Total Bleeding Events Research Articles

Rivaroxaban versus enoxaparin for thromboprophylaxis after total hip or knee arthroplasty: a meta-analysis of randomized controlled trials

Rivaroxaban is a newly developed oral medicine that direct inhibits factor Xa for the prevention and treatment of thromboembolic disorders. The objective of this study was to compare the efficacy and safety of rivaroxaban versus enoxaparin, a medicine routinely used for thromboprophylaxis after total hip or knee arthroplasty. We performed a meta-analysis of relevant randomized controlled trials (RCTs) identified in PubMed, Cochrane library, and Embase. The primary efficacy outcome for our meta-analysis was total venous thromboembolism (VTE) and all-cause mortality. The primary safety outcome was bleeding events, which were categorized as major, clinically relevant non-major, or minor events. Eight RCTs, involving 15,586 patients, were included in our meta-analysis. Compared to enoxaparin, thromboprophylaxis with rivaroxaban was associated with significantly fewer VTE and all-cause mortality [9,244 patients, risk ratio (RR) 0.56, 95% confidence interval (CI) 0.39-0.80] cases and a similar incidence of bleeding cases (major bleeding events: 13,384 patients, RR 1.65, 95% CI 0.93-2.93; clinically relevant non-major bleeding events: 13,384 patients, RR 1.21, 95% CI 0.98-1.50; total bleeding events, 13,384 patients, RR 1.10, 95% CI 0.97-1.24). The total hip or knee arthroplasty subgroup analysis revealed consistent efficacy and safety findings. Rivaroxaban was more effective than the recommended dose of enoxaparin and had a similar safety profile for thromboprophylaxis after hip and knee arthroplasty.

Direct thrombin inhibitors versus vitamin K antagonists or low molecular weight heparins for prevention of venous thromboembolism following total hip or knee replacement

Patients who have undergone total hip or knee replacement (THR, TKR) have a high risk of developing venous thromboembolism (VTE) following surgery, despite appropriate anticoagulation with warfarin or low molecular weight heparin (LMWH). New anticoagulants are under investigation. To examine the efficacy and safety of prophylactic anticoagulation with direct thrombin inhibitors (DTIs) versus LMWH or vitamin K antagonists in the prevention of VTE in patients undergoing THR or TKR. The Cochrane Peripheral Vascular Disease Group searched their Specialized Register (last searched 12 March 2010) and CENTRAL (last searched 2010, Issue 2). Randomised controlled trials. Three reviewers independently assessed methodological quality and extracted data in pre-designed tables. The reported follow-up events were included We included 14 studies included involving 21,642 patients evaluated for efficacy and 27,360 for safety. No difference was observed in major VTE in DTIs compared with LMWH in both types of operations (odds ratio (OR) 0.91; 95% confidence interval (CI) 0.69 to 1.19), with high heterogeneity (I(2) 71%). No difference was observed with warfarin (OR 0.85; 95% CI 0.63 to 1.15) in TKR, with no heterogeneity (I(2) 0%).More total bleeding events were observed in the DTI group (in ximelagatran and dabigatran but not in desirudin) in patients subjected to THR (OR 1.40; 95% CI 1.06, 1.85; I(2) 41%) compared with LMWH. No difference was observed with warfarin in TKR (OR 1.76; 95% CI 0.91 to 3.38; I(2) 0%). All-cause mortality was higher in the DTI group when the reported follow-up events were included (OR 2.06; 95% CI 1.10 to 3.87).Studies that initiated anticoagulation before surgery showed less VTE events; those that began anticoagulation after surgery showed more VTE events in comparison with LMWH. Therefore, the effect of the DTIs compared with LMWH appears to be influenced by the time of initiation of coagulation more than the effect of the drug itself.The results obtained from sensitivity analysis, did not differ from the analysed results; this strengthens the value of the results. Direct thrombin inhibitors are as effective in the prevention of major venous thromboembolism in THR or TKR as LMWH and vitamin K antagonists. However, they show higher mortality and cause more bleeding than LMWH. No severe hepatic complications were reported in the analysed studies. Use of ximelagatran is not recommended for VTE prevention in patients who have undergone orthopedic surgery. More studies are necessary regarding dabigatran.

Safety and tolerability of an immediate-release formulation of the oral direct thrombin inhibitor AZD0837 in the prevention of stroke and systemic embolism in patients with atrial fibrillation

AZD0837 is an investigational oral anticoagulant which is converted to the active form, AR-H067637, a selective direct thrombin inhibitor. The present study, a multicentre, randomised, parallel-group, dose-guiding study, assessed the safety and tolerability of an immediate-release formulation of AZD0837 compared with dose-adjusted warfarin in the prevention of stroke and systemic embolic events in atrial fibrillation (AF) patients. Two hundred fifty AF patients with at least one additional risk factor for stroke were randomised to receive either immediate-release AZD0837 (150mg twice daily [bid] or 350mg bid, blinded treatment) or dose-adjusted warfarin (international normalised ratio 2.0-3.0, open treatment) for three months. The safety and tolerability of 150mg bid AZD0837 appeared to be as good as that of warfarin. Total bleeding events were six with 150mg bid AZD0837, 15 with 350mg bid AZD0837 and eight with warfarin. Alanine aminotransferase elevations (>3xupper limit of normal) were infrequent, without apparent differences between treatment groups. A numerically higher incidence of serious adverse events was observed with 350mg bid AZD0837 compared with 150mg bid, with six of 13 being cardiac related, all with different diagnoses. An increase in mean serum creatinine of approximately 10% was observed in both AZD0837 groups, which returned to baseline after completion of therapy. There were no strokes, transient ischaemic attacks or cerebral haemorrhages with any of the treatments. In conclusion, the safety and tolerability of 150mg bid immediate-release AZD0837 appeared to be as good as that of dose-adjusted warfarin. However, larger studies will be needed to define the safety profile of AZD0837.

Venous Thromboembolism in Hospitalized Patients With Heart Failure

Heart failure (HF) is a common cardiovascular cause of hospitalizations in the United States and the most frequent reason among patients aged 65 years and older.1 A recent report by the National Hospital Discharge Survey showed an increase in the number of hospital admissions with a diagnosis of HF from ≈1.3 million in 1979 to 3.9 million in 2004, with 30% to 35% of these carrying a primary diagnosis of HF.2 Recent data from several large registries of HF hospitalizations have demonstrated in-hospital mortality as high as 4% to 7%.3,4 Contributing to this is a significant incidence of VTE among hospitalized patients with HF.5 In addition, VTE is associated with thromboembolic complications, which are associated with long-term sequelae including postthrombotic syndromes, venous stasis, venous ulcers, chronic thromboembolic pulmonary hypertension, and pulmonary embolism (PE).6–8 These conditions are often associated with edema and chronic pain, which can have a significant impact on mobility and quality of life. Recurrent VTE and PE are also common complications reported in as many as 30% of patients.9 Published information suggests that despite availability of effective therapy and existence of practice guidelines,10,11 there is a significant underutilization of VTE prophylaxis in hospitalized patients with HF.12–15 Analysis of the Acute Decompensated Heart Failure National Registry revealed that of 71 376 patients eligible for VTE prophylaxis only 21 847 (31%) received prophylactic regimen.16 An analysis of the PREMIER database showed that although 79% of 34 286 patients admitted with HF received an order for VTE prophylaxis, only 15.8% received recommended appropriate prophylactic regimen in terms of the type of medications, dose, and duration of therapy.17 These data clearly demonstrate the need for increased awareness of prevention of VTE in hospitalized patients with HF. Therefore, the purpose of this article …

Thrice weekly warfarin administration in haemodialysis patients

Medication adherence in haemodialysis patients is often challenging due to a high pill burden, complex and dynamic medication regimens and limited patient self-interest in care. The purpose of this study was to investigate the time within target INR and safety profile of thrice weekly warfarin administration in haemodialysis patients with a clinical indication for anticoagulation and documented nonadherence to medications. Thirty-seven patients from two haemodialysis units in Winnipeg, Manitoba, Canada, were recruited, and 17 patients were treated with thrice weekly warfarin and compared to 20 patients treated with daily warfarin therapy. The patients were followed for 1 year with weekly international normalized ratio (INR), dosage and adverse events recorded. The primary outcome was percentage of time with INR in target and sub (<1.5)- and supra (>4)-therapeutic INR. Adverse events were recorded in the two groups. The thrice weekly group had a higher burden of comorbidity (Charlson comorbidity index of 6.35 +/- 1.77 versus 4.55 +/- 1.64, P = 0.003) compared to the daily dosage group. In the thrice weekly dosage group, time within target INR was higher (56.9 versus 49.3%, P = 0.008), and time with supra-therapeutic INR > 4 lower (2.7 versus 4.3%, P = 0.03). Total bleeding events (7 versus 6) and major bleeding events (3 versus 2 events) were similar between the two groups. In this pilot study, thrice weekly warfarin appears to be a safe and feasible dosing strategy in a select patient population. A randomized controlled trial of thrice weekly warfarin is warranted.

Dabigatran With or Without Concomitant Aspirin Compared With Warfarin Alone in Patients With Nonvalvular Atrial Fibrillation (PETRO Study)

This is the first evaluation of dabigatran, an oral direct thrombin inhibitor, in patients with atrial fibrillation (AF). Patients (n = 502) were randomized to receive blinded doses of 50-, 150-, or 300-mg dabigatran twice daily alone or combined with 81- or 325-mg aspirin or open-label warfarin administered to achieve an international normalized ratio of 2 to 3 for 12 weeks. Dabigatran plasma concentrations, activated partial thromboplastin time, D-dimer, urinary 11-dehydrothromboxane B(2) (DTB2), and liver function were measured at baseline and at 1, 2, 4, 8, and 12 weeks. Clinical end points were assessed according to the treatment received at the time of the event. Overall, 92% of patients completed the study. Major hemorrhages were limited to the group treated with 300-mg dabigatran plus aspirin (4 of 64), and the incidence was significant versus 300-mg dabigatran alone (0 of 105, p <0.02). Total bleeding events were more frequent in the 300-mg (39 of 169, 23%) and 150-mg (30 of 169, 18%) dabigatran groups compared with the 50-mg groups (7 of 107, 7%; p = 0.0002 and p = 0.01, respectively). Thromboembolic events were limited to the 50-mg dabigatran dose groups (2 of 107, 2%). The mean trough d-dimer measurements were suppressed for the 2 highest doses of dabigatran and warfarin (international normalized ratio of 2 to 3). Aminotransferase levels >3 times the upper limit of normal were observed in 0.9% of the dabigatran recipients and in none of the warfarin recipients. Two dabigatran recipients had aminotransferase levels >5 times the upper limit of normal as a result of gallstones, which resolved. Trough activated partial thromboplastin time values were 1.2, 1.5, and 1.8 times the baseline level for the 50-, 150-, and 300-mg dabigatran groups, respectively. DTB2 concentrations after 12 weeks of 50-, 150-, and 300-mg dabigatran treatment were increased by 31%, 17%, and 23%, respectively, versus baseline (p = 0.02, p = 0.03, and p = 0.0004). In conclusion, major bleeding events were limited to patients treated with dabigatran 300 mg plus aspirin and thromboembolic episodes were limited to the 50-mg dabigatran groups. The 2 highest doses of dabigatran suppress D-dimer concentrations. Serious liver toxicity was not seen. The significance of the increase of DTB2 concentrations in dabigatran-treated patients needs resolution.

Comparison of laparoscopic linear staplers in clinical practice

Only one previous study has evaluated the clinical safety of the 2 laparoscopic linear stapling devices available. Our study compared these staplers using laparoscopic gastric bypass as the standard procedure. A total of 400 consecutive patients were prospectively studied. Group A (200 patients) underwent gastric bypass with the Endo-GIA Universal 6-row stapler (Autosuture) used, and group B (200 patients) underwent the procedure with the Ethicon 6-row stapler used. The measured parameters included stapler misfires, staple line bleeding, staple line leaks, unexplained gastrointestinal bleeding, unexplained intra-abdominal bleeding, total bleeding events, and total adverse events. Both groups were similar in preoperative body mass index, age, and gender. Both groups had a single staple line leak (0.5%; P = 1.0). Three (0.25% of staple firings) misfires occurred in group B. No misfires occurred in group A (P = .25). Gastrointestinal bleeding, staple line bleeding, and unexplained intra-abdominal bleeding occurred in 6 (3%), 2 (1%), and 5 (2.5%) patients in group A and in 1 (0.5%), 0 (0%), and 2 (1%) patients in group B (P = .12, P = .5, and P = .45, respectively). Total bleeding events occurred in 13 patients (6.5%) in group A and in 3 patients (1.5%) in group B (P = 0.019). The total number of patients with an adverse event was 14 (7%) in group A and 7 (3.5%) in group B (P = .18). The results of our study have shown that the Ethicon 6-row stapler had more misfires and the Autosuture Endo-GIA 6-row stapler resulted in more bleeding complications. Only the difference in total bleeding events reached statistical significance but the difference in the total number of adverse events was not statistically significant. Therefore, in our experience both devices were equally safe and effective.

Anticoagulation therapy in patients with chronic atrial fibrillation: a retrospective claims data analysis

ABSTRACTObjectives: This study assessed the risk of thromboembolic events and bleeding complications among atrial fibrillation patients.Methods: A cohort of patients with chronic non-valvular atrial fibrillation were identified from medical claims (diagnosis codes 427.31 and 427.32). Subjects were identified from 1 January 1998–31 December 2000 and were continuously enrolled for 6 months prior to the first occurring atrial fibrillation medical claim. Cox proportional hazards analysis with time varying covariates was used for the event analysis.Results: Of 6764 subjects retained for analysis, 3541 (52.4%) were exposed to warfarin. Adjusting for baseline characteristics, warfarin exposure was associated with lower likelihood of an arterial thromboembolic event compared to no exposure (HR: 0.710, CI: 0.540–0.934). No benefit was found in the use of warfarin in the prevention of intracranial events (HR: 1.119, CI: 0.929–1.349). Use of warfarin increased the risk of minor bleeding events (HR: 3.600, CI: 2.537–5.109), and all bleeding events (HR: 1.502, CI: 1.289–1.749).Conclusions: The risk of arterial thromboembolic events was associated with warfarin exposure as expected. An increase in the risk of minor and total bleeding events among patients treated with warfarin was observed. The results of this study suggest that there may be a gap between the clinical trial and coagulation clinic performance of warfarin in reducing the risk of thromboembolic events versus what is achievable in general practice.

Low rate of bleeding and thrombotic complications of oral anticoagulant therapy independent of age in the real-practice of an anticoagulation clinic.

Over past years, there has been a world-wide increase in oral anticoagulant treatment (OAT). This study was aimed at evaluating the efficacy and safety of OAT managing in a real-practice situation. Nine hundred and three consecutive unselected patients referred for the control of OAT to the Anticoagulation Clinic of the University of Florence were studied. The total follow-up period was 1679 patient-years. The rate of total, major and fatal bleeding events was 5.0, 1.1 and 0.06 per 100 patient-years, respectively. In patients with a target International Normalized Ratio (INR) > or = 3, a significantly higher rate of bleeding (P = 0.02) with respect to patients with a target INR < 3 was observed. The rate of all thrombotic events was 3.8 per 100 patient-years. The rate of major and fatal thrombotic events were 2.4 and 0.4 per 100 patient-years, respectively. At INR >/= 4.5 the rate of bleeding was significantly higher (P = 0.005) than at lower INR. At INR < 2 the rate of all thrombotic events was significantly higher (P = 0.00001) with respect to more elevated intensities of anticoagulation. A low incidence of complications may be obtained even in elderly outpatients on OAT followed at an anticoagulation clinic.