Weight-adjusted tinzaparin for venous thromboembolism prophylaxis in bariatric surgery patients weighing 160 kg or more.

INTRODUCTION: Bariatric surgery patients experience an increased risk of venous thromboembolism (VTE), however, the optimal dose of low-molecular-weight heparin for VTE prophylaxis remains uncertain. Currently, St. Joseph's Healthcare Hamilton utilizes a weight-adjusted tinzaparin dosage (50 to 75 units/kg rounded to nearest pre-filled syringe) for postoperative VTE prophylaxis. OBJECTIVES: This study analyzed the safety of weight-adjusted tinzaparin for VTE prophylaxis in bariatric surgery patients weighing ≥160 kg. METHODS: This was a retrospective study involving patients weighing ≥160 kg that underwent bariatric surgery from September 2015 to September 2019. Patients received a single dose of weight-adjusted subcutaneous unfractionated heparin (UFH) [5000 or 7500 IU] immediately prior to surgery, subcutaneous UFH [5000 IU, 7500 IU, or unspecified] immediately postoperatively, and either 10,000 or 14,000 IU of tinzaparin, beginning on the day after surgery, for 10 days. Intra-operative sequential compression devices could be used at the attending surgeon's discretion. Occurrence of VTE and major bleeding within 30 days of surgery were assessed. RESULTS: A total of 389 patients were included for analysis, all patients received in-hospital follow-up while 349 patients had also 30-day follow-up. For the primary safety and efficacy analysis of in-hospital events, VTE and major bleeding rates were 0.26% [95% CI 0.01%-1.44%] (1/389) and 0.77% [95% CI 0.21%-2.24%] (3/389) respectively. For patients with 30-day follow-up VTE and major bleeding rates were 0.57% [95% CI 0.1%-2.07%] (2/349) and 1.43% [95% CI 0.61%-3.3%] (5/349) respectively. CONCLUSIONS: Weight-adjusted tinzaparin was associated with a low risk of bleeding and VTE events, supporting its use for VTE prophylaxis for patients weighing ≥160 kg.

Weight-adjusted tinzaparin for the prevention of venous thromboembolism after bariatric surgery.

Essentials The optimal dose and duration of thromboprophylaxis after bariatric surgery are unclear. We evaluated the safety of weight-adjusted tinzaparin prophylaxis in 1212 patients. In-hospital rates of venous thromboembolism and major bleeding were 0.2% and 1.8% respectively. In a sub-set of patients, trough anti-Xa levels did not show excessive anticoagulant activity. SUMMARY: Background Patients undergoing bariatric surgery are at moderate to high risk of venous thromboembolism (VTE). The optimal dose and duration of anticoagulant prophylaxis is uncertain. Objective To evaluate the safety of extended-duration weight-adjusted tinzaparin after bariatric surgery. Patients/methods We conducted a single-center retrospective cohort study of consecutive patients undergoing bariatric surgery who received weight-adjusted tinzaparin 4500-14 000 IU daily (75 IU kg-1 rounded to the nearest prefilled syringe) for 10 days after surgery (7-9 days post-hospital discharge). Primary safety outcomes were the frequency of VTE and major bleeding within 30 days of surgery in patients receiving at least one dose of tinzaparin. Results A total of 1279 patients undergoing bariatric surgery between July 2009 and December 2012 were reviewed, of whom 1212 received weight-adjusted tinzaparin. Safety outcomes were collected for 819 patients at 30 days, and for 1212 patients in-hospital only. The median age was 45.0 years, median weight was 130.0 kg and 98.8% of patients underwent gastric bypass or sleeve gastrectomy. In patients completing 30 days of follow-up, VTE occurred in 4/819 (0.5%) and major bleeding occurred in 13/819 patients (1.6%). In-hospital rates of VTE and major bleeding during surgical admission were 3/1212 (0.2%) and 22/1212 (1.8%), respectively. Conclusions Extended thromboprophylaxis with weight-adjusted tinzaparin appears to be a safe strategy after bariatric surgery, with low rates of postoperative VTE and major bleeding.

Age-adjusted D-dimer to rule out deep vein thrombosis: findings from the PALLADIO algorithm.

Essentials The accuracy of the age-adjusted D-dimer in suspected venous thromboembolism is still debated. We assessed the performance of age-adjusted D-dimer combined with the PALLADIO algorithm. The age-adjusted threshold can reduce the need for imaging tests compared to the fixed cut-off. The safety of this approach should be confirmed in large management studies. SUMMARY: Background Age-adjusted D-dimer has been proposed to increase specificity for the diagnosis of venous thromboembolism (VTE). However, the accuracy of this threshold has been recently questioned. Objectives To assess the diagnostic performance of age-adjusted D-dimer combined with clinical pretest probability (PTP) in patients with suspected deep vein thrombosis (DVT). Methods PALLADIO (NCT01412242) was a multicenter management study that validated a new diagnostic algorithm, incorporating PTP, D-dimer (using the manufacturer's cut-off) and limited or extended compression ultrasonography (CUS) in outpatients with clinically suspected DVT. Patients with unlikely PTP and negative D-dimer had DVT ruled out without further testing (group 1); patients with likely PTP or positive D-dimer underwent limited CUS (group 2); patients with likely PTP and positive D-dimer underwent extended CUS (group 3). Patients with DVT ruled out at baseline had a 3-month follow-up. In this post-hoc analysis we evaluated age-adjusted D-dimer cut-off (defined as age times 10 µg L-1 , or age times 5 µg L-1 for D-dimers with a lower manufacturer's cut-off, in patients > 50 years). Results In total, 1162 patients were enrolled. At initial visit, DVT was detected in 4.0% of patients in group 2 and 53.0% in group 3. The age-adjusted D-dimer, compared with the fixed cut-off, resulted in 5.1% (95% CI, 4.0-6.5%) reduction of CUS. The incidence of symptomatic VTE during follow-up was: 0.24% (95% CI, 0.04-1.37) in group 1; 1.12% (95% CI, 0.44-2.85) in group 2; and 1.89% (95% CI, 0.64-5.40) in group 3. Conclusions The PALLADIO algorithm using age-adjusted D-dimer slightly decreased the number of required imaging tests, but this approach should be confirmed in large management studies.

D-dimer levels and recurrence in patients with unprovoked VTE and a negative qualitative D-dimer test after treatment.

BACKGROUND: The rate of recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who had a negative qualitative D-dimer test one month after stopping anticoagulant therapy was higher than expected in the D-dimer Optimal Duration Study (DODS). OBJECTIVES: To determine whether quantitative D-dimer levels using a low threshold, age- and sex-specific thresholds, or repeated measurements, would improve identification of patients at low risk of recurrent VTE. MATERIALS AND METHODS: D-dimer levels were quantified in banked samples from 307 patients in DODS who had a negative qualitative D-dimer test while on, and 1month after stopping, anticoagulant therapy and the rates of recurrent VTE were determined in patients with D-dimer levels below various predefined thresholds. RESULTS: The rate (per patient year) of recurrent VTE was: 5.9% with D-dimer levels<250µg/l at one month; 5.2% with D-dimer levels between 250 and 499µg/l at one month; 5.0% with D-dimer levels less than predefined age- and sex-specific thresholds at one month; and 6.3% when D-dimer levels were <500µg/l at both one and 7months after stopping anticoagulant therapy. These rates are similar to the overall event rate of 6.3% in patients who stopped treatment. CONCLUSIONS: Among unprovoked VTE patients who had a negative qualitative D-dimer test during and after anticoagulant therapy, low D-dimer thresholds, age and sex-adjusted thresholds or repeated measurements, did not identify subgroups with a very low rate of recurrence.

Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery.

The periprocedural management of patients receiving chronic therapy with oral anticoagulants (OACs), including vitamin K antagonists (VKAs) such as warfarin and direct OACs (DOACs), is a common clinical problem. The optimal perioperative management of patients receiving chronic OAC therapy is anchored on four key principles: (i) risk stratification of patient-related and procedure-related risks of thrombosis and bleeding; (ii) the clinical consequences of a thrombotic or bleeding event; (iii) discontinuation and reinitiation of OAC therapy on the basis of the pharmacokinetic properties of each agent; and (iv) whether aggressive management such as the use of periprocedural heparin bridging has advantages for the prevention of postoperative thromboembolism at the cost of a possible increase in bleeding risk. Recent data from randomized trials in patients receiving VKAs undergoing pacemaker/defibrillator implantation or using heparin bridging therapy for elective procedures or surgeries can now inform best practice. There are also emerging data on periprocedural outcomes in the DOAC trials for patients with non-valvular atrial fibrillation. This review summarizes the evidence for the periprocedural management of patients receiving chronic OAC therapy, focusing on recent randomized trials and large outcome studies, to address three key clinical scenarios: (i) can OAC therapy be safely continued for minor procedures or surgeries; (ii) if therapy with VKAs (especially warfarin) needs to be temporarily interrupted for an elective procedure/surgery, is heparin bridging necessary; and (iii) what is the optimal periprocedural management of the DOACs? In answering these questions, we aim to provide updated clinical guidance for the periprocedural management of patients receiving VKA or DOAC therapy, including the use of heparin bridging.

Rapid quantitative D-dimer to exclude pulmonary embolism: a prospective cohort management study.

UNLABELLED: ESSENTIALS: It is not known if D-dimer testing alone can safely exclude pulmonary embolism (PE). We studied the safety of using a quantitative latex agglutination D-dimer to exclude PE in 808 patients. 52% of patients with suspected PE had a negative D-dimer test and were followed for 3 months. The negative predictive value of D-dimer testing alone was 99.8%, suggesting it may safely exclude PE. BACKGROUND: Strategies are needed to exclude pulmonary embolism (PE) efficiently without the need for imaging tests. Although validated rules for clinical probability assessment can be combined with D-dimer testing to safely exclude PE, the rules can be complicated or partially subjective, which limits their use. OBJECTIVES: To determine if PE can be safely excluded in patients with a negative D-dimer without incorporating clinical probability assessment. PATIENTS/METHODS: We enrolled consecutive outpatients and inpatients with suspected PE from four tertiary care hospitals. All patients underwent D-dimer testing using the MDA D-dimer test, a quantitative latex agglutination assay. PE was excluded in patients with a D-dimer less than 750 µg FEU L(-1) without further testing. PATIENTS: with D-dimer levels of 750 µg FEU L(-1) or higher underwent standardized imaging tests for PE. All patients in whom PE was excluded had anticoagulant therapy withheld and were followed for 3 months for venous thromboembolism (VTE). Suspected events during follow-up were adjudicated centrally. RESULTS: Eight hundred and eight patients were enrolled, of whom 99 (12%) were diagnosed with VTE at presentation. Four hundred and twenty (52%) patients had a negative D-dimer level at presentation and were not treated with anticoagulants; of these, one had VTE during follow-up. The negative predictive value of D-dimer testing for PE was 99.8% (95% confidence interval, 98.7-99.9%). CONCLUSIONS: A negative latex agglutination D-dimer assay is seen in about one-half of patients with suspected PE and reliably excludes PE as a stand-alone test.

Effect of standardized perioperative dabigatran interruption on the residual anticoagulation effect at the time of surgery or procedure.

UNLABELLED: ESSENTIALS: Anticoagulants need to be stopped preprocedure so there is little or no remaining anticoagulant effect. We assessed the residual anticoagulant effect with standardized interruption for patients on dabigatran. With this protocol, 80-86% of patients had no residual anticoagulant effect at the time of a procedure. A standardized perioperative dabigatran protocol appears to be safe, but requires further study. BACKGROUND: In patients taking dabigatran who require treatment interruption for a surgery/procedure, a sufficient interruption interval is needed so that there is little or no residual anticoagulant effect at the time of the surgery/procedure. METHODS: A prospective cohort study of patients receiving dabigatran (110 mg or 150 mg twice daily) who required an elective surgery/procedure and received a standardized dabigatran interruption protocol based on surgery/procedure bleeding risk and renal function was performed. Before the surgery/procedure, a blood sample was taken for measurement of the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and dilute thrombin time (dTT). We determined the proportion of all patients and those having a high bleeding risk surgery/procedure with normal coagulation test results at the time of the surgery/procedure. The APTT and dTT were considered to be most likely to reflect a dabigatran anticoagulant effect. Patients were followed up for 30 days postprocedure to assess for bleeding and thromboembolism. RESULTS: One hundred and eighty-one patients were studied: 118 with low bleeding risk, and 63 with high bleeding risk. For all patients, the proportions with normal PT, APTT, TT dTT levels were 92.8%, 79.6%, 33.1%, and 80.7%, respectively. In patients with high bleeding risk, the proportions with normal PT, APTT, TT dTT levels were 93.7%, 85.7%, 57.1%, and 87.3%, respectively. During follow-up, there was one (0.6%) major bleed, there were nine (5.0%) minor bleeds, and there was one (0.6%) transient ischemic attack. CONCLUSIONS: In patients receiving dabigatran who require an elective surgery/procedure, a standardized interruption protocol yielded 80-86% of patients with no residual anticoagulant effect at the time of surgery/procedure, and with a low incidence of bleeding.

Risk of recurrence after a first unprovoked venous thromboembolism: external validation of the Vienna Prediction Model with pooled individual patient data.

BACKGROUND: In order to stratify patients with a first unprovoked venous thromboembolism (VTE) according to their recurrence risk and to identify those who would actually benefit from indefinite anticoagulation, three prediction models have been developed so far; none of them has been yet externally validated. OBJECTIVE: To externally validate the Vienna Prediction Model (VPM), a prediction guide for estimating the recurrence risk after a first unprovoked VTE developed through Cox modeling and including sex, D-dimer and index VTE site as predictors. PATIENTS/METHODS: Nine hundred and four patients pooled from five prospective studies evaluating the prognostic value of D-dimer for VTE recurrence served as the validation cohort. The validity of the VPM in stratifying patients according to their relative recurrence risk (discrimination) and in predicting the absolute recurrence risk (calibration) was tested with survival analysis methods. RESULTS: The ability of the VPM to distinguish patients' risk for recurrent VTE in the validation cohort was at least as good as in the original cohort, with a calibration slope of 1.17 (95% confidence interval 0.71-1.64; P = 0.456 for the hypothesis of a significant difference from 1), and a c-statistic of 0.626 (vs. 0.651 in the original derivation cohort). The VPM absolute predictions in terms of cumulative rates tended to underestimate the observed recurrence rates at 12 months. CONCLUSIONS: By using a pooled individual patient database as a validation cohort, we confirmed the ability of the VPM to stratify patients with a first unprovoked VTE according to their risk of recurrence.

Real-world variability in dabigatran levels in patients with atrial fibrillation.

BACKGROUND: In clinical practice, physicians are given the choice of selecting one of two dabigatran doses based on patient characteristics, with the lower dose typically used in patients at a higher risk of bleeding. OBJECTIVES: The objectives of the study were to (i) estimate the inter- and intra-patient variability in dabigatran levels with 110 mg (DE110) and 150 mg (DE150) doses, (ii) examine the effect of physicians' dose selection on levels in DE110 and DE150 subgroups, and (iii) explore whether a single trough measurement identifies patients with extreme levels on subsequent visits. METHODS: In this prospective observational study of 100 patients with atrial fibrillation (AF), peak and trough levels of dabigatran were measured with the Hemoclot(®) assay at baseline and every 2 months thereafter (maximum four visits). RESULTS: Inter-patient variability in dabigatran levels (geometric coefficient of variation [gCV], 51-64%) was greater than intra-patient variability (gCV, 32-40%). Similar medians and distributions of levels were observed in DE110 and DE150 subgroups. Patients receiving DE110 were older, had lower renal function and weighed less than those receiving DE150. Up to 40% of patients whose trough levels were in the upper extremes, and up to 80% of patients whose trough levels were in the lower extremes at baseline, showed subsequent levels that fell in the middle quartiles. CONCLUSIONS: Our data support the practice of selecting the dabigatran dose based upon clinical characteristics because it results in similar levels of drug exposure in patients given DE110 or DE150. They do not support the concept that a single Hemoclot(®) measurement reliably identifies patients with consistently high or low values.

Reduced-dose warfarin or interrupted warfarin with heparin bridging for pacemaker or defibrillator implantation: a randomized trial.

BACKGROUND: Perioperative management with reduced-dose warfarin is of potential interest by eliminating the need for bridging while still maintaining a degree of anticoagulation. The outcomes of this regimen have not been well determined. METHODS: In a randomized controlled trial we compared two regimens for management of anticoagulation with warfarin in patients with implantation of a pacemaker or defibrillator. Half dose of warfarin for 3-6 days, depending on the baseline international normalized ratio (INR), before surgery aiming at an INR of ≤ 1.7 was compared with interrupted warfarin for 5 days with preoperative bridging with low-molecular-weight heparin (LMWH) at therapeutic dose for 2.5 days. Main safety outcome was pocket hematoma. Secondary outcomes were major bleeding, thromboembolism - all within 1 month, days of hospitalization and number of patients requiring correction of INR with vitamin K. RESULTS: The study was planned for 450 patients but it was discontinued prematurely due to a change in practice. Pocket hematoma occurred in 4 of 85 patients (5%) randomized to the bridged regimen and in 3 of 86 patients (3%) randomized to reduced-dose warfarin. One pocket hematoma in each group was severe. There were no major hemorrhages or thromboembolism within the 1-month window. Duration of hospitalization was similar in the two groups. Correction of INR the day before surgery with vitamin K had to be used for significantly more patients in the reduced-dose warfarin group (41%) than in the bridged regimen group (6%). CONCLUSION: The reduced-dose warfarin regimen appeared to have similar safety after device implantation as interrupted warfarin with preoperative LMWH bridging. Due to premature discontinuation no firm conclusion can be drawn. The reduced-dose warfarin regimen often failed to achieve the intended preoperative INR. ClinicalTrials.gov Identifier: NCT 02094157.

Risk of stroke after surgery in patients with and without chronic atrial fibrillation.

SUMMARY BACKGROUND: The extent to which chronic atrial fibrillation affects the risk of postoperative stroke is largely unknown. OBJECTIVES: We sought to determine the 30-day rate of stroke among patients with and without chronic AF who underwent 10 different types of surgery. PATIENTS/METHODS: The crude incidence of stroke was retrospectively determined using a population-based linked administrative database of hospitalized patients who underwent specified operations between 1 January 1996 and 30 November 2005. The risk of stroke in patients with AF was adjusted for age, race, sex, presence of diabetes, heart failure, hypertension and prior stroke. RESULTS: The overall 30-day rate of stroke in 69 202 patients with chronic AF was 1.8% (95% CI, 1.7-1.9%) vs. 0.6% (CI, 0.58-0.62%) in 2 470 649 patients without AF. The risk-adjusted odds of a postoperative stroke in patients with chronic AF were 2.1 (CI, 2.0-2.3). The highest incremental difference in the crude rate of stroke was observed in patients undergoing neurologic or vascular surgery, with a difference of approximately 2%. CONCLUSION: Patients with chronic AF had twice the risk of postoperative stroke. Randomized trials are needed to determine if aggressive perioperative anticoagulation can reduce the incidence of postoperative stroke in patients with AF.

The long-term risk of cancer in patients with a first episode of venous thromboembolism.

BACKGROUND: In patients with venous thromboembolism (VTE), 15-20% will have prevalent cancer when VTE is diagnosed but little is known about such patients' long-term risk, time course and predictors of new cancer. PATIENTS AND METHODS: We studied an inception cohort of patients with a first VTE who were not diagnosed with cancer within 3 months after VTE and who had follow-up for up to 120 months. We determined the annual risk for a new cancer [number of events and 95% confidence interval (CI)] per 100 person-years in all patients and in those with unprovoked VTE and identified predictors for new cancer. RESULTS: We studied 1852 patients with VTE who received anticoagulant therapy for 12 months (mean) and were followed for 4.2 years (mean). During follow-up, there were 105 (5.7%) patients diagnosed with new cancer during the period after the initial 3 months from diagnosis, for an annual risk of 1.32 (CI, 1.09-1.60) per 100 person-years. The risk for new cancer appeared uniform over time. The annual risk for new cancer was more than 2-fold higher in patients presenting with unprovoked compared with those with provoked VTE [1.76 (CI, 1.39-2.20) vs. 0.83 (CI, 0.58-1.16) per 100 person-years; P<0.001]. Clinical predictors for new cancer were increasing age [hazard ratio (HR), 1.23; CI, 1.05-1.44] and unprovoked VTE (HR, 1.86; CI, 1.21-2.87). CONCLUSION: In patients with a first VTE and without prevalent cancer, the risk for new cancer is about 1-2% per year, appears to be uniform over time, and is higher in patients with unprovoked VTE and those with advanced age.