Evolving role of bivalirudin in percutaneous coronary interventions; impact of the REPLACE-2 study

Percutaneous coronary interventions are being used with increasing frequency nowadays for the treatment of patients with coronary heart disease. Acute thrombotic complications remain one of the major limitations of these procedures for which unfractionated heparin has been the standard foundation anticoagulant. It has, however, many limitations and disadvantages that necessitated research and development of alternative anticoagulant therapies. The direct thrombin inhibitor bivalirudin has been approved as a substitute for heparin in patients undergoing angioplasty for unstable angina based on data in higher-risk patients where bivalirudin resulted in lower rates of ischaemic and bleeding complications compared to heparin. This evidence was collected prior to the widespread use of platelet glycoprotein (GP) IIb/IIIa receptor blockers, thienopyridines and intracoronary stents, considered standard practice for such patients today. The REPLACE-2 study was carried out to establish whether, in the current era, bivalirudin used with provisional GP IIb/IIIa blockade if necessary during the procedure could provide equivalent protection from ischaemic events compared with the gold standard of heparin plus routine GP IIb/IIIa blockade. With advantages with regards to bleeding, ease of use and reduced cost, bivalirudin use with provisional GP IIb/IIIa inhibitors in low-to-moderate risk percutaneous coronary interventions allows GP IIb/IIIa receptor antagonists to be used in a selective fashion, rather than in all patients. In this article, background rationale for bivalirudin use in this setting is reviewed as well as past research in this area. Additionally, the implications of the REPLACE-2 study in establishing where bivalirudin fits into our current interventional cardiology practice and future directions are presented.     

经皮冠状动脉介入治疗79例临床分析

目的探讨经皮冠状动脉介入治疗的可行性、安全性和成功率。方法选择该院2005年1月~2009年7月经皮股动脉穿刺冠状动脉腔内成形术（PTCA）及支架术79例患者为研究对象。结果A型病变支架术成功率100%（36/36）,B型病变成功率98.9%（88/89）,C型病变成功率95.3%（41/43）。1例分叉、弯曲、偏心性病变和2例慢性闭塞性病变（CTO）因指引导丝不能通过病变致手术失败,总成功率为98.2%。结论经皮冠状动脉介入治疗创伤小,恢复快,安全且成功率高。     

Comparison of patient outcomes with bivalirudin versus unfractionated heparin in percutaneous coronary intervention

OBJECTIVE: To compare clinical outcomes and glycoprotein IIb-IIIa inhibitor use in patients undergoing percutaneous coronary intervention (PCI) who received bivalirudin or unfractionated heparin (UFH) in a real-world setting. DESIGN: Retrospective cohort analysis. SETTING: University-affiliated medical center. PATIENTS: One thousand seventy-five adult patients who underwent PCI and received either bivalirudin (539 patients) or UFH (536 patients) from April 1, 2003-April 1, 2004. MEASUREMENT AND MAIN RESULTS: Patient data on demographics, comorbidities, laboratory values, and reports of radiologic examinations, cardiac catheterizations, and discharge summaries were obtained. Outcomes evaluated included rates of in-hospital mortality, myocardial infarction, revascularization, and length of stay (LOS), as well as Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) and Thrombosis in Myocardial Infarction (TIMI) bleeding categorization. Bivalirudin use was associated with a significant reduction in TIMI major (5.0% vs 9.7%, p=0.003), REPLACE-2 major (5.4% vs 12.9%, p<0.001), and TIMI minor (1.7% vs 6%, p<0.001) bleeding complications compared with UFH use. Significantly fewer patients in the bivalirudin group received glycoprotein IIb-IIIa inhibitors (27.3% vs 62.7%, p<0.001). Patients receiving bivalirudin had significantly fewer myocardial infarctions after catheterization (10.7% [40/375] vs 18.0% [51/284], p=0.007). No differences were noted in mortality and revascularization rates between groups. A shortened LOS was observed in the bivalirudin group. CONCLUSIONS: This real-world analysis that included high-risk patients provides further evidence that bivalirudin is an attractive alternative to UFH because of a decrease in bleeding events without compromising efficacy.     

比伐芦定对比肝素联合替罗非班用于PCI围手术期抗凝治疗的药物经济学

目的：对比研究比伐芦定及普通肝素联合糖蛋白受体拮抗剂替罗非班（H-T）用于中国急性冠脉综合征（ACS）患者经皮冠状动脉介入（PCI）围手术期抗凝治疗的成本效果,为中国人群PCI围手术期抗凝治疗药物的合理选用提供理论依据。方法：参考我国随机、双盲、多中心Ⅲ期临床实验BRIGHT的研究结果,通过建立决策树模型及Markov长期外推模型,模拟计算使用比伐芦定或H-T治疗患者的调整质量生命年（QLAYs）及治疗成本,对比伐芦定用于中国人群PCI抗凝治疗的成本效益进行分析和研究。结果：比伐芦定和H-T组的治疗总成本分别为46 404.80元和43 552.14元,使用比伐芦定患者可获得的QALYs为10.07,采用H-GPI治疗方案的患者QALYs为9.98。增量成本效果分析显示,采用比伐芦定可提高患者的健康效益（△E>0）,但同时增加了治疗成本（△C>0）,其增量成本效果比（ICER）为28 575.77元/QALYs,小于3倍部分城市人均GDP,提示采用比伐芦定具有成本效果优势。一维敏感度分析显示本研究结果稳定可靠。结论：在我国目前整体经济形势下,与H-T的二联抗凝方案相比,比伐芦定用于PCI抗凝具有成本效果优势,可替代传统抗凝方案用于ACS患者PCI围手术期抗凝治疗。     

经皮冠状动脉介入治疗急性心肌梗死手术期使用比伐卢定的安全性和有效性分析

目的 探讨对经皮冠状动脉介入治疗急性心肌梗死手术期使用比伐卢定的安全性和有效性。方法 收集邢台市第三医院2014年1月至2016年6月的急性心肌梗死(AMI)拟行经皮冠状动脉介入(PCI)的病人217例为研究对象,随机数字表法分为观察组(比伐卢定组)和对照组(肝素组),统计分析其安全性和有效性。结果 观察组病死率4例(4.30%)明显低于对照组17例(13.71%)(χ²=4.452, P=0.020);观察组的主要心脏不良事件发生率、大出血发生率、输血发生率、血小板减少发生率均明显低于对照组,差异有统计学意义(P<0.05);但支架内血栓发生率两组差异无统计学意义(P>0.05)。结论 与肝素相比,AMI病人行PCI手术期使用比伐卢定,能够获得更好的抗凝疗效,并且还能显著减少血小板减少发生率,具有相对较好的安全性和抗栓疗效。     

An update on the clinical use of drug-coated balloons in percutaneous coronary interventions

ABSTRACT

Introduction: Drug-coated balloons (DCB) promise to deliver anti-proliferative drugs and prevent restenosis leaving nothing behind. Although, randomized clinical trials have demonstrated their efficacy for the treatment of in-stent restenosis, clinical evidence supporting their use in other coronary applications is still lacking.

Areas Covered: This review summarizes the development status of clinically available DCB technologies and provides an update on the current data for their coronary use.

Expert Opinion: Current generation DCB prevent restenosis by delivering paclitaxel particles on the surface of the vessel wall. Although clinically available technologies share a common mechanism of action, important differences in pharmacokinetic behavior and safety profiles do exist. Future technological improvements include the development of coatings displaying: high transfer efficiency; low particle embolization potential; and alternative drug formulations. Optimized balloon-based delivery systems and drug encapsulation technologies also promise to improve the technical limitations of current generation DCB. Although proving clinical superiority against DES may prove to be difficult in mainstream applications (i.e., de novo), new generation DCB technologies have the potential to achieve a strong position in the interventional field in clinical settings in which the efficacy of DES use is not proven or justified (i.e., bifurcations).     

Pharmacological approach of no-reflow phenomenon related with percutaneous coronary interventions

The no-reflow phenomenon (NRP) is characterized by an inadequate myocardial tissue perfusion in the presence of a patent epicardial coronary artery. It generally occurs after temporary occlusion of the artery causing myocardial ischemia and necrosis that persist after relief of the vessel occlusion, without evidence of epicardial mechanical obstruction. Currently, the main scenario of NRP is the setting of percutaneous coronary interventions (PCI), especially in patients with acute myocardial infarction or saphenous vein graft disease, and its occurrence is associated with adverse clinical outcomes. Pathophysiology of NRP is not fully understood but it seems to be related with microvascular damage. Several mechanisms have been involved, such as distal microembolization, interstitial and intracellular edema, coronary spasm and capillary plugging. Diagnosis of NRP is generally based on clinical and angiographic data. Several methods have been proposed for the assessment of NRP, such as electrocardiography, myocardial contrast echocardiography, contrast-enhanced magnetic resonance imaging, nuclear imaging or positron emission tomography, that have demonstrated additional prognostic value over angiography. There are different pharmacological and mechanical approaches for the prevention of NRP but none of them have demonstrated a clear efficacy. The treatment of established NRP is mainly based on the administration of coronary vasodilators, like adenosine, verapamil or nitroprusside, but clinical results are frequently disappointing. The objective of this review is to describe the state of the art of the pathophysiology, diagnosis and pharmacological management of NRP.     

Direct thrombin inhibitors for the treatment of acute coronary syndromes and during percutaneous coronary interventions

As acute coronary syndromes are principally sustained by plaque complication and subsequent thrombus formation, anticoagulant therapy plays a central role in avoiding ischemic events; its main targets are thrombin activity and generation. Despite its limitations, such as its scarce ability to activate bound thrombin and its unpredictable pharmacological response, heparin is the most widely used drug for this purpose. Direct thrombin inhibitors are biologically superior to heparin principally because they inhibit clot-bound and circulating thrombin without interacting with other plasma proteins. Their clinical role in acute coronary syndromes and during coronary intervention has been tested in several trials. This article overviews the principal trials involving active-site direct thrombin inhibitors in acute coronary syndrome and during coronary intervention and compares their efficacy and safety with unfractionated heparin. It also describes ongoing trials and analyzes further clinical developments such as their use in addition to the glycoprotein IIb/IIIa inhibitors and the potential advantage possible with new agents orally administered.     

Comparison of bolus only with bolus plus infusion of bivalirudin in patients undergoing elective percutaneous coronary intervention: a retrospective observational study

Background: Anticoagulation therapy during percutaneous coronary intervention (PCI) has been the focus of numerous clinical trials. Low-anticoagulant doses have been successfully used in patients undergoing elective PCI, a situation with low-thrombogenic milieu. Objective: The purpose of the study was to evaluate the safety and efficacy of shorter duration of treatment with bivalirudin in patients undergoing elective PCI and receiving optimal antiplatelet therapy. Methods: We compared patients undergoing PCI who received aspirin and clopidogrel loading dose in addition to either conventional bivalirudin dosing (intravenous [IV] bolus of 0.75 + 1.75 mg/kg per h for the duration of PCI; n = 197) or a reduced bivalirudin dose (IV bolus of 0.75 mg/kg; n = 200). Results: Procedural success was obtained in 100% of cases. The primary end point (in-hospital death, acute myocardial infarction, or need for urgent target vessel revascularization) did not differ between both the groups (6 patients [3%] in the conventional dose group vs 5 patients [2.5%] in the reduced dose group). Major bleeding occurred in 1 patient in the conventional dose group (P = nonsignificant [NS]). Minor bleeding occurred in 4 patients (2%) in the conventional dose group vs 5 patients (2.5%) in the reduced dose group (P = NS) and was mainly due to bleeding at entry site. Conclusion: In patients undergoing elective PCI, using bivalirudin as a bolus only dosing may be as effective and less costly when compared with bolus followed by an infusion for the duration of the intervention. A larger study is needed to confirm our findings.     

Intracoronary use of GP IIb/IIIa inhibitors in percutaneous coronary interventions

The glycoprotein (GP) IIb/IIIa receptor is critical to the process of platelet aggregation and thrombus formation as it serves as the final common pathway for platelet aggregation. For this reason, the development of GP IIb/IIIa inhibitors that block fibrinogen binding to the receptor has become an attractive strategy for antiplatelet therapy with an expected strong and specific effect. Presently, there are three commercially available GP IIb/IIIa inhibitors: abciximab, eptifibatide and tirofiban. All three drugs are commonly administered intravenously, and large-scale clinical trials have demonstrated a clear clinical benefit and good safety profile in patients at high risk, especially those undergoing percutaneous coronary interventions (PCI). Recently, several studies tested the intracoronary (IC) route for GP IIb/IIIa inhibitors in order to verify its safety and its possible superiority as compared to the intravenous (IV) route. The majority of the studies testing the IC route were conducted using abciximab and in patients with STEMI with better results in terms of myocardial reperfusion and infarct size and also promising results in terms of clinical outcome. On the IC administration of eptifibatide and tirofiban only some, even if promising, data are available. Larger and randomized studies are warranted to confirm the superiority of the IC route of administration of the GP IIb/IIIa inhibitors to the IV one in patients with coronary artery disease undergoing PCI.     

Significance of aspirin and clopidogrel resistance in patients undergoing percutaneous coronary interventions

Dual antiplatelet therapy (aspirin plus clopidogrel) is mandatory in patients treated with coronary stent implantation. This strategy is highly effective in prevention of stent thrombosis until its struts are covered with endothelium. However, a substantial number of patients still suffer from recurrent ischemic coronary events despite adequate antiplatelet therapy. These events fall into three categories: stent thrombosis, in stent restenosis and events related to other non-stented coronary lesions. Some data suggest that beside other local and systemic factors resistance to aspirin and clopidogrel may be a possible cause of stent thrombosis and ischemic events in patients after coronary interventions. Several mechanisms of antiplatelet drug resistance have been reported including poor compliance, interactions with other drugs, genetic polymorphism or increased platelet turnover. More research is needed to adequately assess the clinical significance and prognostic value of antiplatelet drug resistance detected by laboratory tests in patients undergoing percutaneous intervention. We review published data on mechanisms and the clinical significance of aspirin and clopidogrel resistance in patients after coronary interventions.     

Anticoagulation in patients with heparin-induced thrombocytopenia undergoing percutaneous coronary angiography and interventions

The administration of heparins (unfractionated or fractionated) represents the current standard as anticoagulant treatment during percutaneous coronary intervention in different clinical settings (elective cases and acute coronary syndrome). Since the incidence of heparin-induced thrombocytopenia (HIT) is expected to range between 0.1 and 5%, the application of an appropriate anticoagulant agent has become a mandatory issue. This review will provide current pathophysiological insights of HIT as well as contemporary alternative anticoagulant strategies during PCI in patients with or at risk of HIT.     

Thienopyridines in percutaneous coronary interventions: standard procedures and high risk subsets

Due to the significant clinical and economic consequences of subacute stent thrombosis and the use of more complex devices (brachytherapy, drug eluting stents) in a variety of clinical situations (i.e. acute coronary syndromes), initiation and duration of a combined antiplatelet therapy using aspirin and a thienopyridine drug has become an issue of ongoing discussion in interventional cardiology. This review will provide a short introduction into the pathophysiology of stent thrombosis before standard procedures and critical issues on the use of thienopyridines in the setting of coronary interventions are discussed. Furthermore, clinically relevant issues that are not clearly covered by recommendations or guidelines like thienopyridines after coronary interventions in patients on chronic oral anticoagulation are also addressed.     

Effects of tirofiban on acute systemic inflammatory response in elective percutaneous coronary interventions

SUMMARY

Objective: In this study the effect of a specific glycoprotein IIb/IIIa inhibitor, tirofiban [which also has antiplatelet activity on acute systemic inflammatory responses (IR) during elective percutaneous coronary intervention (PCI)] was evaluated.

Patients and methods: Patients with stable angina pectoris and similar baseline characteristics who angiographically had a single lesion in their coronary arteries with a PCI performed on that lesion were enrolled in the study. One group of patients (control group, n?=?52) received 0.9% NaCl (15?mL/h for 24h) and the other group (tirofiban group, n?=?55) had tirofiban (10|ig/kg bolus infusion in 3min and 0.15jj,g/kg/mir for 24h) in addition to stenting without pre-dilatation. The effect of interventional procedure on levels of cardiac troponin T (cTnT) and several parameters of acute IR (leukocytes, fibrinogen, C-reactive protein, interleukin-1, interleukin-6, interleukin-8 and tumor necrotizing factor-α) was assessed on blood samples obtained from all patients before PCI and at pre-specified time points after PCI.

Results: During the follow-up after PCI, the number of patients becoming cTnT-positive (> 0.1?ng/mL) was greater in the control group [12 (23%) patients vs. 3 (5%) patients, p?=?0.01]. However, both groups had changes (generally observed as elevations) in their levels of all inflammatory parameters during the study and C-reactive protein, interleukin-6 and tumor necrotizing factor-α levels were elevated significantly. Yet, no significant difference occurred between groups due to these changes in any phase of the study (p?>?0.05).

Conclusions: Based on the findings of this study, it was concluded that although tirofiban limits development of myocardial necrosis during elective PCI, it does not directly affect the acute systemic inflammatory responses.     

Effects of tirofiban on acute systemic inflammatory response in elective percutaneous coronary interventions

OBJECTIVE: In this study the effect of a specific glycoprotein IIb/IIIa inhibitor, tirofiban [which also has antiplatelet activity on acute systemic inflammatory responses (IR) during elective percutaneous coronary intervention (PCI)] was evaluated. PATIENTS AND METHODS: Patients with stable angina pectoris and similar baseline characteristics who angiographically had a single lesion in their coronary arteries with a PCI performed on that lesion were enrolled in the study. One group of patients (control group, n = 52) received 0.9% NaCl (15 mL/h for 24 h) and the other group (tirofiban group, n = 55) had tirofiban (10 microg/kg bolus infusion in 3 min and 0.15 microg/kg/min for 24 h) in addition to stenting without pre-dilatation. The effect of interventional procedure on levels of cardiac troponin T (cTnT) and several parameters of acute IR (leukocytes, fibrinogen, C-reactive protein, interleukin-1, interleukin-6, interleukin-8 and tumor necrotizing factor-alpha) was assessed on blood samples obtained from all patients before PCI and at pre-specified time points after PCI. RESULTS: During the follow-up after PCI, the number of patients becoming cTnT-positive (> 0.1 ng/mL) was greater in the control group [12 (23%) patients vs. 3 (5%) patients, p = 0.01]. However, both groups had changes (generally observed as elevations) in their levels of all inflammatory parameters during the study and C-reactive protein, interleukin-6 and tumor necrotizing factor-alpha levels were elevated significantly. Yet, no significant difference occurred between groups due to these changes in any phase of the study (p > 0.05). CONCLUSIONS: Based on the findings of this study, it was concluded that although tirofiban limits development of myocardial necrosis during elective PCI, it does not directly affect the acute systemic inflammatory responses.     

Safety of bivalirudin in patients with coronary artery disease

Introduction: Various limitations of unfractionated heparin (UFH) have triggered a search for new antithrombotic therapies for patients with coronary artery disease (CAD). Bivalirudin is a direct thrombin inhibitor with several pharmacological advantages over UFH and is currently endorsed by practice guidelines, particularly in patients with acute coronary syndromes undergoing percutaneous coronary intervention (PCI). To maximize effectiveness of an antithrombotic regimen and reduce complications, both ischemic and bleeding risks should be known when an antithrombotic strategy is chosen.

Areas covered: This review focuses on the safety and tolerability of bivalirudin in patients with CAD in the setting of currently approved indications. Synthesis of evidence has been made from clinical trials, systematic reviews, meta-analyses and registries (1992 – 2011). The reader is provided with an overview of pharmacological properties of bivalirudin and its efficacy, with special emphasis on its safety in patients with CAD.

Expert opinion: Bivalirudin has an impressive safety profile in CAD patients treated with PCI. Bivalirudin is the antithrombotic of choice in suspected or verified heparin-induced thrombocytopenia. For ST elevation myocardial infarction patients undergoing primary PCI, bivalirudin should become the preferred antithrombotic agent together with early institution of antiplatelet therapy.     

CYP2C19 genotypes and their impact on clopidogrel responsiveness in percutaneous coronary intervention

Background Cytochrome P450 2C19 (CYP2C19) loss-of-function polymorphisms are more common in Asian populations and have been associated with diminished antiplatelet response to clopidogrel. In this era of ‘personalised medicine’, combining genotyping and phenotyping as a strategy to personalise antiplatelet therapy warrants further exploration. Objective This study aimed to investigate the prevalence and impact of CYP2C19*2, *3 and *17 genotypes on clopidogrel responsiveness in a multiethnic Malaysian population planned for percutaneous coronary intervention. Setting Between October 2010 and March 2011, a total of 118 consecutive patients planned for percutaneous coronary intervention were enrolled in Sarawak General Hospital, Borneo. All patients received at least 75 mg aspirin daily for at least 2 days and 75 mg clopidogrel daily for at least 4 days prior to angiography. Method Genotyping for CYP2C19*2 (rs4244285, 681G > A), *3 (rs4986893, 636G > A) and *17 (rs11188072, ?3402C > T) alleles were performed by polymerase chain reaction-restriction fragment linked polymorphism method. Whole blood ADP-induced platelet aggregation was assessed with multiple electrode platelet aggregometry (MEA) using the Multiplate Analyzer. Main outcome measures The distribution of CYP2C19*2, *3 and *17 among different ethnic groups and the association between genotype, clopidogrel responsiveness and clinical outcome were the main outcome measures. Results The highest prevalence of poor metabolisers (carriers of at least one copy of the *2 or *3 allele) was among the Chinese (53.7 %), followed by the Malays (26.9 %), Ibans (16.4 %) and other races (3.0 %). Poor metabolisers (PMs) had the highest mean MEA (303.6 AU*min), followed by normal metabolisers (NMs) with 270.5 AU*min and extensive metabolisers (EMs) with 264.1 AU*min (p = 0.518). Among poor responders to clopidogrel, 65.2 % were PMs and NMs, respectively, whereas none were EMs (p = 0.350). Two cardiac-related deaths were reported. Conclusion There was a diverse inter-ethnic difference in the distribution of CYP2C19 polymorphism. The findings of this study echo that of other studies where genotype appears to have a limited impact on clopidogrel responsiveness and clinical outcome in low-risk patients.     

Safety and efficacy of bivalirudin in acute coronary syndromes

Antithrombotic and powerful antiplatelet therapies, in addition to early percutaneous coronary intervention (PCI) are considered the treatment of choice for moderate- to high-risk patients with acute coronary syndromes (ACS; unstable angina and non-ST-segment elevation myocardial infarction). However, despite the integration of newer therapies including stents, glycoprotein IIb/IIIa inhibitors (GPI), and thienopyridines, the rate of adverse ischemic events still remains unacceptably high. Intensive pharmacologic regimens used to stabilize the disrupted atherosclerotic plaque and support angioplasty as well as surgical revascularization procedures, elicit a high rate of bleeding complications. Recent trials (ACUITY and HORIZONS studies) added evidence regarding safety and efficacy of bivalirudin use in acute coronary syndromes. In summary, is has been shown that bivalirudin alone is safe and effective in the vast majority of patients suffering from acute coronary syndromes and being treated invasively. The cost-effectiveness of such an approach will have to be determined. It remains to be a matter of discussion whether there are still patient subgroups being in need of more aggressive treatment strategies including GPI. In practice, it might be reasonable to perform a baseline assessment of hemorrhagic risk facilitating the choice of an antithrombotic regimen with a favourable safety and efficacy profile. With this tailored therapy it might be possible to further improve outcomes for individual patients with ACS.     

Safety of bivalirudin in patients with coronary artery disease

INTRODUCTION: Various limitations of unfractionated heparin (UFH) have triggered a search for new antithrombotic therapies for patients with coronary artery disease (CAD). Bivalirudin is a direct thrombin inhibitor with several pharmacological advantages over UFH and is currently endorsed by practice guidelines, particularly in patients with acute coronary syndromes undergoing percutaneous coronary intervention (PCI). To maximize effectiveness of an antithrombotic regimen and reduce complications, both ischemic and bleeding risks should be known when an antithrombotic strategy is chosen. AREAS COVERED: This review focuses on the safety and tolerability of bivalirudin in patients with CAD in the setting of currently approved indications. Synthesis of evidence has been made from clinical trials, systematic reviews, meta-analyses and registries (1992 - 2011). The reader is provided with an overview of pharmacological properties of bivalirudin and its efficacy, with special emphasis on its safety in patients with CAD. EXPERT OPINION: Bivalirudin has an impressive safety profile in CAD patients treated with PCI. Bivalirudin is the antithrombotic of choice in suspected or verified heparin-induced thrombocytopenia. For ST elevation myocardial infarction patients undergoing primary PCI, bivalirudin should become the preferred antithrombotic agent together with early institution of antiplatelet therapy.