[Show abstract][Hide abstract] ABSTRACT: The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of venous thromboembolism (VTE) in adult patients with a diagnosis of cancer or for whom cancer is clinically suspected. VTE is a common complication in patients with cancer, which places them at greater risk for morbidity and mortality. Therefore, risk-appropriate prophylaxis is an essential component for the optimal care of inpatients and outpatients with cancer. Critical to meeting this goal is ensuring that patients get the most effective medication in the correct dose. Body weight has a significant impact on blood volume and drug clearance. Because obesity is a common health problem in industrialized societies, cancer care providers are increasingly likely to treat obese patients in their practice. Obesity is a risk factor common to VTE and many cancers, and may also impact the anticoagulant dose needed for safe and effective prophylaxis. These NCCN Guidelines Insights summarize the data supporting new dosing recommendations for VTE prophylaxis in obese patients with cancer.
Journal of the National Comprehensive Cancer Network: JNCCN 09/2015; 13(9):1079-95. · 4.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
It is uncertain whether bridging anticoagulation is necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective operation or other elective invasive procedure. We hypothesized that forgoing bridging anticoagulation would be noninferior to bridging with low-molecular-weight heparin for the prevention of perioperative arterial thromboembolism and would be superior to bridging with respect to major bleeding.
We performed a randomized, double-blind, placebo-controlled trial in which, after perioperative interruption of warfarin therapy, patients were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin (100 IU of dalteparin per kilogram of body weight) or matching placebo administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after the procedure. Warfarin treatment was stopped 5 days before the procedure and was resumed within 24 hours after the procedure. Follow-up of patients continued for 30 days after the procedure. The primary outcomes were arterial thromboembolism (stroke, systemic embolism, or transient ischemic attack) and major bleeding.
In total, 1884 patients were enrolled, with 950 assigned to receive no bridging therapy and 934 assigned to receive bridging therapy. The incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (risk difference, 0.1 percentage points; 95% confidence interval [CI], -0.6 to 0.8; P=0.01 for noninferiority). The incidence of major bleeding was 1.3% in the no-bridging group and 3.2% in the bridging group (relative risk, 0.41; 95% CI, 0.20 to 0.78; P=0.005 for superiority).
In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism and decreased the risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health; BRIDGE ClinicalTrials.gov number, NCT00786474.).
New England Journal of Medicine 06/2015; 373(9). DOI:10.1056/NEJMoa1501035 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recommendations for management of cancer-related venous thromboembolism (VTE) in patients already receiving anticoagulant therapy are based on low quality evidence. This international registry sought to provide more information on outcomes after a breakthrough VTE in relation to anticoagulation strategies.
Patients with cancer and VTE despite anticoagulant therapy were reported to the registry. Data on treatments, VTE events, major bleeding, residual thrombosis symptoms and death were collected for the following 3 months. Breakthrough VTE and subsequent recurrences were objectively verified. Outcomes with different treatment strategies were compared with Cox proportional hazards regression.
We registered 212 patients with breakthrough VTE. Of those, 59% had adenocarcinoma and 73% had known metastases. At the time of the breakthrough event 70% were on low-molecular-weight heparin (LMWH), 27% on a vitamin K antagonist (VKA); 70% had a therapeutic or supratherapeutic dose. After breakthrough the regimen was unchanged therapeutic in 33%, dose increased in 31%, switched to another drug in 24% and other management in 11%. During the 3 following months 11% had another VTE, 8% had major bleeding and 27% died. Of the survivors, 74% had residual thrombosis symptoms. Additional VTE recurrence was less common with LMWH than with VKA (hazard ratio [HR] 0.28; 95% confidence interval [CI], 0.11-0.70) but similar with unchanged or increased anticoagulant intensity (HR 1.09; 95% CI, 0.45-2.63). Bleeding rate did not increase significantly with dose escalation.
Morbidity and mortality is high after cancer-related VTE recurrence despite anticoagulation. Further treatment appears more effective with LMWH than with VKA. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 04/2015; 13(6). DOI:10.1111/jth.12955 · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Venous thromboembolism (VTE) treatment in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low molecular weight heparin (LMWH) for at least 3-6 months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting LMWH treatment beyond 6 months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12 months in cancer-associated VTE.Methods
Patients with active cancer and newly diagnosed VTE were enrolled in a prospective, multicenter study and received subcutaneous dalteparin for 12 months. The rates of bleeding and recurrent VTE were evaluated at months 1, 2-6, and 7-12.FindingsOf 334 patients enrolled, 185 and 109 completed 6 and 12 months of therapy. 49.1% had deep vein thrombosis (DVT); 38.9% had pulmonary embolism (PE); and 12.0% had both on presentation. The overall frequency of major bleeding was 10.2% (34/334). Major bleeding occurred in 3.6% (12/334) in the first month, and 1.1% (14/1237) and 0.7% (8/1086) per patient-month during months 2-6 and 7-12, respectively. Recurrent VTE occurred in 11.1% (37/334); the incidence rate was 5.7% (19/334) for month 1, 3.4% (10/296) during months 2-6, and 4.1% (8/194) during months 7-12. 116 patients died, four due to recurrent VTE and two due to bleeding.InterpretationMajor bleeding was less frequent during dalteparin therapy beyond 6 months. The risk of developing major bleeding complications or VTE recurrence was greatest in the first month of therapy and lower over the subsequent 11 months.This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 03/2015; 13(6). DOI:10.1111/jth.12923 · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The target-specific oral anticoagulants are a class of agents that inhibit factor Xa or thrombin. They are effective and safe compared to warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation and for the treatment of venous thromboembolism, and they are comparable to low-molecular-weight heparin for thromboprophylaxis after hip or knee arthroplasty. For other indications, however, such as the prevention of stroke in patients with mechanical heart valves, initial studies have been unfavorable for the newer agents, leaving warfarin the anticoagulant of choice. Further studies are needed before the target-specific anticoagulants can be recommended for patients with cancer-associated thrombosis or heparin-induced thrombocytopenia. Concerns also persist about difficulties with the laboratory assessment of anticoagulant effect and the lack of a specific reversal agent. For these reasons, we anticipate that the vitamin K antagonists will continue to be important anticoagulants for years to come.
Annual Review of Medicine 01/2015; 66(1):241-53. DOI:10.1146/annurev-med-051113-024633 · 12.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The postthrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT).Objective
In the BioSox study we investigated whether inflammation markers predict the risk of PTS after DVT.Methods
We measured C-reactive protein (CRP), intercellular adhesion molecule (ICAM)-1, interleukin (IL)-6 and IL-10, at baseline, 1 and 6 months after a first proximal DVT among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS.ResultsMedian CRP levels at 1 month, ICAM-1 at baseline, 1 and 6 months, IL-6 at 1 and 6 months, and IL-10 at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression using the median as a cutoff showed relative risks (RR) for PTS of 1.23 (95% confidence interval 1.05 – 1.45), and 1.25 (1.05 – 1.48) for ICAM-1 at 1 and 6 months, respectively; and 1.27 (1.07 – 1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose-response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest trajectory group of ICAM-1 and PTS.Conclusions
In this prospective study ICAM-1 over time was most consistently associated with risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance.This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 12/2014; 13(3). DOI:10.1111/jth.12814 · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
This study assessed the risk of venous thromboembolism (VTE) among privately insured adults in the U.S. with one or more of the following autoimmune diseases: autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE).
Materials and methods:
Using the Truven Health MarketScan® Databases, patients 18-64 years of age with a diagnosis of AIHA, ITP, RA, or SLE in 2007 and a sex and age-group matched comparison group of enrollees were followed up through 2010 to identify VTE events. Survival curve and Cox proportional hazards analyses were conducted to assess differences between groups.
Among patients with AIHA, ITP, RA, or SLE, or >1 of these diseases, the risk of at least one VTE event was 19.74, 7.72, 4.90, 9.89, and 13.35 per 1,000 person-years, respectively; among the comparison group, the risk was 1.91 per 1,000 person-years. The adjusted hazard ratios (aHRs) for VTE among patients with AIHA, ITP, RA, or SLE, or >1 of these diseases (when compared with the comparison group) tended to decline over follow-up time; at 1year, the aHRs were 6.30 (95% confidence interval [CI]: 4.44-8.94), 2.95 (95% CI: 2.18-4.00), 2.13 (95% CI: 1.89-2.40), 4.68 (95% CI: 4.10-5.33), and 5.11 (95% CI: 4.26-6.14), respectively.
Having AIHA, ITP, RA, or SLE, or >1 of these diseases was associated with an increased likelihood of a VTE event. More research is necessary to develop better understanding of VTE occurrence among people with autoimmune diseases.
Thrombosis Research 10/2014; 135(1). DOI:10.1016/j.thromres.2014.10.012 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Although emotional stress is associated with ischemic heart disease (IHD) and related clinical events, sex-specific differences in the psychobiological response to mental stress have not been clearly identified.
We aimed to study the differential psychological and cardiovascular responses to mental stress between male and female patients with stable IHD.
Patients with stable IHD enrolled in the REMIT (Responses of Mental Stress–Induced Myocardial Ischemia to Escitalopram) study underwent psychometric assessments, transthoracic echocardiography, and platelet aggregation studies at baseline and after 3 mental stress tasks. Mental stress–induced myocardial ischemia (MSIMI) was defined as the development or worsening of regional wall motion abnormality, reduction of left ventricular ejection fraction (LVEF) ≥8% by transthoracic echocardiography, and/or ischemic ST-segment change on electrocardiogram during 1 or more of the 3 mental stress tasks.
In the 310 participants with known IHD (18% women, 82% men), most baseline characteristics were similar between women and men (including heart rate, blood pressure, and LVEF), although women were more likely to be nonwhite, living alone (p < 0.001), and unmarried (p < 0.001); they also had higher baseline depression and anxiety (p < 0.05). At rest, women had heightened platelet aggregation responses to serotonin (p = 0.007) and epinephrine (p = 0.004) compared with men. Following mental stress, women had more MSIMI (57% vs. 41%; p < 0.04), expressed more negative (p = 0.02) and less positive emotion (p < 0.001), and demonstrated higher collagen-stimulated platelet aggregation responses (p = 0.04) than men. Men were more likely than women to show changes in traditional physiological measures, such as blood pressure (p < 0.05) and double product.
In this exploratory analysis, we identified clear, measurable, and differential responses to mental stress in women and men. Further studies should test the association of sex differences in cardiovascular and platelet reactivity in response to mental stress and long-term outcomes. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847)
Journal of the American College of Cardiology 10/2014; 64(16):1669–1678. DOI:10.1016/j.jacc.2014.04.087 · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute deep venous thrombosis (DVT) causes leg pain. Elastic compression stockings (ECS) have potential to relieve DVT-related leg pain by diminishing the diameter of distended veins and increasing venous blood flow. It was our objective to determine whether ECS reduce leg pain in patients with acute DVT. We performed a secondary analysis of the SOX Trial, a multicentrerandomised placebo controlled trial of active ECS versus placebo ECS to prevent the post-thrombotic syndrome.The study was performed in24 hospital centres in Canada and the U.S. and included 803 patients with a first episode of acute proximal DVT. We performed active ECS (knee length, 30-40 mm Hg graduated pressure) or placebo ECS (manufactured to look identical to active ECS, but lacking therapeutic compression). Study outcome was leg pain severity assessed on an 11-point numerical pain rating scale (0, no pain; 10, worst possible pain) at baseline, 14, 30 and 60 days after randomisation. Mean age was 55 years and 60% were male. In active ECS patients (n=409), mean (SD) pain severity at baseline and at 60 days were 5.18 (3.29) and 1.39 (2.19), respectively, and in placebo ECS patients (n=394) were 5.38 (3.29) and 1.13 (1.86), respectively. There were no significant differences in pain scores between groups at any assessment point, and no evidence for subgroup interaction by age, sex or anatomical extent of DVT. Results were similar in an analysis restricted to patients who reported wearing stockings every day. In conclusion, ECS do not reduce leg pain in patients with acute proximal DVT.
Thrombosis and Haemostasis 08/2014; 112(6). DOI:10.1160/TH14-05-0430 · 4.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While aspirin is generally effective for prevention of cardiovascular disease, considerable variation in drug response exists, resulting in some individuals displaying high on-treatment platelet reactivity. We used pharmacometabolomics to define pathways implicated in variation of response to treatment. We profiled serum samples from healthy subjects pre- and postaspirin (14 days, 81 mg/day) using mass spectrometry. We established a strong signature of aspirin exposure independent of response (15/34 metabolites changed). In our discovery (N = 80) and replication (N = 125) cohorts, higher serotonin levels pre- and postaspirin correlated with high, postaspirin, collagen-induced platelet aggregation. In a third cohort, platelets from subjects with the highest levels of serotonin preaspirin retained higher reactivity after incubation with aspirin than platelets from subjects with the lowest serotonin levels preaspirin (72 ± 8 vs. 61 ± 11%, P = 0.02, N = 20). Finally, ex vivo, serotonin strongly increased platelet reactivity after platelet incubation with aspirin (+20%, P = 4.9 × 10(-4), N = 12). These results suggest that serotonin is implicated in aspirin response variability.
CPT: Pharmacometrics and Systems Pharmacology 07/2014; 3(7):e125. DOI:10.1038/psp.2014.22
[Show abstract][Hide abstract] ABSTRACT: Current classification criteria for definite Antiphospholipid Syndrome (APS) require the use of three laboratory assays to detect antiphospholipid antibodies (aCL, anti-β2GPI and LA) in the presence of at least one of the two major clinical manifestations (i.e. thrombosis or pregnancy morbidity) of the syndrome. However, several other autoantibodies shown to be directed to other proteins or their complex with phospholipids have been proposed to be relevant to APS but their clinical utility and their diagnostic value remains elusive. This report summarises the findings, conclusions and recommendations of the "APS Task Force 3 - Laboratory Diagnostics and Trends" meeting that took place during the 14th International Congress on Antiphospholipid Antibodies (APLA 2013, September 18-21, Rio de Janeiro, RJ, Brazil).
[Show abstract][Hide abstract] ABSTRACT: According to classification criteria for antiphospholipid syndrome (APS), laboratory diagnosis is based on the detection of antiphospholipid antibodies (aPL) by immunological assays with cardiolipin (aCL) and/or β2 glycoprotein I (aβ2 GPI) as antigen and/or lupus anticoagulants (LA). There is a large variety of assays assessing aPL and despite consensus guidelines, some issues remain unanswered. Factors that contribute to result variability include pre-, post- and analytical conditions, calibration, and assay-specific issues. Recommendations published in 2009 by this Subcommittee for the detection of LA have proven useful in standardization of this assay. Likewise, recommendations for detection of aCL and aβ2 GPI antibodies by immunoassays are needed. This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 03/2014; 36. DOI:10.1111/jth.12537 · 5.72 Impact Factor