Bleeding In Acute Coronary Syndromes Research Articles

Design and rationale of the RadIal Vs. femorAL access for coronary intervention (RIVAL) trial: A randomized comparison of radial versus femoral access for coronary angiography or intervention in patients with acute coronary syndromes

Major bleeding in acute coronary syndromes (ACS) is associated with an increased risk of subsequent mortality and recurrent ischemic events. Observational data and small randomized trials suggest that radial instead of femoral access for coronary angiography/intervention results in fewer bleeding complications, with preserved and possibly improved efficacy. Radial access versus femoral access has yet to be formally evaluated in a randomized trial adequately powered for the comparison of clinically important outcomes. The aim of this study is to evaluate the efficacy and safety of radial versus femoral access for coronary angiography/intervention in patients with ACS managed with an invasive strategy. This was a multicenter international randomized trial with blinded assessment of outcomes. 7021 patients with ACS (with or without ST elevation) have been randomized to either radial or femoral access for coronary angiography/intervention. The primary outcome is the composite of death, myocardial infarction, stroke, or non-coronary artery bypass graft-related major bleeding up to day 30. The key secondary outcomes are (1) death, myocardial infarction, or stroke up to day 30 and (2) non-coronary artery bypass graft-related major bleeding up to day 30. Percutaneous coronary intervention (PCI) success rates will also be compared between the two access sites. The RIVAL trial will help define the optimal access site for coronary angiography/intervention in patients with ACS.

Implications of bleeding in acute coronary syndrome and percutaneous coronary intervention

The advent of potent antiplatelet and antithrombotic agents over the past decade has resulted in significant improvement in reducing ischemic events in acute coronary syndrome (ACS). However, the use of antiplatelet and antithrombotic combination therapy, often in the settings of percutaneous coronary intervention (PCI), has led to an increase in the risk of bleeding. In patients with non-ST elevation myocardial infarction treated with antithrombotic agents, bleeding has been reported to occur in 0.4%–10% of patients, whereas in patients undergoing PCI, periprocedural bleeding occurs in 2.2%–14% of cases. Until recently, bleeding was considered an intrinsic risk of antithrombotic therapy, and efforts to reduce bleeding have received little attention. There have been increasing data demonstrating that bleeding is associated with adverse outcomes, including myocardial infarction, stroke, and death. Therefore, it is imperative to optimize patient outcomes by adopting pharmacological and nonpharmacological strategies to minimize bleeding while maximizing treatment efficacy. In this paper, we present a review of the bleeding classifications used in large-scale clinical trials in patients with ACS and those undergoing PCI treated with antiplatelets and antithrombotic agents, adverse outcomes, particularly mortality associated with bleeding complications, and suggested predictive risk factors. Potential mechanisms of the association between bleeding and mortality and strategies to reduce bleeding complications are also discussed.

Evaluating the need for a practical risk score to predict major bleeding in acute coronary syndromes

The incidence of recurrent adverse ischemic events and death after acute coronary syndromes (ACS): unstable angina, ST-segment elevation myocardial infarction [STEMI] and non-STEMI [NSTEMI]) has been significantly reduced by advances in antithrombotic therapy and invasive treatment strategies [1–4]. However, the use of multiple antiplatelet agents (i.e., aspirin, P2Y12 inhibitors, and glycoprotein IIb/IIIa inhibitors [GPIs]) and antithrombotic therapies (i.e., unfractionated heparin [UFH], lowmolecular weight heparin, factor-Xa inhibitors and direct thrombin inhibitors), in combination with an early invasive approach has increased the risk of bleeding. The incidence of hemorrhagic complications after treatment of ACS ranges from 1 to 10%, depending on differences in patient characteristics, antithrombotic therapies, timing of event reporting and bleeding definitions [5–8]. Despite this heterogeneity, numerous studies have demonstrated that bleeding is associated with an increased risk for both shortand long-term adverse outcomes [5,7–12]. Although the exact mechanisms causing this increased risk after bleeding complications are not fully understood, a number of factors are likely to contribute, such as the cessation of evidence-based therapies (i.e., antiplatelet agents, b-blockers and statins) in patients who bleed, adverse effects of blood transfusion, detrimental effects of acute anemia and a greater prevalence of comorbidities in patients who bleed. In contemporary practice, cardiologists have a wide variety of antiplatelet and antithrombin agents from which to choose. Each individual drug has a different profile of clinical efficacy (suppression of ischemic complications from the ACS event itself, or from the treatments subsequently required, most commonly percutaneous coronary intervention [PCI]) versus complications (principally bleeding). Large randomized clinical trials have demonstrated that treatment strategies that reduce bleeding while effectively suppressing ischemia are associated with improved survival in patients with ACS. The Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS)-5 trial randomized 20,078 patients with non-STelevation ACS to the low-molecular weight heparin enoxaparin or the factor-Xa inhibitor fondaparinux [13]. Fondaparinux was noninferior to enoxaparin in terms of the primary end points of death, myocardial infarction or refractory ischemia at 9 days. Moreover, fondaparinux was associated with significantly reduced rates of major bleeding at 9 days (2.2 vs 4.1%; p < 0.01) and significantly reduced rates of mortality at 30 days (2.9 vs 3.5%; p = 0.02) and 6 months (5.8 vs 6.5%; p = 0.05). The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONSAMI) trial randomized 3602 STEMI patients undergoing primary PCI to treatment with either UFH plus a GPI or the direct thrombin inhibitor bivalirudin. In HORIZONS-AMI, bivalirudin compared with UFH plus a GPI was associated with significantly reduced major bleeding (4.9 vs 8.3%; p < 0.01) at 30-day follow-up, and mortality at 30 days (2.1 vs 3.1%; p = 0.047) and 1 year (3.5 vs 4.8%; p = 0.04) [14,15].

Vascular Closure Devices in Acute Coronary Syndromes: From Arbitrary to a Necessity?

Vascular closure devices (VCDs) were initially developed to improve access site hemostasis and allow for earlier ambulation in patients undergoing diagnostic catheterization and percutaneous coronary intervention (PCI). Though initially thought to be beneficial, large meta-analysis has shown conflicting data regarding whether VCDs alter access site bleeding in a variety of clinical settings. One area of particular interest for the adoption of VCDs has been in the setting of acute coronary syndromes (ACS) in which multiple antiplatelet strategies are often employed leading to a high risk of bleeding. Bleeding in ACS has been shown to be a powerful independent predictor of 30-day mortality. Recently, investigators have reported that VCDs reduce access site bleeding in the setting of ACS. In our review, we use several selected representative clinical trials to provide a historical account for the use of VCDs. We also provide for a review of data as it relates to access site bleeding in ACS along with analysis showing that VCDs may potentially provide for reductions in bleeding and vascular complications in patients with ACS undergoing PCI.

Letter by Boschetti et al Regarding Article, “Predictors of Outcome in Medically Treated Patients With Acute Coronary Syndromes After Angiographic Triage: An Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Substudy”

HomeCirculationVol. 122, No. 20Letter by Boschetti et al Regarding Article, “Predictors of Outcome in Medically Treated Patients With Acute Coronary Syndromes After Angiographic Triage: An Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Substudy” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Boschetti et al Regarding Article, “Predictors of Outcome in Medically Treated Patients With Acute Coronary Syndromes After Angiographic Triage: An Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Substudy” Enrico Boschetti, MD, Marcella De Paolis, MD and Federica Piccioni, MD Enrico BoschettiEnrico Boschetti University Hospital (Azienda Ospedaliera S.Maria) Terni, Italy (Boschetti, De Paolis, Piccioni) Search for more papers by this author , Marcella De PaolisMarcella De Paolis University Hospital (Azienda Ospedaliera S.Maria) Terni, Italy (Boschetti, De Paolis, Piccioni) Search for more papers by this author and Federica PiccioniFederica Piccioni University Hospital (Azienda Ospedaliera S.Maria) Terni, Italy (Boschetti, De Paolis, Piccioni) Search for more papers by this author Originally published16 Nov 2010https://doi.org/10.1161/CIRCULATIONAHA.110.959551Circulation. 2010;122:e523To the Editor:Goto et al1 showed that in medically treated patients enrolled in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial, bleeding within 30 days is decreased with bivalirudin, which confirms the results previously reported in the overall data analysis. We think that the low prevalence of hemorrhagic complications in this subgroup should be attributed mainly to the earlier discontinuation of antithrombin therapy rather than to the merely diagnostic type of invasive procedure, because an intervention after a coronary angiography accounts for quite a small adjunctive risk, especially in the “radial era.”Bleeding in acute coronary syndrome has been recognized as a major risk factor of death. Pocock et al2 have recently shown that its impact is not limited to the first days; it continues to be significant over a relatively long time, with bleeding worsening outcomes for up to 1 year after its occurrence.Considering that death after a hemorrhagic complication is frequently of ischemic origin, it would be reasonable to keep all subjects with previous bleeding at risk of ischemic events, according to the intention-to treat principle. If hemorrhagic complications are first a competing risk, they subsequently become an additional covariate predictive of the combined ischemic end point. The 131 patients with a major bleeding were not kept in the 1-year analysis,1 which leaves their final destiny undetectable, both as a whole group and as distinct subgroups defined by treatment allocation.Enrico Boschetti, MDMarcella De Paolis, MDFederica Piccioni, MD University Hospital (Azienda Ospedaliera S.Maria) Terni, ItalyDisclosuresNone.

Letter by Dregelid Regarding Article, “Impact of Femoral Vascular Closure Devices and Antithrombotic Therapy on Access Site Bleeding in Acute Coronary Syndromes: The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Trial”

HomeCirculation: Cardiovascular InterventionsVol. 3, No. 3Letter by Dregelid Regarding Article, “Impact of Femoral Vascular Closure Devices and Antithrombotic Therapy on Access Site Bleeding in Acute Coronary Syndromes: The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Trial” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Dregelid Regarding Article, “Impact of Femoral Vascular Closure Devices and Antithrombotic Therapy on Access Site Bleeding in Acute Coronary Syndromes: The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Trial” Einar Dregelid, MD Einar DregelidEinar Dregelid Search for more papers by this author Originally published1 Jun 2010https://doi.org/10.1161/CIRCINTERVENTIONS.110.954156Circulation: Cardiovascular Interventions. 2010;3:e12To the Editor:The study by Sanborn et al1 is a post hoc analysis in which multiple statistical tests have been made in an exploratory manner to examine the possible differences in access-site bleeding (ASB) with or without a vascular closure device (VCD). If P values <0.05 are used for statistical significance, a high false discovery rate for significant differences is to be expected.Patients with a major ASB were allotted to 7 end-point subgroups, but the sum of the patients in the subgroups is greater than the total number with major ASB. Therefore, many patients have been allotted to several subgroups and included in several analyses.The only end-point subgroup comparison showing a significant difference was the ≥5-cm-diameter hematoma end point, inconsequential concerning the need for intervention or surgical correction. The difference between the VCD and the no-VCD groups concerning requirement for interventional or surgical correction of ASB, with a P value of 0.048, may be because of chance.Patients who did not receive a VCD may have been more prone to develop an ASB because of a higher rate of hypertension and renal insufficiency. They may have received more intense platelet inhibition because of a higher rate of elevated biomarkers, and their higher rate of anemia may have increased the likelihood of intervention because of hemorrhage.VCD complications can result in permanent tissue malfunction or loss and severe infections.2,3 There is no proof to support the belief of the authors that contemporary VCD complication rates are decreasing. A realistic VCD complication rate on the order of 1:275 among the 4307 patients would result in 16 complications, most of them far more serious than the 16 ASBs in their study, requiring interventional, presumably transfusions, or surgical correction.3,4 In addition, late undetected complications may occur.2The use of a VCD has not been demonstrated to improve survival. In contrary, their use has been followed by serious complications. Although bleeding is a predictor of 30-day mortality in invasively managed patients, the implied assumption that VCD use can reduce the mortality is presently unfounded.Some of the authors may have a vested interest in the performance of firms producing VCDs.Einar Dregelid, MD Department of Vascular Surgery Haukeland University Hospital Bergen, NorwayDisclosuresNone.

A Risk Score to Predict Bleeding in Patients With Acute Coronary Syndromes

The aim of this study was to develop a practical risk score to predict the risk and implications of major bleeding in acute coronary syndromes (ACS). Hemorrhagic complications have been strongly linked with subsequent mortality in patients with ACS. A total of 17,421 patients with ACS (including non-ST-segment elevation myocardial infarction [MI], ST-segment elevation MI, and biomarker negative ACS) were studied in the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) and the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trials. An integer risk score for major bleeding within 30 days was developed from a multivariable logistic regression model. Non-coronary artery bypass graft surgery (CABG)-related major bleeding within 30 days occurred in 744 patients (7.3%) and had 6 independent baseline predictors (female sex, advanced age, elevated serum creatinine and white blood cell count, anemia, non-ST-segment elevation MI, or ST-segment elevation MI) and 1 treatment-related variable (use of heparin + a glycoprotein IIb/IIIa inhibitor rather than bivalirudin alone) (model c-statistic = 0.74). The integer risk score differentiated patients with a 30-day rate of non-CABG-related major bleeding ranging from 1% to over 40%. In a time-updated covariate-adjusted Cox proportional hazards regression model, major bleeding was an independent predictor of a 3.2-fold increase in mortality. The link to mortality risk was strongest for non-CABG-related Thrombolysis In Myocardial Infarction (TIMI)-defined major bleeding followed by non-TIMI major bleeding with or without blood transfusions, whereas isolated large hematomas and CABG-related bleeding were not significantly associated with subsequent mortality. Patients with ACS have marked variation in their risk of major bleeding. A simple risk score based on 6 baseline measures plus anticoagulation regimen identifies patients at increased risk for non-CABG-related bleeding and subsequent 1-year mortality, for whom appropriate treatment strategies can be implemented.

Response to Letter Regarding Article, “Impact of Femoral Vascular Closure Devices and Antithrombotic Therapy on Access Site Bleeding in Acute Coronary Syndromes: The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Trial”

Response: We thank Dr Dregelid for his letter regarding our report on the impact of femoral vascular closure devices (VCDs) on major access site bleeding (ASB) in the contemporary ACUITY trial.1 We agree that the main advantage in the VCD group is the significant reduction in large hematomas with a trend toward reduced surgical or percutaneous correction of vascular injury. We would emphasize that large hematomas are not inconsequential because they may cause considerable patient discomfort and prolong hospital stay. We also agree with Dr Dregelid's concern of a high false discovery rate from secondary post hoc analyses. We therefore stated in the Discussion section that this report was a “nonrandomized, …

Impact of Femoral Vascular Closure Devices and Antithrombotic Therapy on Access Site Bleeding in Acute Coronary Syndromes

Background— The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial demonstrated that bivalirudin monotherapy significantly reduces major bleeding compared with heparin (unfractionated or enoxaparin) or bivalirudin plus a glycoprotein IIb/IIIa inhibitor in acute coronary syndromes. Whether vascular closure devices (VCD) impact these results is unknown. Therefore, this study sought to determine whether VCD impact major access site bleeding (ASB) in patients with acute coronary syndromes undergoing early invasive management by the femoral approach. Methods and Results— Major ASB in ACUITY was defined as ASB requiring interventional or surgical correction, hematoma ≥5 cm at the access site, retroperitoneal bleeding, or hemoglobin drop ≥3 g/dL with ecchymosis or hematoma &lt;5 cm, oozing blood, or prolonged bleeding (&gt;30 minutes) at the access site. Stepwise logistical regression was performed to identify the independent determinants of ASB. Of 11 621 patients undergoing angiography with or without percutaneous coronary intervention by the femoral approach, 4307 (37.1%) received a VCD and 7314 (62.9%) did not. Rates of major ASB were lower with VCD compared with no VCD (2.5% versus 3.3%, relative risk, 0.76; 95% CI, 0.61 to 0.94; P =0.01) and were lowest in patients treated with bivalirudin monotherapy and a VCD (0.7%). Stepwise logistic regression revealed that a VCD (odds ratio, 0.78; 95% CI, 0.61 to 0.99; P =0.04) and bivalirudin monotherapy (odds ratio, 0.35; 95% CI, 0.25 to 0.49; P &lt;0.0001) were both independent determinates of freedom from major ASB. Conclusion— In patients with acute coronary syndromes undergoing an early invasive management strategy by the femoral approach, the use of a VCD, bivalirudin monotherapy, or both minimizes rates of major ASB. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00093158.

A reduction in bleeding in acute coronary syndromes? Let's not rain on the parade!

Bleeding is a frequently observed complication in patients suffering from acute coronary syndromes (ACS), as well as in patients submitted to percutaneous coronary interventions (PCI) or coronary artery bypass graft surgery (CABG). The rate of bleeding events varies greatly between reports, and depends mainly on the clinical setting, the baseline characteristics of the patients, the pharmacological environment, and the choice of vascular access in the case of invasive strategy. The rate of bleeding can also vary considerably depending on the scale used to measure haemorrhagic events. Among the many predictors of bleeding, the most powerful are age, sex, renal failure, use of glycoprotein (GP) IIb/IIIa inhibitors, vascular access, previous history of bleeding, and inappropriate dosage of antithrombotic therapies, particularly anticoagulants and GP IIb/IIIa inhibitors. Until recently, bleeding was considered to be inherent to the modern management of ACS, and was thought to be the price to pay to achieve an improvement in outcome. Basically, bleeding was a non-event. However, several reports have shown bleeding to be associated with a higher risk of death, myocardial infarction (MI), or stroke at 30 days and in the long term, irrespective of the clinical setting.1,2 In this context, a reduction in the rate of bleeding complications led to an improvement in outcome in at least two trials, and indeed even a reduction in death, MI, and stroke.3,4 The loop is therefore closed—more bleeding leads to an excess of death and ischaemic events, but less bleeding reduces the risk of death and ischaemic events. The exact mechanisms that mediate the … *Corresponding author. Tel: +33 381 668 539, Fax: +33 381 668 582, Email: jpbassan{at}univ-fcomte.fr

Ticagrelor was more effective than clopidogrel, with no increase in major bleeding in acute coronary syndromes

Source Citation Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045-57. 19717846

Has the frequency of bleeding changed over time for patients presenting with an acute coronary syndrome? The global registry of acute coronary events.

AimsTo determine whether changes in practice, over time, are associated with altered rates of major bleeding in acute coronary syndromes (ACS).Methods and resultsPatients from the Global Registry of Acute Coronary Events were enrolled between 2000 and 2007. The main outcome measures were frequency of major bleeding, including haemorrhagic stroke, over time, after adjustment for patient characteristics, and impact of major bleeding on death and myocardial infarction. Of the 50 947 patients, 2.3% sustained a major bleed; almost half of these presented with ST-elevation ACS (44%, 513). Despite changes in antithrombotic therapy (increasing use of low molecular weight heparin, P < 0.0001), thienopyridines (P < 0.0001), and percutaneous coronary interventions (P < 0.0001), frequency of major bleeding for all ACS patients decreased (2.6 to 1.8%; P < 0.0001). Most decline was seen in ST-elevation ACS (2.9 to 2.1%, P = 0.02). The overall decline remained after adjustment for patient characteristics and treatments (P = 0.002, hazard ratio 0.94 per year, 95% confidence interval 0.91–0.98). Hospital characteristics were an independent predictor of bleeding (P < 0.0001). Patients who experienced major bleeding were at increased risk of death within 30 days from admission, even after adjustment for baseline variables.ConclusionDespite increasing use of more intensive therapies, there was a decline in the rate of major bleeding associated with changes in clinical practice. However, individual hospital characteristics remain an important determinant of the frequency of major bleeding.

Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement.

In patients undergoing percutaneous coronary intervention (PCI), a link between bleeding and excess mortality has been demonstrated. A potential association of platelet response to clopidogrel and bleeding has not been well established yet. The aim of the present study was to assess the impact of clopidogrel responsiveness on the risk of bleeding in clopidogrel-treated patients undergoing PCI. Patients (n=2533) undergoing PCI after pretreatment with 600 mg of clopidogrel were enrolled in this study. Blood was obtained directly before PCI. Adenosine-diphosphate (ADP)-induced platelet aggregation was assessed on a Multiplate analyzer. The primary endpoint was the incidence of in-hospital Thrombolysis in Myocardial Infarction (TIMI) major bleeding and the secondary endpoint was in-hospital TIMI minor bleeding. Receiver-operator curve (ROC) analysis was used to derive the optimal platelet aggregation value defining enhanced clopidogrel responders for the association of measurements with major bleeding. Thirty-four (1.3%) major bleeding events and 137 (5.4%) minor bleeding events were observed. The risk of a major bleeding was significantly higher in patients (n=975) with an enhanced response to clopidogrel as compared with the remaining patients (n=1558) (2.2 vs. 0.8%, unadjusted odds ratio (OR) 2.6, 95% confidence interval (CI) 1.3-5.2, P=0.005; adjusted OR 3.5, 95% CI 1.6-7.3, P=0.001). No significant differences between both groups were observed for the occurrence of minor bleeding events (P=0.68). Enhanced clopidogrel responsiveness is associated with a higher risk of major bleeding. Whether guidance of antiplatelet treatment based on platelet function testing proves useful for avoiding bleeding events warrants further investigation.

Relationship between baseline haemoglobin and major bleeding complications in acute coronary syndromes

In patients with acute coronary syndromes (ACS), the negative impact of baseline haemoglobin levels on ischaemic events, particularly death, is well established, but the association with bleeding risk is less well studied. The aim of this study was to assess the impact of baseline haemoglobin levels on major bleeding complications. Pooled analysis of OASIS 5 and 6 data involving 32 170 patients with ACS with and without ST-segment elevation was performed. The association between baseline haemoglobin and major bleeding or ischaemic events was examined using multiple regression model. were 30-day rates of major bleeding, death, and death/myocardial infarction (MI) analysed according to baseline haemoglobin levels. Baseline haemoglobin level independently predicted the risk of overall, procedure-related, and non-procedure-related major bleedings at 30 days [odds ratio (OR) 0.94, 95% CI 0.90-0.98; OR 0.94, 95% CI 0.90-0.99; and OR 0.89, 95% CI 0.83-0.95, respectively, per 1 g/dL haemoglobin increment above 10 g/dL]. In addition, a curvilinear relationship between baseline haemoglobin levels and death at 30 days was observed with a 6% decrease in the risk for every 1 g/dL haemoglobin increment above 10 g/dL up to 15.9 g/dL (OR 0.94, 95% CI 0.90-0.98) and a 19% increase above this value (OR 1.19, 95% CI, 0.98-1.43). A similar relationship for the composite outcome of death/MI was observed. A low baseline haemoglobin level is an independent predictor of the risk of major bleeding in ACS as well as of the risk of death and death and MI. Among other predictors of bleeding risk, baseline haemoglobin should be taken into account in patients presenting with ACS. ClinicalTrials.gov number, NCT00139815. http://clinicaltrials.gov/ct2/show/NCT00139815?term=NCT00139815&rank=1.

Stopping the Hemorrhage

Aggressive management of high-risk non–ST-elevation acute coronary syndrome patients has focused on reducing ischemic complications with potent medications and mechanical interventions1,2 but at the cost of increased rates of major bleeding and associated adverse outcomes.3,4 The American College of Cardiology/American Heart Association 2007 guidelines for management of patients with unstable angina/non–ST-elevation myocardial infarction (NSTEMI)1 stress the importance of balancing antithrombotic and interventional therapies with therapeutic risk, and they urge special attention in groups at high bleeding risk, including women, the elderly, and those with renal insufficiency. For risk-prone groups, careful selection and dose adjustment of antithrombotics is encouraged, but no specific instruction for calculating bleeding risk or modifying treatment is provided. Article p 1873 The European Society of Cardiology’s 2007 guidelines for the diagnosis and treatment of non–ST-segment elevation acute coronary syndromes2 also recognize and devote a special section to bleeding complications, covering predictors of bleeding risk, the impact of bleeding on prognosis, the management of bleeding complications, and the impact of blood transfusions on outcomes. Major bleeding has been reported in 2% to 8% of non–ST-elevation acute coronary syndrome patients, with higher rates noted in broad-based registries (as in CRUSADE: Can Rapid risk stratification of Unstable angina patients Suppress Adverse outcomes with Early implementation of the ACC/AHA guidelines) than in controlled clinical trials. Complicating therapeutic decision making is the observation that baseline predictors of bleeding, ie, old age, female sex, renal dysfunction, and baseline anemia, also predict the risk of death due to ischemic complications. The impact of bleeding on prognosis is increasingly recognized. Major bleeding in the Global Registry of Acute Coronary Events (GRACE) was significantly associated with in-hospital death (adjusted OR 1.645). In registries and trials of more than 30 000 patients, major bleeding was associated with a 4-fold increase in the …

Abstract 2027: Validation of a Bleeding Risk Score for Acute Coronary Syndromes

Background: a number of prospective registries have identified independent predictors of bleeding during hospitalization for acute coronary syndromes (ACS). However, no score is validated to estimate individual risk of bleeding in ACS. Objectives and Methods: in order to create and validate a score for estimating risk of bleeding at admission of patients with ACS, independent predictors of bleeding reported in the GRACE registry ( Circulation 2007 ; 116 : 2793 –2801 ) were utilized according to the following rule: the presence of variables with odds ratio (OR) ≥ 2.5 in the GRACE registry added 3 points to the score, OR = 1.5–2.4 added 2 points and those with OR &lt; 1.5 added 1 point. Only information available at admission were considered: previous history of bleeding (3 points), creatinine clearance &lt; 30 ml/min (2 points), clearance = 30 – 60 ml/min (1 point), female gender (2 points), each 10 years of aging after 30 years old (1 point), ST-segment depression (1 point), peripheral artery disease (1 point), smoking (1 point). In order to validate the score, a sample of 383 consecutive individuals (66±12 yo, 58% males) admitted with ACS between 1999 and 2007 was studied. Inclusion criteria were defined as chest discomfort with at least one of the following: ST-segment elevation, ST-segment depression, T wave inversion, positive troponin or previous coronary artery disease. Major bleeding was defined as hematocrit fall ≥ 10%, blood transfusion of at least 2 units, intracerebral bleeding or fatal bleeding. Results: incidence of major bleeding was 3.1%. The bleeding score statistically predicted major bleeding (C-statistics=0.66; 95%IC = 0.52– 0.80). Patients in the first two quartiles of score distribution (1– 4 points) experienced the lowest risk of bleeding (1.6%), those in the third quartile (6 points) had intermediate risk (2.7%) and individuals in the fourth quartile (7–10 points) had the highest risk observed (6%, P=0.089). When sample population was dichotomized according to the best cut-off point in risk discrimination, those with a score ≥ 7 had 6% risk of bleeding, compared to individuals with a score &lt; 7 (1.9%, P=0.03). Conclusion: the tested score discriminates bleeding risk and is a potentially useful tool in clinical decision during acute coronary syndromes.

The risk of iatrogenic bleeding in acute coronary syndromes and long-term mortality

This review examines the association between bleeding and adverse outcomes in patients with acute coronary syndrome and explores mechanisms behind this association and strategies for reducing bleeding complications in acute coronary syndrome. Bleeding is a common complication of antithrombotic treatment in acute coronary syndrome, and major bleeding occurs in around 5% of patients. Important risk factors for major bleeding include increasing age, female sex, renal impairment, and invasive procedures. Recent studies suggest that major bleeding in patients with acute coronary syndrome is independently associated with an increase of early and long-term morbidity and mortality. This may be due to the direct effects of anaemia and hypovolaemia, the treatment modification or withdrawal, or the adverse effects of transfusion. Bleeding complications may be reduced by use of new antithrombotic agents and by improved attention to dosing with current agents. Future studies should examine the effects on overall morbidity and mortality of strategies designed to reduce bleeding complications in patients with acute coronary syndrome. There is a need to apply uniform definitions of bleeding severity. Future trials should report all clinically relevant bleeding outcomes and transfusions. Studies are needed to investigate methods to reduce the risk of bleeding, better understand mechanisms of adverse outcome after bleeding, and establish best practice for the management of bleeding including appropriate use of transfusion in patients with acute coronary syndrome.

Bleeding Is Bad…. Isn’t It?

Advances in antithrombin and antiplatelet therapy have traditionally been associated with reductions in myocardial infarction and other thrombotic events in patients who have experienced an acute coronary syndrome (ACS), are undergoing a percutaneous coronary intervention (PCI), or are receiving long-term therapy for secondary prevention of stable vascular disease. Although individual trials of antithrombotic therapy have rarely been able to demonstrate that the reduction in ischemic events leads to a reduction in mortality (the most important end point), meta-analyses have often suggested that this is the case.1 And because myocardial infarction is an independent correlate of mortality, a link between a reduction in ischemic events and reduced mortality makes intuitive sense. Article p 2793 Unfortunately, more potent anticoagulants and antiplatelet agents are also associated with an increased risk of bleeding, especially when used in combination with one another, as is usually the case. Furthermore, there is a well-established body of evidence that indicates an association between bleeding and ischemic events.2,3 It has been unclear, however, whether the link between bleeding and thrombosis is the result of bleeding after the initial development of a thrombotic complication (and its treatment) or if bleeding precedes the development of an ischemic complication and actually leads to (actually causes) thrombosis. In support of the former possibility is that patients who, because of the presence of thrombus, undergo a longer or more complicated procedure, receive a higher dose or longer duration of antithrombotic medication, or require an intra-aortic balloon pump are surely more prone to bleed. However, the possibility that hemorrhage actually leads to thrombosis rather than results from it is supported by the observation that hemorrhage is a potent stimulus for thrombosis; all patients would surely die if bleeding did not trigger at least a local thrombotic reaction. Furthermore, as the Global Registry of …

Prognostic impact of major bleeding in patients with acute coronary syndromes.A systematic review and meta-analysis

The causative relationship between major bleeding in acute coronary syndromes (ACS) and the increase in mortality and morbidity has frequently been suggested in recent pharmaco-invasive trials and registries. However, the magnitude of this increased risk is the subject of debate. In order to determine the prognostic significance of major bleeding in ACS, we have conducted a systematic review and meta-analysis. Databases were searched for articles published up to March 2007. Any study, either retrospective or prospective, assessing the impact of major bleeding in patients with ACS was included if all-cause mortality was reported as an outcome measure.Data from 10 studies involving a total of 133,597 patients with ACS at baseline, of whom 3,644 had major bleeding (2.7%) were included in a meta-analysis using a random-effects model. An overall pooled relative risk (RR) mortality increase of 7.6 (95% CI; 5.5-10.4) was found in patients with major bleeding. Although most of the 95% confidence intervals (CIs) for the primary studies overlapped, some heterogeneity was observed (Chi2 for heterogeneity, P <0.0001), hence the need for the random-effects meta-analysis. However, the overall effect was highly significant (Z=12.65; P <0.00001). Major bleeding in ACS was also associated with a statistically significant increase in the secondary endpoints assessed including acute myocardial infarction (AMI), and stroke. This meta-analysis indicates that major bleeding in patients with ACS is a strong predictor of in-hospital or 30-day death and AMI. The pooled estimates presented should alert clinicians and interventionalists to the importance of prevention of major bleeding in patients hospitalised with ACS.

Adverse Impact of Bleeding on Prognosis in Patients With Acute Coronary Syndromes

The use of multiple antithrombotic drugs and aggressive invasive strategies has increased the risk of major bleeding in acute coronary syndrome (ACS) patients. It is not known to what extent bleeding determines clinical outcome. Using Cox proportional-hazards modeling, we examined the association between bleeding and death or ischemic events in 34,146 patients with ACS enrolled in the Organization to Assess Ischemic Syndromes and the Clopidogrel in Unstable Angina to Prevent Recurrent Events studies. Patients with major bleeding were older, more often had diabetes or a history of stroke, had a lower blood pressure and higher serum creatinine, more often had ST-segment changes on the presenting ECG, and had a 5-fold-higher incidence of death during the first 30 days (12.8% versus 2.5%; P < 0.0001) and a 1.5-fold-higher incidence of death between 30 days and 6 months (4.6% versus 2.9%; P = 0.002). Major bleeding was independently associated with an increased hazard of death during the first 30 days (hazard ratio, 5.37; 95% CI, 3.97 to 7.26; P < 0.0001), but the hazard was much weaker after 30 days (hazard ratio, 1.54; 95% CI, 1.01 to 2.36; P = 0.047). The association was consistent across subgroups according to cointerventions during hospitalization, and there was an increasing risk of death with increasing severity of bleeding (minor less than major less than life-threatening; P for trend = 0.0009). A similar association was evident between major bleeding and ischemic events, including myocardial infarction and stroke. In ACS patients without persistent ST-segment elevation, there is a strong, consistent, temporal, and dose-related association between bleeding and death. These data should lead to greater awareness of the prognostic importance of bleeding in ACS and should prompt evaluation of strategies to reduce bleeding and thereby improve clinical outcomes.