[Show abstract][Hide abstract] ABSTRACT: Coronary calcification in patients with end-stage renal disease (ESRD) is associated with an increased risk of cardiovascular outcomes and death from all causes. Previous evidence has been limited by short follow-up periods and inclusion of a heterogeneous cluster of events in the primary analyses.
To describe coronary calcification in patients incident to ESRD, and to identify whether calcification predicts vascular events or death.
Prospective substudy of an inception cohort.
Tertiary care haemodialysis centre in Ontario (St Joseph's Healthcare Hamilton).
Patients starting haemodialysis who were new to ESRD.
At baseline, clinical characterization and spiral computed tomography (CT) to score coronary calcification by the Agatston-Janowitz 130 scoring method. A primary outcome composite of adjudicated stroke, myocardial infarction, or death.
We followed patients prospectively to identify the relationship between cardiac calcification and subsequent stroke, myocardial infarction, or death, using Cox regression.
We recruited 248 patients in 3 centres to our main study, which required only biochemical markers. Of these 164 were at St Joseph's healthcare, and eligible to participate in the substudy; of these, 51 completed CT scanning (31 %). Median follow up was 26 months (Q1, Q3: 14, 34). The primary outcome occurred in 16 patients; 11 in the group above the median and 5 in the group below (p = 0.086). There were 26 primary outcomes in 16 patients; 20 (77 %) events in the group above the coronary calcification median and 6 (23 %) in the group below (p = 0.006). There were 10 deaths; 8 in the group above the median compared with 2 in the group below (p = 0.04). The hazard ratios for coronary calcification above, compared with below the median, for the primary outcome composite were 2.5 (95 % CI 0.87, 7.3; p = 0.09) and 1.7 (95 % CI 0.55, 5.4; p = 0.4), unadjusted and adjusted for age, respectively. For death, the hazard ratios were 4.6 (95 % CI 0.98, 21.96; p = 0.054) and 2.4 (95 % CI 0.45, 12.97; p = 0.3) respectively.
We were limited by a small sample size and a small number of events.
Respondent burden is high for additional testing around the initiation of dialysis. High coronary calcification in patients new to ESRD has a tendency to predict cardiovascular outcomes and death, though effects are attenuated when adjusted for age.
[Show abstract][Hide abstract] ABSTRACT: The Food and Drug Administration approval of ruxolitinib for treatment of myelofibrosis and polycythemia vera has changed the management of patients with myeloproliferative neoplasms. Yet the impact of this therapy on risk of thrombosis, a major cause of morbidity and mortality among these patients, remains unknown. The aim of this study was to evaluate the impact of ruxolitinib on the risk of thrombosis among patients with polycythemia vera or myelofibrosis. Following identification of randomized controlled trials comparing ruxolitinib to standard care or placebo, rates of thrombosis, including venous and arterial thrombosis, were analyzed using fixed effects models. Rates of thrombosis were significantly lower among patients treated with ruxolitinib [risk ratio 0.45, 95% confidence interval (CI) 0.23-0.88]. Subgroup analysis of venous and arterial thrombosis demonstrated similar risk ratios, which did not reach statistical significance (risk ratio 0.46, 95% CI 0.14-1.48 and RR 0.42, 95% CI 0.18-1.01, respectively). In conclusion, our analysis suggests that JAK2 inhibition with ruxolitinib decreases the risk of arterial and/or venous thrombosis in patients with polycythemia vera or myelofibrosis. These findings will require confirmation in a prospective study.
Blood coagulation & fibrinolysis: an international journal in haemostasis and thrombosis 11/2015; DOI:10.1097/MBC.0000000000000446 · 1.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors. Methods Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. Results Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported. Conclusions Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725 .).
New England Journal of Medicine 11/2015; DOI:10.1056/NEJMoa1510991 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Critically ill patients appear to be at high risk of developing deep vein thrombosis (DVT) and pulmonary embolism during their stay in the intensive care unit (ICU). However, little is known about the clinical course of venous thromboembolism in the ICU setting. We therefore evaluated, through a systematic review of the literature, the available data on the impact of a diagnosis of DVT on hospital and ICU stay, duration of mechanical ventilation and mortality in critically ill patients. We also tried to determine whether currently adopted prophylactic measures need to be revised and improved in the ICU setting.
Materials and methods:
MEDLINE and EMBASE databases were searched up to week 4 of June 2012. Two reviewers selected studies and extracted data. Pooled results are reported as relative risks and weighted mean differences and are presented with 95% confidence intervals (CI).
Seven studies for a total of 1,783 patients were included. A diagnosis of DVT was frequent in these patients with a mean rate of 12.7% (95% CI: 8.7-17.5%). DVT patients had longer ICU and hospital stays compared to those without DVT (7.28 days; 95% CI: 1.4-13.15; and 11.2 days; 95% CI: 3.82-18.63 days, respectively). The duration of mechanical ventilation was significantly increased in DVT patients (weighted mean difference: 4.85 days; 95% CI: 2.07-7.63). DVT patients had a marginally significant increase in the risk of hospital mortality (relative risk 1.31; 95% CI: 0.99-1.74; p=0.06), and a not statistically significant increase in the risk of ICU mortality (RR 1.64; 95% CI: 0.91-2.93; p=0.10).
A diagnosis of DVT upon ICU admission appears to affect clinically important outcomes including duration of ICU and hospital stay and hospital mortality. Larger, prospective studies are warranted.
[Show abstract][Hide abstract] ABSTRACT: Background:
Whether and when to resume oral anticoagulant therapy for patients who survive warfarin-related intracranial hemorrhage (ICH) remains a dilemma lacking consensus recommendations and high-quality evidence to guide clinical decision making.
To determine the incidences of recurrent ICH, thrombosis, and death in relation to resumption or non-resumption of warfarin therapy during the 365days after incident ICH.
We conducted a retrospective cohort study of adult patients in an integrated healthcare delivery system who were receiving warfarin therapy at the time of incident (index) ICH between 1/1/2000 and 12/31/2007 and survived to hospital discharge. The primary outcomes were recurrent ICH, thrombosis (stroke, systemic embolism, and venous thromboembolism), and all-cause mortality during the 365days following index ICH. Patients were assigned to one of two groups defined by warfarin therapy resumption after the index ICH.
There were 160 patients discharged from the hospital following warfarin-related index ICH; of these 54 (33.8%) resumed warfarin therapy and 106 (66.2%) did not. Recurrent ICH occurred in a numerically greater, but statistically non-significant, proportion of patients who did not resume warfarin therapy (7.6% vs. 3.7%, p=0.497). Similarly, patients who did not resume warfarin had a three-fold higher (12.3% vs. 3.7%, p=0.092) and approximately two-fold higher (31.1% vs. 18.5%, p=0.089) rates of thrombosis and all-cause mortality, respectively, during follow up.
Resumption of warfarin therapy following warfarin-associated ICH appeared not to be associated with increased risk of recurrent ICH but trended toward reduced thrombosis and all-cause mortality.
Thrombosis Research 10/2015; DOI:10.1016/j.thromres.2015.10.002 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Failure to recognize the presence of competing risk or to account for it may result in misleading conclusions. We aimed to perform a competing risk analysis to assess the efficacy of the low molecular weight heparin dalteparin versus unfractionated heparin (UFH) in venous thromboembolism (VTE) in medical-surgical critically ill patients, taking death as a competing risk.This was a secondary analysis of a prospective randomized study of the Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT) database. A total of 3746 medical-surgical critically ill patients from 67 intensive care units (ICUs) in 6 countries receiving either subcutaneous UFH 5000 IU twice daily (n = 1873) or dalteparin 5000 IU once daily plus once-daily placebo (n = 1873) were included for analysis.A total of 205 incident proximal leg deep vein thromboses (PLDVT) were reported during follow-up, among which 96 were in the dalteparin group and 109 were in the UFH group. No significant treatment effect of dalteparin on PLDVT compared with UFH was observed in either the competing risk analysis or standard survival analysis (also known as cause-specific analysis) using multivariable models adjusted for APACHE II score, history of VTE, need for vasopressors, and end-stage renal disease: sub-hazard ratio (SHR) = 0.92, 95% confidence interval (CI): 0.70-1.21, P-value = 0.56 for the competing risk analysis; hazard ratio (HR) = 0.92, 95% CI: 0.68-1.23, P-value = 0.57 for cause-specific analysis. Dalteparin was associated with a significant reduction in risk of pulmonary embolism (PE): SHR = 0.54, 95% CI: 0.31-0.94, P-value = 0.02 for the competing risk analysis; HR = 0.51, 95% CI: 0.30-0.88, P-value = 0.01 for the cause-specific analysis. Two additional sensitivity analyses using the treatment variable as a time-dependent covariate and using as-treated and per-protocol approaches demonstrated similar findings.This competing risk analysis yields no significant treatment effect on PLDVT but a superior effect of dalteparin on PE compared with UFH in medical-surgical critically ill patients. The findings from the competing risk method are in accordance with results from the cause-specific analysis.clinicaltrials.gov Identifier: NCT00182143.
Medicine 09/2015; 94(36):e1479. DOI:10.1097/MD.0000000000001479 · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Direct oral anticoagulants (DOACs) are widely used as an alternative for warfarin. However, the impact of DOAC on mortality outcomes compared with warfarin remains unclear.Objective
To estimate the mortality outcomes in patients treated with DOACs versus warfarin (or other vitamin K antagonist).MethodsMEDLINE, EMBASE and CENTRAL databases (inception to September 2014), conference abstracts and www.clinicaltrials.gov, without language restriction. Studies were selected if there were phase III, randomized trials comparing DOACs to warfarin in patients with non-valvular atrial fibrillation or venous thromboembolism.ResultsThirteen RCTs involving 102 707 adult patients were included in the analysis. The case-fatality rate of major bleeding was 7.57% [95% CI, 6.53-8.68, I2 = 0%] in patients taking DOACs and 11.04% [95% CI, 9.16-13.07, I2 = 33.3%] in patients taking warfarin. The rate of fatal bleeding in adult patients receiving DOACs was 0.16 per 100 patient-years [95% CI, 0.12-0.20, I2 = 36.5%]. When compared with warfarin, DOACs were associated with significant reductions in fatal bleeding (RR, 0.53, 95% CI, 0.43-0.64, I2 = 0%), cardiovascular mortality (RR, 0.88, 95% CI, 0.82-0.94, I2 = 0%) and all-cause mortality (RR, 0.91, 95% CI, 0.87-0.96, I2 = 0%).Conclusions
The use of DOACs compared with warfarin is associated with a lower rate of fatal bleeding, case-fatality rate of major bleeding, cardiovascular mortality and all-cause mortality.This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 09/2015; 13(11). DOI:10.1111/jth.13139 · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Central venous catheter-related thrombosis (CRT) is a complication seen in patients requiring long-term intravenous access. Treatment of CRT is not standardized and international guidelines for treatment are based on extrapolation of evidence from lower extremity thrombosis. We performed a systematic review of the literature to evaluate if duration of anticoagulation affects the risk of recurrent venous thrombosis, post-thrombotic syndrome, or major hemorrhage. We searched PubMed, Embase, Medline, CINAHL, Cochrane, and ACP Journal club for studies of CRT treated with anticoagulation. Of 1648 titles and abstracts, 23 studies met our inclusion criteria. No randomized trials were identified. Duration of anticoagulation varied from 8days to more than 6months. Outcomes of patients with upper extremity thrombosis due to CRT or other etiologies were often combined. The incidence of post-thrombotic syndrome varied between 0 and 75% depending on the definition used. Seven percent of patients with upper extremity thrombosis treated with anticoagulation experienced recurrent deep vein thrombosis and 2.8% experienced pulmonary embolism. Major hemorrhage was reported in 2.8-4.9% of anticoagulated patients. Prospective studies evaluating the optimal duration of anticoagulation in patients with CRT are needed.
Thrombosis Research 09/2015; DOI:10.1016/j.thromres.2015.08.020 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Dabigatran, a direct thrombin inhibitor, is effective for the treatment of venous thromboembolism and prevention of stroke and systemic embolism from atrial fibrillation. The most effective means of reversing the anticoagulant effect of dabigatran in patients who have bleeding complications is unknown.Objectives
To document the clinical outcomes of patients undergoing renal replacement therapy (RRT) for dabigatran-associated bleeding.Methods
We searched MEDLINE and EMBASE up to May 2015. Articles were selected if the patients presented with dabigatran-associated bleeding, underwent RRT for dabigatran removal and reported an effect on bleeding.ResultsThe search yielded 22 studies representing 35 unique patient cases. Median patient age was 74.1 years (range: 56-94). Thirteen patients (37.1%) were female and 32 (91.4%) patients received dabigatran for atrial fibrillation. Twenty-three patients (65.7%) underwent intermittent hemodialysis, 10 patients (28.6%) underwent continuous renal replacement therapy (CRRT) and 2 patients underwent both intermittent hemodialysis and CRRT. Following RRT, there were significant reductions in dabigatran concentrations (P-value=0.001). Rebound of the dabigatran concentration was reported in 12 (57.1%) patients following cessation of RRT. Hemostasis was reportedly achieved in 24 patients (70.6%) and 10 patients (29.4%) died due to bleeding.Conclusions
In patients with dabigatran associated bleeding, RRT appears to be effective in reducing dabigatran concentrations and in case reports this has been associated with a reduction in duration and/or severity of bleeding. However, a rebound in concentrations may be seen following withdrawal of RRT suggesting that a prolonged course of RRT may be more effective.This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 08/2015; 13(10). DOI:10.1111/jth.13117 · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gastrointestinal (GI) bleeding commonly complicates anticoagulant therapy. We aimed to systematically review the published literature to determine the risk of thromboembolism, recurrent GI bleeding and mortality for patients on long-term anticoagulation who experience GI bleeding based on whether anticoagulation therapy was resumed. We performed a systematic review of phase III randomised controlled trials and cohort studies in patients with atrial fibrillation or venous thromboembolism who received oral anticoagulant. We searched MEDLINE, EMBASE and CENTRAL (from 1996-July 2014), conferences abstracts (from January 2006-July 2014) and www.clinicaltrials.gov (up to the last week of July 2014) with no language restriction. Two reviewers independently performed study selection, data extraction and study quality assessment. A total of three studies were included in the meta-analysis. The resumption of warfarin was associated with a significant reduction in thromboembolic events (hazard ratio [HR] 0.68, 95 % confidence interval [CI] 0.52 to 0.88, p < 0.004, I²=82 %). There was an increase in recurrent GI bleeding but not statistically significant for patients who restarted warfarin compared to those who did not (HR 1.20, 95 % CI 0.97 to 1.48, p = 0.10, I² = 0 %). Resumption of warfarin was associated with significant reduction in mortality (HR 0.76, 95 % CI 0.66 to 0.88, p < 0.001, I² = 87 %). This meta-analysis demonstrates that resumption of warfarin following interruption due to GI bleeding is associated with a reduction in thromboembolic events and mortality without a statistically significant increase in recurrent GI bleeding.
Thrombosis and Haemostasis 05/2015; 114(4). DOI:10.1160/TH15-01-0063 · 4.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The acute phase of venous thromboembolism (VTE) treatment focuses on the prompt and safe initiation of full-dose anticoagulation to decrease morbidity and mortality. Immediate management consists of resuscitation, supportive care, and thrombolysis for patients with haemodynamically significant pulmonary embolism (PE) or limb-threatening deep-vein thrombosis (DVT). Patients with contraindications to anticoagulants are considered for vena cava filters. Disposition for the acute treatment of VTE is then considered based on published risk scores and the patient's social status, as the first seven days carries the highest risk for VTE recurrence, extension and bleeding due to anticoagulation. Next, a review of: immediate and long-term bleeding risk, comorbidities (i. e. active cancer, renal failure, obesity, thrombophilia), medications, patient preference, VTE location and potential for pregnancy should be undertaken. This will help determine the most suitable anticoagulant for immediate treatment. The non-vitamin K antagonist oral anticoagulants (NOACs), including the factor Xa inhibitors apixaban, edoxaban and rivaroxaban as well as the direct-thrombin inhibitor dabigatran, are increasing the convenience of and options available for VTE treatment. Current options for immediate treatment include low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), fondaparinux, apixaban, or rivaroxaban. LMWH or UFH may be continued as monotherapy or transitioned to treatment with a VKA, dabigatran or edoxaban. This review describes the upfront treatment of VTE and the evolving role of NOACs in the contemporary management of VTE.
Thrombosis and Haemostasis 05/2015; 113(6). DOI:10.1160/TH14-12-1036 · 4.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Among patients with isolated below-knee fractures, previous studies have detected asymptomatic deep vein thrombosis in 10%-40% using contrast venography. However, the clinical relevance of these thrombi is unknown; there is considerable uncertainty about the risk: benefit of routine thromboprophylaxis and clinical practice guidelines differ in their recommendations.
In this multicenter, double-blind trial, 265 patients with isolated lower leg fractures requiring surgery were randomized to subcutaneous dalteparin 5000 units or matching placebo once daily for 2 weeks with bilateral Doppler ultrasound (DUS) of the proximal leg veins on postoperative day 14±2 and 3-month follow-up. The primary effectiveness outcome was clinically important venous thromboembolism (CIVTE), defined as the composite of symptomatic venous thromboembolism within 3 months after surgery and asymptomatic proximal deep vein thrombosis on DUS. The primary safety outcome was major bleeding.
Two hundred fifty-eight patients (97%) were included in the primary outcome analysis for effectiveness (130: dalteparin; 128: placebo). Incidence of CIVTE in the dalteparin and placebo groups was 1.5% and 2.3%, respectively (absolute risk reduction, 0.8%; 95% confidence interval, -2.0 to 3.0). There were no fatal pulmonary emboli or major bleeding.
The overall incidence of CIVTE after surgically repaired, isolated tibia, fibula, and ankle fractures was low (1.9%; 95% confidence interval, 0.7-4.7), with no observed differences between dalteparin and placebo either for CIVTE or safety. Recruitment was stopped at the first interim analysis. This study also demonstrates the substantial discrepancy in venous thromboembolism rates between trials that use venographic outcomes compared with more clinically relevant outcomes.
Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
[Show abstract][Hide abstract] ABSTRACT: Aspirin in venous thromboembolismAspirin is well established in its efficacy for secondary prevention of arterial thrombosis . In venous thrombosis, however, Several early studies failed to demonstrate a beneficial effect during aspirin use for the prevention of venous thromboembolism (VTE). However these early studies were, in general, small and thus may have lacked power to detect the efficacy of aspirin for the prevention of VTE.The first convincing evidence to the efficacy of aspirin for VTE prevention was a meta-analysis from the Antiplatelet Trialists’ Collaboration. This study included more than 8000 patients from 53 randomized trials of antiplatelet thromboprophylaxis including patients undergoing general surgery, orthopedic surgery and high risk medical patients . This trial found that antiplatelet therapies (mostly aspirin) were associated with a significant reduction in the incidence of VTE (reduction 39 %; P = 0.00001) without a significant increase in the risk of maj ...
Journal of Thrombosis and Thrombolysis 03/2015; 39(3). DOI:10.1007/s11239-015-1196-4 · 2.17 Impact Factor