update on relevant clinical trials and European Society of Cardiology guidelines, which clearly indicated a place for this treatment if a PCI center could not be reached within approximately 90 min after the start of symptoms, but thrombolytic treatment could be started before 3–6 h.
Ellen Bøhmer (Oslo University Hospital, Ullevål, Oslo Norway) presented the main results from the recent Norwegian study on District treatment of ST-Elevation Myocardial Infarction (NORDISTEMI) trial, where long transfer to PCI center indicated prehospital thrombolytic therapy, and the patients were then randomized to either immediate transport to the PCI center or conservative clinical stabilization at the local hospital before ‘elective’ PCI on a clinical basis (median: 5.5 days later). The results clearly indicated that immediate transfer to PCI was superior in avoiding reinfarction and new ischemic events, although without a significant influence on quality-of-life scores Citation[9]. Preliminary results also indicated that the increased cost of immediate transfer to PCI was only approximately €400 per patient, as compared with the ‘conservatively’ treated group.
A special session was devoted to the problem of bleeding in acute coronary syndromes treated according to recent guidelines. Agneta Siegbahn (Uppsala University Hospital, Uppsala, Sweden) gave an update on the risk factors for clinical events in patients with ACS who experienced major bleeding – that is, mainly anemia, blood transfusion, discontinuation of antithrombotic therapy and the basic condition with chronic hypercoagulability. The focus was on platelet–monocyte interactions and localized thrombin generation. Robert Storey focused on the various definitions of bleeding, and Joao Morais (Hospital Santo Andre, Leiria, Portugal) gave an update on relevant clinical trials where the poor prognosis in patients with ACS and major bleeding was underlined. Patients with more than two antithrombotic principles ‘on board’ were especially prone to bleeding, particularly low-weight female individuals and patients with reduced renal function.
In a special session on atrial fibrillation (a prothrombotic state), Gregory Lip (University of Birmingham Centre for Cardiovscular Sciences, Birmingham, UK) emphasized the fact that the relevant thrombus in the atrial appendage was a fibrin-rich thrombus, and that the D-dimer product predicted stroke outcome, even during oral anticoagulation. Arnljot Tveit (Bærum Hospital, Vestre Viken HF, Norway) gave evidence for the importance of the fibrinolytic inhibitor PAI-1 as a predictor for relapse of AF after elective cardioversion, and linked the levels of PAI-1 to overweight and high BMI Citation[10]. Ingebjørg Seljeflot (Oslo University Hospital, Ullevål, Oslo, Norway) introduced the endogenous inhibitor of nitric oxide synthase, asymmetric dimethyl arginine, as a marker of endothelial dysfunction in patients with AF.
Lars Wallentin gave a lecture on “Where to go”, related to future research in the field. He suggested that future research should focus on the basic mechanisms of atherothrombosis and bleeding, and that smaller clinical trials based on these results should probably replace the extremely costly multicenter trials, with the ‘noninferiority’ aims being relatively small clinical event rates, which have been undertaken in recent decades.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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