Four phase III studies compared oral rivaroxaban with subcutaneous enoxaparin for the prevention of venous thromboembolism (VTE) after total hip or knee arthroplasty (THA or TKA). A pooled analysis ...of these studies compared the effect of rivaroxaban with enoxaparin on symptomatic VTE plus all-cause mortality and bleeding events, and determined whether these effects were consistent in patient subgroups. Patients (N=12,729) aged ≥18 years and scheduled for elective THA or TKA received rivaroxaban 10 mg once daily or enoxaparin 40 mg once daily or 30 mg every 12 hours. The composite of symptomatic VTE and all-cause mortality, the prespecified primary efficacy endpoint and adjudicated bleeding events were analysed in the day 12± 2 active treatment pool. Subgroup analyses of these outcomes were performed over the total treatment period. In the day 12± 2 pool, the primary efficacy endpoint occurred in 29/6,183 patients receiving rivaroxaban (0.5%) versus 60/6,200 patients receiving enoxaparin (1.0%; p=0.001). Major bleeding occurred in 21 (0.3%) versus 13(0.2%) patients, p=0.23; major plus non-major clinically relevant bleeding in 176(2.8%) versus 152 (2.5%) patients, p=0.19; and any bleeding in 409 (6.6%) versus 384 (6.2%) patients, p=0.38, respectively. The reduction of symptomatic VTE plus all-cause mortality was consistent across prespecified subgroups (age, gender, body weight, creatinine clearance) in the total treatment period. Compared with enoxaparin regimens, rivaroxaban reduces the composite of symptomatic VTE and all-cause mortality after elective THA or TKA, with a small increase in bleeding, no signs of compromised liver safety and fewer serious adverse events.
Venous thromboembolism is a common complication in patients with malignant disease. One of the environments in which patients can present with symptomatic thromboembolic disease is in the ...postoperative period. Operation in the patient with cancer increases the risk of thromboembolic complications some two to three fold. A variety of methods have been evaluated for the prevention of thromboembolic disease in cancer surgical patients. The most extensively investigated are the pharmacologic methods, including low-dose unfractionated heparin and low molecular weight heparin. These agents are recommended for the prevention of thromboembolic disease during hospital stay. For selected high-risk populations, extended thromboprophylaxis into the postdischarge period is also recommended.
Rivaroxaban (Xarelto) is an oral, direct factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. The aim was to compare the population ...pharmacokinetics (PK) and pharmacodynamics (PD) of twice-daily (bid) and once-daily (od) rivaroxaban in patients undergoing total hip replacement (THR). Blood samples were collected from patients enrolled in two phase IIb, dose-ranging studies undertaken to investigate rivaroxaban for thromboprophylaxis after THR. A sparse sampling technique was used and the samples were pooled for PK and PD analysis, which used non-linear mixed effect modelling. Rivaroxaban PK (samples from 758 patients) were well described by an oral, one-compartment model; age and renal function influenced clearance, and body surface area affected volume of distribution. When comparing the same total daily doses, maximum plasma concentrations of rivaroxaban were higher and minimum plasma concentrations were lower with od dosing, compared with bid dosing; however, the 90% intervals overlapped. The area under the plasma concentration-time curve was 18-30% higher in the od than in the bid study. Prothrombin time in seconds (samples from 1181 patients) correlated with rivaroxaban plasma concentrations in a linear fashion in both studies. In conclusion, the PK and PD of rivaroxaban were predictable when given either bid or od. These findings, along with the suggested efficacy and safety of rivaroxaban in the phase II studies, relative to enoxaparin, supported the selection of a convenient, once-daily 10 mg rivaroxaban dose for investigation in phase III studies.
Randomized controlled trials (RCTs) are considered the gold standard for estimating the effectiveness of a treatment. However, in many instances they are impractical to conduct because of time ...limitations, cost restrictions, or ethical reasons. As a consequence, non-randomized observational studies have an important role in comparative effectiveness and safety research since they can address issues that would not be possible using conventional RCT methodology. Observational studies can be strategically designed to reduce the risk of potential sources of bias by emulating the design principles of an equivalent but ideal randomized trial – the target trial – that would answer the research question of interest.
In this article, we review some of the necessary components of observational studies required for valid causal inference within the framework of target trial emulation, so as to avoid common methodological pitfalls of study design. We discuss the assumptions of consistency, time-zero specification, exchangeability and positivity. To illustrate these concepts in a context where existing knowledge is well-established through clinical trials, we evaluate and compare the treatment effects of vitamin K antagonists (VKA) against no VKA (No VKA) on the treatment of atrial fibrillation from two real-world observational studies, namely the GARFIELD-AF and ORBIT-AF registries. Results are compared with those of published RCTs.
There is limited information on the influence of body mass index (BMI) on clinical outcomes in patients with venous thromboembolism (VTE).
Investigate the influence of BMI on baseline ...characteristics, treatment patterns, and 24-month outcomes in VTE patients.
GARFIELD-VTE is a prospective, non-interventional study of 10 869 patients with objectively confirmed VTE. Patients were grouped according to BMI: <18.5 (underweight; n = 214); 18.5-24.9 (normal; n = 2866); 25.0-29.9 (overweight; n = 3326); ≥30 (obese; n = 3073).
Compared with patients with a normal BMI, obese patients were more frequently Caucasian (77.4% vs. 57.9%), treated in the outpatient setting (30.4% vs. 23.1%), and had previous VTE (17.5% vs. 11.7%). Active cancer was associated with lower BMI (underweight: 30.4%, normal: 13.5%, overweight: 9.4%, obese: 7.0%). At baseline, overweight and obese patients less often received parenteral therapy alone (16.7% and 14.4%) compared with those with an underweight or normal BMI (30.8% and 21.6%). Obese patients more commonly remained on anticoagulants for ≥2-years compared to those with a normal BMI (52.3% vs. 37.7%). After 24-months, the risk of all-cause mortality was lower in overweight and obese patients than in those with normal BMI (adjusted hazard ratio 95% CI; 0.75 0.63-0.89 and 0.59 0.49-0.72, respectively). Underweight patients more often experienced major bleeding (2.45 1.41-4.26) and all-cause mortality (1.90 1.43-2.53) than patients with a normal BMI. Recurrent VTE was comparable among groups.
Underweight VTE patients have the highest risk of mortality and major bleeding. The risk of mortality in obese VTE patients is lower than that in VTE patients with a normal BMI.
Asymptomatic atrial fibrillation is often detected incidentally. Prognosis and optimal therapy for asymptomatic compared with symptomatic atrial fibrillation is uncertain. This study compares ...clinical characteristics, treatment, and 2-year outcomes of asymptomatic and symptomatic atrial fibrillation presentations.
Global Anticoagulant Registry in the Field-Atrial Fibrillation (GARFIELD-AF) is a global, prospective, observational study of newly diagnosed atrial fibrillation with ≥1 stroke risk factors (http://www.clinicaltrials.gov, unique identifier: NCT01090362). Patients were characterized by atrial fibrillation-related symptoms at presentation and the CHA2DS2-VASc score. Two-year follow-up recorded anticoagulation patterns (vitamin K antagonist, direct oral anticoagulants, parenteral therapy) and outcomes (stroke/systemic embolism, all-cause mortality, and bleeding).
At presentation, of 52,032 eligible patients, 25.4% were asymptomatic and 74.6% symptomatic. Asymptomatic patients were slightly older (72 vs 70 years), more often male (64.2% vs 52.9%), and more frequently initiated on anticoagulation ± antiplatelets (69.4% vs 66.0%). No difference in events (adjusted hazard ratios, 95% confidence interval) for nonhemorrhagic stroke/systemic embolism (1.19, 0.97-1.45), all-cause mortality (1.06, 0.94-1.20), or bleeding (1.02, 0.87-1.19) was observed. Anticoagulation was associated with comparable reduction in nonhemorrhagic stroke/systemic embolism (0.59, 0.43–0.82 vs 0.78, 0.65–0.93) and all-cause mortality (0.69, 0.59-0.81 vs 0.77, 0.71-0.85) in asymptomatic versus symptomatic, respectively.
Major outcomes do not differ between asymptomatic and symptomatic atrial fibrillation presentations and are comparably reduced by anticoagulation. Opportunistic screening-detected asymptomatic atrial fibrillation likely has the same prognosis as asymptomatic atrial fibrillation at presentation and likely responds similarly to anticoagulation thromboprophylaxis.
In experimental systems, interference with coagulation can affect tumor biology. Furthermore, it has been suggested that low molecular weight heparin therapy may prolong survival in patients with ...cancer. The primary aim of this study was to assess survival at 1 year of patients with advanced cancer.
Patients with advanced malignancy (N = 385) were randomly assigned to receive either a once-daily subcutaneous injection of dalteparin (5,000 IU), a low molecular weight heparin, or placebo for 1 year.
The Kaplan-Meier survival estimates at 1, 2, and 3 years after randomization for patients receiving dalteparin were 46%, 27%, and 21%, respectively, compared with 41%, 18%, and 12%, respectively, for patients receiving placebo (P =.19). In an analysis not specified a priori, survival was examined in a subgroup of patients (dalteparin, n = 55; and placebo, n = 47) who had a better prognosis and who were alive 17 months after randomization. In these patients, Kaplan-Meier survival estimates at 2 and 3 years from randomization were significantly improved for patients receiving dalteparin versus placebo (78% v 55% and 60% v 36%, respectively, P =.03). The rates of symptomatic venous thromboembolism were 2.4% and 3.3% for dalteparin and placebo, respectively, with bleeding rates of 4.7% and 2.7%, respectively.
Dalteparin administration did not significantly improve 1-year survival rates in patients with advanced malignancy. However, the observed improved survival in a subgroup of patients with a better prognosis suggests a potential modifying effect of dalteparin on tumor biology.
Experimental studies and indirect clinical evidence suggest that low molecular weight heparins may have antineoplastic effects. We investigated the influence of a low molecular weight heparin ...dalteparin on the survival of patients with active cancer and acute venous thromboembolism.
Survival data were examined in a posthoc analysis in patients with solid tumors and venous thromboembolism who were randomly assigned to dalteparin or a coumarin derivative for 6 months in a multicenter, open-label, randomized, controlled trial. All-cause mortality at 12 months was compared between treatment groups in patients with and without metastatic malignancy. The effect of dalteparin on survival was compared between the two patient subgroups.
During the 12-month follow-up period, 356 of 602 patients with solid tumors and acute venous thromboembolism died. Among patients without metastatic disease, the probability of death at 12 months was 20% in the dalteparin group, as compared with 36% in the oral anticoagulant group (hazard ratio, 0.50; 95% CI, 0.27 to 0.95; P = .03). In patients with metastatic cancer, no difference in mortality between the treatment groups was observed (72% and 69%, respectively; hazard ratio, 1.1; 95% CI, 0.87 to 1.4; P = .46). The observed effects of dalteparin on survival were statistically significantly different between patients with and without metastatic disease (P = .02).
The use of dalteparin relative to coumarin derivatives was associated with improved survival in patients with solid tumors who did not have metastatic disease at the time of an acute venous thromboembolic event. Additional studies are warranted to investigate these findings.
Background Atrial fibrillation (AF) is associated with high rates of morbidity and mortality. Patients with AF carry a fivefold increased risk of stroke and the risk of death from AF-related stroke ...is doubled. Current management is often inadequate, leaving patients at risk for a potentially fatal or disabling event. The purpose of the GARFIELD registry is to evaluate the management and outcomes of patients with newly diagnosed non-valvular AF at risk for stroke. Design The GARFIELD registry is an observational, multicenter, prospective study of patients with newly diagnosed AF and one or more additional risk factors for stroke. The aim is to enroll 55,000 patients at >1,000 centers in 50 countries. Enrollment will take place in five independent, sequential, prospective cohorts. An additional retrospective validation cohort of 5,000 patients with established AF and at least one additional risk factor for stroke will be conducted in parallel with cohort one. The study started in December 2009, with a planned recruitment period of 4 years and a minimum of 2-year follow-up for each patient. Summary The GARFIELD registry will provide valuable insights into the clinical management and related outcomes of AF patients throughout many regions of the world and across the spectrum of healthcare systems. By capturing data from unselected patients treated in everyday practice, the registry has the potential to identify best practices as well as deficiencies in available treatment options for specific patient populations and to describe how therapeutic strategies, patient care, and outcomes will evolve over time.
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