The non-vitamin K antagonist oral anticoagulants (NOACs), rivaroxaban, apixaban and dabigatran, h... more The non-vitamin K antagonist oral anticoagulants (NOACs), rivaroxaban, apixaban and dabigatran, have been shown, in phase 3 trials, to be effective for thromboprophylaxis in patients undergoing elective hip or knee arthroplasty. Results from prior studies suggested that the safety of anticoagulants in such patients was improved if the first post-operative dose was delayed for at least 6 hours after surgery. The timing of the first post-operative dose of the NOACs tested in phase 2 studies differed among the 3 NOACs; dabigatran was started 1 to 4 hours post-operatively, whereas rivaroxaban and apixaban were started at least 6 and 12 hours, post-operatively, respectively. Our review of the timing of initiation of thromboprophylaxis in randomized trials provides three related lessons. First, clinical trials performed before the NOACs were evaluated demonstrated that delaying the first dose of prophylactic anticoagulation until after major surgery is effective and safe. Second, the optimal timing of the first dose of prophylactic anticoagulation after surgery depends on the dose that is selected. Third, the results of the phase 3 trials with NOACs for thromboprophylaxis support the concept that acceptable efficacy and safety can be achieved when the appropriate first post-operative dose of anticoagulant is delayed for at least 6 hours after surgery.
DEAR SIR, In a recent study, we demonstrated that use of a clinical model to determine pretest pr... more DEAR SIR, In a recent study, we demonstrated that use of a clinical model to determine pretest probability was valuable in the management of patients with suspected pulmonary embolism (PE) [1]. The goal of that study was to utilize lower extremity ultrasound imaging, repeated over 2 weeks if the initial ultrasound was negative, as the predominant diagnostic strategy and, thereby, limiting the need for angiography. The safety of that management strategy was validated; however, the approach was cumbersome as it required the performance of a large number of ultrasounds, the vast majority of which were normal. It has been reported that, in the absence of risk factors for venous thromboembolism (VTE) and symptoms of deep vein thrombosis (DVT), very few patients with suspected PE have abnormal ultrasound results [2]. As this could change the diagnostic, we undertook an evaluation of this observation in our study cohort. All patients were evaluated by a physician to determine the clinical pretest probability for PE using a clinical model. Ventilation-perfusion lung scans and bilateral compression ultrasound from the common femoral vein to the trifurcation of the calf veins were then performed in all patients [3]. The diagnostic algorithm is outlined in Fig. 1. Anticoagulant therapy was withheld in patients unless, as outlined in the algorithm, PE or DVT was diagnosed. Patients were de®ned as PE+ if one or more of the following occurred: abnormal pulmonary angiography, abnormal ultrasound or venography, high probability ventilation-perfusion lung scan plus moderate or high pretest probability; or VTE within the 3 month follow-up period. All other patients were classi®ed as PE±. Patients were followed-up for 90 days and those with suspected VTE, at any time in the 90-day period, underwent objective testing performed in a standardized way [1]. We determined the accuracy of ultrasound for detection of DVT for each of the following four categories of patients with suspected PE: those patients with (i) both clinical symptoms of DVT and risk factors for VTE, (ii) symptoms of DVT but no risk factors, (iii) risk factors but no symptoms of DVT and (iv) neither symptoms nor risk factors. In our analysis, risk factors included previous DVT/PE (objectively diagnosed by ultrasonography, venography, angiography or high probability ventilationperfusion lung scan), major surgery within 4 weeks (12 weeks in the original study), immobilization for more than 3 days in the preceding 4 weeks, cancer, the postpartum period (the 6 weeks postdelivery), lower limb paralysis, lower limb fracture or cast within 12 weeks, strong family history (>1 ®rst degree relative with VTE, or a family member with a thrombophilia). Of the 1401 eligible patients 147 refused consent, two had inadequate ventilation-perfusion lung scans and 13 were lost in follow-up due to moving from the study region. Thus, 1239 patients were evaluated of whom 155 had previous DVT or PE. Of the 1239 valuable patients, 334 (27%) had normal perfusion scans, 736 (59%) had nondiagnostic probability ventilation-perfusion lung scans, and 169 (14%) had high probability ventilation-perfusion lung scans. Including events in the 3 month follow-up period, four patients (1.2%) were PE+ in the normal perfusion scan group, 62 patients were PE+ in the nondiagnostic probability ventilationperfusion lung scan group (8%), and 151 (89%) were PE+ in the high probability ventilation-perfusion lung scan group. Overall 17.5% (217) of patients were PE+. The initial ultrasound was abnormal in 97 of the PE+ patients for a sensitivity of 45%. Serial testing detected a further 13 cases of DVT. Thus, the sensitivity of serial ultrasound testing for PE was 52% (110/217) and the speci®city was 99% (997/1007±15 patients with normal lung scans had normal impedance plethysmograJournal of Internal Medicine 2001; 250: 262±264
Successful coronary thrombolysis depends on rapidly restoring blood flow and maintaining patency ... more Successful coronary thrombolysis depends on rapidly restoring blood flow and maintaining patency of the infarct-related artery. Although widely used as an adjunct to lytic therapy, heparin is limited in its ability to produce these effects. Since the limitations of heparin may reflect its inability to inactivate clot-bound thrombin, we developed a rat model of tissue plasminogen activator (t-PA) induced thrombolysis to compare doses of heparin, hirudin, hirulog (a synthetic hirudin-derived peptide), and D-Phe-Pro-ArgCH2Cl (PPACK) that produced a 4-fold prolongation of the baseline activated partial thromboplastin time (APTT) with saline in terms of their ability to accelerate thrombolysis and to prevent reocclusion. A thrombus rich in red cells and fibrin was formed in the distal aorta by applying an external constrictor after denuding the endothelium with a balloon catheter. Thrombolysis was induced with t-PA (1 mg/kg bolus, followed by 1 mg kg-1 h-1 over 30 min) and the rats were then randomized to receive a concomitant 80 min infusion of a thrombin inhibitor or saline. By continuously monitoring blood flow and pre- and post-stenotic blood pressures, the time to clot lysis, and the number of reocclusions were determined. Compared to saline, heparin had no significant effect on these variables.(ABSTRACT TRUNCATED AT 250 WORDS)
The low specificity of ventilation-perfusion lung scanning complicates the management of patients... more The low specificity of ventilation-perfusion lung scanning complicates the management of patients with suspected pulmonary embolism. To determine the safety of a clinical model for patients with suspected pulmonary embolism. Prospective cohort study. Five tertiary care hospitals. 1239 inpatients and outpatients with suspected pulmonary embolism. A clinical model categorized pretest probability of pulmonary embolism as low, moderate, or high, and ventilation-perfusion scanning and bilateral deep venous ultrasonography were done. Testing by serial ultrasonography, venography, or angiography depended on pretest probability and lung scans. Patients were considered positive for pulmonary embolism if they had an abnormal pulmonary angiogram, abnormal ultrasonogram or venogram, high-probability ventilation-perfusion scan plus moderate or high pretest probability, or venous thromboembolic event during the 3-month follow-up. All other patients were considered negative for pulmonary embolism. Rates of pulmonary embolism during follow-up in patients who had a normal lung scan and those with a non-high-probability scan and normal serial ultrasonogram were compared. Pretest probability was low in 734 patients (3.4% with pulmonary embolism), moderate in 403 (27.8% with pulmonary embolism), and high in 102 (78.4% with pulmonary embolism). Three of the 665 patients (0.5% [95% CI, 0.1% to 1.3%]) with low or moderate pretest probability and a non-high-probability scan who were considered negative for pulmonary embolism had pulmonary embolism or deep venous thrombosis during 90-day follow-up; this rate did not differ from that in patients with a normal scan (0.6% [CI, 0.1% to 1.8%]; P > 0.2). Management of patients with suspected pulmonary embolism on the basis of pretest probability and results of ventilation-perfusion scanning is safe.
Journal of Thrombosis and Haemostasis, Mar 1, 2015
In clinical practice, physicians are given the choice of selecting one of two dabigatran doses ba... more 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. 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. 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). 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. 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.
In acute coronary syndrome without ST elevation, the role of unfractionated and low-molecular-wei... more In acute coronary syndrome without ST elevation, the role of unfractionated and low-molecular-weight heparin in aspirin-treated patients remains unclear, and there is conflicting evidence regarding the efficacy and safety of low-molecular-weight heparin (LMWH) relative to unfractionated heparin. We did a systematic overview of the randomised trials to assess the effect of unfractionated heparin and LMWH on death, myocardial infarction, and major bleeding. Randomised trials comparing unfractionated heparin or LMWH with placebo or untreated control, or comparing unfractionated heparin with LMWH, for the short-term and long-term management of patients with acute coronary syndrome without ST elevation, were identified by electronic and manual searches and through contact with experts and industry representatives. Odds ratios for death, myocardial infarction, and major bleeding were calculated for each trial, and results for the individual trials were combined by a modification of the Mantel-Haenszel method. 12 trials, involving a total of 17157 patients, were included. The summary odds ratio (OR) for myocardial infarction or death during short-term (up to 7 days) unfractionated heparin or LMWH compared with placebo or untreated control was 0.53 (95% CI 0.38-0.73; p=0.0001) or 29 events prevented per 1000 patients treated; during short-term LMWH compared with unfractionated heparin was 0.88 (0.69-1.12; p=0.34); and during long-term LMWH (up to 3 months) compared with placebo or untreated control was 0.98 (0.81-1.17; p=0.80). Long-term LMWH was associated with a significantly increased risk of major bleeding (OR 2.26, [95% CI 1.63-3.14], p<0.0001), which is equivalent to 12 major bleeds per 1000 patients treated. In aspirin-treated patients with acute coronary syndrome without ST elevation, short-term unfractionated heparin or LMWH halves the risk of myocardial infarction or death. There is no convincing difference in efficacy or safety between LMWH and unfractionated heparin. Long-term LMWH has not been proven to confer benefit additional to aspirin and there is no evidence to support its use after the first 7 days.
... MB, Ph.D., William Geerts, MD, Michael Kovacs, MD, Jeffrey I. Weitz, MD, K. Susan Robinson, M... more ... MB, Ph.D., William Geerts, MD, Michael Kovacs, MD, Jeffrey I. Weitz, MD, K. Susan Robinson, MD, Renaud ... Hélène Desmurs-Clavel, Jacques Ninet, Pascal Gaucherand, Rene Charles Rudigoz, Michel Berland, Fabienne Champion, Marie Christine Trzeciak. ... Shannon M. Bates. ...
The non-vitamin K antagonist oral anticoagulants (NOACs), rivaroxaban, apixaban and dabigatran, h... more The non-vitamin K antagonist oral anticoagulants (NOACs), rivaroxaban, apixaban and dabigatran, have been shown, in phase 3 trials, to be effective for thromboprophylaxis in patients undergoing elective hip or knee arthroplasty. Results from prior studies suggested that the safety of anticoagulants in such patients was improved if the first post-operative dose was delayed for at least 6 hours after surgery. The timing of the first post-operative dose of the NOACs tested in phase 2 studies differed among the 3 NOACs; dabigatran was started 1 to 4 hours post-operatively, whereas rivaroxaban and apixaban were started at least 6 and 12 hours, post-operatively, respectively. Our review of the timing of initiation of thromboprophylaxis in randomized trials provides three related lessons. First, clinical trials performed before the NOACs were evaluated demonstrated that delaying the first dose of prophylactic anticoagulation until after major surgery is effective and safe. Second, the optimal timing of the first dose of prophylactic anticoagulation after surgery depends on the dose that is selected. Third, the results of the phase 3 trials with NOACs for thromboprophylaxis support the concept that acceptable efficacy and safety can be achieved when the appropriate first post-operative dose of anticoagulant is delayed for at least 6 hours after surgery.
DEAR SIR, In a recent study, we demonstrated that use of a clinical model to determine pretest pr... more DEAR SIR, In a recent study, we demonstrated that use of a clinical model to determine pretest probability was valuable in the management of patients with suspected pulmonary embolism (PE) [1]. The goal of that study was to utilize lower extremity ultrasound imaging, repeated over 2 weeks if the initial ultrasound was negative, as the predominant diagnostic strategy and, thereby, limiting the need for angiography. The safety of that management strategy was validated; however, the approach was cumbersome as it required the performance of a large number of ultrasounds, the vast majority of which were normal. It has been reported that, in the absence of risk factors for venous thromboembolism (VTE) and symptoms of deep vein thrombosis (DVT), very few patients with suspected PE have abnormal ultrasound results [2]. As this could change the diagnostic, we undertook an evaluation of this observation in our study cohort. All patients were evaluated by a physician to determine the clinical pretest probability for PE using a clinical model. Ventilation-perfusion lung scans and bilateral compression ultrasound from the common femoral vein to the trifurcation of the calf veins were then performed in all patients [3]. The diagnostic algorithm is outlined in Fig. 1. Anticoagulant therapy was withheld in patients unless, as outlined in the algorithm, PE or DVT was diagnosed. Patients were de®ned as PE+ if one or more of the following occurred: abnormal pulmonary angiography, abnormal ultrasound or venography, high probability ventilation-perfusion lung scan plus moderate or high pretest probability; or VTE within the 3 month follow-up period. All other patients were classi®ed as PE±. Patients were followed-up for 90 days and those with suspected VTE, at any time in the 90-day period, underwent objective testing performed in a standardized way [1]. We determined the accuracy of ultrasound for detection of DVT for each of the following four categories of patients with suspected PE: those patients with (i) both clinical symptoms of DVT and risk factors for VTE, (ii) symptoms of DVT but no risk factors, (iii) risk factors but no symptoms of DVT and (iv) neither symptoms nor risk factors. In our analysis, risk factors included previous DVT/PE (objectively diagnosed by ultrasonography, venography, angiography or high probability ventilationperfusion lung scan), major surgery within 4 weeks (12 weeks in the original study), immobilization for more than 3 days in the preceding 4 weeks, cancer, the postpartum period (the 6 weeks postdelivery), lower limb paralysis, lower limb fracture or cast within 12 weeks, strong family history (>1 ®rst degree relative with VTE, or a family member with a thrombophilia). Of the 1401 eligible patients 147 refused consent, two had inadequate ventilation-perfusion lung scans and 13 were lost in follow-up due to moving from the study region. Thus, 1239 patients were evaluated of whom 155 had previous DVT or PE. Of the 1239 valuable patients, 334 (27%) had normal perfusion scans, 736 (59%) had nondiagnostic probability ventilation-perfusion lung scans, and 169 (14%) had high probability ventilation-perfusion lung scans. Including events in the 3 month follow-up period, four patients (1.2%) were PE+ in the normal perfusion scan group, 62 patients were PE+ in the nondiagnostic probability ventilationperfusion lung scan group (8%), and 151 (89%) were PE+ in the high probability ventilation-perfusion lung scan group. Overall 17.5% (217) of patients were PE+. The initial ultrasound was abnormal in 97 of the PE+ patients for a sensitivity of 45%. Serial testing detected a further 13 cases of DVT. Thus, the sensitivity of serial ultrasound testing for PE was 52% (110/217) and the speci®city was 99% (997/1007±15 patients with normal lung scans had normal impedance plethysmograJournal of Internal Medicine 2001; 250: 262±264
Successful coronary thrombolysis depends on rapidly restoring blood flow and maintaining patency ... more Successful coronary thrombolysis depends on rapidly restoring blood flow and maintaining patency of the infarct-related artery. Although widely used as an adjunct to lytic therapy, heparin is limited in its ability to produce these effects. Since the limitations of heparin may reflect its inability to inactivate clot-bound thrombin, we developed a rat model of tissue plasminogen activator (t-PA) induced thrombolysis to compare doses of heparin, hirudin, hirulog (a synthetic hirudin-derived peptide), and D-Phe-Pro-ArgCH2Cl (PPACK) that produced a 4-fold prolongation of the baseline activated partial thromboplastin time (APTT) with saline in terms of their ability to accelerate thrombolysis and to prevent reocclusion. A thrombus rich in red cells and fibrin was formed in the distal aorta by applying an external constrictor after denuding the endothelium with a balloon catheter. Thrombolysis was induced with t-PA (1 mg/kg bolus, followed by 1 mg kg-1 h-1 over 30 min) and the rats were then randomized to receive a concomitant 80 min infusion of a thrombin inhibitor or saline. By continuously monitoring blood flow and pre- and post-stenotic blood pressures, the time to clot lysis, and the number of reocclusions were determined. Compared to saline, heparin had no significant effect on these variables.(ABSTRACT TRUNCATED AT 250 WORDS)
The low specificity of ventilation-perfusion lung scanning complicates the management of patients... more The low specificity of ventilation-perfusion lung scanning complicates the management of patients with suspected pulmonary embolism. To determine the safety of a clinical model for patients with suspected pulmonary embolism. Prospective cohort study. Five tertiary care hospitals. 1239 inpatients and outpatients with suspected pulmonary embolism. A clinical model categorized pretest probability of pulmonary embolism as low, moderate, or high, and ventilation-perfusion scanning and bilateral deep venous ultrasonography were done. Testing by serial ultrasonography, venography, or angiography depended on pretest probability and lung scans. Patients were considered positive for pulmonary embolism if they had an abnormal pulmonary angiogram, abnormal ultrasonogram or venogram, high-probability ventilation-perfusion scan plus moderate or high pretest probability, or venous thromboembolic event during the 3-month follow-up. All other patients were considered negative for pulmonary embolism. Rates of pulmonary embolism during follow-up in patients who had a normal lung scan and those with a non-high-probability scan and normal serial ultrasonogram were compared. Pretest probability was low in 734 patients (3.4% with pulmonary embolism), moderate in 403 (27.8% with pulmonary embolism), and high in 102 (78.4% with pulmonary embolism). Three of the 665 patients (0.5% [95% CI, 0.1% to 1.3%]) with low or moderate pretest probability and a non-high-probability scan who were considered negative for pulmonary embolism had pulmonary embolism or deep venous thrombosis during 90-day follow-up; this rate did not differ from that in patients with a normal scan (0.6% [CI, 0.1% to 1.8%]; P > 0.2). Management of patients with suspected pulmonary embolism on the basis of pretest probability and results of ventilation-perfusion scanning is safe.
Journal of Thrombosis and Haemostasis, Mar 1, 2015
In clinical practice, physicians are given the choice of selecting one of two dabigatran doses ba... more 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. 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. 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). 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. 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.
In acute coronary syndrome without ST elevation, the role of unfractionated and low-molecular-wei... more In acute coronary syndrome without ST elevation, the role of unfractionated and low-molecular-weight heparin in aspirin-treated patients remains unclear, and there is conflicting evidence regarding the efficacy and safety of low-molecular-weight heparin (LMWH) relative to unfractionated heparin. We did a systematic overview of the randomised trials to assess the effect of unfractionated heparin and LMWH on death, myocardial infarction, and major bleeding. Randomised trials comparing unfractionated heparin or LMWH with placebo or untreated control, or comparing unfractionated heparin with LMWH, for the short-term and long-term management of patients with acute coronary syndrome without ST elevation, were identified by electronic and manual searches and through contact with experts and industry representatives. Odds ratios for death, myocardial infarction, and major bleeding were calculated for each trial, and results for the individual trials were combined by a modification of the Mantel-Haenszel method. 12 trials, involving a total of 17157 patients, were included. The summary odds ratio (OR) for myocardial infarction or death during short-term (up to 7 days) unfractionated heparin or LMWH compared with placebo or untreated control was 0.53 (95% CI 0.38-0.73; p=0.0001) or 29 events prevented per 1000 patients treated; during short-term LMWH compared with unfractionated heparin was 0.88 (0.69-1.12; p=0.34); and during long-term LMWH (up to 3 months) compared with placebo or untreated control was 0.98 (0.81-1.17; p=0.80). Long-term LMWH was associated with a significantly increased risk of major bleeding (OR 2.26, [95% CI 1.63-3.14], p<0.0001), which is equivalent to 12 major bleeds per 1000 patients treated. In aspirin-treated patients with acute coronary syndrome without ST elevation, short-term unfractionated heparin or LMWH halves the risk of myocardial infarction or death. There is no convincing difference in efficacy or safety between LMWH and unfractionated heparin. Long-term LMWH has not been proven to confer benefit additional to aspirin and there is no evidence to support its use after the first 7 days.
... MB, Ph.D., William Geerts, MD, Michael Kovacs, MD, Jeffrey I. Weitz, MD, K. Susan Robinson, M... more ... MB, Ph.D., William Geerts, MD, Michael Kovacs, MD, Jeffrey I. Weitz, MD, K. Susan Robinson, MD, Renaud ... Hélène Desmurs-Clavel, Jacques Ninet, Pascal Gaucherand, Rene Charles Rudigoz, Michel Berland, Fabienne Champion, Marie Christine Trzeciak. ... Shannon M. Bates. ...
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