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不同剂量氯吡格雷对急性冠脉综合征患者氯吡格雷抵抗及超敏C反应蛋白、P选择素水平影响.pdf48页
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安徽医科大学硕士学位论文 目 录
中英文缩略词表…………………………………………………………2
中文摘要…………………………………………………………………3
英文摘要…………………………………………………………………5
正文………………………………………………………………………7
引言…………………………………………………………………7
材料与方法…………………………………………………………8
结果…………………………………………………………………11
讨论…………………………………………………………………16
结论…………………………………………………………………29
参考文献……………………………………………………………31
附录………………………………………………………………37
个人简历……………………………………………………………37
致谢…………………………………………………………………38
综述…………………………………………………………………39 1 安徽医科大学硕士学位论文 中英文及缩写对照表
英文缩写 中文全称 英文全称
ACS 急性冠脉综合征 Acute coronary syndrome
ADP 二磷酸腺苷 Adenosine diphosphate
BMI 体重指数 Body mass index
CR 氯吡格雷抵抗 Clopidogrel resistance
CRP C反应蛋白 C-Reactive Protein
hs-CRP 超敏C反应蛋白 High sensitivity C-Reactive Protein
PCI 经皮冠状动脉介入术 Pevcutaneous coronary intervention
TEG 血栓弹力图 Thrombelastography
UA 不稳定型心绞痛 Unstable angina
VASP 血管扩张剂刺激磷酸蛋白
Vasodilator-stimulated 2 安徽医科大学硕士学位论文
不同剂量氯吡格雷对急性冠脉综合征患者的氯吡
正在加载中，请稍后...Atherothrombosis and the role of antiplatelet therapy - STEG - 2011 - Journal of Thrombosis and Haemostasis -
Wiley Online Library
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Summary.& Atherothrombosis remains a major global public health problem. Chronic atherosclerotic disease is often clinically silent and coexists across vascular beds, but when complicated by thrombosis can result in acute coronary syndrome, stroke, transient ischaemic attack and critical limb ischaemia. Platelets play a role in the development of chronic atherosclerotic disease and are a key mediator of clinical events in atherothrombosis. Numerous trials have examined the role of antiplatelet agents in primary and secondary prevention and several new antiplatelet drugs are under development. In secondary prevention, there is evidence of clear benefit of single and in some cases dual antiplatelet therapy in the prevention of recurrent cerebro-vascular complications. Dual antiplatelet therapy has emerged as the standard of care in acute coronary syndromes, with aspirin typically being used in combination with clopidogrel or one of the newer more potent antiplatelet agents. Conversely, in chronic stable coronary disease, no benefit has yet been convincingly demonstrated from dual antiplatelet therapy. In cerebro-vascular disease, aspirin monotherapy remains the cornerstone of prevention of recurrent events, with clopidogrel or the combination of aspirin and dipyridamole being only modestly more efficacious. In primary prevention, the evidence for the routine use of aspirin or any other antiplatelet agent is mixed and suggests this should only be considered on an individual basis in high-risk groups where the thrombotic risk outweighs the risk of major bleeding complications.IntroductionAtherothrombosis is a leading global public health problem, since it is the major disease underlying acute myocardial infarction (MI) and the most frequent cause of stroke, both of which are currently (and are expected to remain) the two leading causes of death in the world []. A sustained decrease in the incidence and case-fatality of cardiovascular (CV) disease in industrialised countries is unfortunately largely offset by a genuine epidemic of CV disease in low- and middle-income countries. The term atherothrombosis refers to the fact that while atherosclerosis is a progressive chronic disease,
it is only when atherosclerosis is complicated by thrombosis (generally caused by plaque rupture or erosion) that clinical manifestations, often life-threatening, appear. Depending on the arterial bed affected, clinical events are acute coronary syndromes (ACS), stroke or transient ischaemic attacks and critical limb ischaemia. Given that risk factors predisposing to atherosclerosis are largely the same across the various arterial beds affected, it is not surprising that many patients have either silent or clinically overt disease across several arterial territories. Data from the large international Reduction of Atherothrombosis for Continued Health (REACH) registry [] have shown that clinically overt poly-vascular disease affects approximately one quarter of patients with coronary artery disease (CAD), 40% of patients with cerebro-vascular disease and the majority (62%) of patients with peripheral artery disease (). Likewise, both autopsy series [] and in vivo imaging studies [] have shown a high prevalence of obstructive CAD among patients with a recent stroke and no prior known history of CAD.Figure&1. &Prevalence of polyvascular disease among stable outpatients with CAD, cerebrovascular disease and PAD in the REACH registry (2).Role of platelets in atherothrombosisApart from their key role in primary haemostasis in preventing blood loss in response to injury, platelets also play several key roles in atherothrombosis. First and foremost, platelet activation and formation of a flow-limiting thrombosis under the high shear rate conditions found in arteries is often the key factor responsible for the abrupt transition from stable, generally clinically silent, arterial disease to the symptomatic, life-threatening clinical manifestations: acute coronary syndromes, ischaemic strokes and transient ischaemic attacks, and critical limb ischaemia. Such events do not occur at random, but are generally related to rupture or erosion of the cap covering an atheromatous plaque, and are thought to be the consequence of local or systemic inflammatory processes. Such explosive localised formation of arterial thrombus at the site of arterial injury may actually occur more frequently than previously thought, since it may resolve through local repair at the many sites of spontaneous arterial injury [], but can also progress to flow-limiting arterial thrombosis, overt symptoms and sometimes fatal events. The role of platelets in these processes is further exemplified by the fact that antiplatelet drugs are extremely effective at preventing these events and their recurrences in patients at high-risk.Platelets also contribute to the development of chronic atherosclerotic lesions by adhering to the vessel wall at sites of endothelial-cell activation, releasing adhesive ligands which may recruit monocytes and macrophages and initiate the formation of platelet-monocyte aggregates, and by releasing inflammatory and mitogenic mediators into the local microenvironment (for a complete review, see [])The various antiplatelet agents available clinicallyThe major classes of antiplatelet agents act at a number of different sites on the platelet. ().Figure&2. &Site of action of major classes of antiplatelet drugs.Aspirin and other thromboxane antagonistsAspirin irreversibly inhibits platelet cyclo-oxygenase (COX)-1, an enzyme responsible for the formation of prostaglandin PGH2, the precursor of thromboxane A2. This effect is achieved even at low dose aspirin (as low as 30&mg per day at repeated doses []). There are, however, other pathways for thromboxane generation, which are insensitive to the effect of aspirin and is the reason for developing thromboxane receptor antagonists such as sulotroban, ifetroban or terutroban. Unfortunately, thus far, these compounds have not demonstrated a benefit in clinical outcome studies and their development appears halted.Phosphodiesterase inhibitorsA combined formulation of dipyridamole and aspirin has been developed, and aims to combine the COX-1 inhibition of aspirin with the vasodilator and antiplatelet properties of dipyridamole. It is administered twice a day and has been tested in large outcome trials, particularly in secondary prevention of stroke []. Cilostazol is a selective inhibitor of phosphodiesterase type III (PDE3) in both platelets and vascular smooth muscle cells. It&s antiplatelet and vasodilator effects have been studied in the setting of peripheral vascular disease [], acute coronary syndromes [] and cerebrovascular disease [].Thienopyridines and other P2Y12 blockersThienopyridines, such as ticlopidine, clopidogrel and prasugrel are able to affect platelet activation and aggregation through irreversible inhibition of the platelet P2Y12 receptor. These agents are pro-drugs, which require metabolism via liver cytochrome P-450 isozymes. Because of this metabolic activation, which is variable [] and in part genetically determined [] the response to ticlopidine and clopidogrel is highly variable and can be low. Persistent on-treatment high platelet reactivity has been linked to reductions in clinical efficacy []. Prasugrel has a much more efficient metabolic conversion, which explains a faster and more profound inhibition of platelets than clopidogrel, despite the fact that the active metabolites of both drugs are equipotent on platelets in vitro []. Rapidly active reversible P2Y12 antagonists have been designed: ticagrelor (oral only) elinogrel (intravenous and oral) [] and cangrelor (intravenous only). These agents do not require metabolic activation by the liver and gut and are therefore able to achieve rapid platelet inhibition, within 1&3&h after dosing for ticagrelor and almost immediately for cangrelor. Because of the reversible nature of the ADP receptor antagonism, these agents require repeated administration (bid for ticagrelor) or continued infusion (for cangrelor).Thrombin receptor antagonistsThrombin is arguably the most potent activator of platelets and hence the associated platelet receptors are a natural target for inhibition []. Platelet thrombin receptors, called protease-activated receptors (PAR), have a very high affinity for thrombin and the most important of these in humans is the PAR-1 receptor []. In preclinical models and small clinical trials PAR-1 inhibition has been shown to inhibit thrombin mediated platelet activation without an increase in bleeding. It is this capacity to inhibit pathological thrombosis but not adversely affect protective haemostasis that distinguishes thrombin receptor antagonists (TRAs) from the ADP and TXA2 pathway inhibitors which affect both routine haemostasis and pathological thrombosis.There are two oral antagonists of PAR-1 currently in clinical development: vorapaxar (SCH530348; Merck, NJ, USA) [] and atopaxar (E5555, Eisai, Tokyo, Japan) []. Both have been shown in preclinical trials to exert antiplatelet effects without increasing bleeding times. Atopaxar showed early promise in a 2-arm phase II Japanese trial (J-LANCELOT) involving patients with ACS and high risk CAD []. The primary safety endpoint of the trial was bleeding events and there was no increase in clinically significant bleeding, although there was a dose-dependent trend towards increased nuisance bleeding. Two further phase II atopaxar studies, Lancelot CAD (NCT) and Lancelot ACS (NCT) are shortly to be published. Vorapaxar was under evaluation in two large phase III trials (TRA-CER, NCT and TRA-2P, NCT), which are nearing completion. Recently, however, the data and safety monitoring board for the trials intervened recommending that patients with a previous history of stroke not receive verapaxar due to an excess risk of intracranial haemorrhage. As a result TRA-CER patients have discontinued the study drug immediately and only patients with a history of MI and peripheral vascular disease are continuing to receive the drug within TRA-2P TIMI 50. Results from both the Vorapaxar trials are expected later this year.Glycoprotein IIb/IIIa blockersActivation of the GPIIb/IIIa receptor is the final common pathway of platelet aggregation and is inhibited by abciximab, eptifibatide and tirofiban. These intravenous agents provide potent inhibition of platelet aggregation. They have been available almost 20&years and well studied clinically in acute coronary syndromes and for percutaneous coronary interventions (PCI) [].Use of antiplatelet agents in secondary prevention of atherothrombosisIn patients with established atherothrombotic disease, there is a high risk of recurrence of potentially fatal vascular events: MI, stroke and vascular death. The risk is greater in patients who have previously had acute thrombotic events, particularly if the event occurred &&12&months ago []. As time elapses, the risk declines somewhat but will remain higher than for patients without established disease.There is a strong evidence base to support the benefit of antiplatelet therapy in this setting: a collaborative meta-analysis of randomized trials of antiplatelet therapy established that antiplatelet therapy (in fact, mostly aspirin in these studies) reduced the risk of death, MI and stroke by approximately a quarter [].CADAcute coronary syndromes& In patients with ST elevation and non-ST elevation ACS, there is conclusive evidence that aspirin improves clinical outcomes [] and that combined dual antiplatelet therapy with aspirin and clopidogrel is superior to aspirin alone: adding clopidogrel to aspirin reduced mortality in STEMI in the COMMIT trial [], improved clinical and angiographic outcomes in STE-ACS treated with thrombolytic therapy in the CLARITY trial [] and reduced the composite of CV death, MI and stroke in the CURE trial. The benefits of dual antiplatelet therapy are, therefore, present regardless of the type of ACS and whether or not these patients undergo PCI. For this reason, international guidelines consistently recommend combined dual antiplatelet therapy with aspirin and clopidogrel for up to 12&months [].Because the antiplatelet effect of clopidogrel is delayed (due to the need for metabolic transformation) variable and modest, there have been attempts to improve dual antiplatelet therapy. A double loading dose and maintenance dose of clopidogrel (600&mg loading dose followed by 150&mg daily for 1&week and 75&mg daily thereafter) was compared to the standard regimen (300&mg loading dose followed by 75&mg daily) in non-ST-elevation ACS patients in the large CURRENT/OASIS 7 trial []. Overall, there was no reduction in the primary endpoint of CV death, MI and stroke, but a pre specified analysis of the approximately 75% of patients who went on to undergo PCI demonstrated a 15% relative reduction in the composite endpoint []. Prasugrel was compared to clopidogrel, (using a 300&mg loading dose and a 75&mg maintenance dose regimen), &on top of aspirin& in ACS patients in whom PCI was decided, in the TRITON/TIMI-38 trial: it reduced the composite endpoint of CV death, MI and stroke by approximately 19%, but at the expense of a 32% increase in TIMI major bleeding (excluding bleeds related to coronary artery bypass surgery) [] and with bleeding clustering in patients with a prior history of stroke/TIA, low body weight (&&60&kg) and older age (&&75&years). For this reason, prasugrel is not recommended in these three subgroups. Whether the benefits of prasugrel over clopidogrel can be extended to ACS patients treated medically is being explored in the TRILOGY-ACS trial []. Ticagrelor was also compared to clopidogrel but was given to all ACS patients, regardless of whether these patients went on to PCI, coronary artery bypass grafting surgery (CABG) or to medical therapy alone. Importantly, the clopidogrel control arm allowed reloading with clopidogrel at the time of PCI. In the PLATO trial, ticagrelor reduced the primary composite endpoint of CV death, MI and stroke by 16% but with a 21% reduction in CV death and no increase in major bleeding, whether analyzed using the PLATO or the TIMI bleeding scales []. The lack of increase in major bleeding appears to reflect the net effect of a modest but significant increase in non-CABG-related major bleeding and a non-significant reduction in CABG-related bleeds, which offset each other. The latter is understandable given the reversibility of effect of ticagrelor.In the era of potent oral dual antiplatelet therapy, the role of GPIIb/IIIa blockers has dwindled: there is only a marginal benefit for ACS patients treated conservatively [] and the large EARLY ACS trial did not demonstrate a reduction in the primary endpoint with upstream eptifibatide therapy compared to placebo in addition to aspirin and clopidogrel in patients with NSTE-ACS []. However, the ISAR-REACT2 trial showed that in NSTE-ACS patients going to PCI, adding abciximab at the time of PCI was associated with clinical benefit and that this benefit was entirely confined to patients with elevated troponin []. This would suggest that GPIIb/IIIa blockers do not have a role in the routine upstream management of ACS patients before PCI but are probably useful at the time of PCI if patients have elevated troponin. Somewhat similarly, while there are benefits to use of GPIIb/IIIa blockers (with most of the evidence accumulated with abciximab) in primary PCI for ST elevation MI, upstream treatment in the ambulance failed to provide clinical benefit in the FINESSE trial (but was associated with increased bleeding) [], but was associated with borderline benefit in the ON-TIME2 trial []. Overall, this suggests that the role of GPIIb/IIIa blockers will become a case-by-case decision as oral antiplatelet therapy becomes more potent and rapidly active with the emergence of newer agents.Whether adding inhibition of PAR-1 to dual antiplatelet therapy will improve outcomes after ACS is being explored in the large TRA-CER trial [] comparing vorapaxar to placebo on top of dual antiplatelet therapy after ACS.The role of cangrelor in the setting of ACS patients undergoing PCI is still unclear after two large phase III trials failed to achieve their primary efficacy endpoint []. Yet, there were some indications of potential benefits, including a reduction in mortality in one of the trials, which were suggestive enough to lead to a third ongoing trial (CHAMPION-Phoenix, NCT) testing the role of this agent in PCI.Chronic stable CAD& Beyond 12&months after an ACS or in stable CAD patients, there is yet no evidence of a benefit of dual antiplatelet therapy compared to single therapy alone. Aspirin is effective in this setting and clopidogrel only yields modest benefits compared to aspirin, with a 9% relative reduction in the CAPRIE trial []. Dual antiplatelet therapy was tested in the CHARISMA trial combining patients with CAD, cerebrovascular disease, peripheral arterial disease and patients in primary prevention but at high-risk. In that trial, clopidogrel failed to improve clinical outcomes overall []. Further analysis suggested a possible interaction between clopidogrel treatment and the setting: secondary prevention patients appeared to derive benefit whereas there was potential harm in primary prevention patients. A post-hoc analysis confined to patients with prior events suggested a benefit of dual antiplatelet therapy but this deserves confirmation by a new trial [].In patients with a remote MI, new trials are in preparation with elinogrel (ECLIPSE trial) and ticagrelor (PEGASUS/TIMI-54 trial, NCT). A somewhat related trial is underway comparing vorapaxar to placebo on top of aspirin in the secondary prevention of atherothrombosis setting (TRA-2P/TIMI 50 trial, NCT). Whether it will be feasible to &push the envelope& of antiplatelet therapy further without clinically unacceptable bleeding will emerge from these studies.Cerebrovascular diseaseAntiplatelet therapy is the cornerstone of prevention of recurrent ischaemic stroke. Aspirin has been shown to reduce the risk of recurrent stroke and other major vascular events by 13% (95% CI 6&19%) [] at the expense of a relative increase in the risk of major bleeding by 70%, but with a modest annual increase (0.13% 95% CI 0.08&0.20%). A number of other antiplatelet agents, such as triflusal, dipyridamole, ticlopidine, terutroban [] have been compared to aspirin and provide either no efficacy benefit or only marginal benefits. The best results have been obtained with either clopidogrel or the combination of aspirin and dipyridamole taken twice daily [], although a large trial failed to demonstrate a difference in the prevention of CV death, MI and stroke from either of these two agents []. These agents are modestly more effective than aspirin but are also more expensive. Cilostazol has also been used in smaller trials for the long-term secondary prevention of stroke and reduced the risk of stroke by 39% (95% CI: 9&59%) compared with placebo [] and by 38% (95% CI: &26&70%) compared with aspirin []. A recent larger randomised control trial also found Cilostazol to be non-inferior to aspirin for the prevention of stroke after an ischaemic stroke, and was associated with fewer haemorrhagic events. []. Larger trials are awaited to confirm these findings. The role of newer antiplatelet agents with more consistent efficacy than clopidogrel, aspirin, or the combination of aspirin and dipyridamole is still unclearAt the acute phase of stroke, the meta-analysis of the CAST (Chinese Acute Stroke Study) and the IST (International Stroke trial) with 40&000 patients included that aspirin 160&300&mg per day given with 48&h of symptom onset is more effective than no aspirin in reducing recurrent vascular event at 6&months. Whether dual antiplatelet therapy (aspirin plus clopidogrel) started within 12&h of symptom onset is more effective than aspirin alone in reducing 90-days vascular events is under evaluation in the POINT and the CHANT trials after that a meta-analysis suggested a beneficial effect of early onset dual antiplatelet therapy [].Peripheral artery disease (PAD)Patients with PAD suffer from claudication but will usually die from CV complications of atherosclerosis in the brain or the heart. Therefore, antiplatelet therapy may be a logical therapy to prevent CV events in this population, regardless of the presence of claudication. The ATC meta-analysis found a reduction of approximately one-quarter of CV events in PAD patients, which appeared consistent for patients with claudication, prior history of surgery or prior history of peripheral angioplasty []. A more recent meta-analysis of 18 randomised trials in 5269 patients with PAD assessed the effect of aspirin, alone or in combination with dipyridamole on the risk of CV event []. Despite combining trials, this analysis had limited power and found a non-significant 12% relative risk reduction in CV outcomes from aspirin. More recently, several trials have explored the role of aspirin in the primary prevention of CV events in patients with PAD and were somewhat more negative: in the Popadad study, there was no evidence of benefit of aspirin in primary prevention of CV events and mortality in diabetic patients with an ankle-brachial pressure index &&1.0 but no symptomatic CV disease []. Likewise, in the AAA trial, in individuals without clinical CV disease identified from the general population on the basis of low ankle-brachial index (&&0.96) the administration of aspirin did not reduce vascular events compared to placebo []. Therefore, in PAD patients without otherwise established CV disease, we are missing strong evidence from a benefit of routine aspirin.More potent antiplatelet interventions using clopidogrel (which was compared to aspirin in the CAPRIE trial and appeared to provide marginal benefit []) or the combination of aspirin and clopidogrel equally show little evidence of benefit in routine practice. The latter combination was compared to aspirin alone in the CASPAR trial but failed to improve limb or systemic outcomes in PAD patients requiring below-knee bypass grafting. []Use of antiplatelet agents in primary prevention of atherothrombosisGiven the magnitude of atherothrombosis in terms of public health, the ability to reduce the risk of CV events such as CV death, MI and stroke, even by a modest amount, using antiplatelet therapy would seem appealing. Yet, the evidence for the role of antiplatelet therapy in primary prevention of atherothrombosis is at best sketchy: in the recent collaborative meta-analysis of individual participant data from randomized trials performed by the Anti-Thrombotic Trialists (ATT) collaboration [], treatment with aspirin yielded a 12% reduction in CV events, due mainly to a reduction of approximately 20% of nonfatal MI but without any effect on vascular mortality and with an increase in major bleeding risk. While there have been suggestions that there might be a differential effect of aspirin on the prevention of MI and stroke in men compared to women [], this was not borne out by the ATT meta-analysis. Overall, these results do not suggest to routinely use aspirin (or any other antiplatelet agent) for primary prevention of atherothrombosis, other than on an individual basis, weighing the risks of thrombosis vs. bleeding. One patient group at particularly high-risk of thrombosis and CV events is patients with diabetes mellitus. In diabetics, the risk of CV events is two to 4-fold that of individuals without diabetes []. The role of aspirin for the primary prevention of CV events in diabetics was recently reviewed: the currently available evidence is not definitive: aspirin may produce a non-significant modest reduction in the risk of MI (by approximately 9%) and stroke (by approximately 15%) in diabetics, which must be weighed against a 50&55% increase in the risk of major bleeding and in intracranial bleeding. This resulted in the recommendation that use of low dose (75&162&mg per day) aspirin is reasonable for prevention in diabetics who are at increased CV risk (10-year risk of CV events &&10%) and who are not at increased risk of bleeding (based on a history of previous gastro-intestinal bleeding, peptic ulcer disease or concurrent use of other medications increasing bleeding risk). This population includes most men over the age of 50&years and women over 60&years who have one or more major risk factors. Aspirin should not be recommended for prevention in adult diabetics at low CV risk. Two large trials [] are ongoing to provide information regarding the role of aspirin for CV prevention specifically among diabetics.ConclusionAtherothrombosis remains a major global public health problem. Antiplatelet therapy has proven efficacy in secondary prevention but the evidence for its net benefit in primary prevention is less well established. Historically aspirin and the P2Y12 receptor blocker, clopidogrel have represented the gold standard in dual antiplatelet therapy, however limitations in drug efficacy and the phenomenon of high on treatment platelet reactivity in a subset of individuals has led to the development of new drugs. More potent and in some cases reversible P2Y12 receptor antagonists have been extensively studied and antagonists of thrombin receptors, thromboxane, and phosphodiesterase type III are all the subject of ongoing trials. At the same time, the development of near patient platelet function testing will provide the opportunity in the future for customisation of therapy not just to the clinical context but also to an individual&s in vivo response to established antiplatelet regimes. In the context of atherothrombotic disease these developments should further our understanding of balancing the antithrombotic benefits of antiplatelet therapy with their inherent associated bleeding risks.Disclosure of Conflict of InterestsThe authors state that they have no conflict of interests.
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