Risk Factors For Major Bleeding Research Articles

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.

Venous thromboembolism and bleeding in critically ill patients with severe renal insufficiency receiving dalteparin thromboprophylaxis: prevalence, incidence and risk factors

BackgroundCritically ill patients with renal insufficiency are predisposed to both deep vein thrombosis (DVT) and bleeding. The objective of the present study was to evaluate the prevalence, incidence and predictors of DVT and the incidence of bleeding in intensive care unit (ICU) patients with estimated creatinine clearance <30 ml/min.MethodsIn a multicenter, open-label, prospective cohort study of critically ill patients with severe acute or chronic renal insufficiency or dialysis receiving subcutaneous dalteparin 5,000 IU once daily, we estimated the prevalence of proximal DVT by screening compression venous ultrasound of the lower limbs within 48 hours of ICU admission. DVT incidence was assessed on twice-weekly ultrasound testing. We estimated the incidence of major and minor bleeding by daily clinical assessments. We used Cox proportional hazards regression to identify independent predictors of both DVT and major bleeding.ResultsOf 156 patients with a mean (standard deviation) creatinine clearance of 18.9 (6.5) ml/min, 18 had DVT or pulmonary embolism within 48 hours of ICU admission, died or were discharged before ultrasound testing – leaving 138 evaluable patients who received at least one dose of dalteparin. The median duration of dalteparin administration was 7 days (interquartile range, 4 to 12 days). DVT developed in seven patients (5.1%; 95% confidence interval, 2.5 to 10.1). The only independent risk factor for DVT was an elevated baseline Acute Physiology and Chronic Health Evaluation II score (hazard ratio for 10-point increase, 2.25; 95% confidence interval, 1.03 to 4.91). Major bleeding developed in 10 patients (7.2%; 95% confidence interval, 4.0 to 12.8), all with trough anti-activated factor X levels ≤ 0.18 IU/ml. Independent risk factors for major bleeding were aspirin use (hazard ratio, 6.30; 95% confidence interval, 1.35 to 29.4) and a high International Normalized Ratio (hazard ratio for 0.5-unit increase, 1.68; 95% confidence interval, 1.07 to 2.66).ConclusionIn ICU patients with renal insufficiency, the incidence of DVT and major bleeding are considerable but appear related to patient comorbidities rather than to an inadequate or excessive anticoagulant from thromboprophylaxis with dalteparin.Clinical Trial RegistrationNumber NCT00138099.

Bleeding during critical illness: A prospective cohort study using a new measurement tool

To estimate the incidence, severity, duration and consequences of bleeding during critical illness, and to test the performance characteristics of a new bleeding assessment tool. Clinical bleeding assessments were performed prospectively on 100 consecutive patients admitted to a medical-surgical intensive care unit (ICU) using a novel bleeding measurement tool called HEmorrhage MEasurement (HEME). Bleeding assessments were done daily in duplicate and independently by blinded, trained assessors. Inter-rater agreement and construct validity of the HEME tool were calculated using phi. Risk factors for major bleeding were identified using a multivariable Cox proportional hazards model. Overall, 90% of patients experienced a total of 480 bleeds of which 94.8% were minor and 5.2% were major. Inter-rater reliability of the HEME tool was excellent (phi = 0.98, 95% CI: 0.96 to 0.99). A decrease in platelet count and a prolongation of partial thromboplastin time were independent risk factors for major bleeding but neither were renal failure nor prophylactic anticoagulation. Patients with major bleeding received more blood transfusions and had longer ICU stays compared to patients with minor or no bleeding. Bleeding, although primarily minor, occurred in the majority of ICU patients. One of five patients experienced a major bleed which was associated with abnormal coagulation tests but not with prophylactic anticoagulants. These baseline bleeding rates can inform the design of future clinical trials in critical care that use bleeding as an outcome and HEME is a useful tool to measure bleeding in critically ill patients.

Incidence of Major Bleeding Complication of Warfarin Therapy in Japanese Patients With Atrial Fibrillation

During anticoagulation for prevention of stroke in patients with non-valvular atrial fibrillation (NVAF), bleeding is the most serious complication. In Western countries, the incidences of major bleeding and intracranial hemorrhages with low-dose warfarin are known to occur at a rate of 0.4-1.3% and 0.2% per year, respectively. The purpose of this study was to investigate the incidence and risk factors for major bleeding related with warfarin therapy in Japanese patients with NVAF. From August 2004 to July 2005, 667 NVAF patients treated with warfarin for NVAF were followed-up. The target prothrombin time-international normalized ratio (PT-INR) value was set at 1.6-2.6 (low-dose warfarin). The exposure on warfarin was 503 patient-years (average PT-INR 2.00 +/-0.40). During the follow-up period, 12 major bleeding complications occurred (2.38% per patient-year), which included 3 intracranial hemorrhages (0.60% per patient-year). Among the patients' characteristics, average PT-INR > or =2.27 during the study was identified as an independent risk factor for major bleeding. The incidence of major bleeding and intracranial hemorrhages in Japanese NVAF patients with low-dose warfarin therapy was 2.38% and 0.60% per patient-year, respectively, which is higher than in Westerners.

Comparison of Bleeding in Patients With Nonvalvular Atrial Fibrillation Treated With Ximelagatran or Warfarin

Ximelagatran is a novel direct thrombin inhibitor that can be administered as a fixed oral dose, without the need for anticoagulant monitoring. We undertook a pooled analysis of 7329 patients with nonvalvular atrial fibrillation from the Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation III and V trials to compare bleeding outcomes in patients who received ximelagatran, 36 mg twice daily, or warfarin sodium (target international normalized ratio, 2.0-3.0). We determined annual risk of bleeding (any, major), case-fatality rate, time course and anatomic sites of major bleeding, and risk factors for major bleeding with ximelagatran and warfarin treatment. Annual incidence of any bleeding was 31.75% with ximelagatran and 38.82% with warfarin (relative risk reduction, 18.2%; 95% confidence interval [CI], 13.0-23.1; P<.001). Annual incidence of major bleeding was 2.01% with ximelagatran and 2.68% with warfarin (relative risk reduction, 25.1%; 95% CI, 3.2-42.1; P = .03). Case-fatality rate of bleeding was comparable in ximelagatran- and warfarin-treated patients (8.16% vs 8.09%; P = .98). Cumulative incidence of major bleeding was higher with warfarin than ximelagatran after 24 months of treatment (4.7% vs 3.7%; P = .04). Anatomic sites of bleeding were comparable with both treatments. Risk factors for bleeding with ximelagatran were as follows (hazard ratios and 95% CIs in parentheses): diabetes mellitus (1.81; 1.19-2.77; P = .006), previous stroke or transient ischemic attack (1.78; 1.16-2.73; P = .008), age 75 years or greater (1.70; 1.33-2.18; P<.001), and aspirin use (1.68; 1.08-2.59; P = .02). Risk factors for bleeding in warfarin-treated patients were previous liver disease (4.88; 1.55-15.39; P = .007); aspirin use (2.41; 1.69-3.43; P<.001); and age 75 years or greater (1.26; 1.03-1.52; P = .02). Treatment with ximelagatran, 36 mg twice daily, is associated with a lower risk of bleeding than warfarin in patients with nonvalvular atrial fibrillation. Aspirin use and increasing age were associated with an increased risk of bleeding in ximelagatran- and warfarin-treated patients.

Severe Thrombocytopenia, Type 2B von Willebrand Disease and Pregnancy

VON Willebrand’s Disease (vWD) is the most common inherited bleeding disorder in humans with an estimated incidence as high as 2–3% in the general population. Characterized by abnormal platelet interactions with the subendothelium or other platelets, the disease is caused by changes in the multimeric glycoprotein, von Willebrand’s Factor (vWF). Types 1 and 3 vWD are associated with relative or absolute quantitative defects in the protein, respectively. Type 1 vWD accounts for 70% of all cases and is likely to temporally improve in parturients as a result of an increase in vWF and factor VIII with pregnancy. Type 2 vWD has qualitative abnormalities and comprises 20–30% of all vWD diagnoses. A unique subtype, type 2B, accounts for less than 20% of all type 2 vWD and is characterized by an increased affinity of vWF for platelet glycoprotein Ib, resulting in spontaneous binding and clearance of both vWF and platelets. This feature allows type 2B, unlike most other vWD variants, to be exacerbated by pregnancy and to exhibit a poor or worsening response to desmopressin (DDAVP; Aventis, Bridgewater, NJ). We present the management of a parturient with type 2B vWD who had severe thrombocytopenia during the peripartum period.

Risk Factors for Bleeding in Patients with Nonvalvular Atrial Fibrillation Who Are Receiving Anticoagulant Therapy with Ximelagatran or Warfarin: Findings from the SPORTIF III and V Trials.

Background: Ximelagatran is a novel oral direct thrombin inhibitor that is as effective as warfarin in preventing stroke and other thromboembolic complications in patients with nonvalvular atrial fibrillation (AF). Risk factors for bleeding with warfarin are known, but risk factors for bleeding with ximelagatran have not been described. Unlike warfarin, ximelagatran has a predictable anticoagulant effect, does not require anticoagulation monitoring, has a low potential for interactions with drugs, food, or alcohol, and is not affected by genetic polymorphisms. We undertook an exploratory analysis of a large patient database to identify conventional and novel risk factors for bleeding in ximelagatran-treated patients, in warfarin-treated patients, and in all patients, irrespective of treatment.Methods: We undertook a pooled analysis of the SPORTIF III and V trials trials, which included 7329 patients with nonvalvular AF who received oral ximelagatran, 36 mg twice daily, or warfarin, administered to achieve a target international normalized ratio of 2.0–3.0. Patients had nonvalvular AF and 1 or more risk factors for stroke: hypertension; age ≥75 years; previous stroke, transient ischemic attack (TIA) or systemic embolism; left ventricular dysfunction; age ≥65 years and coronary artery disease; or age ≥65 years and diabetes mellitus. Major exclusion criteria were: mitral stenosis; previous heart valve surgery; transient AF; increased risk for bleeding. Multivariate logistic regression analysis was used to identify independent risk factors for major bleeding. The hazard ratio (HR) for major bleeding, and corresponding 95% confidence interval (CI), was calculated for each variable in the regression model.Results: The Table presents risk factors in which there was a significant or a non-significant (NS) association with major bleeding in ximelagatran-treated or warfarin-treated patients, and in the combined patient population.Risk factorXimelagatran-treated patients, HR (95% CI)Warfarin-treated patients, HR (95% CI)Combined patient population, HR (95% CI)Aspirin use1.65 (1.07, 2.55)2.40 (1.69, 3.42)1.96 (1.49, 2.58)Increasing age1.03 (1.01, 1.05)1.06 (1.03, 1.08)1.04 (1.03, 1.06)Prior liver diseaseNS4.96 (1.57, 15.62)NSPrior stroke or TIA1.78 (1.16, 2.73)NSNSDiabetes mellitus1.80 (1.18, 2.75)NS1.39 (1.05, 1.86)Asian raceNSNS1.99 (1.16, 3.42)Statin use0.62 (0.39, 0.97)0.61 (0.42, 0.88)0.62 (0.39, 0.97)Conclusions: Overall, the bleeding risk was lower with ximelagatran compared with warfarin. Aspirin use and increasing age were associated with an increased risk of bleeding in both ximelagatran- and warfarin-treated patients. Statin use was associated with a decreased risk for bleeding in both groups.

Managing Complications of Anticoagulant Therapy

Understanding the frequency, risk factors, and management of anticoagulant-induced adverse events will assist clinicians in optimizing patient outcomes. The most frequent adverse event of all anticoagulants is major bleeding. Risk factors for major bleeding have been identified with the heparin compounds, the direct thrombin inhibitors (DTIs), fondaparinux, and warfarin therapy. Understanding these risk factors can help prevent bleeding events. For cases of clinically significant bleeding, reversal agents exist primarily for heparin and warfarin. Although less common, nonbleeding adverse events of anticoagulant therapy can also be life threatening. The heparin compounds are associated with the development of heparin-induced thrombocytopenia (HIT) and osteoporosis. HIT can result in life-threatening thrombosis and is usually managed with a DTI. Nonbleeding adverse events with warfarin therapy include skin reactions and the development of venous limb gangrene. Appropriate initiation of warfarin therapy may decrease the risk of venous limb gangrene.

Dosing Practices and Risk Factors for Bleeding in Patients Receiving Enoxaparin for the Treatment of an Acute Coronary Syndrome

To describe dosing practices and to identify risk factors for bleeding in patients with an acute coronary syndrome (ACS) who received treatment with enoxaparin. Retrospective chart review. Coronary care unit of a tertiary-care teaching hospital. Patients with a discharge diagnosis of an ACS who received at least one dose of enoxaparin, 1 mg/kg, were eligible for this study. Enoxaparin dosing practices, factors that might influence the safety of enoxaparin administration, and bleeding events were documented. Multivariable regression analysis was used to identify independent predictors of bleeding in this clinical setting. Of 208 patients with an ACS who received enoxaparin, 48 patients (23%) received a dose that was > 10% or < 10% of the recommended 1 mg/kg dose, 18 patients (9%) did not have body weight documentation to guide enoxaparin dosing, and 17 patients (8%) had significant renal impairment (serum creatinine > 150 micromol/L), with the potential for bioaccumulation of enoxaparin. There were 35 bleeding events (17%), of which 8 events (4%) were major. Risk factors for any bleeding (major or minor) were increasing patient age (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.13 to 2.20), coadministered nonsteroidal anti-inflammatory or antiplatelet drug therapy (OR, 2.38; 95% CI, 1.06 to 5.38), and number of enoxaparin doses (OR, 2.15; 95% CI, 1.25 to 3.68). Risk factors for major bleeding were increasing patient age (OR, 2.56; 95% CI, 1.05 to 6.28) and coadministered clopidogrel (OR, 7.70; 95% CI, 1.16 to 51.9). In this clinical practice assessment of patients with an ACS, the use of enoxaparin was suboptimal, with the potential to increase bleeding complications. Coadministered clopidogrel, other drugs that affect hemostasis, and increasing age conferred an increased bleeding risk.

Complications of oral anticoagulant therapy: bleeding and nonbleeding, rates and risk factors.

Oral anticoagulant therapy is very effective in preventing thromboembolism. Its major complication is hemorrhage. The rate of intracranial bleeding from randomized trials and observational studies ranges from 0.1 to 0.9% per year and largely depends on the International Normalized Ratio (INR) target range. Risk factors for this often-fatal complication include INR intensity, older age, cerebrovascular disease, and hypertension. Recent insights into the pathogenesis of intracerebral hemorrhage have focused on underlying arterial vasculopathies that predispose to bleeding, particularly in the elderly. The rate of major extracranial hemorrhage on oral anticoagulant therapy ranges from 0.4 to 2% per year. Different definitions of major hemorrhage, INR target ranges, age distribution, burden of comorbid illness, and type of coumarin challenge comparability of studies. Additional risk factors for major hemorrhage include history of gastrointestinal bleeding, concurrent use of antiplatelet or nonsteroidal anti-inflammatory drugs, genetic differences in warfarin metabolism, INR variability, type of coumarin, comorbid illnesses, and duration of oral anticoagulant therapy.

Oral anticoagulant therapy in patients with atrial fibrillation.

In the absence of contraindications, patients with atrial fibrillation and at least one major risk factor for stroke should receive long-term oral anticoagulant treatment to prevent atrial thrombus formation. Because age of more than 75 years is a major risk factor for stroke, but is also a risk factor for major bleeding, the decision to treat elderly patients with anticoagulants should be made on an individual basis.

Low-dose warfarin in rehabilitating stroke survivors

Background: Patients undergoing rehabilitation after thromboembolic stroke have a relatively high incidence of venous thromboembolism (VTE). Warfarin, with a target international normalized ratio (INR) of 2.0–3.0 is effective for the prevention of VTE. However, because stroke is a major risk factor for bleeding with warfarin, a less intense regimen (target INR<2.0), might safely prevent VTE in stroke rehabilitation patients. Methods: This study was a randomized, double-blind, placebo-controlled trial of 2 mg of warfarin in patients undergoing rehabilitation following completed stroke. The major efficacy endpoint was symptomatic, objectively proven VTE or asymptomatic VTE detected by monthly duplex ultrasonography (DU) of the proximal leg veins or mandatory bilateral contrast venography performed at the end of the study. The major safety endpoint was bleeding. Results: There were 475 patients screened for enrollment, 355 had one or more exclusion criterion, and 17 had previously undetected proximal DVT on admission. Of the 103 eligible and consenting patients, 56 received warfarin and 47 received placebo. Of the randomized patients, 88 had successful venography (47 warfarin and 41 placebo). In the warfarin group, three (8%) patients had DVT and one (2%) had proximal DVT whereas in the placebo group, seven (20%) had DVT and five (13%) had proximal DVT. The risk ratio for any DVT in warfarin-treated patients relative to placebo-treated patients was 0.39 (95% confidence interval (CI), 0.13–1.37). For proximal DVT, the risk ratio was 0.17 (95% CI, 0.01–1.4). No patients suffered major bleeding. Conclusions: A fixed dose of 2 mg of warfarin per day in patients undergoing stroke rehabilitation is safe and associated with a relative risk reduction of about 80% in the incidence of proximal DVT and 60% in overall DVT.

Abstracts of literature

Abstracts of literature

Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin

PURPOSE: To evaluate the accuracy and clinical utility of the Outpatient Bleeding Risk Index for estimating the probability of major bleeding in outpatients treated with warfarin. The index was previously derived in a retrospective cohort of 556 patients from a different hospital (derivation cohort). SUBJECTS AND METHODS: We enrolled 264 outpatients starting warfarin (validation cohort) to validate the index prospectively. All patients were identified upon hospital discharge, and physician estimates of the probability of major bleeding were obtained before discharge in the validation cohort. RESULTS: Major bleeding occurred in 87 of 820 outpatients (6.5%/yr). The index included four independent risk factors for major bleeding: age 65 years or greater; history of gastrointestinal bleeding; history of stroke; and one or more of four specific comorbid conditions. In the validation cohort, the index predicted major bleeding: the cumulative incidence at 48 months was 3% in 80 low-risk patients, 12% in 166 intermediate-risk patients, and 53% in 18 high-risk patients (c index, 0.78). The index performed better than physicians, who estimated the probability of major bleeding no better than expected by chance. Of the 18 episodes of major bleeding that occurred in high-risk patients, 17 were potentially preventable. CONCLUSIONS: The Outpatient Bleeding Risk Index prospectively classified patients according to risk of major bleeding and performed better than physicians. Major bleeding may be preventable in many high-risk patients by avoidance of over-anticoagulation and nonsteroidal anti-inflammatory agents.

Liver biopsy: Increased risks in patients with cancer

Nine thousand two hundred twelve liver biopsies were performed according to a defined protocol, and data were prospectively recorded to identify risk factors for major bleeding. There were 10 fatal and 22 nonfatal hemorrhages (0.11% and 0.24%, respectively). By comparison with a control group that did not hemorrhage, malignancy, age, sex, and the number of passes were the only predictable risk factors. The risk of fatal hemorrhage in patients with malignancy is estimated to be 0.4%; for nonfatal hemorrhage, 0.57%. In patients undergoing liver biopsy for nonmalignant disease, the risks are 0.04% and 0.16%, respectively.

A 21-year experience with major hemorrhage after percutaneous liver biopsy

Nine thousand two hundred twelve liver biopsies were performed according to a defined protocol, and data were prospectively recorded to identify risk factors for major bleeding. There were 10 fatal and 22 nonfatal hemorrhages (0.11% and 0.24%, respectively). By comparison with a control group that did not hemorrhage, malignancy, age, sex, and the number of passes were the only predictable risk factors. The risk of fatal hemorrhage in patients with malignancy is estimated to be 0.4%; for nonfatal hemorrhage, 0.57%. In patients undergoing liver biopsy for nonmalignant disease, the risks are 0.04% and 0.16%, respectively.

Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy

To determine the incidence of major bleeding in outpatients treated with warfarin and to identify predictive factors known at the start of therapy. The records of 565 patients starting outpatient therapy with warfarin upon discharge from a university hospital were reviewed. Follow-up information was obtained for 562 patients (99.5%). Bleeding was classified as major or minor using explicit criteria. The cumulative incidence of bleeding was estimated by means of survival analysis. Independent risk factors for major bleeding were identified using Cox regression analysis in 375 randomly chosen patients; they were tested in the remaining 187 patients. Major bleeding occurred in 65 patients (12%) and was fatal in 10 patients (2%). The cumulative incidences of major bleeding at one, 12, and 48 months were 3%, 11%, and 22%, respectively. The monthly risk of major bleeding decreased over time, from 3% during the first month of outpatient therapy to 0.3% per month after the first year of therapy. Five independent risk factors for major bleeding--age 65 years or greater, history of stroke, history of gastrointestinal bleeding, a serious comorbid condition (recent myocardial infarction, renal insufficiency, or severe anemia), atrial fibrillation--predicted major bleeding in the testing group; the cumulative incidence of major bleeding at 48 months was 2% in 57 low-risk patients, 17% in 110 middle-risk patients, and 63% in 20 high-risk patients. These findings provide a quantitative basis for evaluating the risk of major bleeding in individual patients at the start of outpatient therapy with warfarin. Whether the risk of bleeding can be reduced in high-risk patients without reducing the benefit of therapy remains to be determined.