Advances in invasive evaluation and treatment of patients with ischemic heart disease
Hoeven, B.L. van der
Citation
Hoeven, B. L. van der. (2008, May 8). Advances in invasive evaluation and treatment of patients with ischemic heart disease. Retrieved from https://hdl.handle.net/1887/12862
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CHAPTER 1
General introduction and outline of the thesis
B.L. van der Hoeven
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
9
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Ischemic heart disease
Ischemic heart disease is an important cause of morbidity and mortality worldwide, especially in developed countries. Before the introduction of current treatment strategies, most deaths due to ischemic heart disease were caused by an acute myocardial infarction.
Community studies, performed before 1970, demonstrated that the fatality rate within the first month of a heart attack was between 30 and 50% [1,2]. About half of these deaths occured within the first 2 hours after onset of symptoms. The initial mortality (<2 hours) seems to be virtually unchanged over last 30 years and occurs mostly outside the hospital [3]. In contrast, the in-hospital mortality, and consequently the late mortality, declined dramatically [4-9]. The introduction of the Coronary Care Unit (CCU) resulted in a significant reduction in 30-days mortality due to a major reduction in fatal arrhythmic events [10,11]. After the introduction of fibrinolytic therapy [12], aspirin [13-15] and ACE- inhibitors [16-18] the short-term mortality rate has been further reduced to less than 15%, at least in patients qualifying for this therapeutic options. Mechanical revascularization therapy, the latest major improvement, by Percutaneous Coronary Intervention in the acute phase of the myocardial infarction, resulted in a further reduction of early and late mortality to an average of around 5-15% at 12 months [19-22]. Mortality depends mainly on age, sex, infarct location and size, the presence of heart failure at presentation in the hospital, and co-morbidities such as diabetes mellitus or renal insufficiency [22-30]. Since the majority of the patients presenting in a hospital with an acute myocardial infarction became survivors, long-term treatment strategies to prevent a second heart attack or complications of the initial heart attack (such as ventricular arrhythmias or heart failure) became more important. Secondary prevention by aspirin [13,31,32] and HMG-coA- reductase inhibitors (statins) [33,34] have reduced the relative risk of a second heart attack by more than 30%. B-blockers [35,36], ACE-inhibitors [16-18,37], AT-II-blockers [38]
and Aldosteron blockers [39] have further improved the long-term prognosis by improving ventricular function. The risk of sudden cardiac death after an acute heart attack, due to ventricular arrhythmia’s, was significantly reduced by B-blockers [35,36] and Implantable Cardioverter Defibrillators (ICD’s) [40-42]. Further improvement can be achieved by implementation of AHA/ACC/ESC guidelines into clinical practice to optimize patient's risk profile and to minimize doctor's limitations and non-evidence based preferences, which seems to result in a better outcome [43-45].
In the Netherlands, since the early eighties mortality due to ischemic heart disease gradually declined [46]. Mortality due to ischemic heart disease in men, corrected for age distribution within the whole population at a specific time point, was 215/100.000 deaths in 1980 and declined to 95/100.000 deaths in 2005 (56% reduction). For women it declined from 132/100.000 deaths to 69/100.000 deaths (48% reduction). Although difficult to attribute to a specific development, the decline in mortality may be partly the effect of more aggressive preventive strategies in high risk patients (e.g. patients with diabetes mellitus or smokers), better recognition of symptoms resulting in earlier diagnosis and
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treatment, the introduction of new drugs, broader application of mechanical revascularization therapy in patients with acute myocardial infarction, and better treatment of acute and long-term complications such as heart failure and arrhythmias.
Despite these improvements, ischemic heart disease is still one of the most important causes of mortality and morbidity. In the Netherlands, in 2005, 30% of all deaths were caused by ischemic heart disease [46]. The majority (71%) caused by acute myocardial infarction.
Pathophysiology of ischemic heart disease
Ischemic heart disease is caused by atherosclerosis. Atherosclerosis is a chronic inflammatory disease of the arteries characterized by different stages of development and influenced by several risk factors [47]. The clinical presentation of atherosclerosis can be stable angina pectoris, an acute coronary syndrome or sudden cardiac death [48,49].
Generally accepted risk factors influencing the process of atherosclerosis, thereby increasing the risk of ischemic heart disease are: increased age, male sex, diabetes mellitus, smoking, dyslipidemia, hypertension, abdominal obesity, psychosocial factors and unhealthy diet [50].
A schematic overview of the development of atherosclerosis is given in Figure 1 [48].
Endothelial dysfunction is considered to be the initial step of atherosclerosis, which can be caused by several factors like dyslipidemia, vaso-active hormones related to hypertension or advanced glycosylation end products associated with hyperglycemia.
Endothelial dysfunction induces the expression of adhesion molecules, which may finally result in sticking of circulating leucocytes (mainly monocytes and T-lymphocytes) to the vessel wall and transmigration of the leucocytes to the intima. The leucocytes interact with endothelial and smooth muscle cells of the vessel wall by pro-inflammatory mediators resulting in migration of smooth muscle cells from the media to the intima. In this stage extracellular lipids start to accumulate within the intima. The smooth muscle cells proliferate within the intimal space and produce extracellular matrix proteins. When the lesion further evolves, a lipid core develops as the result of accumulation of macrophages, which bind and engulf modified lipoproteins and transform into foam cells.
Moreover, additional leucocytes are attracted by the production of inflammatory cytokines produced by the intimal leucocytes and vessel wall cells. In this stage the lipid core is covered by a thick fibrous cap. The next step is that due to overproduction of matrix-degrading proteinases the thick caps starts thinning and weakening. Moreover, within the lipid core inflammatory mediators cause expression of tissue factor, which is a potent pro-coagulant. Although there is in general some narrowing of the lumen of the coronary artery at this stage, the flow of blood is not compromised due to compensatory enlargement of the vessel, the so-called positive remodeling. However, when the fibrous cap, at some time, ruptures at a point of weakening, blood comes in direct contact with
General introduction and outline of the thesis
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the pro-coagulant lipid core resulting in the formation of an intracoronary thrombus.
Depending on the amount of luminal obstruction by the thrombus, this may occur without symptoms or cause an acute coronary syndrome. If the thrombus resolves, the fibrous cap may heal by smooth muscle cell proliferation and collagen production under influence of mediators released from degrading platelets within the thrombus. If thrombus resolves, the lesion transforms into a more advanced fibrous and calcified stable lesion, which may compromise the lumen of the vessel. The clinical presentation of this type of lesion is stable angina, which is characterized by chest pain provoked by physical or emotional stress. During stress, oxygen demand and coronary blood flow increases to fulfill the increased myocardial demand, which is than compromised by the stenosis. As depicted in Figure 1, thrombus formation may not only occur after plaque rupture but also after erosion of the endothelial layer, depending on the local pro-thrombotic and fibrinolytic balance and the turbulence of blood flow. Although plaque erosion frequently occurs in advanced stenotic atherosclerotic lesions, it may also occur during earlier stages of the atherosclerotic process, with or without previous plaque rupture.
The vulnerable plaque
As described above, several risk factors have been identified as risk factors for ischemic heart disease. However it is difficult in individual patients with these risk factors to predict subsequent ischemic events. Therefore, the focus of research has been directed to development of in vivo techniques to identify high risk atherosclerotic plaques prone to cause events [51,52]. Identification of high risk atherosclerotic lesions may be the first step in the development of a more tailored approach of individual patients for primary or secondary prevention of ischemic events. These high risk atherosclerotic lesions associated with ischemic cardiac events are called vulnerable plaques. Several techniques have been developed to assess the different components of the vulnerable plaque, like intravascular ultrasound imaging, angioscopy, magnetic resonance imaging, palpography or thermography [53-62]. Using these techniques, discrimination between non-vulnerable and vulnerable plaques is searched for by comparing plaque components or characteristics like plaque burden, elasticity, temperature, cap-thickness, necrotic core size, necrotic core location or leukocyte infiltration. However, although promising results have been achieved until now it is not possible to predict ischemic events using these techniques.
Treatment of ischemic heart disease
The treatment of atherosclerosis depends on the clinical presentation and is focused on prevention and modification of risk factors promoting atherosclerosis, treatment of acute ischemic events, and secondary prevention. Several guidelines have discussed these
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treatment strategies in detail [63-67]. Primary focus of treatment is the prevention of death or myocardial infarction due to ischemic heart disease.
In asymptomatic patients primary preventive strategies can be applied focusing on improving a healthier life-style (including healthy food intake, regular physical exercise, avoiding overweight and quitting smoking), early diagnosis and adequate treatment of diabetes mellitus, cholesterol lowering and treatment of hypertension. However, in general, in these patients atherosclerosis or ischemia has not been demonstrated. The indication for preventive therapy therefore depends on the estimated risk of events related to atherosclerosis and the cost-benefit ratio of the applied strategies.
If the patient has stable angina, atherosclerosis and/or myocardial ischemia needs to be proven and treated with life-style changes and drugs. Moreover, depending on the severity and location of coronary artery stenoses compromising blood flow to the myocardium, mechanical revascularization by Percutaneous Coronary Intervention (PCI) or Coronary
1. 2. 3. 4. 5. 6. 7.
Figure 1. Development and complications of a human atherosclerotic plaque
On top. The development of the atherosclerotic lesion is depicted in time from normal artery (1) to atheroma that caused clinical manifestations (5-7). On the bottom. Cross sections of different stages of the atherosclerotic lesion. 1. Normal artery. 2. Endothelial dysfunction and recruitment of leucocytes resulting in lipid accumulation in the intimal space. 3. Evolution to fibrofatty stage due to foam cell formation and amplification of leukocyte recruitment, smooth muscle cell migration and proliferation. 4. Expression of tissue factor resulting in weakening of the fibrous cap. 5. Rupture of a fibrous cap resulting in thrombus formation. 6. Thrombus resorbs and the lesion evolves to an advanced fibrous and calcified plaque. 7. Thrombus formation due to erosion of the endothelial layer. See text for further explanation. Adapted from Libby, et al. [48].
General introduction and outline of the thesis
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Artery Bypass Grafting (CABG) can be performed to relieve symptoms and/or to improve prognosis.
If the patient experiences an acute coronary syndrome, the extent and location of myocardial ischemia on the electrocardiogram determines the approach. The presence of ST-segment elevation on the ECG indicates transmural ischemia caused by complete obstruction of the vessel lumen by a thrombus on top of a ruptured or eroded atherosclerotic plaque. The myocardium behind the occlusion is at acute risk of dying.
Multiple studies demonstrated that this clinical syndrome needs mechanical revascularization (primary PCI with stent implantation) as soon as possible [19,21,68-70].
By mechanical revascularization the ongoing process of ischemia is stopped and (further) myocardial damage can be avoided. This results in a smaller infarct size and better long- term outcome. Primary PCI should be combined with anti-thrombotic drugs to improve the balance between endogenous pro-thrombotic and fibrinolytic activity resulting in blockage of further thrombus formation, promotion of thrombus resolution and minimizing peripheral embolization during mechanical revascularization. In case the ECG does not demonstrate ST-segment elevation but ST-segment depression or no clear signs of ischemia (and the patient still experiences angina pectoris) there is no clear evidence of transmural ischemia and complete luminal obstruction by the thrombus is in general absent or the extent of transmural ischemia is limited. Therefore, the first goal of therapy in acute coronary syndromes without ST-segment elevation is the application of anti- thrombotic and plaque stabilizing drugs to avoid further thrombus formation and complete occlusion of the coronary artery, and to promote healing of the atherosclerotic lesion.
In general, all patients with symptomatic atherosclerosis and/or evidence of ischemia should be treated with anti-thrombotic therapy, beta-blockers, HMG-CoA reductase inhibitors (statins) and ACE-inhibitors. Briefly, anti-thrombotic therapy reduces the risk of intracoronary thrombus formation if plaque rupture or erosion occurs. B-blockers reduce oxygen consumption of the myocardium, improve coronary perfusion and reduce the risk of arrhythmias. Statins inhibit plaque growth, reduce systemic and intra-plaque inflammatory activity and improve endothelial function. Finally, ACE-inhibitors improve left ventricular remodeling and stabilize atherosclerotic lesions. Besides these drugs, the patient should be instructed and supported to practice a healthy life-style to lower the risk of a first or second event.
Mechanical revascularization therapy
In patients with stable angina mechanical revascularization can be performed by PCI or CABG. In general, in these patients mechanical revascularization does not improve the prognosis and the primary objective of this therapy is relieve of symptoms [71-76].
Recently, this was underlinded by the results of the COURAGE study which demonstrated
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that in patients with stable coronary artery disease and an left ventricular ejection fraction of more than 30% with adequate relieve of syptoms on medical therapy, PCI as an adjunct to optimal medical therapy did not result in a reduction of the long-term risk of death or myocardial infarction [77]. Although PCI resulted in the short term in a better reduction of anginal symptoms, after 5 years the angina free survival was comparable.
Therefore, only in limited circumstances mechanical revascularization improves the prognosis such as left main disease, ischemic cardiomyopathy or ischemia induced ventricular arrhythymia’s.
Initially, mechanical revascularization was performed by CABG. Since 1976 PCI is the revascularization strategy of first choice in patients with symptomatic stable obstructive single- or two-vessel disease despite medical treatment [78]. The long-term survival free of death or myocardial infarction after PCI is comparable to CABG, although some studies indicate that CABG may have a survival advantage in multi-vessel disease, especially in patients with impaired ejection fraction or diabetes mellitus [79-88]. Moreover, the survival free of angina or free of re-revascularization procedures is lower after CABG because of the risk of restenosis after PCI, as will be discussed hereafter.
Initially, PCI was performed by balloon dilatation alone [78]. In that era PCI was a procedure with a relatively high risk, mainly due to dissections of the coronary artery, which could induce thrombosis or cause obstruction of blood flow. Moreover, acute re- narrowing of the lumen occurred frequently due to elastic recoil of the vessel. The introduction of the intracoronary stent was a breakthrough since a better final enlargement of the lumen could be achieved by scaffolding the stenosis and dissections could be sealed against the vessel wall [89-92]. Currently, routine implantation of stents is performed in up to 90% of the procedures. The initial relatively high risk of early stent thrombosis in 2-5% of the patients was overcome by the introduction of thienopyridins and adjunct high-pressure post-dilatation of the stents [92-94].
In-stent restenosis
Background and risk factors
Since the introduction of PCI, recurrent luminal narrowing (restenosis) has been a major drawback. Restenosis is caused by three types of response of the vessel wall: elastic recoil, neointimal hyperplasia and negative remodeling [95,96]. Elastic recoil is caused by the properties of the vessel wall and is the passive inward response of the elastic vessel wall after deflation of the angioplasty balloon. Neointimal hyperplasia is the accumulation of smooth muscle cells and extracellular matrix within the intima, which is formed as a response on damage of the vessel wall during balloon angioplasty and chronic stretch of the vessel wall by a stent. Negative remodeling is the chronic constrictive healing
General introduction and outline of the thesis
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response after damage of the vessel wall resulting in a smaller vessel size. After balloon angioplasty the major contributors to restenosis are elastic recoil and negative remodeling. Implantation of stents results in a reduction of restenosis and is therefore performed almost routinely. However, dependent on the clinical characteristics, vessel diameter and lesion characteristics, angiographic restenosis occurred in 15-40% of the patients resulting in the need for additional revascularization procedures in 9-15% of the patients [97-100]. Although the implanted stent prohibits elastic recoil and virtually eliminates negative remodeling, restenosis after stent implantation is mainly caused by neointimal hyperplasia, which is more exaggerated. Most important risk factors for in- stent restenosis are diabetes mellitus, small vessel size, lesion length, implanted stent length and final minimal luminal diameter.
Pathophysiology of restenosis
As outlined above, in-stent restenosis is predominantly due to neointimal hyperplasia. De development of neointimal hyperplasia is a complex process which is only partly understood and can be divided in different phases over time [101-104]. The trigger for neointimal formation is endothelial denudation in combination with damage of the internal elastic membrane and media, often extending into the adventitia, and chronic stretch of the vessel wall by the implanted stent. First, fibrin deposits and thrombocytes accumulate around the stent struts. Hereafter, an inflammatory response due to activated thrombocytes and damage of the vessel wall occurs within days after stent implantation.
The magnitude of this response depends on the extent of damage of the vessel wall and strut penetration into the lipid cores within the plaque. Leucocytes are attracted due the expression of adhesion molecules such as P-selectin (expressed on thrombocytes, causing transmigration of leucocytes across the thrombocytes) and Mac-1 (promoting adhesion of polymorphonuclear leucocytes and monocytes to endothelial cells). Activated thrombocytes and leucocytes produce chemo-attractant proteins such as MCP-1, resulting in endothelial and smooth muscle cell proliferation. This initial inflammatory phase is followed by a phase of smooth muscle cell migration from media and adventitia into the intima. These migrated smooth muscle cells undergo a phenotypic modulation from contractile cells to dividing and synthesizing cells, producing extracellular matrix which is the main component of neointimal tissue. This process is controlled by various growth factors, cytokines, and proto-oncogenes regulating the cell-cycle with the Gap (G)1, DNA synthesis (S), G2 and mitosis (M) phases (Figure 2). Activation of the cell cycle depends on the phosphorylation of cyclins and cyclin-dependent kinases complexes. Most important cyclin-dependent kinase inhibitor is p27
kip, which regulates the transition from the G1 to the S phase. After passing this phase, the cell commits to progress the whole cell cycle through the M phase. After 3 to 6 months the proliferative response of the vessel wall diminishes and remodeling of the neointimal tissue occurs resulting in a reduction of around 25% of the neointimal volume [105,106].
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Treatment and prevention of in-stent restenosis
In-stent restenosis is difficult to treat. Long-term success rate is limited because of the risk of recurrent restenosis, depending on the extent and localization of the restenosis [107]. Several therapies, such as balloon dilatation, cutting balloon dilatation and additional stenting had only limited success. The only therapy which was successful was intracoronary brachtherapy [108,109]. However, the disadvantage of this therapy was delayed re-endothelialization resulting in an increased risk of stent thrombosis and a late catch-up of in-stent restenosis. Therefore, the focus of research was directed towards the prevention of in-stent restenosis. Several strategies have been studied, such as improvement of stent design (strut thickness, stent geometry) [110,111], application of bio-inert or anti-thrombotic stent surface materials (gold, carbon, phosphorylcholine) [112-118], improvement in implantation techniques (direct stenting, IVUS-guided stent implantation) [119-121], post-procedural intracoronary brachytherapy (β- or γ-radiation) [122-124] or adjunct medical therapy (abciximab, statins, dexamethason) [125-130].
Although these strategies in general did result in some reduction of the restenosis rate, the beneficial effect was limited or application was restricted because of costs, availability or side-effects. The introduction of drug-eluting stents was a significant step forward in the prevention of restenosis, which was the start of a new era in interventional cardiology.
G1 S
G2 M
G0
p27kip1↑
sirolimus everolimus zotarolimus
microtubule stabilization
paclitaxel
ribonucleic acid synthesis↓
Figure 2. The cell cycle and points of application of various anti-restenotic drugs
actinomycin
General introduction and outline of the thesis
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Drug-eluting stents
The drug-eluting stent is a sophisticated device using the combination of stent properties to inhibit recoil and negative remodeling with drugs that inhibit neointimal proliferation, utilizing the stent as a local delivery platform. The advantage of local drug release is that higher local tissue concentrations of the drug can be achieved and that systemic side- effects of the drug can be avoided.
The drug
Since restenosis is a complex process involving thrombosis, inflammation, endothelial function, smooth muscle cell migration and proliferation, and extracellular matrix production, various drugs have been investigated targeting at one or several of these processes. Figure 2 demonstrated the targets of the drugs investigated in the largest clinical trials thus far [131-138]. Most of these drugs have been originally used as chemotherapeutic agent, agent for anti-transplant rejection, or immunosuppressive agent. Besides their biological effects, these drugs have their own farmacological profile, which influence achieving optimal tissue levels and the possibilities for loading on a stent [139-141]. Tissue levels depend on lipophilic or lipophobic characteristics, molecular weight and the degree of protein binding of the used drug [142,143] . Moreover, lesion characteristics such as thrombus plays a role in drug-distribution within the vessel wall [144]. Some drugs can be loaded directly onto the metallic surface of the stent, but most drugs need a polymer coating, which forms a reservoir for the drug.
The polymer
Besides the stent and the drug, a polymer coating is in general part of the drug-eluting stent. This polymer coating is used to bind the drug to the stent and to optimize release kinetics. Until recently, the polymer was the major limiting factor in the development of drug-eluting stents. Initially all biodegradable or non-biodegradable polymers induced an increased inflammatory reaction and enhanced neointimal proliferation [145]. Currently used polymers are biologically inert and stable for at least six months or biodegradable without causing an increased proliferative response, although some studies indicate that some of these polymers have an adverse effect on the vessel wall or may induce a local toxic allergic response [146-151] . New developments are inorganic coatings which should result in reduced platelet activation and inflammatory response [152,153].
The stent
The ideal drug-eluting stent is flexible, has an excellent radial strength and a large surface area to load one or more drugs. The gaps between the struts have to be small to get optimal and equal distribution of the drug over the target lesion [140,154]. Stent material, electrophysiological properties and biocompatibility of the stent surface also
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influence neointimal proliferation [111,155]. Currently, all stents used as a drug delivery vehicle are conventional stents, not specially designed for this purpose. Although unknown, the design of these stents could be non-optimal to be used as a drug-eluting stent. New stents are under investigation which are specifically designed for drug-release [156]. Theoretically, a drug-eluting biodegradable stent may be the ideal solution to prevent in-stent restenosis [157]. The stent will be degraded over time and chronic stretch, inducing neointimal proliferation, will be prevented.
Clinical trials comparing drug-eluting stents with bare-metal stents
Several drug-eluting stents have been investigated in clinical trials (Table 2, including references). Most promising results are achieved with the polymer-based sirolimus-eluting stent (Cypher
TM, Cordis, Johnson&Johnson), polymer-based paclitaxel-eluting stent (Taxus
TM, Boston Scientific), polymer-based zotarolimus-eluting stent (Endeavor
TM, Medtronic) and polymer-based everolimus-eluting stent (Xience V
TM/Promus
TM, Abbott/Boston Scientific). Implantation of these stents did reduce the restenosis rate and the subsequent need for repeat target lesion revascularization in patients with stable and unstable lesions. Treatment with other drug-eluting stents failed in reducing restenosis (non-polymer based paclitaxel-eluting stents (Deliver
TM), tacrolimus-eluting carbon stent (Janus
TM)) or resulted in an increased adverse event rate, including death or myocardial infarction (polymer-based actinomycin-eluting stent (Action
TM), polymer sleeve paclitaxel- eluting stent (Quadds
TM)). Therefore, the efficacy and safety achieved with a specific drug-eluting stent cannot automatically be extrapolated to other drug-eluting stents. As described above, the results are dependent on the complex interaction between the drug, the polymer and the stent. Moreover, patient and lesion dependent factors play a role. In general, the benefit of drug-eluting stents compared to bare-metal stents is larger in high risk lesions or patients, such as long lesions and small vessels and patients with diabetes mellitus. None of the studies did demonstrate a reduction in death or myocardial infarction rates. Therefore, according to current knowledge, drug-eluting stents do not improve the prognosis of the patient.
Clinical trials comparing different drug-eluting stents
Thus far, limited number of studies are performed comparing the outcome of different types of drug-eluting stents (Table 3, including references). The largest studies (REALITY and SIRTAX), comparing Cypher
TMwith Taxus
TMstent implantation, reported conflicting results. Compared to Taxus
TMstents, Cypher
TMstents seem to be more effective in reducing restenosis in lesions at high risk of restenosis such as lesions in small vessels, long lesions and in patients with diabetes mellitus. Moreover, as demonstrated by Kastrati et al. (Table 2), Cypher
TMstents are more effective for the treatment of in-stent restenosis.
In a recent meta-analysis comparing the outcome of all randomized trials with Cypher
TMand Taxus
TMstents, it was demonstrated that Cypher
TMstents were associated with a
General introduction and outline of the thesis
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lower target lesion revascularization rate compared to Taxus
TMstents. The difference in target lesion revascularization rate can be attributed to the difference in angiographic outcome. In general, Cypher
TMstents demonstrate less in-segment late luminal loss (±0.20mm) than Taxus
TMstents (±0.35mm). In-stent late luminal loss for these devices is
±0.00mm and ±0.35mm, respectively. The amount of late luminal loss is strongly correlated to the risk of target lesion revascularization [158]. Therefore, there is a clear difference between these drug-eluting stents in their biological potency to inhibit neointimal proliferation. However, the clinical outcome is not only determined by this biological effect. The efficacy of these devices is also determined by the patient risk profile to develop restenosis and lesion charactertics. As discussed above, most important risk factors for restenosis are diabetes mellitus, vessel reference diameter, lesion length and lesion complexity, which remains the same after drug-eluting stent implantation [159]. This may explain why Cypher
TMstents are found to be more effective in reducing target lesion revascularization rates in small vessels, long lesions and patients with diabetes mellitus compared to Taxus
TMstents.
Stent thrombosis
Since the introduction of drug-eluting stents considerable debate is ongoing concerning the safety of these devices, since drug-eluting stents may be associated with an increased risk of stent thrombosis, especially late after stent implantation. Stent thrombosis is a rare but life-threatening complication and results in death in up to 45% of the cases [160,161]. Stent thrombosis got attention after several studies and numerous case-reports demonstrated that stent thrombosis can occur very late after stent implantation, especially after withdrawal of dual anti-platelet therapy [160-175]. Moreover, histopathological animal and human studies demonstrated delayed re-endothelialization and healing of the vessel wall after drug-eluting stent implantation [176-178]. After bare- metal stent implantation, stent thrombosis occurred almost exclusively within 30 days and is mainly related to procedure-related variables, such as untreated dissections and stent underdeployment [92]. After bare-metal stent implantation late stent thrombosis is incidentally reported [179,180]. It is assumed that the prevalence of late stent thrombosis after bare-metal stent implantation is very rare, although exact numbers are lacking. In contrast, after drug-eluting stent implantation stent thrombosis beyond 1 year after implantation has been reported frequently. Risk factors associated with late stent thrombosis after drug-eluting stents are premature discontinuation of dual-antiplatelet therapy, diabetes mellitus, renal failure, bifurcation stenting or stent implantation during acute myocardial infarction. Moreover, late stent thrombosis has been associated with late stent malapposition as assessed by IVUS imaging [181,182]. Late stent thrombosis may annihilate and limit the beneficial effects of drug-eluting stents on restenosis. However, the randomized controlled trials thus far, reported no increased rate of stent thrombosis [183]. It should be taken into account that these trials generally investigated low-risk
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lesions and were underpowered to detect significant differences for this rare event. The use of drug-eluting stents in the ‘real world’, in all type of lesions and patients, may be associated with a higher risk of stent thrombosis, although this risk is generally low (<2%).
[166, 179, 184-188]. Furthermore, the discussion about the risk of late stent thrombosis is complicated by use of different definitions of stent thrombosis. Recently, a new definition has been developed [189]. In this definition stent thrombosis is categorized as definite, probable or possible, dependent on angiographic and clinical parameters (Table 1).
Moreover, stent thrombosis has been categorized as acute (0 – 24 hours after stent implantation), subacute (>24 hours – 30 days after stent implantation), late (30 days – 1 year after stent implantation) and very late (>1 year after stent implantation). Preferably, these definitions should be applied in all studies to compare the risk of stent thrombosis between the various drug-eluting stents and between various patient or lesion subsets.
As pointed out above, withdrawal of dual anti-platelet therapy is a risk factor of (very) late stent thrombosis after drug-eluting stent implantation. Currently, it is not clear how long the dual anti-platelet therapy should be continued. Current guidelines recommend a period of 12 months after stent implantation. However, histopathological data have demonstrated that incomplete healing after drug-eluting stent implantation may be present up to three years after implantation. Therefore, it seems reasonable to continue the dual anti-platelet beyond 12 months in individual patients depending on the presence of diabetes mellitus, renal failure, complexicity of the treated lesion and the total implanted stent length, which are factors additionally increasing the risk of late stent thrombosis.
General introduction and outline of the thesis
Definite stent thrombosis
- Angiographic confirmation of stent thrombosis:
The presence of an occlusive or non-occlusive thrombus that originates in the stent or in the segment 5mm proximal or distal to the stent and the presence of at least 1 of the following criteria within 48 hour time window:
- Acute onset of ischemic symptoms at rest
- New ischemic ECG changes that suggest acute ischemia - Typical rise and fall in cardiac biomarkers
- Pathological confirmation of stent thrombosis Probable stent thrombosis
- Any unexplained death within the first 30 days after stent implantation
- Any myocardial infarction that is related to documented ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause
Possible stent thrombosis
- Any unexplained death from 30 days after stent implantation
Table 1. Academic Research Consortium criteria for stent thrombosis [189]
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Long-term outcome
From animal studies it is known that drug-eluting stents delay the restenotic process, but that the long-term outcome is comparable to bare-metal stents [190,191]. However, thus far no late catch-up phenomenon has been observed in humans and the five years outcome of the first study with sirolimus-eluting stents (RAVEL) is very promising [192].
Results of other studies should be awaited to draw definite conclusions.
Implantation technique
After the results of the SIRIUS study, it became clear that restenosis after drug-eluting stent implantation occurred not only within the stented segment but also at the stent edges, just outside the stent. This was caused by a mismatch between the balloon dilated segment (the injured segment) and the stented segment. Based on this insight, the stent implantation technique was changed in the E- and C-SIRIUS studies. In those studies direct stent implantation was applied as much as possible and the protocol mandated that the pre-dilated segment should be completely covered by the stent and that post-dilation should be performed within the stented segment only. Vessel damage outside the stent may induce restenosis, since that segment is not exposed to the drug released from the stent. This became a major issue in bifurcation stenting. Studies demonstrated that especially the ostium of the side-branch is a location of focal restenosis [193-200].
Moreover, bifurcation stenting is a risk factor for stent thrombosis, possibly by inadequate strut apposition or stent deformation during balloon inflation. Studies are ongoing to improve the implantation technique in these lesions.
IVUS imaging and drug-eluting stents
IVUS imaging is a costly, but easy technique to evaluate acute and long-term results of stent implantation in detail. Using IVUS imaging it has been demonstrated that restenosis after stent implantation was mainly due to neointimal growth [95]. Moreover, IVUS imaging allows evaluation of the effects of drug-eluting stents on the vessel wall and plaque behind the stent and at the stent edges. By IVUS it has been demonstrated that there are clear differences in the amount of neointimal growth and distribution between various drug-eluting stents and bare-metal stents. However, most important contribution of IVUS in the evaluation of stents is the evaluation of stent deployment, late stent malapposition and vessel remodeling [93,119,121,181,201-210]. Late stent malapposition may be a sign of insufficient stent deployment during implantation, reduction of plaque behind the stent, or the result of positive remodeling (Figure 3). Since late stent malapposition has been associated with stent thrombosis, this is an important finding [181]. In the majority of cases late malapposition was developed during the follow-up period and associated with focal positive remodeling behind the stent. Long-term follow-
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up is currently ongoing to evaluate whether this is associated with late stent thrombosis or restenosis [211].
Objective and outline of this thesis
The aim of this thesis was to evaluate a mouse model of restenosis, to study plaque characteristics in STEMI patients by intravascular ultrasound imaging, to implement and evaluate a guideline based treatment protocol for STEMI patients, and to evaluate the efficacy and safety of drug-eluting stents in specific subgroups such as patients with acute myocardial infarction.
In Chapter 2 and 3 animal studies on the pre-clinical evaluation of drug-eluting stents are presented. The development of a drug-eluting cuff mouse model to study restenosis is described in Chapter 2. Chapter 3 reports on a study evaluating the systemic and local effects of dexamethasone on neointimal formation in that mouse model. Chapter 4 describes a study evaluating dexamethasone-eluting stents in insulin and non-insulin dependent diabetic patients with stable coronary artery disease. Chapter 5 reports on the distribution and characteristics of calcified spots along the culprit vessel of STEMI patients as studied by gray-scale intravascular ultrasound imaging. Chapter 6 describes a study in which the plaque characteristics of culprit lesions in STEMI patients were studied by virtual histology intravascular ultrasound imaging. Aim of that study was to evaluate whether these lesions fulfill virtual histology intravascular ultrasound derived vulnerable
General introduction and outline of the thesis
The stent cross-sectional area (purple) remains unchanged during the follow-up period, while the lumen cross-sectional area (red) increases due to positive remodeling (increase in external elastic membrane cross-sectional area (green)). The arrow indicates the stent malapposition site. L denotes lumen.
Figure 3. Late stent malapposition developed by positive remodeling of the vessel wall
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plaque criteria. Chapter 7 describes the MISSION! project, which is a treatment protocol to optimize the pre-clinical, clinical and post-clinical STEMI patient care according to current guidelines. Main parts of this thesis are Chapters 8-10, describing the outcome of the MISSION! Intervention Study, a prospective randomized controlled trial comparing the efficacy and safety of sirolimus-eluting stents and bare-metal stents in STEMI patients.
Chapter 8 reports on the primary angiographic outcome (in-segment late luminal loss at 9 months), secondary clinical outcome (death, recurrent myocardial infarction, repeat revascularization) and the rate of stent malapposition at 9 months. In Chapter 9 the differences in angiographic and clinical outcome of this study between women and men are presented. Chapter 10 is also a sub-study of the MISSION! Intervention Study, focusing on the predictors and mechanisms of early and late stent malapposition after sirolimus- eluting and bare-metal stent implantation in STEMI patients. Finally, a general summary, conclusions and future perspectives are described in English and Dutch, respectively.
Part of this introduction is adapted from B.L. van der Hoeven et al. Drug-eluting stents: Results, Promises and Problems. Int J Cardiol 2005;99:9-17.
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130. Versaci F, Gaspardone A, Tomai F et al. Immunosuppressive therapy for the prevention of restenosis after coronary artery stent implantation (IMPRESS study). J Am Coll Cardiol 2002;40:1935-42.
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