Showing papers by "Marc Carrier published in 2019"

Apixaban to Prevent Venous Thromboembolism in Patients with Cancer

Abstract: Background Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis. Methods We conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main safety outcome was a major bleeding episode. Results Of the 574 patients who underwent randomization, 563 were included in t...

Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant

Abstract: Importance Patients with atrial fibrillation (AF) who use a direct oral anticoagulant (DOAC) and request elective surgery or procedure present a common clinical situation yet perioperative management is uncertain. Objective To investigate the safety of a standardized perioperative DOAC management strategy. Design, Setting, and Participants The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study conducted at 23 clinical centers in Canada, the United States, and Europe enrolled and screened patients from August 1, 2014, through July 31, 2018. Participants (n = 3007) had AF; were 18 years of age or older; were long-term users of apixaban, dabigatran etexilate, or rivaroxaban; were scheduled for an elective surgery or procedure; and could adhere to the DOAC therapy interruption protocol. Interventions A simple standardized perioperative DOAC therapy interruption and resumption strategy based on DOAC pharmacokinetic properties, procedure-associated bleeding risk, and creatinine clearance levels. The DOAC regimens were omitted for 1 day before a low–bleeding-risk procedure and 2 days before a high–bleeding-risk procedure. The DOAC regimens were resumed 1 day after a low–bleeding-risk procedure and 2 to 3 days after a high–bleeding-risk procedure. Follow-up of patients occurred for 30 days after the operation. Main Outcomes and Measures Major bleeding and arterial thromboembolism (ischemic stroke, systemic embolism, and transient ischemic attack) and the proportion of patients with an undetectable or minimal residual anticoagulant level ( Results The 3007 patients with AF (mean [SD] age of 72.5 [9.39] years; 1988 men [66.1%]) comprised 1257 (41.8%) in the apixaban cohort, 668 (22.2%) in the dabigatran cohort, and 1082 (36.0%) in the rivaroxaban cohort; 1007 patients (33.5%) had a high–bleeding-risk procedure. The 30-day postoperative rate of major bleeding was 1.35% (95% CI, 0%-2.00%) in the apixaban cohort, 0.90% (95% CI, 0%-1.73%) in the dabigatran cohort, and 1.85% (95% CI, 0%-2.65%) in the rivaroxaban cohort. The rate of arterial thromboembolism was 0.16% (95% CI, 0%-0.48%) in the apixaban cohort, 0.60% (95% CI, 0%-1.33%) in the dabigatran cohort, and 0.37% (95% CI, 0%-0.82%) in the rivaroxaban cohort. In patients with a high–bleeding-risk procedure, the rates of major bleeding were 2.96% (95% CI, 0%-4.68%) in the apixaban cohort and 2.95% (95% CI, 0%-4.76%) in the rivaroxaban cohort. Conclusions and Relevance In this study, patients with AF who had DOAC therapy interruption for elective surgery or procedure, a perioperative management strategy without heparin bridging or coagulation function testing was associated with low rates of major bleeding and arterial thromboembolism.

Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis

Abstract: Objectives To determine the rate of a first recurrent venous thromboembolism (VTE) event after discontinuation of anticoagulant treatment in patients with a first episode of unprovoked VTE, and the cumulative incidence for recurrent VTE up to 10 years. Design Systematic review and meta-analysis. Data sources Medline, Embase, and the Cochrane Central Register of Controlled Trials (from inception to 15 March 2019). Study selection Randomised controlled trials and prospective cohort studies reporting symptomatic recurrent VTE after discontinuation of anticoagulant treatment in patients with a first unprovoked VTE event who had completed at least three months of treatment. Data extraction and synthesis Two investigators independently screened studies, extracted data, and appraised risk of bias. Data clarifications were sought from authors of eligible studies. Recurrent VTE events and person years of follow-up after discontinuation of anticoagulant treatment were used to calculate rates for individual studies, and data were pooled using random effects meta-analysis. Sex and site of initial VTE were investigated as potential sources of between study heterogeneity. Results 18 studies involving 7515 patients were included in the analysis. The pooled rate of recurrent VTE per 100 person years after discontinuation of anticoagulant treatment was 10.3 events (95% confidence interval 8.6 to 12.1) in the first year, 6.3 (5.1 to 7.7) in the second year, 3.8 events/year (95% confidence interval 3.2 to 4.5) in years 3-5, and 3.1 events/year (1.7 to 4.9) in years 6-10. The cumulative incidence for recurrent VTE was 16% (95% confidence interval 13% to 19%) at 2 years, 25% (21% to 29%) at 5 years, and 36% (28% to 45%) at 10 years. The pooled rate of recurrent VTE per 100 person years in the first year was 11.9 events (9.6 to 14.4) for men and 8.9 events (6.8 to 11.3) for women, with a cumulative incidence for recurrent VTE of 41% (28% to 56%) and 29% (20% to 38%), respectively, at 10 years. Compared to patients with isolated pulmonary embolism, the rate of recurrent VTE was higher in patients with proximal deep vein thrombosis (rate ratio 1.4, 95% confidence interval 1.1 to 1.7) and in patients with pulmonary embolism plus deep vein thrombosis (1.5, 1.1 to 1.9). In patients with distal deep vein thrombosis, the pooled rate of recurrent VTE per 100 person years was 1.9 events (95% confidence interval 0.5 to 4.3) in the first year after anticoagulation had stopped. The case fatality rate for recurrent VTE was 4% (95% confidence interval 2% to 6%). Conclusions In patients with a first episode of unprovoked VTE who completed at least three months of anticoagulant treatment, the risk of recurrent VTE was 10% in the first year after treatment, 16% at two years, 25% at five years, and 36% at 10 years, with 4% of recurrent VTE events resulting in death. These estimates should inform clinical practice guidelines, enhance confidence in counselling patients of their prognosis, and help guide decision making about long term management of unprovoked VTE. Systematic review registration PROSPERO CRD42017056309.

Extended thromboprophylaxis with low-molecular weight heparin (LMWH) following abdominopelvic cancer surgery.

Abstract: Background Venous thromboembolism (VTE) includes deep vein thrombosis (DVT) and pulmonary embolism (PE). Certain abdominopelvic cancer surgeries are associated with a six to 14-fold increased risk of DVT versus surgeries for benign disease, and extended thromboprophylaxis using perioperative LMWHs may further reduce VTE rates over standard duration administration. This review assesses the value of extended low molecular weight heparin (LMWH) thromboprophylaxis as a recommended strategy after abdominopelvic cancer surgery. Data sources Six eligible randomized controlled trials (RCTs), seven meta-analyses (MAs), and five non-randomized cohort studies were identified evaluating extended versus standard thromboprophylaxis following abdominopelvic cancer surgery. Findings and conclusions Available evidence showed significantly reduced rates of VTE for extended versus standard LMWH thromboprophylaxis following abdominopelvic cancer surgery, with some studies showing trends toward reduced rates of symptomatic VTE events. Many of these studies showed significantly reduced rates of proximal DVT and some showed trends toward reduced PE, suggesting potentially important clinical benefits.

Extended treatment of venous thromboembolism: a systematic review and network meta-analysis.

Abstract: Objective To evaluate efficacy and safety of oral anticoagulant regimens and aspirin for extended venous thromboembolism (VTE) treatment. Methods We searched MEDLINE, Embase, CENTRAL and conference proceedings for randomised controlled trials studying vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) or aspirin for secondary prevention of VTE beyond 3 months. ORs (95% credible intervals) between treatments were estimated using random-effects Bayesian network meta-analysis. Results Sixteen studies, totaling more than 22 000 patients, were included. Compared with placebo or observation and with aspirin, respectively, the risk of recurrent VTE was lower with standard-intensity VKAs (0.15 (0.08 to 0.24) and 0.23 (0.09 to 0.54)), low-dose factor Xa inhibitors (0.16 (0.06 to 0.38) and 0.25 (0.09 to 0.66)), standard-dose factor Xa inhibitors (0.17 (0.08 to 0.33) and 0.27 (0.11 to 0.65)) and the direct thrombin inhibitor (0.15 (0.04 to 0.37) and 0.23 (0.06 to 0.74)) although the risk of major bleeding was higher with standard-intensity VKAs (4.42 (1.99 to 12.24) and 4.14 (1.17 to 18.86)). Effect estimates were consistent in male patients and those with index pulmonary embolism or with unprovoked VTE and in sensitivity analyses. In addition, compared with placebo or observation, the risk of all-cause mortality was reduced with standard-intensity VKAs (0.44 (0.20 to 0.87)) and low-dose factor Xa inhibitors (0.38 (0.12 to 0.995)). Conclusions Standard-intensity VKAs and DOACs are more efficacious than aspirin for extended VTE treatment. Despite a higher risk of major bleeding, standard-intensity VKAs was associated with a lower risk of all-cause mortality. Since overall efficacy and safety of standard-intensity VKAs and DOACs are in equipoise, patient factors, costs and patient preferences should be considered when recommending extending anticoagulation treatment.

Treatment of Superficial Vein Thrombosis: A Systematic Review and Meta-Analysis

Abstract: Background The optimal first line treatment for patients with isolated superficial venous thrombosis (SVT) of the lower extremity is unknown. Objective This article reports estimates of the rate of venous thromboembolic complications among patients with SVT according to treatment. Materials and Methods A systematic review and meta-analysis was performed using unrestricted searches of electronic databases. Reported events were transformed to event per 100 patient-years of follow-up and a random effects model was used to calculate pooled rates according to pre-specified treatment categories. The primary outcome was the occurrence of deep vein thrombosis (DVT) or pulmonary embolism (PE) during the study follow-up period. Results Seventeen articles, including 6,862 patients, were included in the meta-analysis. Fondaparinux had the lowest event rate with 1.4 events per 100 patient-years of follow-up (95% confidence interval [CI], 0.5–2.8, I 2 = 18%). Pooled event rates for DVT or PE ranged from 9.3 to 16.6 events per 100 patient-years across other treatment categories, and the pooled event rate for no treatment/placebo was 10.5 events per 100 patient-years (95% CI, 3.0–22.0). Major bleeding was low and similar across all treatment categories. Heterogeneity was moderate to high for most pooled estimates. Conclusion While pooled event rates suggest that fondaparinux achieves the lowest rate of DVT or PE, low-quality evidence for other treatments prevents firm conclusions about the optimal treatment for SVT.

Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH

Abstract: A. A . KHORANA,* S . NOBLE ,† A. Y . Y . LEE ,‡ G. SOFF ,§ G. MEYER , ¶ C. O’CONNELL** and M. CARR IER†† *Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; †Marie Curie Palliative Care Research Centre, Cardiff University, Cardiff, UK; ‡Department of Medicine, University of British Columbia, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; §Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; ¶Department of Respiratory Disease, Hopital Europeen Georges Pompidou, AP-HP, INSERM CIC1418 and Universit e Paris Descartes, Sorbonne Paris Cit e, Paris, France; **Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA; and ††Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, Ontario, Canada

Low-molecular-weight-heparin versus a coumarin for the prevention of recurrent venous thromboembolism in high- and low-risk patients with active cancer: a post hoc analysis of the CLOT Study

Abstract: In patients with active cancer and acute venous thromboembolism (VTE), the low-molecular-weight-heparin (LMWH) dalteparin is more effective than vitamin K antagonist (VKA) in reducing the risk of recurrent venous thromboembolism (rVTE) without increasing the risk of bleeding. However, the relative benefit of LMWH versus VKA in patients with active cancer at high or low risk of rVTE and bleeding is unclear. This post hoc analysis used data from the CLOT study to explore the efficacy and safety of LMWH versus VKA in preventing recurrent thrombosis in high- and low-risk patients with active cancer. High-risk patients were defined by metastatic disease and/or antineoplastic treatment at baseline; low-risk patients presented with neither. Among high-risk patients, rVTE occurred in 25/318 (8%) (LMWH) versus 53/314 (17%) (VKA) (hazard ratio, 0.44; p = 0.001). No significant difference was detected in the rate of major or any bleeding. The 6-month mortality rate was 40% (LMWH) versus 41% (VKA). In low-risk patients, 2/20 (10%) (LMWH) had rVTE versus 0/24 (0%) (VKA) (hazard ratio, not estimable; p = 0.998). No significant difference was detected in the rate of major or any bleeding. The 6-month mortality rate was 20% (LMWH) versus 29% (VKA). In patients with cancer-associated thrombosis at high risk of rVTE and bleeding, the LMWH dalteparin was more effective than VKA in reducing the risk of rVTE without increasing the risk of bleeding. No difference in rate of rVTE or bleeding was observed between LMWH and VKA among low-risk patients.

Anticoagulation for Subsegmental Pulmonary Embolism

Abstract: Anticoagulation for Subsegmental Pulmonary Embolism? This interactive feature about a patient with a single subsegmental pulmonary embolus offers a case vignette accompanied by essays that either s...

Treatment of Venous Thromboembolism in Cancer. Historical Perspective and Evolving Role of the Direct Oral Anticoagulants.

Abstract: The management of cancer-associated thrombosis (CAT) is complex, and treatment strategies have been evolving over the past 15 years. It is well recognized that oral vitamin K antagonists are difficult to use in cancer patients, with higher rates of treatment failure and bleeding complications than in non-cancer patients. Low-molecular-weight-heparin (LMWH) became the widely accepted standard of care for treatment of cancer-associated thrombosis, following the CLOT study comparing dalteparin with warfarin in 2003. LMWH remains widely used for the treatment of CAT. However, in the past two years, several studies have served to validate direct oral anticoagulants as a safe and effective alternative to LMWH. Two randomized clinical trials comparing edoxaban and rivaroxaban with dalteparin, and several retrospective studies have shown the efficacy of edoxaban and rivaroxaban for the treatment of CAT. However, there is an evidence of increased bleeding with the DOACs, particularly gastrointestinal or urinary tract bleeding in patients with lesions within the gastrointestinal or urinary tracts. This chapter discusses the ongoing development of optimal treatment strategies for cancer-associated thrombosis.

What's new in the prevention and treatment of cancer-associated thrombosis?

Abstract: Venous thromboembolism (VTE) is a common complication in ambulatory cancer patients receiving chemotherapy. Current clinical guidelines recommend against the use of routine primary thromboprophylaxis in unselected ambulatory cancer patients. The Khorana score is a risk assessment tool derived and prospectively validated for the identification of cancer patients at high risk of thrombotic complications. Recently, 2 randomized, controlled trials have assessed the use of low-dose direct oral Xa inhibitors, apixaban and rivaroxaban, for the prevention of cancer-associated thrombosis in ambulatory patients at intermediate to high risk of VTE (Khorana score ≥2). Taken together, these trials have shown that low-dose direct oral Xa inhibitors reduce the risk of VTE in this patient population without a significant increase in major bleeding. These results should encourage clinicians to consider the use of primary thromboprophylaxis in ambulatory cancer patients at intermediate to high risk of VTE who do not have any apparent risk factors for bleeding. The direct oral Xa inhibitors have also been assessed in the acute management of cancer-associated thrombosis. Current evidence suggests that these drugs are a convenient, effective, and safe option for the management of acute VTE in many cancer patients. Low-molecular weight heparin, however, may continue to be the treatment of choice depending on the presence of bleeding risk factors, the type of cancer, drug-drug interactions, and patient preferences.

Efficacy and safety of Xa inhibitors for the treatment of cancer-associated venous thromboembolism

Abstract: Introduction: Cancer patients with cancer-associated thrombosis (CAT) are at an elevated risk of recurrent venous thromboembolism (VTE) and of major bleeding while receiving treatment with anticoagulation. Recently, Xa inhibitors have been assessed in cancer patients for the treatment of CAT, providing clinicians and patients with more treatment options.Areas covered: In this narrative review, the authors evaluate the evidence regarding the efficacy and safety of edoxaban, rivaroxaban, and apixaban in the treatment of CAT.Expert opinion: Xa inhibitors are an effective, safe, and convenient option for the treatment of CAT. Overall, they may be associated with a lower risk of recurrent VTE in cancer patients. Certain subgroups of cancer patients may be at increased risk of major bleeding while on treatment with Xa inhibitors, when compared to low-molecular-weight-heparin (LMWH). The current published data suggests an increase in gastrointestinal (GI) major bleeding in patients with GI malignancies. ...

Mitplan: A planning approach to mitigating concurrently applied clinical practice guidelines

Abstract: As the overall population ages, patient complexity and the scope of their care is increasing. Over 60% of the population over 65 years of age suffers from multi-morbidity, which is associated with over two times as many patient-physician encounters. Yet clinical practice guidelines (CPGs) are developed to treat a single disease. To reconcile these two competing issues, we developed a framework for identifying and addressing adverse interactions in multi-morbid patients managed according to multiple CPGs. The framework relies on first-order logic (FOL) to represent CPGs and secondary medical knowledge and FOL theorem proving to establish valid patient management scenarios. In this work, we leverage the framework’s representation capabilities to simplify its mitigation process and cast it as a planning problem represented using the Planning Domain Definition Language (PDDL). We demonstrate the framework’s ability to identify and mitigate adverse interactions using planning actions, add support for durative clinical actions, and show the improved interpretability of management plan recommendations in the context of both proof-of-concept and clinical examples.