Facilitated angioplasty with combo therapy among patients with ST-segment elevation myocardial infarction: a meta-analysis of randomized trials

Introduction

Time to treatment has been shown to be a major determinant of mortality in primary angioplasty. The aim of the current study was to perform a meta-analysis of randomized trials evaluating the benefits from pharmacologic facilitation with adjunctive glycoprotein (Gp) IIb-IIIa inhibitors + reduced lytic therapy vs adjunctive Gp IIb-IIIa inhibitors among patients with ST-segment elevation myocardial infarction (MI).

Methods

We obtained results from all randomized trials comparing facilitated PCI with adjunctive Gp IIb-IIIa inhibitors and reduced lytic therapy vs adjunctive Gp IIb-IIIa inhibitors among patients with ST-segment elevation MI (STEMI). The literature was scanned by formal searches of electronic databases (MEDLINE and CENTRAL) from January 1990 to December 2007. The following key words were used: randomized trial, MI, reperfusion, primary angioplasty, pharmacologic facilitation, facilitated angioplasty, combo therapy, fibrinolysis, thrombolysis, half-dose lytic therapy, duteplase, reteplase, tenecteplase, alteplase, abciximab, tirofiban, eptifibatide, and Gp IIb-IIIa inhibitors. Angiographic end points were the rate of preprocedural and postprocedural thrombolysis in MI (TIMI) 3 flow. Clinical end points assessed were mortality and reinfarction at 30-day follow-up, whereas major bleeding complications were assessed as safety end point. No language restriction was applied.

Results

We identified 6 randomized trials, including 2684 patients with STEMI. Even though combo therapy was associated with a significant improvement in preprocedural TIMI 3 flow (44.3% vs 15.2%, P < .0001, P_het < .0001), it did not improve the rate of postprocedural TIMI 3 flow (91.5% vs 91.2%, P = .12). No benefits were observed in terms of 30-day mortality (4.2% vs 4.6%, P = .66, P_het = .22) and/or 30-day reinfarction (1.3% vs 1.3%, P = .84). However, combo therapy was associated with higher risk of major bleeding complications (5.8% vs 3.9%, P = .03).

Conclusions

This meta-analysis shows that among patients with STEMI undergoing primary angioplasty, pharmacologic facilitation with combined reduced-dose thrombolytic therapy and Gp IIbIIIa inhibitors is not superior to Gp IIb-IIIa inhibitors alone and, thus, may not be routinely recommended. However, future randomized trials should investigate whether this strategy may further improve outcome when applied within the first hours from symptoms onset, especially in patients undergoing transferring for primary angioplasty.     

Randomized,double‐blind comparison of effects of abiciximab bolus only vs. on‐label regimen on ex vivo inhibition of platelet aggregation in responders to clopidogrel undergoing coronary stenting

Summary. Background: On top of aspirin, an abciximab bolus‐only regimen results in a 30% drop in platelet inhibition at 6 h as compared with the on‐label regimen. The concomitant administration of high loading dose clopidogrel, by bridging with abciximab bolus, may sustain suppression of platelet activity over time. Objectives: To investigate the non‐inferiority of abciximab bolus‐only and concomitant high loading dose clopidogrel vs. abciximab bolus + infusion with respect to the inhibition of platelet aggregation (IPA) as determined by light transmission aggregometry. Patients/Methods: Seventy‐three patients with non‐ST segment elevation acute coronary syndromes underwent double‐blind randomization to abciximab bolus followed by a 12‐h placebo infusion and concomitant 600‐mg clopidogrel vs. abciximab bolus + a 12‐h infusion and 300 mg of clopidogrel. IPA was determined by light transmission aggregometry throughout 24 h. Clopidogrel poor responsiveness was defined as ≥ 50% 5 μmol L^?1 ADP‐induced maximum platelet aggregation. Results: In clopidogrel responders (n = 68), IPA after 20 μmol L^?1 ADP at 4 h was 89% ± 13% in the bolus‐only arm vs. 92% ± 14% in the bolus + infusion arm (P = 0.011 for non‐inferiority). IPA after 5 or 20 μmol L^?1 ADP and 5 or 15 μmol L^?1 TRAP and the proportion of patients showing ≥ 80% IPA did not differ at any time point, irrespective of clopidogrel responsiveness status. Thirty‐day outcomes were similar, whereas hemoglobin (0.91 ± 0.8 vs. 0.5 ± 0.7 g dL^?1; P = 0.01) and platelet count mean drop (41.7 ± 57 vs. 18.6 ± 34 10⁹ L^?1; P = 0.042) were significantly reduced in the bolus‐only arm. Conclusions: Withholding abciximab post‐bolus infusion in patients receiving high loading dose clopidogrel does not impair platelet inhibition throughout 24 h, and has the potential to improve the safety profile of the drug at reduced costs.     

Low‐molecular‐weight heparins vs. unfractionated heparin in the setting of percutaneous coronary intervention for ST‐elevation myocardial infarction: a meta‐analysis

Summary. Background: The aim of the current study was to perform two separate meta‐analyses of available studies comparing low‐molecular‐weight heparins (LMWHs) vs. unfractionated heparin (UFH) in ST‐elevation myocardial infarction (STEMI) patients treated (i) with primary percutaneous coronary intervention (pPCI) or (ii) with PCI after thrombolysis. Methods: All‐cause mortality was the pre‐specified primary endpoint and major bleeding complications were recorded as the secondary endpoints. Relative risk (RR) with a 95% confidence interval (CI) and absolute risk reduction (ARR) were chosen as the effect measure. Results: Ten studies comprising 16 286 patients were included. The median follow‐up was 2 months for the primary endpoint. Among LMWHs, enoxaparin was the compound most frequently used. In the pPCI group, LMWHs were associated with a reduction in mortality [RR (95% CI) = 0.51 (0.41–0.64), P < 0.001, ARR = 3%] and major bleeding [RR (95% CI) = 0.68 (0.49–0.94), P = 0.02, ARR = 2.0%] as compared with UFH. Conversely, no clear evidence of benefits with LWMHs was observed in the PCI group after thrombolysis. Meta‐regression showed that patients with a higher baseline risk had greater benefits from LMWHs (r = 0.72, P = 0.02). Conclusions: LMWHs were associated with greater efficacy and safety than UFH in STEMI patients treated with pPCI, with a significant relationship between risk profile and clinical benefits. Based on this meta‐analysis, LMWHs may be considered as a preferred anticoagulant among STEMI patients undergoing pPCI.     

A new method to quantify postexercise ST‐deviation – the ST‐deficit. A study in men at high and low‐risk for coronary heart disease

Background Quantitative heart rate adjusted exercise ST criteria like μV/beats per minute (bpm) improve the diagnostic accuracy of the exercise ECG. However, there are few quantitative HR adjusted postexercise variables available. The aim of the present exercise study was to evaluate a new such variable from computerized averaging of the postexercise ECG. Methods The presence of possible myocardial ischaemia in a population based sample of 74 elderly male hypertensives at high‐risk of coronary heart disease, and in 42 age‐matched clinically healthy males (reference group) at low‐risk was assessed by exercise ECG. All men had a normal resting ECG without signs of ischaemia. Variables studied: standard ST‐criteria, ST/HR slope ≤–2·4 μV · bpm^–1, shape of the rate‐recovery loop, the latter also with a new quantitative variable, the ST‐deficit. Results In spite of a normal resting ECG many subjects showed an abnormal ST/HR slope during exercise, 43% in the hypertension group and 26% in the reference group. An abnormal rate‐recovery loop (ST‐deficit) also contributed substantially to identify patients with possible myocardial ischaemia, 30 vs. 10%, respectively (P<0·02); cumulatively for the two HR adjusted criteria 53% vs. 29%, respectively (P<0·02). Mean ST‐deficit was significantly lower in the high‐risk group. Conclusions Effort‐related myocardial ischaemia is frequently silent in elderly high‐risk hypertensives and necessitates testing, preferably with computerized exercise ECG and heart rate adjusted ST criteria. A new quantitative variable to assess the postexercise rate‐recovery loop in the time domain, the ST‐deficit is described. This variable seems to effectively discriminate between subjects with low and high‐risk for coronary heart disease and thus provides new information. Further studies are warranted to validate this variable against myocardial perfusion scintigraphy and coronary angiography.     

Troponin level and efficacy of abciximab in patients with acute coronary syndromes undergoing early intervention after clopidogrel pretreatment

Objective We investigated how does troponin level (TnT) affect the benefit achieved by abciximab in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) after pretreatment with a high loading dose of clopidogrel. Methods The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 2) trial included 2,022 patients with non-ST elevation ACS undergoing PCI who were randomized to abciximab or placebo after pretreatment with 600 mg of clopidogrel. The patients were divided into groups with elevated TnT level (n = 1,049) and no elevated TnT level (n = 973). The primary end point of the trial was the composite of death, myocardial infarction and urgent reintervention at 30 days. Results In patients with elevated TnT level the incidence of the primary end point was 13.1% in the abciximab group Vs. 18.3% in the placebo group [relative risk (RR): 0.70; 95% confidence interval (CI), 0.52–0.95, P = 0.02]. The combined incidence of death or myocardial infarction was 12.9% in the abciximab group vs. 17.9% in the placebo group (RR: 0.71; 95% CI, 0.52–0.96, P = 0.03). In contrast, the incidence of the primary end point in patients with no elevated TnT level was identical in both treatment groups (4.6%). The risk of bleeding was not related to TnT level. Conclusions Baseline troponin level affects the benefit of abciximab in patients with ACS undergoing PCI after pretreatment with a high loading dose of clopidogrel. Abciximab reduces the risk of ischemic events only in patients with ACS and elevated troponin level.     

Safety and efficacy of protease‐activated receptor‐1 antagonists in patients with coronary artery disease: a meta‐analysis of randomized clinical trials

Summary. Background: Thrombin receptor antagonists blocking protease‐activated receptor‐1 (PAR‐1) on platelets represent a new class of oral antiplatelet agents for patients with atherothrombotic disease manifestations. Objectives: We investigated the safety and efficacy of PAR‐1 antagonists in patients with coronary artery disease (CAD). Patients/Methods: Randomized, placebo‐controlled trials of the PAR‐1 antagonists atopaxar or vorapaxar in CAD patients were identified. The primary safety endpoint was the composite of Thrombolysis In Myocardial Infarction (TIMI) clinically significant bleeding. The primary efficacy endpoint was the composite of death, myocardial infarction (MI) or stroke. Results: A total of 41 647 patients from eight trials were included. PAR‐1 antagonists were associated with higher risks of TIMI clinically significant (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.39–1.57, P < 0.001), major (OR 1.46, 95% CI 1.28–1.67, P < 0.001) and minor (OR 1.67, 95% CI 1.40–2.00, P < 0.001) bleeding than placebo in the fixed‐effects model. PAR‐1 antagonists reduced the composite of death, MI or stroke as compared with placebo (OR 0.87, 95% CI 0.81–0.92, P < 0.001), driven by a lower risk of MI (OR 0.85, 95% CI 0.78–0.92, P < 0.001). Conversely, PAR‐1 antagonists and placebo did not differ in terms of risk of death (OR 0.99, 95% CI 0.90–1.09, P = 0.81) or stroke (OR 0.96, 95% CI 0.84–1.10, P = 0.59). Conclusions: PAR‐1 antagonists decrease ischemic events in patients with CAD as compared with placebo, mainly driven by a reduction in MI, at the cost of an increased risk of clinically significant bleeding.     

经抽吸导管早期应用维拉帕米对急性心肌梗死再灌注无复流的疗效观察

目的 探讨经抽吸导管冠状动脉内早期给予维拉帕米治疗急性ST 段抬高心肌梗死(AMI)患者直接经皮冠状动脉介入治疗(P-PCI)术中无复流现象的疗效.方法 168 例AMI 患者进行直接PCI 术,先行抽吸导管抽吸血栓后,随机分成两组,A 组(n ＝86):经抽吸导管向靶病变远端给予维拉帕米100 ～200 μg/次,总量不超过600 μg;B 组(n ＝82):支架植入发生无复流现象后再通过指引导管向冠状动脉内给予维拉帕米100 ～200 μg/次,总量不超过600 μg.造影评价给药前后冠状动脉血流心肌梗死溶栓试验(TIMI)分级和TI-MI 心肌组织灌注分级(TMPG),评价术后1 h 心电图ST 段下降情况.结果 术后A 组TIMI 3 级血流比例明显高于B 组(91.86% vs.80.49%,P <0.05);术后A 组TMPG 3 级比例明显高于B 组(88.37% vs.75.61%,P <0.05);A 组心电图ST 段迅速下降比例明显高于B 组(80.23% vs.65.85%,P <0.05).结论 早期经抽吸导管向靶病变远端给予维拉帕米较传统方法进一步减少了AMI 患者P-PCI 术中无复流现象的发生.     

Acute and subacute stent thrombosis after primary percutaneous coronary intervention for ST‐segment elevation myocardial infarction: incidence,predictors and clinical outcome

Summary. Background: Early coronary stent thrombosis occurs most frequent after primary percutaneous coronary intervention (PCI) for ST‐segment elevation myocardial infarction (STEMI). Objectives: To identify the specific predictors of, respectively, acute and subacute stent thrombosis in patients after primary PCI for STEMI. Patients/Methods: Consecutive STEMI patients with angiographically confirmed early stent thrombosis were enrolled and compared in a 2 : 1 ratio with a matched control group. Clinical outcome was collected up to 1 year. Results: Of 5842 STEMI patients treated with primary PCI, 201 (3.5%) presented with a definite early stent thrombosis. Of these, 97 (1.7%) had acute stent thromboses and 104 (1.8%) had subacute stent thromboses. Postprocedurally discovered dissection, undersizing and smaller stent diameter were the strongest predictors for acute stent thrombosis. No glycoprotein IIb/IIIa therapy and the use of drug‐eluting stents were also associated with acute stent thrombosis. Lack of clopidogrel therapy in the first 30 days after the index PCI was the strongest predictor for subacute stent thrombosis. Mortality rates at 1‐year follow‐up were lower for acute stent thrombosis than for subacute stent thrombosis (8.3% vs. 13.2%, P = 0.294). The incidence of definite recurrent stent thrombosis at 1‐year follow up was significantly lower after a first definite acute stent thrombosis than after a first definite subacute stent thrombosis (6.4% vs. 19.3%, P = 0.007 at 1 year). Conclusions: The specific risk factors for, respectively, acute and subacute stent thrombosis after primary PCI vary greatly. Mortality rates are high for both categories of stent thrombosis. However, recurrent stent thrombosis occurs more frequently after subacute stent thrombosis.     

Sex,age and normal post‐anticoagulation D‐dimer as risk factors for recurrence after idiopathic venous thromboembolism in the Prolong study extension

Summary. Background: The PROLONG randomized study showed that patients with an abnormal D‐dimer after anticoagulation suspension for a first unprovoked episode of venous thromboembolism (VTE) benefited from anticoagulation resumption. Patients with normal D‐dimer after anticoagulation suspension had a low recurrence rate (4.4% patient–years) but their anticoagulation optimal duration remained uncertain. Objectives: To assess whether sex and age, in combination with normal D‐dimer, are risk factors for VTE recurrence in patients enrolled in the PROLONG study extended follow‐up. Methods: D‐dimer was measured at 1 month after anticoagulation suspension. Patients with a normal D‐dimer did not resume anticoagulants, whereas patients with an abnormal D‐dimer were randomized either to resume or not anticoagulants. Primary outcome was recurrent VTE. Results: After excluding patients resuming anticoagulants for abnormal D‐dimer, recurrences were higher in males than females [7.4% patient‐years – 47/639 vs. 4.3% patient‐years – 27/626; hazard ratio (HR) = 1.7; P = 0.027] and in patients aged 65 or older than in younger patients (8.4% patient‐years – 50/598 vs. 3.6% patient‐years – 24/667; HR = 2.1; P = 0.003). In patients with normal D‐dimer and younger than 65, recurrences were higher in males than in females (5.1% vs. 0.4% patient–years; adjusted HR = 10.6; P = 0.023) and both females and males aged 65 years or older had more recurrences (6.6% and 8.1% patient‐years, respectively, adjusted HR: 16.0; P = 0.008 and 16.0; P = 0.008, respectively) than females younger than 65. Conclusions: In patients with idiopathic VTE and a normal D‐dimer at 1 month after anticoagulation suspension, females younger than 65 had a very low risk of recurrence.     

Predictors of major bleeding in peri‐procedural anticoagulation management

Summary. Background: Appropriate periprocedural management for chronically anticoagulated patients requires assessment of patient‐specific thrombosis and bleeding risks. However, predictors of post‐procedure bleeding are unknown. Objectives: To determine the 3‐month cumulative incidence and independent predictors of peri‐procedural bleeding in chronically anticoagulated patients requiring temporary warfarin interruption for an invasive procedure. Methods: In a protocol driven, cohort study design, all patients referred to the Mayo Clinic Thrombophilia Center for peri‐procedural anticoagulation management (1997–2007; n = 2182), were followed forward in time to determine the 3‐month cumulative incidence of peri‐procedural bleeding (Kaplan–Meier product limit) and potential predictors of bleeding (Cox proportional hazards). Decisions to ‘bridge’ with low‐molecular‐weight heparin were based on estimated thromboembolism and bleeding risk. Results: Indications for chronic anticoagulation included venous thromboembolism (38%), atrial fibrillation (30%) and mechanical heart valves (27%). Of these, 1496 (69%) patients received bridging therapy. The 3‐month cumulative incidence rates of major and overall bleeding were 2.1% and 5.1%, respectively. Major bleeding occurred more frequently in patients receiving bridging therapy (3% vs. 1%; P = 0.017). Independent predictors (hazard ratio; 95% confidence interval) of major bleeding included mitral mechanical heart valve (2.2; 1.1–4.3), active cancer (1.8; 1.0–3.1), prior bleeding history (2.6; 1.5–4.5) and re‐initiation of heparin therapy within 24 h after the procedure (1.9; 1.1–3.4). Conclusion: Factors predisposing to peri‐procedural bleeding are primarily patient‐specific. Premature heparin re‐initiation is an avoidable provider‐specific variable to consider.     

Warfarin for atrial fibrillation in community‐based practise

Summary. Background: Previous studies of anticoagulation for atrial fibrillation (AF) have predominantly occurred in academic settings or randomized trials, limiting their generalizability.Objective: To describe the management of patients with AF anticoagulated with warfarin in community‐based practise.Methods: We enrolled 3396 patients from 101 community‐based practises in 38 states. Data included demographics, comorbidities, and International Normalized Ratio (INR) values. Outcomes included time in therapeutic INR range (TTR), stroke, and major hemorrhage.Results: The mean TTR was 66.5%, but varied widely among patients: 37% had TTR above 75%, while 34% had TTR below 60%. The yearly rates of major hemorrhage and stroke were 1.90 per 100 person‐years and 1.00 per 100 person‐years. Four percent of patients (n = 127) were intentionally targeted to a lower INR, and spent 42.7% of time with an INR below 2.0, compared to 18.8% for patients with a 2.0–3.0 range (P < 0.001). Mean TTR for new warfarin users (57.5%) remained below that of prevalent users through the first six months. Patients with interruptions of warfarin therapy had lower TTR than all others (61.6% vs. 67.2%, P < 0.001), which corrected after deleting low peri‐procedural INR values (67.0% vs. 67.4%, P = 0.73).Conclusions: Anticoagulation control varies widely among patients taking warfarin for AF. TTR is affected by new warfarin use, procedural interruptions, and INR target range. In this community‐based cohort of predominantly prevalent warfarin users, rates of hemorrhage and stroke were low. The risk versus benefit of a lower INR target range to offset bleeding risk remains uncertain.     

Efficacy and safety of anticoagulants in the prevention of venous thromboembolism in patients with acute cerebral hemorrhage: a meta‐analysis of controlled studies

Summary. Aim: The role of anticoagulants for the prevention of venous thromboembolism in acute hemorrhagic stroke is uncertain. We performed an updated meta‐analysis of studies to obtain the best estimates of the efficacy and safety of anticoagulants for the prevention of venous thromboembolism in patients with acute hemorrhagic stroke. Methods: Using electronic and manual searches of the literature, we identified randomized and non‐randomized studies comparing anticoagulants (unfractionated heparin or low‐molecular‐weight heparin or heparinoids) with treatments other than anticoagulants (elastic stockings, intermittent pneumatic compression or placebo) in patients with acute hemorrhagic stroke. Study outcomes included symptomatic and asymptomatic deep venous thrombosis (DVT), symptomatic and asymptomatic pulmonary embolism (PE), any hematoma enlargement or death. Risk ratios (RRs) for individual outcomes were calculated for each study and data from all studies were pooled using the Mantel‐Haenszel method. Results: Four studies (two randomized) involving 1000 patients with acute hemorrhagic stroke met the criteria for inclusion in this meta‐analysis. Compared with other treatments, anticoagulants were associated with a significant reduction in PE (1.7% vs. 2.9%; RR, 0.37; 95% CI, 0.17–0.80; P = 0.01), a DVT rate of 4.2% compared with 3.3% (RR, 0.77; 95% CI, 0.44–1.34; P = 0.36), an increase in any hematoma enlargement (8.0% vs. 4.0%; RR, 1.42; 95% CI, 0.57–3.53; P = 0.45), and a non‐significant reduction in mortality (16.1% vs. 20.9%; RR, 0.76; 95% CI, 0.57–1.03; P = 0.07). Conclusions: Our findings indicate that in patients with hemorrhagic stroke, early anticoagulation is associated with a significant reduction in PE and a non‐significant reduction in mortality, with the trade‐off of a non‐significant increase in hematoma enlargement. These results must be taken with caution and should encourage the assessment of the clinical benefit of antithrombotic prophylaxis in patients with cerebral bleeding by properly designed clinical trials.     

High on‐aspirin platelet reactivity as measured with aggregation‐based,cyclooxygenase‐1 inhibition sensitive platelet function tests is associated with the occurrence of atherothrombotic events

Summary. Background: High on‐aspirin platelet reactivity (HAPR) is associated with atherothrombotic events following percutaneous coronary intervention (PCI). The aim of the present study was to identify the platelet function test sensitive for platelet cyclooxygenase‐1 inhibition that best predicts atherothrombotic events. Methods and results: Nine hundred and fifty‐one consecutive patients on dual antiplatelet therapy undergoing elective PCI were enrolled. On‐aspirin platelet reactivity was measured in parallel by arachidonic acid (AA)‐induced light transmittance aggregometry (AA‐induced LTA), the VerifyNow® Aspirin Assay (VerifyNow® Aspirin Assay), the arachidonic acid prestimulated IMPACT‐R (IMPACT‐R AA) and the PFA‐100 collagen/epinephrine cartridge (PFA COL/EPI). Cut‐offs for HAPR were established by receiver‐operator characteristic curve analysis. At 1‐year follow‐up, the composite of all‐cause death, non‐fatal acute myocardial infarction, stent thrombosis and ischemic stroke occurred more frequently in patients with HAPR when assessed by LTA [10.1% vs. 6.0%, P = 0.020 (n = 925)] and VerifyNow^® [13.3% vs. 5.9%, P = 0.015 (n = 422)]. The VerifyNow^® ASA assay (AUC = 0.78) and, to a lesser extent, AA‐induced LTA (AUC = 0.73) added significantly to a model consisting of clinical and procedural risk factors in predicting atherothrombotic events. In contrast, the IMPACT‐R (n = 791) and the PFA Collagen/Epinephrine (n = 719) were unable to discriminate between patients with and without primary endpoint at 1‐year follow‐up. None of the platelet function tests was able to identify patients at risk for bleeding. Conclusions: AA‐induced LTA and the VerifyNow^® ASA test were able to identify aspirin‐treated patients undergoing PCI with stenting at risk for atherothrombotic events. The VerifyNow^® Aspirin Assay had the highest predictive accuracy. None of the tests was able to identify patients at higher risk of bleeding.     

One-year clinical outcomes with abciximab in acute myocardial infarction: results of the BRAVE-3 randomized trial

Purpose

In the Bavarian Reperfusion Alternatives Evaluation (BRAVE)-3 study upstream administration of abciximab additional to 600 mg clopidogrel loading did not reduce the infarct size in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary interventions. The aim of this study was to investigate 1-year clinical outcomes in the BRAVE-3 study patients.

Methods

A total of 800 patients with acute STEMI within 24 h from symptom onset, all treated with 600 mg of clopidogrel were randomized in a double-blind fashion to receive either abciximab (n = 401) or placebo (n = 399) in the intensive care unit before being sent to the catheterization laboratory.

Results

The main outcome of interest of the present study, the composite of death, recurrent myocardial infarction, stroke or revascularization of the infarct-related artery (IRA) at 1 year, was 23.0% (92 patients) in the abciximab versus 25.7% (102 patients) in the placebo group [relative risk (RR) = 0.90, 95% confidence interval (CI) 0.67–1.20; P = 0.46]. The combined incidence of death, recurrent myocardial infarction or stroke was 9.3% in the abciximab group versus 6.0% in the placebo group (RR = 1.55, 95% CI 0.93–2.58; P = 0.09). There was a significant reduction of the IRA revascularization with abciximab compared to placebo (16.3 vs. 22.3%, RR = 0.71, 95% CI 0.52–0.98; P = 0.04).

Conclusion

In patients with STEMI, all receiving 600 mg clopidogrel, abciximab did not improve overall clinical outcomes at 1 year after primary coronary stenting.     

PRODIGE: a randomized placebo‐controlled trial of dalteparin low‐molecular‐weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma

Summary. Background and objectives: Venous thromboembolism (VTE) occurs in 20–30% of patients with malignant glioma per year of survival. We tested the efficacy of long‐term dalteparin low‐molecular‐weight heparin (LMWH) for prevention of VTE in these patients. Patients/methods: Adults with newly diagnosed malignant glioma were randomized to receive dalteparin 5000 anti‐Xa units or placebo, both subcutaneously once daily for 6 months starting within 4 weeks of surgery. Treatment continued for up to 12 months. The primary outcome was the cumulative risk of VTE over 6 months. The target sample size was 512 patients. Events were adjudicated by a committee unaware of treatment. Results: The trial began in 2002 and closed in May 2006 because of expiration of study medication. Ninety‐nine patients were randomized to LMWH and 87 to placebo. Twenty‐two patients developed VTE in the first 6 months: nine in the LMWH group and 13 in the placebo group [hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.19–1.4, P = 0.29]. At 6 months, there were three major bleeds on LMWH and none on placebo; at 12 months, 5 (5.1%) major bleeds on LMWH and 1 (1.2%) on placebo occurred (HR = 4.2, 95% CI: 0.48–36, P = 0.22). All major bleeds were intracranial and occurred while on study medication. The 12‐month mortality rates were 47.8% for LMWH and 45.4% for placebo (HR = 1.2, 95% CI: 0.73–2.0, P = 0.48). Conclusions: Trends suggesting reduced VTE and increased intracranial bleeding were seen in the LMWH thromboprophylaxis group. The role of long‐term anticoagulant thromboprophylaxis in patients with brain tumors remains uncertain.     

G‐protein β3 subunit polymorphism and bleeding in the orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction 16 trial

Summary. Background: Variability in platelet response to antiplatelet drugs is heritable. A common single base substitution (825C>T) in the G‐protein beta polypeptide 3 (GNB3) gene leads to alternative splicing (41‐amino‐acid deletion) of the human G‐protein β3 (Gβ3) subunit. This truncated protein carried by GNB3 T allele carriers is linked to coronary artery disease and implicated as a genetic marker of drug response. Large studies of Caucasians associate T allele carriage with lower platelet reactivity.Objectives: To evaluate whether the GNB3 genotype would predispose to bleeding in patients treated with a GPIIb/IIIa receptor antagonist. Methods: GNB3 genotype distribution was determined in DNA samples from patients in the orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction (OPUS–TIMI) 16 genetic sub‐study. Impact of genotype on the bleeding endpoint and the composite primary endpoint of death, myocardial infarction (MI), re‐hospitalization for ischemia and urgent revascularization was estimated in the treatment and placebo arm. Results: Out of 887 patients, 45.1% carried the GNB3 CC genotype, 44.5% CT and 10.4% TT. Interaction between T allele carriership and treatment for bleeding was significant (P = 0.008). This reflects the fact that GNB3 non‐T carriers treated with orbofiban had no bleeding effect compared with placebo (RR = 0.92, 95% CI 0.55–1.55) whereas T carriers did (RR = 2.62, 95% CI 1.58–4.35, P < 0.001). Interaction between T allele carriership and treatment was not significant for the primary endpoint (P = 0.18) or MI (P = 0.69). Conclusion: The GNB3 T allele significantly increased bleeding in patients treated with the platelet antagonist orbofiban. Our findings suggest that risk of bleeding associated with an antiplatelet agent is heritable and may be dissociated from risk of thrombosis.     

Coronary stenting and abciximab in primary angioplasty for ST-segment-elevation myocardial infarction

Advances in anti-platelet therapy and improvement of stent deployment techniques have improved the safety and efficacy of stenting in the setting of ST-segment-elevation myocardial infarction (STEMI). However, in randomized trials, routine coronary stenting does not reduce mortality and re-infarction, compared to balloon angioplasty. Further, the benefits in target vessel revascularization seem to be reduced when applied to unselected patients with STEMI. Direct stenting represents an attractive strategy with potential benefits in terms of myocardial perfusion. Future large randomized trials are needed to evaluate whether this strategy has a significant impact on outcome, and to provide a cost-benefit analysis of the unrestricted use of drug-eluting stents in this high-risk subset of patients. The additional use of abciximab reduces mortality in primary angioplasty. Since the feasibility of long-distance transportation has been shown in several randomized trials, early pharmacological pre-treatment may confer further advantages by early recanalization and shorter ischaemic time, particularly in high-risk patients. Further randomized trials are needed to clarify the potential benefits from early abciximab administration and the potential role of small molecules in primary angioplasty for STEMI.     

Pegylated granulocyte‐colony stimulating factor versus non‐pegylated granulocyte‐colony stimulating factor for peripheral blood stem cell mobilization: A systematic review and meta‐analysis

Granulocyte‐colony stimulating factor (G‐CSF) mobilizes and increases the amount of hematopoietic stem cells in peripheral blood, enabling its harvest by few apheresis procedures. The pegylated G‐CSF has longer half‐life and is given once only, which is more comfortable for patients, whereas the non‐pegylated requires multiple daily injection because of its short half‐life. We summarized results of randomized trials comparing the efficacy and safety of pegylated and non‐pegylated G‐CSF for peripheral blood stem cell mobilization. We searched the Cochrane CENTRAL, MEDLINE, EMBASE, and two conference proceedings. Two authors made the selection, extracted data and evaluated methodological quality using GRADE independently. We used random‐effects model for meta‐analysis. We found 3956 records and retrieved 47 full texts. We included eight randomized trials with a total number of 554 randomized and 532 analyzed subjects. The meta‐analysis included five trials because not all trials reported the same outcomes. Pooling data from two studies shows no evidence for a difference in the successful mobilization rate (CD34+ cell ≥ 2 × 10⁶/kg collected) between pegfilgrastim 6 mg (early administration) and filgrastim 5 µg/kg/day (147 participants; risk ratio (RR) 0.87, 95% confidence interval (95%CI) 0.67‐1.11; P = .26). Pooling data from three studies shows no difference in the incidence of adverse events between pegylated and non‐pegylated G‐CSF (170 participants; RR 0.86, 95%CI 0.34‐2.17; P = .75). No difference found on the quantity of CD34+ cells collected, number of apheresis procedure in successful mobilization, level of peak PB CD34+ cells achieved, and day of neutrophil and platelet engraftment.     

The CD14++CD16+ monocyte subset and monocyte‐platelet interactions in patients with ST‐elevation myocardial infarction

Summary. Aim: Monocytes contribute to both myocardial damage and repair by virtue of subset heterogeneity. The dynamics and functional characteristics of the three human monocyte subsets, including the unique CD14++CD16+ subset, and their contributions to monocyte platelet aggregates (MPAs) following ST‐elevation myocardial infarction (STEMI) are unknown. We aimed to examine dynamic changes and relation to left ventricular ejection fraction (LVEF) of the three human monocyte subsets and their aggregates with platelets following STEMI. Methods: Three monocyte subsets, CD14++CD16?CCR2+ (‘classical’, Mon1), CD14++CD16+CCR2+ (‘intermediate’, Mon2) and CD14+CD16++CCR2? (‘non‐classical’, Mon3), and their contribution to MPAs were analyzed by flow cytometry in 50 patients with STEMI, 40 patients with stable coronary artery disease (CAD) and 40 healthy volunteers. Study parameters were measured within 24 h of primary percutaneous coronary intervention (PCI) (day1) and on days 3, 7 and 30. Monocyte activation was assessed by measuring the nuclear factor κB (NFκB) pathway. LVEF was assessed 6 weeks after STEMI. Correlations between monocyte subsets/MPAs and plasma cytokines and troponin were assessed. Results: We observed marked differences in subset dynamics, with a prominent increase in Mon2 (P < 0.0001) but no changes in Mon3. Significant increases in Mon2 CD14 (P = 0.002) and CCR2 (P < 0.0001) expression, and reduction in CD16 expression (P = 0.001) were seen. NFκB pathway activity increased most prominently in Mon2 (P = 0.007). Mon2 count correlated with peak troponin (r = 0.31, P = 0.04) and plasma interleukin (IL)‐6 (r = 0.65, P < 0.0001) and IL‐10 (r = 0.34, P = 0.017). Mon1 correlated with IL‐6 (r = 0.55, P < 0.0001). Reduced Mon2 expression of CD16 on day 1 was independently predictive of higher LVEF (β = ?0.37, P = 0.013). The increase in MPA count following STEMI persisted at 1 month. Conclusion: The Mon2 ‘intermediate’ subset has unique dynamic and functional characteristics following STEMI and significant correlations with troponin, plasma cytokines and convalescent left ventricular function. The persistent increase in MPA count 30 days after STEMI may affect monocyte subset functional activity.     

Comparison of the CELLEX™ and UVAR‐XTS™ closed‐system extracorporeal photopheresis devices in the treatment of chronic graft‐versus‐host disease

Extracorporeal Photopheresis (ECP) is a cellular immunotherapy frequently used for steroid‐refractory graft‐versus‐host disease (GVHD). Chronic GVHD (cGVHD), response to ECP is associated with survival benefit. The UVAR‐XTS^TM system and the more recently developed CELLEX^TM device (both Therakos^TM) are the mainstay for ECP‐delivery in the UK and US. No comparison of treatment outcomes has been reported. We retrospectively compared cGVHD response and steroid reduction and withdrawal in patients treated exclusively over 12 months with either the XTS (n = 51) or CELLEX (n = 50). Our hypothesis was that there would be no difference in clinical outcome or steroid changes in the 2 matched cohorts. We also compared infection incidence, infection‐related death (IRD), and treatment time. Significant clinical improvement and regular capacity to reduce or cease steroids was encountered in both cohorts; at 6 months of ECP 70% of cutaneous cGvHD patients had partial or complete responses and 85% of patients receiving steroids pre‐ECP had reduced dosage. In the XTS group we unexpectedly encountered both superior steroid reduction (86% dose at least halved vs. 61% for CELLEX, P = 0.01) and withdrawal (15 vs. 5 CELLEX, P = 0.01) and a trend for superior skin disease response in the CELLEX‐treated cohort at 3 months. No inter‐relationship was evident. Halving or greater reduction of steroid dose by 3 or 6 months was associated with reduced risk of IRD in the XTS cohort as was withdrawal at 6 months for the combined cohorts. By 6 months, XTS‐treated patients had experienced fewer antibiotic‐requiring infections (mean 1.9 vs. 2.8, P = 0.025). Origins for the disparities are unclear and warrant investigation.