[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: 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; 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; DOI:10.1111/jth.13117 · 5.72 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
[Show abstract][Hide abstract] ABSTRACT: Hereditary hemochromatosis leads to an increased lifetime risk for end-organ damage due to excess iron deposition. Guidelines recommend that genetic testing be performed in patients with clinical suspicion of iron overload accompanied by elevated serum ferritin and transferrin saturation levels.
To evaluate guideline adherence and the clinical and economic impact of HFE genetic testing.
The electronic charts of patients submitted for HFE testing in 2012 were reviewed for genetic testing results, biochemical markers of iron overload and clinical history of phlebotomy.
A total of 664 samples were sent for testing, with clinical, biochemical and phlebotomy data available for 160 patients. A positive C282Y homozygote or C282Y⁄H63D compound heterozygote test result was observed in 18% of patients. Patients with an at-risk HFE genotype had significantly higher iron saturation, serum iron and hemoglobin (P<0.001), without higher ferritin or liver enzyme levels. Fifty percent of patients referred for testing did not have biochemical evidence of iron overload (transferrin saturation >45% and ferritin level >300 μg⁄L). Patients were four times more likely to undergo phlebotomy if they were gene test positive (RR 4.29 [95% CI 2.35 to 7.83]; P<0.00001).
One-half of patients referred for testing did not exhibit biochemical evidence of iron overload. Many patients with biochemical evidence of iron overload, but with negative genetic test results, did not undergo phlebotomy. A requisition to determine clinical indication for testing may reduce the use of the HFE genetic test. Finally, improvement of current genetic test characteristics would improve rationale for the test.
A significant proportion of hemochromatosis genetic testing does not adhere to current guidelines and would not alter patient management.
Canadian journal of gastroenterology = Journal canadien de gastroenterologie 02/2015; 29(1):41-5. · 1.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Rituximab is commonly used as a treatment for primary immune thrombocytopenia to induce and maintain remission. The benefit of adding rituximab to standard-of-care treatment is uncertain. Methods: We did a systematic review and meta-analysis of randomised controlled trials assessing the efficacy and safety of rituximab for treatment of adults with primary immune thrombocytopenia. We searched Medline, Embase, and the Cochrane database in duplicate and independently from inception up to July 31, 2014, for relevant studies. Primary outcomes were the proportion of patients achieving a complete platelet count response and a partial platelet count response (as defined in primary studies) that was maintained until the end of follow-up. We also assessed bleeding, infection, and infusion reactions. Findings: Our database search returned 468 abstracts, of which five trials (with total of 463 patients) were eligible for analysis. No patients had splenectomy at the time of enrolment. Median follow-up was 6 months (IQR 6-12). Complete response (>100 × 109 platelets per L without rescue therapy) was more common with rituximab than with standard of care (weighted proportions: 46·8% vs 32·5%; relative risk [RR] 1·42, 95% CI 1·13-1·77; p=0·0020). Partial response was not significantly different between groups (57·6% vs 46·7%; RR 1·26, 95% CI 0·95-1·67; p=0·11). Rituximab was not associated with a reduction in bleeding (9·2% vs 5·2%; RR 1·34, 95% CI 0·63-2·87; p=0·44) or an increase in infections (20·1% vs 12·1%; RR 1·40, 95% CI 0·87-2·26; p=0·17). Interpretation: Rituximab can improve complete platelet count responses by 6 months in patients with immune thrombocytopenia. Evidence for sustained responses beyond 6-12 months is limited. Clinicians must consider the goals of treatment before prescribing rituximab. Funding: None.
[Show abstract][Hide abstract] ABSTRACT: Choosing Wisely Canada (CWC), a medical stewardship campaign, encourages dialogue between physicians and patients to promote high-quality decision-making. Medical societies develop lists of tests, treatments, and procedures that are unnecessary, reduce value, and may cause harm. The Canadian Hematology Society (CHS) elicited suggestions for CWC recommendations from its members and received 35 unique suggestions. A working group rated these based on their potential for harm, benefit, frequency of use and value. Twelve highly ranked items were subjected to systematic evidence review. The final items were included in the list if they were of sufficient evidence base and met pre-defined core principles. The CHS-CWC recommendations are: to avoid IVIG treatment for asymptomatic immune thrombocytopenia, not bridge warfarin in low-risk patients going for procedures, not perform thrombophilia testing in the workup of early pregnancy loss, avoid fine-needle aspiration in lymphoma diagnosis, and not transfuse red blood cells for an arbitrary hemoglobin threshold. Through implementation of these recommendations, physicians will reduce potential harm to patients and increase the value of health care.
Annals of Hematology 02/2015; 94(4). DOI:10.1007/s00277-015-2304-4 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Venous thromboembolism is a common complication in cancer patients, and thromboembolism is the second most common cause of death after cancer progression. A number of clinical practice guidelines provide recommendations for the management of cancer-associated thrombosis. However, the guidelines lack recommendations covering commonly encountered clinical challenges (for example, thrombocytopenia, recurrent venous thromboembolism, etc.) for which little or no evidence exists. Accordingly, recommendations were developed to provide expert guidance to medical oncologists and other health care professionals caring for patients with cancer-associated thrombosis. The current expert consensus was developed by a team of 21 clinical experts. For each identified clinical challenge, the literature in medline, embase, and Evidence Based Medicine Reviews was systematically reviewed. The quality of the evidence was assessed, summarized, and graded. Consensus statements were generated, and the experts voted anonymously using a modified Delphi process on their level of agreement with the various statements. Statements were progressively revised through separate voting iterations and were then finalized. Clinicians using these recommendations and suggestions should tailor patient management according to the risks and benefits of the treatment options, patient values and preferences, and local cost and resource allocations.
[Show abstract][Hide abstract] ABSTRACT: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is recognized as a common complication in critically ill patients. Risk factors including critical illness, mechanical ventilation, sedative medications, and central venous catheter insertion are major contributing factors to the high risk of VTE. Because of their impaired cardiopulmonary reserve, PE arising from thrombosis in the deep veins of the calf that propagates proximally is poorly tolerated by critically ill patients. Pharmacologic prophylaxis with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) has been shown to decrease the incidence of VTE in medical, surgical, and critically ill patients. As a result, over the past decades, VTE prophylaxis had become a standard of preventive measure in the intensive care unit (ICU). In clinical practice, the rate of VTE prophylaxis varies and may be inadequate in some centers. A perception of a high bleeding risk in critically ill patients is a major concern for most physicians that may lead to inadequate prophylaxis.
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
Seminars in Thrombosis and Hemostasis 01/2015; 41(01). DOI:10.1055/s-0034-1398386 · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To identify risk factors for failure of anticoagulant thromboprophylaxis in critically ill patients in the ICU.
Multivariable regression analysis of thrombosis predictors from a randomized thromboprophylaxis trial.
Sixty-seven medical-surgical ICUs in six countries.
Three thousand seven hundred forty-six medical-surgical critically ill patients.
All patients received anticoagulant thromboprophylaxis with low-molecular-weight heparin or unfractionated heparin at standard doses.
Independent predictors for venous thromboembolism, proximal leg deep vein thrombosis, and pulmonary embolism developing during critical illness were assessed. A total of 289 patients (7.7%) developed venous thromboembolism. Predictors of thromboprophylaxis failure as measured by development of venous thromboembolism included a personal or family history of venous thromboembolism (hazard ratio, 1.64; 95% CI, 1.03-2.59; p = 0.04) and body mass index (hazard ratio, 1.18 per 10-point increase; 95% CI, 1.04-1.35; p = 0.01). Increasing body mass index was also a predictor for developing proximal leg deep vein thrombosis (hazard ratio, 1.25; 95% CI, 1.06-1.46; p = 0.007), which occurred in 182 patients (4.9%). Pulmonary embolism occurred in 47 patients (1.3%) and was associated with body mass index (hazard ratio, 1.37; 95% CI, 1.02-1.83; p = 0.035) and vasopressor use (hazard ratio, 1.84; 95% CI, 1.01-3.35; p = 0.046). Low-molecular-weight heparin (in comparison to unfractionated heparin) thromboprophylaxis lowered pulmonary embolism risk (hazard ratio, 0.51; 95% CI, 0.27-0.95; p = 0.034) while statin use in the preceding week lowered the risk of proximal leg deep vein thrombosis (hazard ratio, 0.46; 95% CI, 0.27-0.77; p = 0.004).
Failure of standard thromboprophylaxis using low-molecular-weight heparin or unfractionated heparin is more likely in ICU patients with elevated body mass index, those with a personal or family history of venous thromboembolism, and those receiving vasopressors. Alternate management or incremental risk reduction strategies may be needed in such patients.
Critical Care Medicine 12/2014; 43(2). DOI:10.1097/CCM.0000000000000713 · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Prothrombin complex concentrates (PCCs) can be used instead of frozen plasma (FP) transfusion to reverse the effect of warfarin. Audits have demonstrated over usage of FP transfusions even before the introduction of PCC. The objective of this study was to determine the appropriateness of current FP transfusion practice in the current era since the introduction of PCCs.MethodsA retrospective cohort study of consecutive patients receiving FP over 3 months was carried out. Each episode of FP use over a 24-h period was adjudicated independently by two reviewers as appropriate (consistent with Canadian/AABB guidelines), appropriate but inconsistent with guidelines or inappropriate. Discrepancies were resolved by a third reviewer. Use of FP to reverse warfarin was considered inappropriate. FP usage from previous years was assessed as baseline.ResultsDuring the study period, 111 FP transfusions were administered. 74·8% of FP usage occurred in the ICU. The proportion of FP transfusions that were deemed appropriate, inconsistent yet appropriate or inappropriate were 33/89 (37·1%), 16/89 (18·0%) and 40/89 (44·9%), respectively, when use of FP for therapeutic plasma exchange was excluded. The most common reasons for inappropriate use were the absence of bleeding with an increased INR or warfarin reversal.Conclusion
Our study is the first to audit FP transfusions in the post-PCC era in Canada. FP usage remains inappropriately high in INR prolongation without another indication or to reverse warfarin. Targeted interventions to reduce FP usage in the future should focus on the ICU and on education about warfarin reversal.
[Show abstract][Hide abstract] ABSTRACT: Background
The availability of Computed Tomography Pulmonary Angiography (CTPA) has led to an increase in the diagnosis of sub-segmental pulmonary embolism (SSPE). Current clinical practice guidelines do not make any treatment distinctions for SSPE, though the benefits of anticoagulation for SSPE have not been established.Objectives
To review the frequency of Pulmonary Embolism and Sub-segmental Pulmonary Embolism identified through CTPA as well as their managementMethods
Cross-sectional review of 2213 patient charts who underwent CTPA in three Hamilton teaching hospitals from 2009-2011. In-depth chart review of patients with SSPE was undertaken to determine the frequency with which patients received anticoagulation therapy for SSPE as well as bleeding complications and recurrent thrombosis.Results2216 CTPAs were reviewed. The frequency of PE was 24.8% (n=550). Of these, the largest pulmonary filling defects were SSPEs in 82 patients (3.9% of total scans and 15.0% of identified PEs). In 55 of these 82 SSPEs, an alternative diagnosis to PE was identified on CT to explain the patients’ symptoms. Approximately 52.4% (n=43) received anticoagulation for SSPE. Major, life-threatening bleeding complications occurred in 2 of the 43 who received anticoagulation for SSPE. There was no documented recurrent thrombosis in any patients with SSPE, with or without anticoagulation.Summary/ConclusionsA substantial proportion of patients were anti-coagulated for SSPE (52%) and two developed life-threatening bleeding complications. Randomized controlled trial data is needed to further investigate the risks and benefits of anticoagulation in patients with SSPE.This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 12/2014; 13(2). DOI:10.1111/jth.12803 · 5.72 Impact Factor