Dissertatie Dr. A.A.C.M. Heestermans

Uitgegeven: 30-06-2010

Dr. A.A.C.M. HeestermansDr. A.A.C.M. Heestermans
Cardioloog
Medisch Centrum Alkmaar, Alkmaar
» Antiplatelet Therapy in Myocardial Infarction and Coronary Stent
   Thrombosis (volledige tekst, PDF)

Promotor: Prof.dr. F. Zijlstra
Copromotores: Dr. A.W.J. van ’t Hof (Isala klinieken, Zwolle), Dr. J.M. ten Berg (St. Antonius ziekenhuis, Nieuwegein)



General Introduction

Part 1. Myocardial Infarction

Cardiovascular diseases are the number one cause of death in the world. An estimated 17.1 million people died from cardiovascular diseases in 2004, representing 29% of all global deaths. Of these deaths, an estimated 7.2 million were due to coronary heart disease [1]. In the Netherlands 31.2% of deaths in 2007 were caused by cardiovascular disease and 8164 deaths were directly related to acute myocardial infarction [2]. Most cases of myocardial infarction are caused by an occlusion of a major coronary artery usually due to physical disruption of an atherosclerotic plaque with subsequent formation of an occluding thrombus [3,4].

Community studies have consistently shown that the overall case fatality rate of patients with presumed myocardial infarction or acute coronary syndrome in the first month is approximately 50%, and of these deaths about half occur within the first 2 hours after symptom onset [5]. This high initial mortality seems to have altered little over the last years in contrast to hospital mortality [6]. With the widespread use of reperfusion therapy, antithrombotic therapy and antiplatelet therapy combined with secondary prevention, the overall 1-month mortality has been reduced to 4-6% [7,8]. European society of cardiology (ESC) guidelines [9] support the use of primary percutaneous coronary intervention (PCI) in patients with the clinical presentation of ST-segment elevation myocardial infarction (STEMI) within 12 h after symptom onset and with persistent ST-segment elevation or new or presumed new left bundle-branch block. Randomized clinical trials comparing timely performed primary PCI with in-hospital ?brinolytic therapy in high-volume, experienced centers have shown more effective restoration of patency, less reocclusion, improved residual left ventricular function and better clinical outcome with primary PCI [10]. In contrast to many other countries, the ambulance system in the Netherlands is highly organized with pre-hospital infarct diagnosis in the majority of patients and rapid transportation to readily available high volume PCI centers with short call to balloon times. Therefore national guidelines in the Netherlands recommend primary PCI as the preferred treatment strategy for patients presenting with STEMI.

Aspirin should be given to all patients with a STEMI as soon as possible after the diagnosis is deemed probable [11]. Clopidogrel is a thienopyridine, which irreversibly blocks the adenosine diphosphate (ADP) receptor P2Y12 on platelets. It is a prodrug and requires dual hepatic activation. Clopidogrel is less well studied in patients with STEMI treated with primary PCI, but there is abundant evidence on its usefulness as an adjunctive antiplatelet therapy on top of aspirin in patients undergoing PCI [12-14]. Based on these data, clopidogrel should be given as soon as possible to all patients with STEMI undergoing primary PCI. A 600 mg loading dose is recommended to achieve a more rapid and stronger inhibition of platelet aggregation [15,16].

Glycoprotein IIb/IIIa inhibitors (abciximab, epti?batide, tirofiban) block the final pathway of platelet aggregation. Several randomized trials have assessed the value of periprocedural administration of i.v. abciximab in addition to aspirin and heparin in the setting of primary PCI. A systematic review of these trials showed that abciximab reduced 30-day mortality by 32% without affecting the risk of hemorrhagic stroke and major bleeding [17]. Other studies, registries, and recommendations, have con?rmed and supported these conclusions [18,19]. However, large registry studies show that in real-world practice, glycoprotein IIb/IIIa blockers are given to only 25-30% of patients with STEMI, often for bailout situations [20,21]. In addition, there is limited information on the additional value of early prehospital IIb/IIIa blockade in addition to dual antiplatelet therapy, including high-dose clopidogrel in patients with acute myocardial infarction. Similarly, the optimal timing of administration of antiplatelet and antithrombotic drugs in this setting is still being debated.

Part 2. Coronary Stent Thrombosis

The treatment of patients with coronary artery disease has altered spectacularly since Andreas Grüntzig [22] introduced PCI in 1977. With a simple expanding balloon at the site of coronary narrowing, it was possible to dilate coronary stenosis and relieve angina. Nevertheless, initial treatment with balloon angioplasty was restricted by elastic recoil, negative remodeling leading to restenosis (35%-45%) and a high percentage of acute closures (5-8%). The introduction of coronary stenting initially was a bailout option to treat acute complications of balloon angioplasty. Although the acute complications of balloon angioplasty could be overcome by coronary stenting a new dreaded complication was introduced: coronary stent thrombosis. The acute thrombotic closure of the coronary stent may result in a life-endangering condition with catastrophic consequences such as acute myocardial infarction or sudden death. Despite aggressive antithrombotic therapy the initial experience of coronary stenting was overshadowed by unacceptable high rates of stent thrombosis and bleeding complications [23]. The introduction of dual antiplatelet therapy with aspirin and the thienopyridine ticlopidine together with an expansion of the indication of coronary stenting from bailout procedures to elective cases resulted in a significant reduction of stent thrombosis (<2%) as well as fewer bleeding complications and led to a breakthrough in the general use of coronary stents [24,25]. Advances in stent implantation techniques, appropriate pretreatment and loading with thienopyridines and the use of glycoprotein IIb/IIIa inhibitors in the setting of acute coronary syndromes led to a further reduction in the incidence of stent thrombosis. At the end of the bare metal stent era, stent thrombosis nearly fell into oblivion because of the prevailing concern of restenosis. The introduction in 2003 of drug-eluting stents resulted in a drastic reduction of neointimal hyperplasia and therefore repeat revascularization procedures. Nevertheless, soon after the introduction of drug-eluting stents, the interventional community was alarmed by reports of a high incidence of very late stent thrombosis [26,27]. Although late stent thrombosis had not been investigated extensively in bare metal stents, the introduction of drug-eluting stents brought this subject again to the attention of the interventional community. In view of the severe consequences of stent thrombosis, great efforts should be directed towards risk stratification to identify those at highest risk, who would probably benefit most from an alternative strategy. Multiple studies and registries have already recognized multiple risk factors contributing to stent thrombosis. However, many of these studies have limitations, mostly related to an overall small sample size with a limited number of cases and many likely correlates are not investigated.

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