The role of platelet glycoprotein IIb / IIIa inhibitors in current treatment of acute coronary syndrome.

Current management of patients with acute coronary syndrome (ACS) includes a dual antiplatelet therapy with acetylsalicylic acid and a platelet P2Y12 receptor inhibitor. For patients without a high risk of bleeding, prasugrel and ticagrelor are preferred, since their effect is more pronounced, less dependent on metabolism of a specific patient, and occurs faster that the effect of clopidogrel. The prescription rate of platelet glycoprotein IIb/IIIa (GP IIb / IIIa) receptor inhibitors has considerably decreased. However, these drugs remain relevant in percutaneous coronary interventions in patients with a high risk of coronary thrombosis or a massive coronary thrombus, in thrombotic complications of the procedure, and in the "no-reflow" phenomenon. The intravenous route of GP IIb / IIIa inhibitor administration provides their effectiveness in patients with difficulties of drug intake or with impaired absorption of oral medications. This review presents clinical and pharmacological characteristics of various GP IIb / IIIa inhibitors and data of randomized clinical studies and registries of recent years that evaluated results of their use in patients with ACS.

Autoimmune disorders of platelet function: systematic review of cases of acquired Glanzmann thrombasthenia and acquired delta storage pool disease.

Acquired platelet function disorders (PFD) are rare bleeding diseases that should be suspected in all patients with unexplained mucocutaneous bleedings of recent onset, with no previous history of haemorrhages, and with normal coagulation test and platelet count. Drug-induced platelet function bleeding disorders are the most frequent PFDs and can easily be identified on the basis of recent administration of platelet-inhibiting drugs. Apart from these, the most challenging acquired PFDs are those caused by autoimmune mechanisms. In fact, demonstration of autoantibodies inhibiting platelet function may be difficult in most non-specialised centres. Among autoimmune PFDs (aPFDs), acquired Glanzmann thrombasthenia (aGT), which is caused by autoantibodies that bind to platelet αIIbß3 integrin, inhibiting its function, is the most frequent. aGT can be associated with underlying haematological malignancies or autoimmune diseases but can also be idiopathic. More rarely, other immune-mediated PFDs can occur, such as acquired delta storage pool disease (aδSPD). Treatment of aPFDs must rely on the control of acute and chronic bleedings, treatment of the underlying disease in secondary forms, and immunosuppressive treatment for autoantibody reduction or eradication. aPFDs may completely resolve upon treatment of any underlying disease that may be present. In primary aPFDs, and in the majority of secondary forms, treatment relies on immunosuppressive therapies.Here we present a systematic review of previously described immune-mediated aGT and aδSPD cases. Clinical and laboratory characteristics, treatments for the control of bleedings and for the eradication of autoantibodies, and responses to treatments are also discussed. Although no guidelines are available for the management of these very rare conditions, presentation of all cases reported so far can help clinicians in the diagnosis and treatment of these life-threatening diseases.

Intracoronary bolus of glycoprotein IIb/IIIa inhibitor as bridging or adjunctive strategy to oral P2Y12 inhibitor load in the modern setting of ST-elevation myocardial infarction.

BACKGROUND: In the acute management of ST-elevation myocardial infarction (STEMI), glycoprotein IIb/IIIa inhibitors (GPIs) bolus not followed by intravenous infusion is potentially advantageous given their fast onset and offset of action, but clinical evidence in a contemporary setting is limited. METHODS: We collected data from consecutive STEMI patients admitted to the cardiac catheterization laboratory of the IRCCS A. Gemelli University Polyclinic Foundation from October 2017 to September 2019. RESULTS: Out of 423 consecutive STEMI patients, 297 met the inclusion and exclusion criteria and were included in the study. Of them, 107/297 (36%) received an intracoronary GPI bolus-only during primary percutaneous coronary intervention (PPCI) not followed by intravenous infusion and 190/297 (64%) received standard antithrombotic therapy. Of the 107 GPI-treated, 22/107 (21%) had P2Y12 inhibitor pretreatment (adjunctive strategy) and 85/107 (79%) did not (bridging strategy). During hospital staying, there was no difference in the primary safety endpoint of TIMI major+minor bleeding (P=0.283), TIMI major (P=0.267) or TIMI minor (P=0.685) bleeding between groups. No stroke event occurred in the GPI group. Despite patients receiving GPI having a significantly higher intraprocedural ischemic burden, no significant differences were found in the efficacy outcomes between groups. Consistent findings were observed for patients receiving GPIs bolus before (bridging strategy) or after (adjunctive strategy) P2Y12 inhibitors, compared to those receiving standard therapy. Multivariate logistic regression analyses did not find any independent predictors significantly associated to the primary and secondary composite endpoints. CONCLUSIONS: In a contemporary real-world population of STEMI patients undergoing PPCI, the use of intracoronary GPIs bolus-only in selected patients at high ischemic risk is safe and could represent a useful antithrombotic strategy both in those pretreated and in those naïve to P2Y12 inhibitors.

Safety of Glycoprotein IIb-IIIa Inhibitors Used in Stroke-Related Treatment: A Systematic Review and Meta-Analysis.

BACKGROUND: Endovascular therapy and intravenous thrombolysis with recombinant tissue plasminogen activator are the 2 most recommended treatments for acute ischemic stroke (AIS). Glycoprotein (GP) IIb-IIIa inhibitors are short-acting selective reversible antiplatelet agents that emerged as promising therapeutic agents for AIS about 10 years ago. Given the unclear safety profile and application coverage of GP inhibitors, we conducted this meta-analysis to explore the same. METHODS: We used GP IIb-IIIa inhibitors, intracranial hemorrhage, and mortality as the key words on Medline, Web of Science, and the Embase databases. Randomized controlled trials, prospective literatures, and retrospective studies in English published between 1990 and 2020 were screened. The outcomes were relative risk (RR) of death and 90-day intracerebral hemorrhage (ICH). We pooled the results in 2 categories and conducted a subgroup analysis stratified by different drugs. The choice of the effects model depended on the value of I 2. RESULTS: In all, 3700 patients from 20 studies were included. No GP IIb-IIIa inhibitors were found to have a remarkable influence on the ICH rate. The RR values of symptomatic ICH for abciximab and eptifibatide were 4.26 (1.89, 9.59) and 0.17 (0.04, 0.69), respectively. Both tirofiban and abciximab could decrease the mortality rate within 90 days. Age > 70 years, National Institutes of Health Stroke Scale > 15, and overall dose > 10 mg are risk factors for ICH events with tirofiban usage. Thrombectomy combined with tirofiban was safe for arterial reocclusion prevention. CONCLUSIONS: In stroke-related treatment, administration of GP IIb-IIIa inhibitors could be safe, but care should be taken regarding drug species and doses. Abciximab can increase the risk of symptomatic intracranial hemorrhage. Tirofiban and eptifibatide can be considered safe in low doses. Suitable patients should be selected using strict criteria.

Use of glycoprotein IIb/IIIa antagonists to prevent stent thrombosis in morphine-treated patients with ST-elevation myocardial infarction.

Morphine can delay absorption of P2Y12-inhibitors in ST-elevation myocardial infarction (STEMI) patients, which has the potential to expose these patients to increased stent thrombosis risk after primary percutaneous coronary intervention (PPCI). Limited evidence exists for pharmacotherapeutic strategies aiming to mitigate this risk. We evaluated the impact of guideline-driven 'routine' glycoprotein IIb/IIIa antagonist (GPI) use in morphine-treated patients undergoing PPCI. A total of 3224 consecutive STEMI patients undergoing PPCI at a large tertiary cardiac center between 2012 and 2017 were evaluated. GPI use and outcomes before and after introduction of a local guideline were compared, and rates of definite stent thrombosis were identified at 24 h and 30 days. GPI use increased from 42.4% to 69.9% after the introduction of the new guideline. Stent thrombosis occurred in 1.3% (26/1947) pre-guideline and 0.6% (7/1244) post-guideline (P = .037). Of the 33 stent thrombosis cases, 90% (27/30) had received morphine, of whom 85.2% (23/27) had not received adjunctive GPI. Complete records for assessing 30-day bleeding rates were only available in 374 patients and, in this subset, there was no significant difference in rates of GUSTO moderate or severe bleeding before vs. after introduction of the local guideline (1.7% vs 2.8%; P = .47) although, in both cohorts combined, any GUSTO bleeding was observed more frequently in GPI-treated patients (21.8%) compared to those not receiving a GPI (10.0%; P = .002). In conclusion, routine GPI use in morphine-treated STEMI patients undergoing PPCI appears to protect against stent thrombosis. Large-scale studies are needed to establish the overall risk-benefit of GPI therapy in morphine-treated PPCI patients and to assess alternative strategies for preventing acute stent thrombosis in these patients.

Effect of Platelet GPIIb/IIIa Receptor Blockade With MK383 on Infarct Size and Myocardial Blood Flow in a Canine Reocclusion Model.

Platelet activation and aggregation during ischemia influence reperfusion-related myocyte necrosis, myocardial perfusion at the microvascular level, and thereby eventual recovery of cardiac performance. Inhibition of platelet activity therefore represents a worthwhile target to reduce cellular injury. The current study examined the effects of MK383 (tirofiban), a potent inhibitor of platelet aggregation, on infarct size and myocardial perfusion in canine subjects to either reocclusion (ie, 120-minute + 60-minute ischemia with intervening reperfusion) or prolonged occlusion (ie, 3 hours) followed by reperfusion (180 minutes). Platelet aggregation, infarct size (tetrazolium staining), coronary blood flow (flow probe), coronary vascular reserve, and myocardial perfusion (microspheres) were evaluated. MK383, administered at the time of reperfusion, produced a modest reduction of tissue necrosis (compared to saline-treated controls) in the reocclusion and prolonged occlusion studies. Blood flow in the infarct-related artery after coronary occlusion was comparable between treatment groups, as was myocardial perfusion in the deeper layers of the ischemic region; coronary vascular reserve decreased progressively during reperfusion. Of note, compensatory changes in blood flow within the adjacent nonischemic myocardium were not observed. In conclusion, we report that that limiting platelet aggregation during reperfusion impacted infarct development. Continued investigation into the mechanisms by which inhibition of platelet activity protects myocardium against ischemia-reperfusion injury and improves clinical outcomes is necessary.

Antithrombotic strategies in the catheterization laboratory for patients with acute coronary syndromes undergoing percutaneous coronary interventions: insights from the EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalized in iTalian cardiac care units Registry.

AIMS: In the last decades, several new therapies have emerged for the treatment of acute coronary syndromes (ACS). We sought to describe real-world patterns of use of antithrombotic treatments in the catheterization laboratory for ACS patients undergoing percutaneous coronary interventions (PCI). METHODS: EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalized in iTalian cardiac care units was a nationwide, prospective registry aimed to evaluate antithrombotic strategies employed in ACS patients in Italy. RESULTS: Over a 3-week period, a total of 2585 consecutive ACS patients have been enrolled in 203 cardiac care units across Italy. Among these patients, 1755 underwent PCI (923 with ST-elevation myocardial infarction and 832 with non-ST-elevation ACS). In the catheterization laboratory, unfractioned heparin was the most used antithrombotic drug in both ST-elevation myocardial infarction (64.7%) and non-ST-elevation ACS (77.5%) undergoing PCI and, as aspirin, bivalirudin and glycoprotein IIb/IIIa inhibitors (GPIs) more frequently employed before or during PCI compared with the postprocedural period. Any crossover of heparin therapy occurred in 36.0% of cases, whereas switching from one P2Y12 inhibitor to another occurred in 3.7% of patients. Multivariable analysis yielded several independent predictors of GPIs and of bivalirudin use in the catheterization laboratory, mainly related to clinical presentation, PCI complexity and presence of complications during the procedure. CONCLUSION: In our contemporary, nationwide, all-comers cohort of ACS patients undergoing PCI, antithrombotic therapies were commonly initiated before the catheterization laboratory. In the periprocedural period, the most frequently employed drugs were unfractioned heparin, leading to a high rate of crossover, followed by GPIs and bivalirudin, mainly used during complex PCI. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02015624.

At least seven days delayed stenting using minimalist immediate mechanical intervention (MIMI) in ST-segment elevation myocardial infarction: the SUPER-MIMI study.

AIMS: The aim of this study was to ascertain whether a minimalist immediate mechanical intervention (MIMI) aiming to restore an optimal Thrombolysis In Myocardial Infarction (TIMI) flow in the culprit artery, followed ≥7 days later by a second percutaneous coronary intervention with intentional stenting, is safe in patients with ST-segment elevation myocardial infarction and large thrombotic burden. METHODS AND RESULTS: SUPER-MIMI was a prospective, observational trial conducted between January 2014 and April 2015 in 14 French centres. A total of 155 patients were enrolled. The pharmacological therapy was left to the operator's discretion. Eighty-one patients (52.3%) had glycoprotein IIb/IIIa inhibitors (GPI) initiated before the end of the first procedure. The median (interquartile range [IQR]) delay between the two procedures was eight (seven to 12) days. Infarct-related artery reocclusion between the two procedures (primary endpoint) occurred in two patients (1.3%), neither of whom received GPI treatment. TIMI flow was maintained or improved between the end of the first procedure and the beginning of the second procedure in all patients. Thrombotic burden and stenosis severity diminished significantly between the two procedures. Stents were ultimately implanted in 97 patients (62.6%). CONCLUSIONS: Deferred stenting (≥7 days) in patients with a high thrombus burden was safe on a background of GPI therapy.

Novel Thrombolytic Drug Based on Thrombin Cleavable Microplasminogen Coupled to a Single-Chain Antibody Specific for Activated GPIIb/IIIa.

BACKGROUND: Thrombolytic therapy for acute thrombosis is limited by life-threatening side effects such as major bleeding and neurotoxicity. New treatment options with enhanced fibrinolytic potential are therefore required. Here, we report the development of a new thrombolytic molecule that exploits key features of thrombosis. We designed a recombinant microplasminogen modified to be activated by the prothrombotic serine-protease thrombin (HtPlg), fused to an activation-specific anti-glycoprotein IIb/IIIa single-chain antibody (SCE5), thereby hijacking the coagulation system to initiate thrombolysis. METHODS AND RESULTS: The resulting fusion protein named SCE5-HtPlg shows in vitro targeting towards the highly abundant activated form of the fibrinogen receptor glycoprotein IIb/IIIa expressed on activated human platelets. Following thrombin formation, SCE5-HtPlg is activated to contain active microplasmin. We evaluate the effectiveness of our targeted thrombolytic construct in two models of thromboembolic disease. Administration of SCE5-HtPlg (4 µg/g body weight) resulted in effective thrombolysis 20 minutes after injection in a ferric chloride-induced model of mesenteric thrombosis (48±3% versus 92±5% for saline control, P<0.01) and also reduced emboli formation in a model of pulmonary embolism (P<0.01 versus saline). Furthermore, at these effective therapeutic doses, the SCE5-HtPlg did not prolong bleeding time compared with saline (P=0.99). CONCLUSIONS: Our novel fusion molecule is a potent and effective treatment for thrombosis that enables in vivo thrombolysis without bleeding time prolongation. The activation of this construct by thrombin generated within the clot itself rather than by a plasminogen activator, which needs to be delivered systemically, provides a novel targeted approach to improve thrombolysis.

Unfractionated heparin versus bivalirudin in patients undergoing primary percutaneous coronary intervention: a SWEDEHEART study.

AIMS: The aim of the study was to compare outcomes in unfractionated heparin (UFH) and bivalirudin-treated patients undergoing primary percutaneous coronary intervention (PPCI). METHODS AND RESULTS: This observational study contained 20,612 PPCI patients treated with either UFH monotherapy or bivalirudin with or without concomitant UFH. Patients with oral anticoagulant or glycoprotein IIb/IIIa inhibitor (GPI) treatment were excluded. The primary outcome measure was definite early stent thrombosis (ST) that occurred at low and similar rates in UFH only and bivalirudin-treated patients: 0.9% vs. 0.8% (adjusted hazard ratio [HR] 1.08, 95% confidence interval [CI]: 0.7-1.65). All-cause death at 30 days occurred in 6.9% vs. 5.4% of patients (adjusted HR 1.23, 95% CI: 1.05-1.44) and within 365 days in 12.1% vs. 8.9% (adjusted HR 1.34, 95% CI: 1.19-1.52) in the two groups, respectively. The incidence of major bleeding within 30 days was 0.8% vs. 0.6% (adjusted HR 1.54, 95% CI: 0.97-2.45). The incidence of reinfarction within 365 days and stroke within 30 days was similar between groups. CONCLUSIONS: In this large, nationwide observational study we found low and similar rates of early ST in UFH only and bivalirudin-treated patients undergoing primary PCI. Mortality was higher in UFH compared with bivalirudin-treated patients.

Optimal anticoagulation prior to cath: Bivalirudin vs. Heparin the saga continues .

During the pre-procedural (medication) phase, the use of bivalirudin monotherapy is associated with the lowest rate of bleeding in patients with Non-ST elevation myocardial infarction (Non-STEMI) undergoing an early invasive strategy. Monotherapy with either bivalirudin or unfractionated heparin (UFH) appear interchangeable in this setting. The use of GPI upstream with either drug should be discouraged due to an increased risk of bleeding and net adverse events. The use of low dose aspirin plus potent P2Y12 inhibitors followed by a transradial approach with implantation of drug-eluting coronary stents with fluorinated polymers represents an strategy that may help limit perioperative ischemic and hemorrhagic complications in these individuals.

Outcome of patients admitted with acute coronary syndrome on palliative treatment: insights from the nationwide AMIS Plus Registry 1997-2014.

OBJECTIVE: Compliance with guidelines is increasingly used to benchmark the quality of hospital care, however, very little is known on patients admitted with acute coronary syndromes (ACS) and treated palliatively. This study aimed to evaluate the baseline characteristics and outcomes of these patients. DESIGN: Prospective cohort study. SETTING: Eighty-two Swiss hospitals enrolled patients from 1997 to 2014. PARTICIPANTS: All patients with ACS enrolled in the AMIS Plus registry (n=45,091) were analysed according to three treatment groups: palliative treatment, defined as use of aspirin and analgesics only and no reperfusion; conservative treatment, defined as any treatment including antithrombotics or anticoagulants, heparins, P2Y12 inhibitors, GPIIb/IIIa but no pharmacological or mechanical reperfusion; and reperfusion treatment (thrombolysis and/or percutaneous coronary intervention during initial hospitalisation). The primary outcome measure was in-hospital mortality and the secondary measure was 1-year mortality. RESULTS: Of the patients, 1485 (3.3%) were palliatively treated, 11,119 (24.7%) were conservatively treated and 32,487 (72.0%) underwent reperfusion therapy. In 1997, 6% of all patients were treated palliatively and this continuously decreased to 2% in 2013. Baseline characteristics of palliative patients differed in comparison with conservatively treated and reperfusion patients in age, gender and comorbidities (all p<0.001). These patients had more in-hospital complications such as postadmission onset of cardiogenic shock (15.6% vs 5.2%; p<0.001), stroke (1.8% vs 0.8%; p=0.001) and a higher in-hospital mortality (25.8% vs 5.6%; p<0.001).The subgroup of patients followed 1 year after discharge (n=8316) had a higher rate of reinfarction (9.2% vs 3.4%; p=0.003) and mortality (14.0% vs 3.5%; p<0.001). CONCLUSIONS: Patients with ACS treated palliatively were older, sicker, with more heart failure at admission and very high in-hospital mortality. While refraining from more active therapy may often constitute the most humane and appropriate approach, we think it is important to also evaluate these patients and include them in registries and outcome evaluations. CLINICAL TRIAL NUMBER: ClinicalTrials.gov Identifier: NCT01 305 785.

Evaluation of procedure-related bleeding risk in patients receiving bivalirudin during percutaneous coronary intervention.

BACKGROUND: Bivalirudin has historically been considered an attractive anticoagulant during percutaneous coronary intervention (PCI) because of reduced bleeding complications reported by early trials. Bivalirudin use during PCIs has been a subject of controversy because of conflicting data and recent findings. OBJECTIVE: To evaluate the clinical characteristics of patients receiving bivalirudin to determine if an opportunity to improve use exists based on risk of procedure-related bleeding. METHODS: This was a single-center, retrospective, observational study (n = 100) of all adult patients who received bivalirudin during cardiac catheterization at St John Hospital and Medical Center from June to August 2013. The risk of bleeding complications associated with PCI was estimated using a clinical risk algorithm developed from the National Cardiovascular Data Registry (NCDR). RESULTS: Treatment with bivalirudin was safe and effective. Of the 100 patients who received bivalirudin, only 34% were identified as having a high risk of procedure-related bleeding according to the NCDR clinical risk algorithm. There was no incidence of stent thrombosis noted and only 1 case of provisional glycoprotein IIb/IIIa inhibitor use. No episodes of Thrombolysis in Myocardial Infarction (TIMI) major bleeding were noted in the study population; however, 1 patient met TIMI minor bleeding criteria. Limitations of this study include small sample size and retrospective nature of the study. CONCLUSION: Opportunities to establish a more cost-effective use of bivalirudin may exist through implementation of protocols incorporating the NCDR risk assessment model.

Rescue treatment of thromboembolic complications during endovascular treatment of cerebral aneurysms: a meta-analysis.

BACKGROUND AND PURPOSE: Intraprocedural thrombus formation during endovascular treatment of intracranial aneurysms is often treated with glycoprotein IIb/IIIa inhibitors and, in some instances, fibrinolytic therapy. We performed a meta-analysis evaluating the safety and efficacy of GP IIb/IIIa inhibitors compared with fibrinolysis. We also evaluated the safety and efficacy of abciximab, an irreversible inhibitor, compared with tirofiban and eptifibatide, reversible inhibitors of platelet function. MATERIALS AND METHODS: We performed a comprehensive literature search for studies on rescue therapy for intraprocedural thromboembolic complications with glycoprotein IIb/IIIa inhibitors or fibrinolysis during endovascular treatment of intracranial aneurysms. We studied rates of periprocedural stroke/hemorrhage, procedure-related morbidity and mortality, immediate arterial recanalization, and long-term good clinical outcome. Event rates were pooled across studies by using random-effects meta-analysis. RESULTS: Twenty-three studies with 516 patients were included. Patients receiving GP IIb/IIIa inhibitors had significantly lower perioperative morbidity from stroke/hemorrhage compared with those treated with fibrinolytics (11.0%; 95% CI, 7.0%-16.0% versus 29.0%; 95% CI, 13.0%-55.0%; P = .04) and were significantly less likely to have long-term morbidity (16.0%; 95% CI, 11.0%-21.0% versus 35.0%; 95% CI, 17.0%-58.0%; P = .04). There was a trend toward higher recanalization rates among patients treated with glycoprotein IIb/IIIa inhibitors compared with those treated with fibrinolytics (72.0%; 95% CI, 64.0%-78.0% versus 50.0%; 95% CI, 28.0%-73.0%; P = .08). Patients receiving tirofiban or eptifibatide had significantly higher recanalization rates compared with those treated with abciximab (83.0%; 95% CI, 68.0%-91.0% versus 66.0%; 95% CI, 58.0%-74.0%; P = .05). No difference in recanalization was seen in patients receiving intra-arterial (77.0%; 95% CI, 66.0%-85.0%) or intravenous GP IIb/IIIa inhibitors (70.0%; 95% CI, 57.0%-80.0%, P = .36). CONCLUSIONS: Rescue therapy with thrombolytic agents resulted in significantly more morbidity than rescue therapy with glycoprotein IIb/IIIa inhibitors. Tirofiban/eptifibatide resulted in significantly higher recanalization rates compared with abciximab.

Risk of thrombocytopenia with glycoprotein IIb/IIIa inhibitors across drugs and patient populations: a meta-analysis of 29 large placebo-controlled randomized trials.

AIMS: Glycoprotein IIb/IIIa inhibitors (GPIs) reduce myocardial infarction and peri-procedural thrombotic complications in patients undergoing percutaneous coronary intervention (PCI); however, they may cause bleeding and thrombocytopenia, which are associated with poor clinical outcomes. Although the risk of bleeding has been well characterized, the extent of the risk of thrombocytopenia remains uncertain. In this meta-analysis, we aim to evaluate the risk of thrombocytopenia associated with GPI compared with placebo across drugs and patient populations. METHODS AND RESULTS: Risk ratios were calculated for thrombocytopenia (<100 000 platelets/mm(3)) and severe thrombocytopenia (<50 000 platelets/mm(3)) in 29 randomized large trials (>1000 patients) of GPI vs. placebo involving a total of 123 419 patients. We used meta-analysis techniques to estimate the summary effect across all trials, in pre-specified sub-groups, and in sensitivity analyses to assess the robustness of the data. Glycoprotein IIb/IIIa inhibitor use increases the rate of thrombocytopenia [risk ratio (RR) = 1.62, 95% confidence interval (CI) 1.48-1.78] and severe thrombocytopenia (RR = 3.52, 95% CI 2.87-4.30) compared with placebo. These findings are consistent by route of administration (oral vs. intravenous). Patients with ST-segment elevation myocardial infarction (RR 2.66, 95% CI 2.12-3.34) and elective PCI (RR 2.78, 95% CI 1.76-4.40) treated with a GPI had higher risks of thrombocytopenia than patients with non-ST-segment elevation acute coronary syndrome (RR 1.41, 95% CI 1.25-1.58; P < 0.001 for heterogeneity by sub-group). CONCLUSIONS: The administration of GPI compared with placebo was associated with a 63% increased risk of thrombocytopenia (<100 000 platelets/mm(3)), and >3-fold increased risk of severe thrombocytopenia (<50 000 platelets/mm(3)). This corresponds to an average of 10-20 additional cases of thrombocytopenia per 1000 patients given GPIs, of which 6-7 cases are severe.

Bivalirudin versus heparin for percutaneous coronary intervention: an updated meta-analysis of randomized controlled trials.

AIMS: Given controversy over anticoagulation regimens for percutaneous coronary intervention (PCI), we performed an updated meta-analysis of randomized controlled trials (RCTs) to compare bivalirudin versus heparin. METHODS AND RESULTS: Medline/Pubmed and Cochrane CENTRAL were searched for all RCTs comparing bivalirudin with provisional glycoprotein IIb/IIIa inhibitor (GPI) use versus heparin with provisional or routine GPI use for PCI. Pooled estimates of 30day outcomes, presented as risk ratios (RR) [95% confidence intervals], were generated with random-effect models. Our analysis included 14 studies with 30,446 patients that were randomized to bivalirudin with provisional GPI use (n=14,869) versus heparin with provisional (n=6451) or routine GPI use (n=9126). There was no significant difference between anticoagulation with bivalirudin compared with heparin for death (RR 0.95 [0.78-1.14]) or myocardial infarction (RR 1.10 [0.97-1.25]). Early stent thrombosis was significantly greater with bivalirudin compared with heparin (RR 1.61 [1.18-2.20], p=0.003), especially in patients undergoing primary PCI (2.15 [1.15-4.03], p=0.02). However, bivalirudin reduced the risk of major bleeding (RR 0.59 [0.51-0.70], p<0.0001) and TIMI major bleeding (RR 0.59 [0.48-0.72], p<0.0001) compared with heparin. Meta-regression analysis demonstrated that bleeding risk with use of heparin significantly increases with increasing GPI use (p=0.02). CONCLUSION: Meta-analysis of 14 RCTs with 30,446 patients demonstrated that bivalirudin is associated with higher risk of stent thrombosis but lower risk of major bleeding compared with heparin.

[A high-volume single center experience of no-reflow post-percutaneous coronary intervention]. / Incidenza del no-reflow calcolata su oltre 19 000 angioplastiche primarie ed elettive in un singolo centro ad alto volume.

BACKGROUND: The no-reflow (NR) phenomenon is frequent in patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). However, its real incidence and prognostic significance, so far derived from relatively small patient cohorts, remain poorly defined. METHODS: We have retrospectively analyzed 19 290 consecutive PCI performed at our hospital between January 1998 and November 2010. NR was defined as a TIMI flow ≤2 at the end of the PCI. RESULTS: In the 1257 patients with STEMI, NR occurred in 9.4% of cases and was more common when the left anterior descending coronary artery was the culprit vessel. STEMI-NR patients had longer ischemic times and more frequently multivessel disease. In the STEMI-NR group, glycoprotein IIb/IIIa inhibitors were used in 60.2%, nitroprusside in 39.6%, thrombus aspiration in 10.7% and adenosine in 8.7%. In the remaining 18033 patients without STEMI undergoing PCI, the NR phenomenon occurred only in 0.2% of cases. STEMI-NR patients had lower left ventricular ejection fraction at discharge (50.3 ± 7.2 vs 44.9 ± 8.4%; p<0.01) and showed higher rates of adverse events (death, non-fatal myocardial infarction, coronary revascularization, new hospital admission for heart failure: 67.8 vs 36.9%, p=0.001), death (25.4 vs 13.2%, p<0.01), myocardial infarction (13.6 vs 4.8%, p<0.01) and hospitalizations for heart failure (13.6 vs 4.8%, p<0.001). CONCLUSIONS: Our data, derived from a large cohort of patients from a single center, allow a more correct estimate of the occurrence and prognostic significance of NR. The NR phenomenon is more common in STEMI patients undergoing primary PCI and has an important negative prognostic value.

Efficacy and safety of a routine early invasive strategy after fibrinolysis stratified by glycoprotein IIb/IIIa inhibitor use during percutaneous coronary intervention: a pre-specified subgroup analysis of the TRANSFER-AMI randomised controlled trial.

OBJECTIVE: We evaluated the efficacy and safety of an early invasive strategy post-fibrinolysis in relation to glycoprotein (GP) IIb/IIIa inhibitor use. METHODS: The Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI) randomised 1059 ST elevation myocardial infarction patients to an early invasive strategy or standard therapy post-fibrinolysis. The primary end point was the composite of death, reinfarction, recurrent ischaemia, new or worsening heart failure, or cardiogenic shock at 30 days. In this pre-specified analysis, we examined efficacy and safety outcomes of an early invasive strategy after stratification by GPIIb/IIIa inhibitor use, which was permitted during percutaneous coronary intervention (PCI) at the discretion of the treating physician. RESULTS: A total of 695 patients (65.6%) received GPIIb/IIIa inhibitors. There was significant heterogeneity (p<0.001) in the efficacy of an early invasive strategy compared to standard therapy, between the strata with GPIIb/IIIa inhibitor use (primary end point 9.6% vs 22.3% respectively, p<0.001) and without GPIIb/IIIa inhibitor use (primary end point 14.8% vs 10.4% respectively, p=0.21). Patients who received GPIIb/IIIa inhibitors had lower Global Registry of Acute Coronary Events (GRACE) risk scores compared to those without GPIIb/IIIa inhibitor use (median 121 vs 130, p<0.001). After adjusting for the interaction between GRACE risk score and treatment assignment, the heterogeneity in the efficacy of an early invasive strategy with respect to GPIIb/IIIa inhibitor use was no longer significant (p interaction=0.08). CONCLUSIONS: The apparent difference in the efficacy of an early invasive strategy between GPIIb/IIIa inhibitor strata likely reflects an association between GPIIb/IIIa inhibitor use and baseline risk. GPIIb/IIIa inhibitor use during PCI at the discretion of the treating physician does not appear to modulate the efficacy of an early invasive strategy post-fibrinolysis. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov/ct2/show/NCT00164190, NCT00164190.

Antithrombotic therapy in patients with acute coronary syndromes: how to make the right choice?

ìAcute coronary syndrome (ACS), a spectrum of clinical scenarios including ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction and unstable angina, is one of the main reasons of hospital admissions and the leading cause of mortality in the developed nations. The underlying pathological substrate in ACS is a rupture of the atherosclerotic plaque leading to either complete or partial thrombosis of the infarct-related vessel. Both activation of platelets and coagulation cascade play a crucial role in thrombus formation. Multiple pharmacological agents have been developed to interfere in this process and to achieve ruptured plaque stabilization. Given the unfavorable impact of bleeding events on clinical outcomes, the development of newer drugs inhibiting platelet aggregation or thrombin formation used for the treatment of patients during acute ACS phase or for the prophylaxis of future ischemic events is targeted on the optimal balance of benefits and risks for each individual. This review provides comprehensive analysis of the current status of antiplatelet and antithrombotic therapy in patients with ACS.