Introduction
Methods
Heparin for treatment of acute VTE |
(1) How should heparin be initiated, including baseline laboratory tests and dosing? |
(2) What weight should be used to calculate dosing, and should obese and low body weight patients be treated differently? |
(3) How should heparin be monitored? |
(4) What data support the benefit of monitoring? |
(5) What is the appropriate therapeutic range? |
(6) When should heparin resistance be suspected? |
(7) What algorithm should be used for dosing adjustments? |
(8) What is the appropriate duration of therapy for heparin for transition to oral anticoagulant therapy? |
(9) How should heparin-induced over-anticoagulation, thrombocytopenia and bleeding be managed? |
LMWH for treatment of acute VTE |
(1) How should LMWH be initiated, including baseline laboratory tests and dosing? |
(2) What weight should be used to calculate dosing, and should obese and low body weight patients be treated differently? |
(3) How should patients with renal impairment be treated? |
(4) How should routine treatment be monitored? |
(5) Is there a role for peak anti-Xa monitoring and for trough anti-Xa monitoring? |
(6) What is the appropriate duration of therapy when transitioning to oral anticoagulant therapy? |
(7) Which patients are acceptable candidates for outpatient treatment of VTE with LMWH? |
(8) How should LMWH-induced over-anticoagulation, thrombocytopenia and bleeding be managed? |
Fondaparinux for treatment of acute VTE |
(1) How should fondaparinux be initiated, including baseline labs and dosing? |
(2) What weight should be used to calculate dosing, and should obese and low body weight patients be treated differently? |
(3) How should patients with renal impairment be treated? |
(4) How should treatment be monitored? |
(5) Is there a role for peak anti-Xa monitoring and for trough anti-Xa monitoring? |
(6) What is the appropriate duration of therapy when transitioning to oral anticoagulant therapy? |
(7) Who is a candidate for outpatient treatment of VTE with fondaparinux? |
(8) Can fondaparinux be used for VTE treatment in the presence of active heparin-induced thrombocytopenia (HIT) or those with a history of HIT? |
(9) How should fondaparinux-induced over-anticoagulation and bleeding be managed? |
Guidance
Heparin for the treatment of acute VTE
Route | Reference | Bolus dose | Maintenance dose |
---|---|---|---|
Continuous infusion | |||
Fixed dose | Hull et al. [1] | 5000 units | 1250–1280 units/ha
|
Weight based | Raschke et al. [6] | 80 units/kg | 18 units/kg/h |
Subcutaneous | |||
Fixed dose | Kearon et al. [4] | 333 units/kg | 250 units/kg every 12 h |
Adjusted dose | Prandoni et al. [3] | 5000 units | 17,500 units every 12 h adjusted to aPTT |
Year | VTE recommendation | Level of evidence |
---|---|---|
2001 [41] | Treat with heparin or LMWH for at least 5 days and overlap with heparin or LMWH for at least 4–5 days
| 1A (in comparison to treatment for 10 days) |
2004 [10] | Initiate vitamin K antagonist with LMWH or heparin on day one and discontinue heparin when INR is stable and >2.0
| 1A |
2008 [32] | Treat with LMWH, heparin or fondaparinux for at least 5 days and until the INR is ≥2 for 24 h
| 1C |
2012 [11] | Recommend early initiation of vitamin K antagonist (same day as parenteral is started) over delayed initiation, and until the INR is 2.0 or above for at least 24 h
| 1B |
To warfarin | To dabigatran or edoxaban | To rivaroxaban or apixaban | |
---|---|---|---|
Initial parenteral therapy | Required | Required | Not required |
From heparin | Start warfarin and heparin concurrently | Start heparin alone | Stop heparin |
Continue heparin for a minimum of 5 days AND until INR > 2.0 | After a minimum of 5 days of heparin, start dabigatran or edoxaban and stop heparin | Give first dose of rivaroxaban or apixaban | |
From LMWH or fondaparinux | Start warfarin and LMWH/fondaparinux concurrently | Start LMWH/fondaparinux alone | Stop LMWH/fondaparinux |
After a minimum of 5 days, stop LMWH/fondaparinux | |||
Continue LMWH/fondaparinux for a minimum of 5 days AND until INR > 2.0 | Give first dose of dabigatran or edoxaban at the time the next dose of LMWH/fondaparinux would have been given | Give first dose of rivaroxaban or apixaban at the time the next dose of LMWH/fondaparinux would have been given |
Guidance
LMWH for the treatment of acute VTE
Guidance
Fondaparinux for the treatment of acute VTE
Conclusion
Question | Guidance statement |
---|---|
Heparin for treatment of acute VTE | |
(1) How should heparin be initiated, including baseline laboratory tests and dosing? | We suggest that total body weight, CBC, PT and aPTT be obtained prior to initiating heparin therapy. Heparin efficacy is related to dose regardless of route. The initial dose is more important than the aPTT in predicting efficacy. Although optimal initial dosing for bolus and continuous infusion remain uncertain, we suggest doses outlined in Table 2, acknowledging that these options have not been compared in head-to-head clinical trials. Internal audits to determine the dose requirement to produce therapeutic anticoagulation based upon the responsiveness of the health-system’s aPTT reagent and coagulation instrument are encouraged |
(2) What weight should be used to calculate dosing, and should obese and low body weight patients be treated differently? | When a weight based heparin dosing strategy is selected, we suggest total body weight for calculating dose and encourage internal audits of protocol performance. For the obese/morbidly obese patient either total body weight or adjusted body weight can be used. Although no increased risk of major bleeding has been reported when morbidly obese patients are managed using total body weight, studies have not included patients weighing above 270 kg. If adjusted body weight is used, prompt attention to initial laboratory results is warranted to ensure the therapeutic threshold is exceeded in a timely manner. Empiric dose caps may increase the risk of initial under anticoagulation in obese and morbidly obese patients. If empiric dose caps are used, individualized initial dosing should be available for obese and morbidly obese patients |
(3) How should heparin be monitored? | The optimal approach to heparin monitoring is unknown. Either aPTT or heparin anti-Xa level monitoring may be used. We suggest using anti-Xa level monitoring in patients with heparin resistance, a prolonged baseline aPTT or altered heparin responsiveness. We suggest the aPTT or anti-Xa level be checked every 6 h until two consecutive therapeutic results are obtained, after which the frequency of monitoring can be extended to once daily |
(4) What data support the benefit of monitoring? | The benefit of monitoring IV heparin once a therapeutic threshold has been exceeded is not well defined. We suggest monitoring of continuous infusion heparin therapy, either using aPTT or anti-Xa, as this is considered standard of care despite the weak evidence base. Monitoring is optional in those receiving SC weight-based heparin therapy |
(5) What is the appropriate therapeutic range? | The optimal heparin therapeutic range is uncertain. The target therapeutic range is less important than ensuring an appropriate initial heparin dose. The CAP recommends the one-time establishment of a heparin concentration-derived aPTT therapeutic range. The cumulative summation method is suggested for range re-evaluation following reagent/instrument change. When anti-Xa monitoring is used, a therapeutic target of 0.3–0.7 units/mL is suggested |
(6) When should heparin resistance be suspected? | We suggest drawing a paired aPTT and heparin anti-Xa level when heparin resistance is suspected. If the aPTT is subtherapeutic and the anti-Xa level is therapeutic, the heparin dose does not require adjustment and subsequent monitoring should occur using the anti-Xa level when feasible. If, despite serial dose increases, both the aPTT and anti-Xa level remain low, true heparin resistance may be present |
(7) What algorithm should be used for dosing adjustments? | We recommend that heparin dosing be guided by a dose adjustment nomogram, and that a weight based heparin dose adjustment algorithm may offer benefit over a fixed adjustment algorithm for the obese patient. More research in defining and assessing the optimal dosage adjustment nomogram is needed |
(8) What is the appropriate duration of therapy for heparin for transition to oral anticoagulant therapy? | Parenteral anticoagulation with heparin should be overlapped with warfarin for at least 5 days and until a single INR is 2.0 or greater. Treatment of VTE with rivaroxaban and apixaban does not require initial parenteral anticoagulation while dabigatran and edoxaban requires a minimum of 5 days of parenteral anticoagulation prior to initiation. See Table 4 for additional details |
(9) How should heparin-induced over-anticoagulation, thrombocytopenia and bleeding be managed? | We suggest protamine sulfate be administered to reverse the effect of heparin when indicated. We suggest that health systems develop and implement guidelines on anticoagulant reversal and HIT evaluation and management |
LMWH for treatment of acute VTE | |
(1) How should LMWH be initiated, including baseline laboratory tests and dosing? | We suggest that total body weight, baseline serum creatinine, CBC, PT and aPTT be obtained prior to initiating LMWH. We suggest that when enoxaparin is used for the treatment of VTE, only the twice daily dosing strategy be used, except in patients with severe renal insufficiency (see below). Further, we suggest that once daily dalteparin can be used for the treatment of both cancer- and non-cancer-associated VTE |
(2) What weight should be used to calculate dosing, and should obese and low body weight patients be treated differently? | We suggest that in all patients, including underweight and obese, LMWH dosing should be based on total body weight. For patients <40 kg, UFH may be more appropriate. For enoxaparin dosing in obese patients, 1 mg/kg BID is preferred over 1.5 mg/kg daily. Dose capping should be avoided. Routine monitoring of peak anti-Xa levels is not recommended in patients on LMWH, whether obese or non-obese |
(3) How should patients with renal impairment be treated? | When LMWH is used for acute treatment of VTE in patients with renal impairment, we suggest that vigilant attention to potential bleeding risk and monitoring for signs and symptoms of bleeding be employed. Renal function should be estimated using the Cockcroft-Gault method for calculating CrCl. In patients with a CrCl < 30 mL/min the use of UFH may be preferred over LMWH and if enoxaparin is used, it should be dosed at 1 mg/kg daily. If LMWH is used for an extended period beyond the usual 5–7 days of treatment, trough anti-Xa measurement may be considered in patients with severe renal dysfunction. LMWH should be avoided in patients with CrCl < 20 mL/min and those receiving renal replacement therapy |
(4) How should routine treatment be monitored? | We suggest all patients receiving LMWH be monitored for signs and symptoms of bleeding and be observed for changes in renal function that may require a dose adjustment. We suggest against the routine use of LMWH anti-Xa monitoring. CBC, platelet count and Scr should be assessed periodically during LMWH treatment |
(5) Is there a role for peak anti-Xa monitoring and for trough anti-Xa monitoring? | We suggest that in limited populations, including patients with severe renal failure, trough anti-Xa levels may have a role in evaluating LMWH accumulation and the need to prolong the dosing interval. We suggest that peak anti-Xa levels not be utilized to evaluate dosing regimens in clinical practice |
(6) What is the appropriate duration of therapy when transitioning to oral anticoagulant therapy? | Parenteral anticoagulation with LMWH should be overlapped with warfarin for at least 5 days and until a single INR is 2.0 or greater. Treatment of VTE with rivaroxaban and apixaban does not require initial parenteral anticoagulation while dabigatran and exoxaban require a minimum of 5 days of parenteral anticoagulation prior to initiation. See Table 4 for additional details. The timing of the first dose of a TSOAC is based on when the next scheduled dose of LMWH would be due |
(7) Which patients are acceptable candidates for outpatient treatment of VTE with LMWH? | We suggest patients with VTE be evaluated to determine treatment setting. Patients with DVT and/or PE who are identified as having a low risk of complications should be treated in the outpatient setting as long as they have adequate home circumstances |
(8) How should LMWH-induced over-anticoagulation, thrombocytopenia and bleeding be managed? | We suggest that protamine sulfate be used to reverse LWMH if major bleeding occurs. The timing of the last dose of LMWH should be assessed when determining if protamine sulfate should be administered and the appropriate dose to be administered. A repeat dose of protamine may be administered if bleeding continues or if the aPTT is prolonged 2–4 h after the initial dose. Patients who develop HIT in response to LMWH should be treated according to current guidelines for HIT |
Fondaparinux for treatment of acute VTE | |
(1) How should fondaparinux be initiated, including baseline labs and dosing? | We suggest that total body weight, baseline serum creatinine, CBC, PT and aPTT be obtained prior to initiating fondaparinux therapy. We suggest dosing fondaparinux based on weight as follows: less than 50 kg: 5 mg SC once daily, 50–100 kg: 7.5 mg SC once daily, and greater than 100 mg: 10 mg SC once daily |
(2) What weight should be used to calculate dosing, and should obese and low body weight patients be treated differently? | We suggest patients be dosed based on total body weight. Patients weighing more than 100 kg should receive fondaparinux 10 mg SC once daily. Patients with a BMI greater than 30 kg/m2 should be dosed based on total body weight. Patients weighing less than 50 kg should receive 5 mg SC once daily |
(3) How should patients with renal impairment be treated? | We suggest that fondaparinux be avoided in patients with a CrCl of less than 30 mL/min. We also suggest that patients with moderate renal insufficiency be monitored closely for bleeding during longer durations of therapy due to potential accumulation |
(4) How should treatment be monitored? | We suggest that most patients receiving fondaparinux do not require therapeutic drug monitoring. If the clinical setting suggests the need to assess accumulation of fondaparinux, we suggest using an anti-Xa assay calibrated for fondaparinux, and we suggest against the use of a PT, aPTT, or ACT |
(5) Is there a role for peak anti-Xa monitoring and for trough anti-Xa monitoring? | If the clinical setting suggests a benefit of measuring trough fondaparinux levels, we suggest a chromogenic anti-Xa with the standardization curve calibrated with fondaparinux. We suggest against using anti-Xa with the standard curves created using a LMWH or UFH |
(6) What is the appropriate duration of therapy when transitioning to oral anticoagulant therapy? | Parenteral anticoagulation with fondaparinux should be overlapped with warfarin for at least 5 days and until a single INR is 2.0 or greater. Treatment of VTE with rivaroxaban and apixaban does not require initial parenteral anticoagulation while dabigatran and edoxaban require a minimum of 5 days of parenteral anticoagulation prior to initiation. See Table 4 for additional details. The timing of the first dose of a TSOAC is based on when the next scheduled dose of fondaparinux would be due |
(7) Who is a candidate for outpatient treatment of VTE with fondaparinux? | We suggest patients with VTE be evaluated to determine the treatment setting. Patients with DVT and/or PE who are identified as having a low risk of complications (see above) should be treated in the outpatient setting as long as they have adequate home circumstances |
(8) Can fondaparinux be used for VTE treatment in the presence of active heparin-induced thrombocytopenia (HIT) or those with a history of HIT? | We suggest that fondaparinux may be used for treatment of VTE in patients with a history of HIT. In patients with acute VTE who develop HIT in response to initial use of UFH/LMWH, we suggest that fondaparinux may be considered as an option for treatment. When fondaparinux is used in patients with acute HIT, we suggest that treatment doses be used |
(9) How should fondaparinux-induced over-anticoagulation and bleeding be managed? | We suggest the use of rFVIIa in the setting of life-threatening bleeding induced by fondaparinux, and that potential benefits must be weighed against thrombotic risk |