Risk Of Major Bleeding Complications Research Articles

Using risk difference as opposed to odds-ratio in meta-analysis. Response

We appreciate the interest of Messori and colleagues [1] in our recent meta-analysis published in the Journal. In the article, we concluded that intensifying antiplatelet therapy on the basis of platelet reactivity testing reduced cardiovascular mortality and stent thrombosis after PCI, without increasing the risk for major bleeding complications [2]. In their letter, the authors raise concerns regarding the methodology used in the meta-analysis, adding results of a post-hoc analysis using risk difference (RD) as opposed to odds ratio (OR). First of all, it should be declared that the choice of OR as an effect estimate in our meta-analysis is entirely appropriate and standard, also supported by the Cochrane collaboration and applied in several previously published impacting meta-analyses [3–6]. The preference of risk ratio (RR) and RD over OR originates from the less straightforward interpretation of the latter due to its mathematical definition that might lead to confusions if OR is misinterpreted as a RR. However, the non-equivalence of the RR and OR does not indicate that either is wrong; both are entirely valid ways of describing an intervention effect [3]. On the other hand, since OR has many advantageous features over RR or RD in statistical modeling and outcome analysis, OR and its timedependent equivalence, hazard ratio (HR) are the most frequently used effect estimates in clinical outcome analyses [3]. Likewise, using OR or HR in a meta-analysis is appropriate and has the advantage of keeping better contact between the original study results and that of the meta-analysis. Notably, the difference between OR and RR is larger in case of analyzing frequent outcomes in a study, but is ignorable in case of rare outcomes, such as in the case of our meta-analysis. Recalculating our findings by using RR as an effect estimate provided almost identical results to the originals, without any impact on statistical significance levels (Table 1). The difference between our results and the post-hoc analysis of Messori and colleagues does not originate from the fundamental differences between OR and RR, but comes from the fact that they estimated RD-s in an analysis including studies without any outcome event. In cases when the standard error cannot be computed from the available information (such as in studies without outcomes in both arms), the software performs a correction to the outcomes andproduces weighted RD values that suggest equivalence between study arms. However, this attempt is seriously questionable, because lack of events does notmeanequivalence. If no events are observed in both groups, the studyprovides no information about the relative probabilityof the event between study arms. Therefore, in such cases, the appropriate and generally applied approach is to use OR or RR as an effect estimate, and studies without events are omitted by the analysis [3]. In addition, since the included trials enrolled highly heterogeneous patient populations regarding the underlying risk for thrombotic and bleeding events, calculation of absolute risk differences (RD) instead of differences in relative event probabilities (OR or RR) is less appropriate and meaningful. However, we acknowledge that a clinical limitation to our meta-analysis was to include a large number of small studies with rare outcomes. Therefore, as highlighted in the limitation section, the exact numerical results of our meta-analysis should be interpreted cautiously as they might be subject to overestimation of treatment effect due to the small sample sizes and rare outcomes. Indeed, we believe that pooling outcome information from all the currently available, randomized, controlled clinical trials into a meta-analysis added significant novel findings to this scientific area justifying its clinical importance. In conclusion, based on the statistical analysis used, the results of our meta-analysis are valid to support the clinical benefits of intensified antiplatelet therapy based on platelet reactivity testing and the concerns of Messori and colleagues cannot be shared.

Vitamin K antagonists versus antiplatelet therapy after transient ischaemic attack or minor ischaemic stroke of presumed arterial origin

People who have had a transient ischaemic attack (TIA) or non-disabling ischaemic stroke have an annual risk of major vascular events of between 4% and 11%. Aspirin reduces this risk by 20% at most. Secondary prevention trials after myocardial infarction indicate that treatment with vitamin K antagonists is associated with a risk reduction approximately twice that of treatment with antiplatelet therapy. To compare the efficacy and safety of vitamin K antagonists and antiplatelet therapy in the secondary prevention of vascular events after cerebral ischaemia of presumed arterial origin. We searched the Cochrane Stroke Group Trials Register (last searched 15 September 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (2008 to September 2011) and EMBASE (2008 to September 2011). In an effort to identify further relevant trials we searched ongoing trials registers and reference lists. We also contacted authors of published trials for further information and unpublished data. Randomised trials of oral anticoagulant therapy with vitamin K antagonists (warfarin, phenprocoumon or acenocoumarol) versus antiplatelet therapy for long-term secondary prevention after recent transient ischaemic attack or minor ischaemic stroke of presumed arterial origin. Two review authors independently selected trials, assessed trial quality and extracted data. We included eight trials with a total of 5762 participants. The data showed that anticoagulants (in any intensity) are not more efficacious in the prevention of vascular events than antiplatelet therapy (medium intensity anticoagulation: relative risk (RR) 0.80, 95% confidence interval (CI) 0.56 to 1.14; high intensity anticoagulation: RR 1.02, 95% CI 0.49 to 2.13). There is no evidence that treatment with low intensity anticoagulation gives a higher bleeding risk than treatment with antiplatelet agents: RR 1.27 (95% CI 0.79 to 2.03). However, it was clear that medium and high intensity anticoagulation with vitamin K antagonists, with an INR of 2.0 to 4.5, were not safe because they yielded a higher risk of major bleeding complications (medium intensity anticoagulation: RR 1.93, 95% CI 1.27 to 2.94; high intensity anticoagulation: RR 9.0, 95% CI 3.9 to 21). For the secondary prevention of further vascular events after TIA or minor stroke of presumed arterial origin, there is sufficient evidence to conclude that vitamin K antagonists in any dose are not more efficacious than antiplatelet therapy and that medium and high intensity anticoagulation leads to a significant increase in major bleeding complications.

Efficacy and safety of early versus late glycoprotein IIb/IIIa inhibitors for PCI

BackgroundGlycoprotein (Gp) IIb/IIIa inhibitors are beneficial for patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). However, optimal drug timing remains inconclusive. Therefore, this study was to perform a meta-analysis of the clinical efficiency and safety of early versus late GpIIb/IIIa inhibitors in STEMI patients undergoing PCI. MethodsA comprehensive search was to identify randomized trials of early versus late GpIIb/IIIa inhibitors in STEMI patients undergoing PCI. The GpIIb/IIIa inhibitors were abciximab and small-molecular Gp inhibitors (SMGP) namely eptifibatide and tirofiban. The efficacy endpoints included pre-procedural Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow, post-procedural TIMI 3 flow, complete ST-segment resolution, left ventricle ejection fraction (LVEF), and mortality. The safety endpoint was the occurrence of major bleeding complications. ResultsNineteen trials were included in the meta-analysis, involving 4209 patients (early 2124 versus late 2085). Early GpIIb/IIIa inhibitors significantly improved pre-procedural TIMI 3 flow, while early abciximab, but not SMGP, further enhanced post-procedural TIMI 3 flow, complete ST-segment resolution, LVEF, and reduced six-month mortality. In addition to clopidogrel loading, only early abciximab improved pre-procedural TIMI 3 flow and complete ST-segment resolution. The rate of major bleeding complications was not increased in early GpIIb/IIIa inhibitors with/without clopidogrel loading. ConclusionsEarly GpIIb/IIIa inhibitors improved pre-procedural TIMI 3 flow and early abciximab provided favorable clinical outcomes in STEMI patients undergoing PCI. On the basis of clopidogrel loading, early abciximab enhanced pre-procedural TIMI 3 flow and ST-segment resolution. These beneficial effects were achieved without increased risks of major bleeding complications.

Benefits from intracoronary as compared to intravenous abciximab administration for STEMI patients undergoing primary angioplasty: A meta-analysis of 8 randomized trials

BackgroundAdjunctive abciximab administration has been demonstrated to reduce mortality and reinfarction in patients with ST-elevation myocardial infarction (STEMI) referred to invasive management. Standard abciximab regimen consists of an intravenous (IV) bolus followed by a 12-h IV infusion. Experimental studies and small clinical trials suggest the superiority of intracoronary (IC) injection of abciximab over IV route. Therefore, the aim of the current study was to perform a meta-analysis of randomized trials (RCTs) to assess the clinical efficacy and safety of IC vs IV abciximab administration in STEMI patients undergoing primary angioplasty. MethodsWe obtained results from all RCTs enrolling STEMI patients undergoing primary percutaneous coronary intervention (PCI). The primary endpoint was mortality, while recurrent myocardial infarction, postprocedural epicardial (TIMI 3) and myocardial (MBG 2–3) perfusion were identified as secondary endpoints. The safety endpoint was the risk of major bleeding complications. ResultsA total of 8 randomized trials were finally included in the meta-analysis, enrolling a total of 3259 patients. As compared to IV route, IC abciximab was associated with a significant improvement in myocardial perfusion (OR [95% CI]=1.76 [1.28–2.42], p<0.001), without significant benefits in terms of mortality (OR [95% CI]=0.85 [0.59–1.23], p=0.39), reinfarction (OR [95% CI]=0.79 [0.46–1.33], p=0.37), or major bleeding complications (OR [95% CI]=1.19 [0.76–1.87], p=0.44). However, we observed a significant relationship between patient's risk profile and mortality benefits from IC abciximab administration (p=0.011). ConclusionsThe present updated meta-analysis showed that IC administration of abciximab is associated with significant benefits in myocardial perfusion, but not in clinical outcome at short-term follow-up as compared to IV abciximab administration, without any excess of major bleedings in STEMI patients undergoing primary PCI. However, a significant relationship was observed between patient's risk profile and mortality benefits from IC abciximab administration. Therefore, waiting for long-term follow-up results and additional randomized trials, IC abciximab administration cannot be routinely recommended, but may be considered in high-risk patients.

Prevention of VTE in Nonorthopedic Surgical Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

VTE is a common cause of preventable death in surgical patients.We developed recommendations for thromboprophylaxis in nonorthopedic surgical patients by using systematic methods as described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.We describe several alternatives for stratifying the risk of VTE in general and abdominal-pelvic surgical patients. When the risk for VTE is very low (< 0.5%), we recommend that no specific pharmacologic (Grade 1B) or mechanical (Grade 2C) prophylaxis be used other than early ambulation. For patients at low risk for VTE (∼1.5%), we suggest mechanical prophylaxis, preferably with intermittent pneumatic compression (IPC), over no prophylaxis (Grade 2C). For patients at moderate risk for VTE (∼3%) who are not at high risk for major bleeding complications, we suggest low-molecular-weight heparin (LMWH) (Grade 2B), low-dose unfractionated heparin (Grade 2B), or mechanical prophylaxis with IPC (Grade 2C) over no prophylaxis. For patients at high risk for VTE (∼6%) who are not at high risk for major bleeding complications, we recommend pharmacologic prophylaxis with LMWH (Grade 1B) or low-dose unfractionated heparin (Grade 1B) over no prophylaxis. In these patients, we suggest adding mechanical prophylaxis with elastic stockings or IPC to pharmacologic prophylaxis (Grade 2C). For patients at high risk for VTE undergoing abdominal or pelvic surgery for cancer, we recommend extended-duration, postoperative, pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis (Grade 1B). For patients at moderate to high risk for VTE who are at high risk for major bleeding complications or those in whom the consequences of bleeding are believed to be particularly severe, we suggest use of mechanical prophylaxis, preferably with IPC, over no prophylaxis until the risk of bleeding diminishes and pharmacologic prophylaxis may be initiated (Grade 2C). For patients in all risk groups, we suggest that an inferior vena cava filter not be used for primary VTE prevention (Grade 2C) and that surveillance with venous compression ultrasonography should not be performed (Grade 2C). We developed similar recommendations for other nonorthopedic surgical populations.Optimal thromboprophylaxis in nonorthopedic surgical patients will consider the risks of VTE and bleeding complications as well as the values and preferences of individual patients.

Mild kidney disease as a risk factor for major bleeding in patients with atrial fibrillation undergoing percutaneous coronary stenting

Bleeding risk is increased in patients with atrial fibrillation (AF) and moderate to severe kidney disease (KD); however, the implication of mild KD on bleeding remains unclear. The aim of this study was to determine whether the presence of mild KD increases risk for major bleeding (MB) in patients with AF undergoing percutaneous coronary intervention with stent implantation (PCI-S). Two hundred eighty-five patients were included. Patients were classified into three kidney function groups: moderate to severe KD (n=91; <60 ml/min/1.73 m²), mild KD (n=139; 60-89 ml/min/1.73 m²) and non-KD (n=55; ≥90 ml/min/1.73 m²). Estimated glomerular filtration rate was calculated using the simplified Modification of Diet in Renal Disease equation. Patients were followed for one year, and the occurrence of MB was obtained in all. A total of 28 patients (9.8%) presented MB. MB complications examined as a function of KD groups revealed that there was a graded increase in MB with worsening renal function (non KD=1.8%, mild KD=7.9%, moderate to severe KD=17.6%; p <0.001). Multivariable Cox regression analysis showed that mild KD was associated with nearly a 2.5-fold (2.43 95% confidence interval 1.11-5.34, p=0.039) increase in the risk of MB as compared with non-KD patients. Other independent predictors of MB were moderate-severe KD, anaemia and triple antithrombotic therapy after PCI-S (C-index=0.76). In this population, mild KD confers a significantly increase in the risk for MB complications. Future studies should assess the potential role of incorporating mild KD into the bleeding risk scales to improve the stratification of these patients.

Ischaemic Stroke - Stenting versus Surgery for Carotid Disease

Extracranial internal carotid artery stenosis is one of the most common and best studied causes of stroke. Revascularisation with carotid endarterectomy (CEA) has been shown to be beneficial for patients with severe stenosis associated with stroke or transient ischaemic attack (TIA) and for many patients with moderate stenosis associated with stroke or TIA. CEA has also been shown to be beneficial for patients with asymptomatic severe stenosis if they have a reasonable expected lifespan and surgical risk, but the benefit is greater for men compared with women. Carotid angioplasty and stenting (CAS) has become a viable alternative procedure for carotid revascularisation with less risk of major bleeding complications and cranial nerve injury. Randomised studies of CEA versus CAS have found that the endovascular approach is associated with a lower risk of myocardial infarction but a higher risk of peri-procedural stroke which has a greater impact on long-term quality of life. Thus, recommending CEA or CAS must be based upon individual patient characteristics and their preferences, but at this point it appears that most patients should still be receiving CEA if an intervention is required.

Clinical efficacy and safety of intracoronary vs. intravenous abciximab administration in STEMI patients undergoing primary percutaneous coronary intervention: A meta-analysis of randomized trials

Adjunctive therapy with abciximab has been proven to reduce mortality and reinfarction in patients with ST-elevation myocardial infarction (STEMI) referred to invasive management. Standard abciximab regimen consists of an intravenous (IV) bolus followed by a 12-h IV infusion. Experimental studies and small clinical trials suggest the superiority of intracoronary (IC) injection of abciximab over the IV route. We aimed to perform a meta-analysis of randomized controlled trials to assess the clinical efficacy and safety of IC vs. IV abciximab administration in STEMI patients undergoing primary percutaneous coronary intervention (PPCI). The primary endpoint was mortality, while recurrent myocardial infarction and target vessel revascularization (TVR) were selected as secondary endpoints. The safety endpoint was the risk of major bleeding complications. A total of six randomized trials were finally included in the meta-analysis, enrolling a total of 1246 patients. Compared to IV route, IC abciximab was associated with a significant reduction in mortality (odds ratio, OR [95% confidence interval (CI)] = 0.43 [0.20 − 0.94], p = 0.03), and TVR (OR [95% CI] = 0.53 [0.29 − 0.99], p = 0.05). No differences in terms of recurrent myocardial infarction (OR [95% CI] = 0.54 [0.23 − 1.28], p = 0.17) or major bleeding complications (OR [95% CI] = 0.91 [0.46 − 1.79], p = 0.79) were observed between the two strategies. The present meta-analysis showed that IC administration of abciximab is associated with significant benefits in mortality at short-term follow-up compared to IV abciximab administration, without any excess of major bleeding in STEMI patients undergoing PPCI. However, further trials are warranted to establish the optimal strategy of abciximab treatment in this setting.

Atherothrombosis and the role of antiplatelet therapy.

Atherothrombosis remains a major global public health problem. Chronic atherosclerotic disease is often clinically silent and coexists across vascular beds, but when complicated by thrombosis can result in acute coronary syndrome, stroke, transient ischaemic attack and critical limb ischaemia. Platelets play a role in the development of chronic atherosclerotic disease and are a key mediator of clinical events in atherothrombosis. Numerous trials have examined the role of antiplatelet agents in primary and secondary prevention and several new antiplatelet drugs are under development. In secondary prevention, there is evidence of clear benefit of single and in some cases dual antiplatelet therapy in the prevention of recurrent cerebro-vascular complications. Dual antiplatelet therapy has emerged as the standard of care in acute coronary syndromes, with aspirin typically being used in combination with clopidogrel or one of the newer more potent antiplatelet agents. Conversely, in chronic stable coronary disease, no benefit has yet been convincingly demonstrated from dual antiplatelet therapy. In cerebro-vascular disease, aspirin monotherapy remains the cornerstone of prevention of recurrent events, with clopidogrel or the combination of aspirin and dipyridamole being only modestly more efficacious. In primary prevention, the evidence for the routine use of aspirin or any other antiplatelet agent is mixed and suggests this should only be considered on an individual basis in high-risk groups where the thrombotic risk outweighs the risk of major bleeding complications.

Ischaemic and bleeding complications with new, compared to standard, ADP-antagonist regimens in acute coronary syndromes: a meta-analysis of randomized trials

Platelets play a pivotal role in the pathogenesis of acute coronary syndromes (ACS) and their inhibition remains a mainstay therapy in this setting. We aimed to perform a meta-analysis of randomized trials to evaluate the benefits of new oral antiplatelet regimens to block platelet ADP-receptors compared to standard-dose clopidogrel (300 mg loading dose followed by 75 mg/daily). We obtained results from all randomized trials enrolling patients with ACS. Primary endpoint was mortality. Secondary endpoints were myocardial infarction and definite in-stent thrombosis. Safety endpoint was the risk of major bleeding complications. We prespecified subanalyses according to new antiplatelet drugs (prasugrel/ticagrelor), high-dose clopidogrel (600 mg) and patients undergoing percutaneous coronary intervention. A total of seven randomized trials were finally included in the meta-analysis (n = 58 591). We observed a significant reduction in mortality (2.9% vs. 3.4%, OR = 0.87, 95% CI 0.79-0.95, P = 0.002), recurrent myocardial infarction (4.2% vs. 5.2%, OR = 0.80, 95% CI 0.74-0.87, P < 0.0001), definite in-stent thrombosis (0.9% vs. 1.7%, OR = 0.52, 95% CI 0.43-0.63, P < 0.0001). The benefits in mortality and reinfarction were driven by the treatment with prasugrel or ticagrelor, without a significant difference in terms of major bleeding complications as compared to standard-dose clopidogrel (5% vs. 4.7%, OR = 1.06 95% CI 0.96-1.17, P = 0.25). This meta-analysis showed that new oral antiplatelet regimens are associated with a significant reduction in mortality, reinfarction and in-stent thrombosis in ACS patients without an overall increase of major bleeding when treated with new antiplatelet drugs.

Risk of Recurrent Venous Thromboembolism and Mortality in Patients With Cancer Incidentally Diagnosed With Pulmonary Embolism: A Comparison With Symptomatic Patients

The routine use of modern computed tomography scanners has led to an increased detection of incidental pulmonary embolism (PE), in particular in patients with cancer. The clinical relevance of these incidental findings is unknown. In this retrospective cohort study, oncology patients in whom PE was objectively proven between 2004 and 2010 and anticoagulant treatment was started, were included. Fifty-one patients with incidental PE and 144 with symptomatic PE were observed for 1 year to compare the risks of recurrent venous thromboembolism (VTE), bleeding complications, and mortality. Kaplan-Meier and Cox survival analyses were performed. Incidental and symptomatic patients did not differ with respect to mean age, sex, cancer type and stage, and risk factors for VTE. As a result from evolving treatment guidelines, approximately half of the patients in both groups received long-term treatment with vitamin K antagonists in stead of currently recommended low-molecular-weight heparin. The 12-month cumulative incidence of recurrent VTE was 13.3% in the incidental group versus 16.9% in the symptomatic group (P = .77). Notably, 20% VTE events recurred after premature termination of anticoagulant therapy. The risk of major bleeding complications was also comparable in the two groups (12.5% for incidental patients and 8.6% for symptomatic patients; P = .5). The respective 12-month mortality risks were 52.9% and 53.3% (P = .7). Our findings suggest that oncology patients diagnosed with and treated for incidental PE, have similar high rates of recurrent VTE, bleeding complications, and mortality, as compared with oncology patients who develop symptomatic PE.

Quality measures and benchmarking for warfarin therapy

The ultimate goal of warfarin therapy, to prevent thromboembolism with the lowest possible risk of major bleeding complications, is most likely to be realized when therapeutic anticoagulation as measured by the international normalized ratio (INR) is quickly achieved and maintained in appropriate candidates. Realizing this goal requires optimal functioning of various anticoagulation management system components. The extent to which these components function smoothly together determines the quality of warfarin therapy management. A quality measure is used to ascertain the degree to which a given system is successfully coordinating care to accomplish a particular therapeutic goal. The quality of care can be evaluated at different levels such as outcomes (e.g. INR results, major bleeding, thromboembolism, death), processes (e.g. method used to adjust warfarin doses), and structures (e.g. clinic organization structure, workload statistics). There is great need for a structured program of quality measurement for warfarin therapy management. The arrival of new options for oral anticoagulation medications increases the need for credible information regarding the site-specific quality of warfarin therapy management because the potential advantages over warfarin therapy associated with some of these agents are in part dependent upon the quality of warfarin therapy management.

The challenge of very old leads: Laser lead extraction of infected or dysfunctional pacemaker or ICD leads implanted for more than 10 years

Objective: Pacemaker or ICD lead removal without technical support is impossible in patients with lead dysfunction more than ten years after lead implantation. Mechanical lead extraction in these patients carries a risk for major bleeding complications. In this retrospective analysis we analysed the risk of laser lead extraction using the excimer laser in patients with &gt;10 yo leads.

Meta-Analysis of Randomized Trials of Glycoprotein IIb/IIIa Inhibitors in High-Risk Acute Coronary Syndromes Patients Undergoing Invasive Strategy

It is still unknown whether upstream administration of glycoprotein (Gp) IIb/IIIa inhibitors, aiming at cooling the culprit lesion before angioplasty, is superior to its selective downstream administration in high-risk patients with acute coronary syndromes (ACSs) undergoing coronary angioplasty. Therefore, the aim of the present study was to perform a meta-analysis of randomized trials comparing upstream to downstream administration of Gp IIb/IIIa inhibitors in high-risk patients with ACS undergoing early invasive strategy. We obtained results from all randomized trials on this issue. The literature was scanned by formal searches of electronic databases from January 1990 to March 2010. The following key words were used: "randomized trial," "myocardial infarction," "ACS," "coronary angioplasty," "upstream," "downstream," "Gp IIb/IIIa inhibitors," "abciximab," "tirofiban," and "eptifibatide." Primary and secondary clinical end points were mortality and myocardial infarction at 30 days, respectively. Major bleeding complications were assessed as a safety end point. Seven randomized trials were included in the meta-analysis, involving 19,929 patients (9,981 or 50.0% in the upstream Gp IIb/IIIa inhibitors group and 9,948 or 50% in the downstream Gp IIb/IIIa inhibitors group). Upstream Gp IIb/IIIa inhibitors did not decrease 30-day mortality (2.0% vs 2.0%, p = 0.84) or recurrence of myocardial infarction (7.0% vs 7.6%, p = 0.11) but were associated with higher risk of major bleeding complications (1.8% vs 1.3%, p = 0.0002). In conclusion, this meta-analysis shows that in high-risk patients with ACS undergoing an early invasive strategy, upstream administration of Gp IIb/IIIa inhibitors does not improve clinical outcome compared to a downstream selective administration, and it is associated with an increased risk of major bleeding complications. Therefore, a strategy of upstream Gp IIb/IIIa inhibitors cannot be recommended.

Ischemic Stroke—Stenting versus Surgery for Carotid Disease

Extracranial internal carotid artery stenosis is one of the most common and best studied causes of stroke. Revascularization with carotid endarterectomy (CEA) has been shown to be beneficial for patients with severe stenosis associated with stroke or transient ischemic attack (TIA) and for many patients with moderate stenosis associated with stroke or TIA. CEA has also been shown to be beneficial for patients with asymptomatic severe stenosis if they have a reasonable expected lifespan and surgical risk, but the benefit is greater for men compared with women. Carotid angioplasty and stenting (CAS) has become a viable alternative procedure for carotid revascularization with less risk of major bleeding complications and cranial nerve injury. Randomized studies of CEA versus CAS have found that the endovascular approach is associated with a lower risk of myocardial infarction but a higher risk of peri-procedural stroke which has a greater impact on long-term quality of life. Thus, recommending CEA or CAS must be based upon individual patient characteristics and their preferences, but at this point it appears that most patients should still be receiving CEA if an intervention is required.

Safety and efficacy of triple antithrombotic therapy after percutaneous coronary intervention in patients needing long-term anticoagulation

Optimal antithrombotic therapy after percutaneous coronary intervention (PCI) is currently undefined in patients requiring long-term anticoagulation. Previous studies comparing triple therapy (TT) of warfarin, aspirin and clopidogrel with standard dual therapy (DT) of aspirin and clopidogrel have yielded conflicting results. Meta-analysis of these studies was performed to evaluate safety and efficacy of TT. A total of 1482 patients from 6 studies were analyzed using the Mantel-Haenszel random effect model to extract incidence of major bleeding. The secondary end point assessed by three of these studies was major adverse cardiac events (MACEs: cardiovascular death, myocardial infarction and thromboembolic complications). The incidence of MACEs was computed using the Mantel-Haenszel fixed effect model. Combined relative risks (RRs) across all of the studies and the 95% confidence intervals (CIs) were determined. A two-sided alpha error <0.05 was considered statistically significant. Baseline characteristics were similar in both groups. Compared with patients receiving DT, the risk of major bleeding was significantly higher in the TT group (RR: 2.74, CI: 1.08-6.98; p=0.034). However, risk of MACE was significantly lower in the TT group (RR: 0.72, CI: 0.56-0.98; p=0.014). In patients requiring long-term anticoagulation after PCI, TT may be superior to DT in reducing the incidence of MACEs, however risk of major bleeding complications is increased significantly.

Aspirin for Acute Coronary Syndromes: Have We Learned the Correct Dose Yet?

Despite its universal use, the optimal dose of aspirin from an efficacy and safety perspective remains unclear. There are wide variations in international practice and a lack of consensus as to the most appropriate dose of aspirin in patients with acute coronary syndromes (ACS), mainly because of the wide range of doses evaluated in early randomized trials of aspirin versus placebo. Comparisons of aspirin dose have been based on observational studies or indirect comparisons from meta-analysis of antiplatelet trials. These studies have suggested that aspirin, in doses>or=300 mg, is similar to aspirin doses 75-100 mg/d for prevention of major vascular events, but that higher doses increase the risk of major bleeding complications. Recently, the CURRENT-OASIS study, a randomized head-to-head comparison of higher-dose (>or=300 mg/d) versus low-dose aspirin (75-81 mg/d) for 1 month in over 25,000 patients with ACS referred for an early invasive strategy demonstrated similar outcomes between higher- and low-dose aspirin for efficacy, with no difference in the risk of major bleeding complications. Results from this mega-trial suggest that low-dose or higher-dose aspirin is a reasonable option in ACS patients undergoing an early invasive strategy.

Bleeding complications after pacemaker or cardioverter-defibrillator implantation in patients receiving dual antiplatelet therapy

Introduction. The aim of the study was to define the prevalence of bleeding events in patients treated with dual antiplatelet therapy (DAT) in comparison with patients receiving only acetylsalicylic acid (ASA).Methods. Prospective two-centre registry of all first implantations of pacemakers, cardioverter-defibrillators and cardiac resynchronisation therapy units in patients receiving ASA (n=194) or DAT (n=53).Results. Bleeding complications were detected in 27 (16.2%) patients in the ASA group and in 13 (24.5%) in the DAT group. There was no significant difference in the overall number of complications between the patients receiving ASA or DAT, although there was a trend towards a higher incidence of overall complication rates in the DAT group (p=0.0637). The incidence of major complications (requiring blood transfusion or surgical intervention or prolonging hospital stay) was low (3.6%), and similar in both groups (3.6 and 3.8% respectively, ns). The rate of minor complications (subcutaneous haematomas) was greater in the DAT group (p=0.015).Conclusions. Treatment with DAT does not increase the risk of major bleeding complications as a result of device implantation; however, minor complications are significantly more frequent. Our results suggest that DAT could be continued in patients undergoing device implantation with a moderate risk of bleeding complications. (Neth Heart J 2010;18:230-5.).

Risk profile and benefits from Gp IIb-IIIa inhibitors among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-regression analysis of randomized trials

AimsSeveral randomized trials and a previous meta-analysis have shown significant benefits from Gp IIb-IIIa inhibitors, especially abciximab. Recent randomized trials (BRAVE-3 and HORIZON trials) have shown no benefits from adjunctive Gp IIb-IIIa inhibitors on the top of clopidogrel administration. However, the relatively low mortality may have hampered the conclusion of these recent trials. Thus, the aim of the current study was to perform an update meta-analysis of randomized trials on adjunctive Gp IIb-IIIa inhibitors in primary angioplasty, and to evaluate by meta-regression analysis, whether the results may be related to risk profile.Methods and resultsWe obtained results from all randomized trials evaluating the benefits of adjunctive Gp IIb-IIIa inhibitors among STEMI patients undergoing primary angioplasty. The literature was scanned by formal searches of electronic databases (MEDLINE and CENTRAL) from January 1990 to September 2008. The following key words were used: randomized trial, myocardial infarction, reperfusion, primary angioplasty, Gp IIb-IIIa inhibitors, abciximab, tirofiban, and eptifibatide. Clinical endpoint was mortality at 30 days. Major bleeding complications were assessed as safety endpoint. No language restriction was applied. A total of 16 randomized trials were finally included in the meta-analysis, involving 10 085 patients (5094 or 50.5% in the Gp IIb-IIIa inhibitors group and 4991 or 49.5% in the control group. Gp IIb-IIIa inhibitors did not reduce 30 day mortality (2.8 vs. 2.9%, P = 0.75) or re-infarction (1.5 vs. 1.9%, P = 0.22), but were associated with higher risk of major bleeding complications (4.1 vs. 2.7%, P = 0.0004). However, we observed a significant relationship between patient's risk profile and benefits from adjunctive Gp IIb-IIIa inhibitors in terms of death (P = 0.008) but not re-infarction (P = 0.25).ConclusionThis meta-analysis shows a significant relationship between benefits in mortality from Gp IIb-IIIa inhibitors and patient's risk profile. Thus, Gp IIb-IIIa inhibitors should be strongly considered among high-risk patients.

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.