Platelet glycoprotein IIb/IIIa-receptor inhibitors in patients with acute coronary syndromes or undergoing percutaneous coronary interventions: a review

BACKGROUND: Over 12.2 million Americans are affected by acute coronary syndromes (ACS) resulting from arterial thrombosis after atherosclerotic plaque rupture. The mechanism of thrombosis is based on the platelet activation pathway, facilitated by expression of the platelet glycoprotein (GP) lIb/Illa receptors. The platelet GP IIb/IIIa-receptor inhibitors represent a new class of drugs, of which abciximab, eptifibatide, and tirofiban have been approved for use in the medical management of ACS and as adjunctive therapy in percutaneous coronary interventions (PCIs). OBJECTIVE: This article reviews the results of published multicenter, randomized, placebo-controlled, double-blind trials of the efficacy and safety of platelet GP IIb/IIIa-receptor inhibitors in patients with coronary artery disease. METHODS: To identify articles for this review, a search of MEDLINE for the years 1994 through 2000 was conducted using the key words myocardial ischemia, unstable angina, angioplasty, stent, abciximab, eptifibatide, tirofiban, lamifiban, and platelet aggregation inhibitors. Relevant review articles were consulted as well as reports of clinical studies. CONCLUSIONS: Three GP IIb/IIIa-receptor inhibitors--abciximab, eptifibatide, and tirofiban-are approved by the US Food and Drug Administration as adjunctive therapy in patients undergoing PCI. Eptifibatide and tirofiban 'are also indicated for the medical management of patients with unstable angina and non-ST-segment-elevation myocardial infarction. The use of GP IIb/IIIa-receptor inhibitors as a component of management with fibrinolytic agents is under investigation. Studies comparing the efficacy of tirofiban and abciximab in patients undergoing planned PCI with intracoronary stent placement are in progress. Until data are available from long-term trials and head-to-head comparisons of these agents, it is not possible to generalize about their overall or comparative efficacy.     

Pharmacokinetics of enoxaparin in patients undergoing percutaneous coronary intervention with and without glycoprotein IIb/IIIa therapy

The pharmacokinetic profile of enoxaparin was established in a substudy involving 1054 patients undergoing percutaneous coronary intervention. Patients enrolled in the National Investigators Collaborating on Enoxaparin 1 (NICE-1) trial received enoxaparin as a 1.0-mg/kg intravenous bolus. Patients enrolled in the NICE-4 trial received enoxaparin as a 0.75-mg/kg intravenous bolus followed by abciximab as a 0.25-mg/kg bolus and a 0.125-mcg/kg/min 12-hour infusion. Blood samples were collected at six time points over 12 hours and analyzed for plasma anti-Xa, anti-IIa, and Heptest (Haemachem Inc., St. Louis, MO) activity using specific and sensitive assay methods. Data were similar in both trials. Plasma anti-Xa, anti-IIa, and Heptest activity peaked shortly after the enoxaparin bolus and declined in parallel over the ensuing 12 hours. Area under the curve and peak activity were greatest for Heptest activity and least for anti-IIa activity. Values for clearance, volume of distribution, volume of distribution at steady state, and elimination rate constant were on the order of 10 mL/h/kg, 48 mL/kg, 45 mL/kg, and 0.22/h, respectively. These measures suggest that the use of abciximab in combination with enoxaparin during percutaneous coronary intervention is unlikely to affect the pharmacokinetics of enoxaparin.     

The long-term cost-effectiveness of clopidogrel plus aspirin in patients undergoing percutaneous coronary intervention in Sweden

BACKGROUND: The Percutaneous Coronary Intervention-Clopidogrel in Unstable Angina to Prevent Recurrent Events (PCI-CURE) study, which examined the effect of adding clopidogrel to aspirin versus aspirin alone in patients with unstable coronary artery disease (CAD) undergoing PCI, found a relative risk reduction in cardiovascular deaths and myocardial infarction among those treated with clopidogrel. In addition, a within-trial cost-effectiveness analysis showed favorable costs per event avoided. However, to estimate the long-term effects, a modeling approach is necessary. OBJECTIVES: The purpose of this study was to estimate the long-term cost-effectiveness of treating patients undergoing PCI with clopidogrel plus aspirin in Sweden. METHODS: A Markov model was developed. Transition probabilities were estimated based on a register of patients treated in the coronary care units at 74 (out of 78) hospitals throughout Sweden. Patients were assumed to be treated for 1 year with an effect based on data from the PCI-CURE study. Costs were collected from published sources and recalculated to year-2004 Euros (Euro 1.00 = USD 1.24). Life-years gained were used as the measure of effectiveness. The perspective was that of the Swedish society, with a separate analysis using a health care cost perspective. RESULTS: After inclusion and exclusion criteria were applied, 3474 patients were included in the model analysis. The model predicted a net gain in survival of 0.04 year per patient when adding clopidogrel. This yielded a net increase of Euros 449 if only direct costs were included; with indirect costs, the net increase was Euros 332. The resulting cost-effectiveness ratios were Euros 10,993 and Euros 8127 per life-year gained. CONCLUSIONS: The predicted cost-effectiveness ratios were well below the threshold values generally considered cost-effective. Adding clopidogrel to aspirin appeared to be cost-effective in this model analysis of patients with unstable CAD undergoing PCI in Sweden.     

择期经皮冠状动脉介入术中达肝素钠抗凝的剂量研究

目的对比择期经皮冠状动脉介入治疗（percutaneous coronary intervention,PCI）术中使用不同剂量的达肝素钠对术后心肌损伤的影响,探讨小剂量达肝素在PCI术中的可行性和安全性。方法采用前瞻性、开放设计,连续入选拟行择期PCI术的冠心病患者共294例,分为达肝素钠10 000U、5 000U组和120U/kg剂量组。术后20～24小时采集血标本,检测血浆肌钙蛋白（cTnI）、肌红蛋白（MYO）水平,并观察住院期间主要不良心血管事件及出血情况。结果 PCI术后cTnI及MYO在3组之间差异无统计学意义（P值分别为0.507及0.078）（P〉0.05）,住院期间均无死亡、心肌梗死、心绞痛复发、紧急血管重建等临床事件发生。结论在择期PCI术中,与术中给予10 000U达肝素比较,术中给予达肝素120U/kg及5 000U同样安全有效,值得在大规模临床研究中进一步研究、证实。     

Clinical development of bivalirudin (Angiox): rationale for thrombin-specific anticoagulation in percutaneous coronary intervention and acute coronary syndromes

As the pathophysiology of acute coronary syndromes (ACS) has been clarified in recent years, major advances have been made in the management of the disease. The magnitude of the thrombotic process triggered upon plaque disruption is modulated by different elements that determine plaque and blood thrombogenicity. Thrombin plays a pivotal role in ACS because of its extensive procoagulant and prothrombotic actions. Antithrombotic therapy and powerful antiplatelet therapies, in addition to early percutaneous coronary intervention (PCI), have become central in the management of ACS. A number of options for anticoagulation regimens are available. However, many agents currently used have significant limitations, recognition of which has led to the development, evaluation and clinical introduction of the class of thrombin-specific anticoagulant agents. This paper will discuss the clinical development of the direct thrombin inhibitor bivalirudin as the core anticoagulant in the contemporary PCI setting and the implications for its use in ACS.     

盐酸替罗非班在急诊冠状动脉介入术中的应用

报告了盐酸替罗非班在84例急性ST段抬高型心肌梗死(ST elevation acute myocardial infarction,STEMI)患者急诊冠状动脉介入术(PCI)中的应用。46例患者术中、术后使用替罗非班,术后24h及30dMACE的发生率明显低于以往只用PCI的患者,并且提高了梗死相关血管(IRA)心肌灌注血流(TIMI),但使用替罗非班组的患者出血事件稍多。总之盐酸替罗非班应用于急诊PCI术治疗急性STEMI患者效果良好,可减少并发症的发生。     

Glycoprotein IIb/IIIa receptor inhibitors in percutaneous coronary intervention and acute coronary syndrome

OBJECTIVE: To review the contemporary role of the glycoprotein (GYP) IIb/IIIa receptor inhibitors abciximab, eptifibatide, and tirofiban in patients undergoing percutaneous coronary intervention (PCI) and those with an acute coronary syndrome (ACS), and to provide an algorithm based on currently available evidence for specific agents. DATA SOURCES: Primary articles were identified by a MEDLINE search (1966-January 2003); references cited in these articles provided additional resources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from data sources were considered for relevant information; this article primarily addresses large, controlled or comparative studies, and meta-analyses. DATA SYNTHESIS: The role of GYP IIb/IIIa inhibitors in patients undergoing PCI and those with ACS has progressed markedly. To date, abciximab has the most robust data in patients undergoing PCI, particularly high-risk individuals. In PCI patients with lower risk (e.g., elective stenting), eptifibatide is a reasonable first-line option. Data do not support tirofiban for routine use in patients undergoing PCI. For individuals with signs and symptoms of ACS, specifically unstable angina or non-ST-segment elevation myocardial infarction (MI), eptifibatide or tirofiban is recommended in high-risk patients when a conservative approach is used (PCI is not planned). Abciximab is not recommended in this situation. In patients with ST-segment elevation MI (STEMI), abciximab is the only GYP IIb/IIIa inhibitor evaluated in large, well-designed investigations. For medical management in combination with a fibrinolytic agent, the role of abciximab remains unclear. For patients undergoing primary PCI for the management of STEMI, the available evidence supports the use of abciximab, albeit further investigation is warranted. CONCLUSIONS: The role of GYP IIb/IIIa inhibitors in clinical cardiology continues to evolve. Choice of the agent depends on situation of use, patient-specific characteristics and risk stratification, and, in the case of ACS, chosen management strategy (medical management or intervention).     

A cost-effectiveness analysis of fluvastatin in patients with diabetes after successful percutaneous coronary intervention

BACKGROUND: The Lescol Intervention Prevention Study (LIPS) was a multinational randomized controlled trial that showed a 47% reduction in the relative risk of cardiac death and a 22% reduction in major adverse cardiac events (MACEs) from the routine use of fluvastatin, compared with controls, in patients undergoing percutaneous coronary intervention (PCI, defined as angioplasty with or without stents). In this study, MACEs included cardiac death, nonfatal myocardial infarction, and subsequent PCI and coronary artery bypass graft. Diabetes was the greatest risk factor for MACEs. OBJECTIVE: This study estimated the cost-effectiveness of fluvastatin when used for secondary prevention of MACEs after PCI in people with diabetes. METHODS: A post hoc subgroup analysis of patients with diabetes from the LIPS was used to estimate the effectiveness of fluvastatin in reducing myocardial infarction, revascularization, and cardiac death. A probabilistic Markov model was developed using United Kingdom resource and cost data to estimate the additional costs and quality-adjusted life-years (QALYs) gained over 10 years from the perspective of the British National Health Service. The model contained 6 health states, and the transition probabilities were derived from the LIPS data. Crossover from fluvastatin to other lipid-lowering drugs, withdrawal from fluvastatin, and the use of lipid-lowering drugs in the control group were included. RESULTS: In the subgroup of 202 patients with diabetes in the LIPS trial, 18 (15.0%) of 120 fluastatin patients and 21 (25.6%) of 82 control participants were insulin dependent (P = NS). Compared with the control group, patients treated with fluvastatin can expect to gain an additional mean (SD) of 0.196 (0.139) QALY per patient over 10 years (P < 0.001) and will cost the health service an additional mean (SD) of 10 pounds ( 448 pounds) (P = NS) (mean [SD] US $16 [$689]). The additional cost per QALY gained was 51 pounds (US $78). The key determinants of cost-effectiveness included the probabilities of repeat interventions, cardiac death, the cost of fluvastatin, and the time horizon used for the evaluation. CONCLUSION: Fluvastatin was an economically efficient treatment to prevent MACEs in these patients with diabetes undergoing PCI.     

Psychological state in patients undergoing coronary artery bypass grafting surgery or percutaneous coronary intervention and their spouses

Percutaneous coronary intervention (PCI) and the coronary artery bypass grafting surgery (CABG) are well accepted treatments for coronary artery disease. Many patients and their spouses experience increased level of stress, anxiety and depression before and after going under the procedure. One hundred and ninety‐six cardiac patients who were candidate for CABG or PCI procedures and their spouses were asked to complete Hospital Anxiety and Depression Scale and General Health Questionnaire‐12 before and 1 month after procedures. Anxiety, depression and stress level in patients and their spouses going under the procedures significantly reduced over time. Scores of anxiety, depression and stress in patients and their spouses were correlated. There was no difference in the level of anxiety, depression and stress between CABG and PCI groups before to after procedures. We suggest providing information about the procedures to both patients and their spouses to deal better with their own psychological state.     

Effectiveness and cost-effectiveness of facilitated percutaneous coronary intervention compared with primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction transferred from community hospitals

BACKGROUND: Primary percutaneous coronary intervention ([PCI], percutaneous transluminal coronary angioplasty+stenting) for ST-segment elevation myocardial infarction (STEMI) is regarded as superior to fibrinolysis even if it means that patients need to be transferred from one center to another to undergo the procedure. However, this inevitable delay between symptom onset and PCI, caused by the time required to travel, might increase the occurrence of cardiac events. A hybrid method called facilitated PCI uses fibrinolysis and/or glycoprotein (GP) IIb/IIIa inhibitors before transfer to a tertiary medical center where urgent PCI might be performed. This approach, however, has not been systematically evaluated. OBJECTIVE: The purpose of this study was to compare the effectiveness (combined end point of in-hospital mortality, reinfarction, stroke, or emergency revascularization) and cost-effectiveness of utilizing a bolus thrombolytic agent with GP IIb/IIIa inhibitor followed by transfer to a tertiary institution for facilitated PCI or standard of care transfer without primary PCI drugs among patients presenting to a community hospital with STEMI. METHODS: This was a prospective, single-center, cohort study comprising data from STEMI patients transferred from community hospitals to Hartford Hospital, Hartford, Connecticut, from the years 2000 to 2003. At the time of analysis, patients receiving primary PCI were matched (1:1) with those receiving facilitated PCI, utilizing propensity scores to assure similar demographics. The combined incidence of major adverse cardiac end points (MACE) and total hospital costs was compared between groups. Non-parametric bootstrapping was conducted to calculate CIs for the incremental cost-effectiveness ratio and generate a quadrant analysis. RESULTS: Based on 254 propensity score-matched patients (127 facilitated PCI and 127 primary PCI), in-hospital MACE and total hospital costs were reduced by 61.3% and US 4563 dollars (2005), respectively, in patients receiving facilitated compared with primary PCI (P=0.021 and P=NS, respectively). Patients receiving facilitated PCI were more likely to have target lesion Thrombolysis in Myocardial Infarction (TIMI) III (normal) blood flow on cardiac catheterization than those receiving primary PCI (49.6% vs 30.7%; P=0.002). However, the rate of TIMI bleeding was similar in both groups (21.3% in the facilitated PCI group vs 18.9% in the primary PCI group). Nonsignificant reductions were observed in both intensive care unit (ICU) and total length of stay (LOS) (0.8 day and 1.0 day, respectively) compared with the primary PCI group. Bootstrap analysis revealed that of 25,000 samplings, facilitated PCI would likely be both more effective and less costly 94.6% of the time. CONCLUSIONS: The use of facilitated PCI in STEMI patients who initially presented to community hospitals and were transferred for PCI appeared to significantly reduce the incidence of MACE, and increase the likelihood of having baseline TIMI III blood flow at time of catheterization. Nonsignificant reductions were observed in total ICU and hospital LOS. However, there did not appear to be a significant effect on the incidence of bleeding in patients receiving facilitated PCI. Bootstrap analysis confirmed that facilitated PCI would be both a more effective and less costly strategy.     

早期肝素化对急性ST段抬高型心肌梗死患者直接经皮冠状动脉介入治疗的疗效

目的 探究直接经皮冠状动脉介入术前(primary percutaneous coronary intervention, pPCI)肝素化对ST段抬高型心肌梗死（ST segment elevation myocardial infarction, STEMI）患者的影响。方法 连续入选STEMI患者117例,随机分为观察组和对照组,观察组确诊为STEMI后立即静脉注射普通肝素5 000 U,对照组于术中给予普通肝素5 000 U。观察肝素启动时间、PCI前活化的凝血时间(activated coagulation time, ACT)、心肌损伤标志物峰值、心肌微循环阻力指数(index of microcirculation resistance, IMR)、其他心肌灌注评估指标。记录术后主要不良事件（major adverse events, MAES）。结果 与对照组比较,观察组肝素给予的时间明显提前（约28 min）,术前ACT明显延长(P=0.000),血栓负荷率低（25.00% vs 43.90%, P=0.032）;造影即刻梗死相关动脉(IRA)的TIMI血流0~1级率低（45.00% vs 68.40%,P=0.011）,TIMI心肌灌注分级(TMPG) 3级率高（75.30% vs 56.10%,P=0.032）,IMR较低（P=0.007）,心肌损伤标志物CK MB峰值低（P=0.007）,心肌灌注缺损面积(perfusion defect area, PDA) 较低（P=0.031）。结论 pPCI术前早期肝素化提高了IRA的开通率,缩短心肌总缺血时间,缩小心肌梗死面积,改善心肌灌注,不增加MAES的风险。     

Rho激酶抑制剂在急性冠脉综合征介入治疗中的应用价值

目的应用SYNTAX评分,观察Rho激酶抑制剂法舒地尔对不同评分组的急性冠脉综合征患者介入术后左心功能、一年支架内再狭窄(ISR)和主要心脏不良事件(MACE)的影响。方法入选急性冠脉综合征患者238例,均经冠脉造影证实存在单支以上的病变,均拒绝行冠脉搭桥手术,按随机数字表法分为治疗组(法舒地尔,n=102)和对照组(n=136),根据SYNTAX评分,每组再分为评分低值亚组(0~22分)、评分值中等亚组(23~32分)和评分值高亚组(≥33分),正规冠心病二级预防治疗,并行冠脉造影和支架植入治疗,随访一年,对比观察2组以及2组的亚组间在术中慢血流或无复流、急性或亚急性支架血栓、左心功能、一年内支架内再狭窄率和MACE事件的差异。结果治疗组和对照组观察的各项指标无显著差异(P0.05),2组对应的评分低值组亚组间以及评分中等值亚组间观察的各项指标无显著差异(P0.05);与对照组的评分高值亚组相比,治疗组的评分高值亚组术中发生慢血流或无复流的比例、1年支架内再狭窄比例和MACE事件的发生率显著降低(P0.05),3个月的左心功能明显改善(P0.05)。结论 Rho激酶抑制剂可显著减少SYNTAX评分高值(≥33分)的ACS患者介入术中慢血流或无复流的发生,改善左心功能,并降低1年内支架内再狭窄率和MACE事件的发生率。     

Outcome after coronary artery bypass surgery and percutaneous coronary intervention in patients with atrial fibrillation and oral anticoagulation

Abstract

Aim. This study was planned to compare the clinical characteristics and outcome of patients on warfarin treatment for atrial fibrillation (AF) undergoing coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI).

Methods. This is a retrospective analysis of 121 patients who underwent isolated CABG and 301 patients who underwent PCI.

Results. PCI patients were older (mean age, 72.9 versus 69.8 years) and more often had prior cardiac surgery (15.9% versus 1.7%) and acute coronary syndrome (53.8% versus 21.5%). CABG patients more often had two- and three-vessel disease (95.0% versus 60.2%) and left main stenosis (32.2% versus 7.0%). The 30-day outcome was similar after PCI and CABG. At 3 years, PCI was associated with lower overall survival (72.0% versus 86.4%, P = 0.006), freedom from repeat revascularization (85.3% versus 98.2%, P < 0.001), freedom from myocardial infarction (83.4% versus 93.8%, P = 0.008), and freedom from major cardiovascular events (57.4% versus 78.9%, P < 0.001). Propensity score adjusted analysis showed that PCI was associated with increased risk of all-cause mortality (P = 0.016, RR 2.166, CI 1.155–4.060), myocardial infarction (P = 0.017, RR 3.161, 95% CI 1.227–8.144), repeat revascularization (P = 0.001, RR 13.152, 95% CI 2.799–61.793), and major cardiac and cerebrovascular complications (P = 0.001, RR 2.347, 95% CI 1.408–3.914). There was no difference in terms of stroke and bleeding episodes at any time point.

Conclusion. In clinical practice, PCI is the preferred revascularization strategy in these frail patients. Patients selected for CABG have a relatively low operative risk and better mid-term outcome in spite of warfarin treatment. The poor prognosis after PCI may mainly reflect frequent co-morbidities in this patient group.     

Genetic testing in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a cost‐effectiveness analysis

Summary. Background: The CYP2C19 genotype is a predictor of adverse cardiovascular events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) treated with clopidogrel. Objectives: We aimed to evaluate the cost‐effectiveness of a CYP2C19*2 genotype‐guided strategy of antiplatelet therapy in ACS patients undergoing PCI, compared with two ‘no testing’ strategies (empiric clopidogrel or prasugrel). Methods: We developed a Markov model to compare three strategies. The model captured adverse cardiovascular events and antiplatelet‐related complications. Costs were expressed in 2010 US dollars and estimated using diagnosis‐related group codes and Medicare reimbursement rates. The net wholesale price for prasugrel was estimated as $5.45 per day. A generic estimate for clopidogrel of $1.00 per day was used and genetic testing was assumed to cost $500. Results: Base case analyses demonstrated little difference between treatment strategies. The genetic testing‐guided strategy yielded the most QALYs and was the least costly. Over 15 months, total costs were $18 lower with a gain of 0.004 QALY in the genotype‐guided strategy compared with empiric clopidogrel, and $899 lower with a gain of 0.0005 QALY compared with empiric prasugrel. The strongest predictor of the preferred strategy was the relative risk of thrombotic events in carriers compared with wild‐type individuals treated with clopidogrel. Above a 47% increased risk, a genotype‐guided strategy was the dominant strategy. Above a clopidogrel cost of $3.96 per day, genetic testing was no longer dominant but remained cost‐effective. Conclusions: Among ACS patients undergoing PCI, a genotype‐guided strategy yields similar outcomes to empiric approaches to treatment, but is marginally less costly and more effective.