Ignite Creation Date:
2024-05-05 @ 5:14 PM
Last Modification Date:
2024-10-26 @ 9:29 AM
Study NCT ID:
NCT00413374
Status:
COMPLETED
Last Update Posted:
2018-06-28
First Post:
2006-12-15
Brief Title:
Once Daily Enoxaparin for Outpatient Treatment of Acute DVT andor Pulmonary Embolism
Sponsor:
Brigham and Womens Hospital
Organization:
Brigham and Womens Hospital
Study Overview
Official Title:
Once Daily Enoxaparin for Outpatient Treatment of Acute Deep Venous Thrombosis andor Pulmonary Embolism
Status:
COMPLETED
Status Verified Date:
2018-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
To investigate the efficacy and safety of once daily enoxaparin as a bridge to warfarin for the outpatient treatment of acute deep venous thrombosis or pulmonary embolism
Detailed Description:
Background and Significance
Low molecular weight heparin LMWH as a bridge to warfarin has become the standard of care for outpatient treatment of acute deep venous thrombosis DVT LMWH is also often prescribed as a bridge to warfarin for patients with acute pulmonary embolism PE In the United States the FDA has approved enoxaparin only for twice daily dosing in outpatient treatment of acute DVT The FDA has also approved enoxaparin for treatment of DVT with or without PE but the FDA has not approved enoxaparin for the treatment of PE without DVT The FDA has also not approved once daily enoxaparin for any DVT or PE treatment indication for outpatients
Once daily dosing of enoxaparin in outpatients with DVT alone DVT with PE or PE without DVT will halve the number of required injections facilitate outpatient treatment and reduce health care costs For example visiting nurses will make one visit daily instead of two visits daily for those patients who are unable self-inject and for those patients who lack family or friends to inject LMWH
Merli et al randomized 900 hospitalized venous thromboembolism VTE patients with acute DVT or PE to one of three treatment groups 1 continuous infusion of unfractionated heparin UFH 2 once daily enoxaparin 15mgkg or 3 twice daily enoxaparin 1mgkg All study patients were inpatients None were outpatients They received once or twice daily enoxaparin or UFH for at least five days and were bridged to warfarin Patients were followed for three months Primary endpoints were recurrent DVT or PE There were no significant differences in recurrent DVT or PE among the 3 treatment groups There were 12 recurrent VTE events in the UFH group 13 in the once daily enoxaparin group and 9 in the twice daily enoxaparin group
The frequency of major hemorrhage did not differ among the three treatment groups Major hemorrhage occurred in 6 of 290 patients 21 in the UFH group 5 of 298 patients 17 in the once daily enoxaparin group and 4 of 312 patients 13 in the twice daily enoxaparin group
Merli et al showed that once daily enoxaparin was as effective and safe as twice daily enoxaparin But this study was done only among hospitalized patients with acute DVT or PE Treatment results in hospitalized patients do not necessarily apply to the outpatient population Therefore the FDA has not approved outpatient DVT or PE treatment with once daily enoxaparin
The BWH Venous Thromboembolism Research Group has an outstanding track record for investigator initiated trials We have recently completed 2 investigator initiated trials with enoxaparin for the treatment of PE One trial was published in Thrombosis and Haemostasis and the other is accepted for publication in Vascular Medicine
Clinically stable PE patients with normal right ventricular size and function as assessed by echocardiogram or chest CT scan are at very low risk of adverse clinical events Either imaging test is excellent for acquiring the information we need to document normal RV size and function These clinically stable PE patients with negative biomarkers troponin and normal right ventricular function can be safely treated as outpatients
Therefore we wish to include in this trial clinically stable patients with acute PE who have normal right ventricular size on chest CT in addition to patients with acute DVT Chest CT with a 4 chamber view with RVDLVD measurement will be performed in all cases by a radiologist with experience in this technique to confirm normal RV size on all PE patients
In this investigator initiated trial we will conduct a feasibility study with once daily enoxaparin as a bridge to warfarin for outpatient treatment of acute DVT or PE
Subject selection
Physicians caring for DVT and PE patients in the noninvasive vascular lab Emergency Department primary care office and inpatient care units at Brigham and Womens Hospital often summon our Group for consultation Our Group will under these circumstances describe this protocol If the referring physician and the patient agrees these patients will be approached for enrollment by physician investigators from the research team
We will study 40 patients with symptomatic DVT or PE confirmed by ultrasound or chest computed tomography respectively and treat them with once daily enoxaparin as a bridge to warfarin In this case-control series we will match 2 historical controls by age and gender to every case Controls who received twice daily enoxaparin as a bridge to warfarin for acute venous thromboembolism will be matched from a retrospective study of previously hospitalized patients Additional characteristics of matched control group will include prior DVT or PE cancer heart disease and pulmonary disease
All patients enrolled in the study will receive enoxaparin 15mgkgday as a bridge to warfarin using at least 4 outpatient doses of enoxaparin and overlapping enoxaparin and warfarin for at least 4 days
Study Procedures
Enrollment Eligible patients with confirmed DVT andor PE who are stable for outpatient treatment will be approached for enrollment
Following enrollment patients will be started on enoxaparin 15mgkgday as a bridge to warfarin Patients will receive overlapping once daily enoxaparin and warfarin for at least 4 days
After enrollment patients will be started on warfarin 75 mg daily Initial INR will be checked on day 3 after starting warfarin Thereafter INR will be checked daily from day 4 to day 7 and until INR is 20 for 2 consecutive days Enoxaparin will be discontinued after a minimum of 4 days and after 2 consecutive values 20 Once enoxaparin is discontinued patients will continue oral warfarin alone All INR tests can be done at any hospital including Brigham and Womens or at a lab that is closer to patients home
Study investigators will perform anticoagulation management after discharge for 30 days with an initial office follow-up visit between days 7 and 13 and a final office visit between days 27 and 33 This will include clinical assessment and blood testing of renal function and international normalized ratio INR Each study visit will take up to 1 hour Each blood test will require 5 ml of patients blood
At the conclusion of the 30-day trial responsibility for anticoagulation including the decision about its duration will revert to the Primary Care Physician
Biostatistical Analysis
The sample size of 40 patients serves to assess the feasibility and safety of once daily enoxaparin therapy as a bridge to warfarin for outpatient treatment of acute DVT andor PE
A composite endpoint of death recurrent venous thromboembolism and major hemorrhage will be assessed at 30 days Comparisons are made on an intention-to-treat basis Separate analyses will also be performed on each individual endpoint
The statistical analysis plan will include specific exploratory subgroup analyses DVT without PE PE without DVT and combined DVT plus PE
The statistical analysis will be by intention to treat In other words once a patient is recruited that patient will be analyzed regardless of protocol violations and regardless of missing data No patient will be excluded from the analyses because of protocol violations missing data or any other reason
Chi-squared testing will be used for statistical analysis For cells with 5 or fewer patients the Fishers Exact Test will be used
Efficacy and safety will be statistically evaluated in a composite endpoint This composite endpoint will include Death recurrent venous thromboembolism and major hemorrhage at 30 days Separate analyses will also be performed on each individual endpoint
Low molecular weight heparin LMWH as a bridge to warfarin has become the standard of care for outpatient treatment of acute deep venous thrombosis DVT LMWH is also often prescribed as a bridge to warfarin for patients with acute pulmonary embolism PE In the United States the FDA has approved enoxaparin only for twice daily dosing in outpatient treatment of acute DVT The FDA has also approved enoxaparin for treatment of DVT with or without PE but the FDA has not approved enoxaparin for the treatment of PE without DVT The FDA has also not approved once daily enoxaparin for any DVT or PE treatment indication for outpatients
Once daily dosing of enoxaparin in outpatients with DVT alone DVT with PE or PE without DVT will halve the number of required injections facilitate outpatient treatment and reduce health care costs For example visiting nurses will make one visit daily instead of two visits daily for those patients who are unable self-inject and for those patients who lack family or friends to inject LMWH
Merli et al randomized 900 hospitalized venous thromboembolism VTE patients with acute DVT or PE to one of three treatment groups 1 continuous infusion of unfractionated heparin UFH 2 once daily enoxaparin 15mgkg or 3 twice daily enoxaparin 1mgkg All study patients were inpatients None were outpatients They received once or twice daily enoxaparin or UFH for at least five days and were bridged to warfarin Patients were followed for three months Primary endpoints were recurrent DVT or PE There were no significant differences in recurrent DVT or PE among the 3 treatment groups There were 12 recurrent VTE events in the UFH group 13 in the once daily enoxaparin group and 9 in the twice daily enoxaparin group
The frequency of major hemorrhage did not differ among the three treatment groups Major hemorrhage occurred in 6 of 290 patients 21 in the UFH group 5 of 298 patients 17 in the once daily enoxaparin group and 4 of 312 patients 13 in the twice daily enoxaparin group
Merli et al showed that once daily enoxaparin was as effective and safe as twice daily enoxaparin But this study was done only among hospitalized patients with acute DVT or PE Treatment results in hospitalized patients do not necessarily apply to the outpatient population Therefore the FDA has not approved outpatient DVT or PE treatment with once daily enoxaparin
The BWH Venous Thromboembolism Research Group has an outstanding track record for investigator initiated trials We have recently completed 2 investigator initiated trials with enoxaparin for the treatment of PE One trial was published in Thrombosis and Haemostasis and the other is accepted for publication in Vascular Medicine
Clinically stable PE patients with normal right ventricular size and function as assessed by echocardiogram or chest CT scan are at very low risk of adverse clinical events Either imaging test is excellent for acquiring the information we need to document normal RV size and function These clinically stable PE patients with negative biomarkers troponin and normal right ventricular function can be safely treated as outpatients
Therefore we wish to include in this trial clinically stable patients with acute PE who have normal right ventricular size on chest CT in addition to patients with acute DVT Chest CT with a 4 chamber view with RVDLVD measurement will be performed in all cases by a radiologist with experience in this technique to confirm normal RV size on all PE patients
In this investigator initiated trial we will conduct a feasibility study with once daily enoxaparin as a bridge to warfarin for outpatient treatment of acute DVT or PE
Subject selection
Physicians caring for DVT and PE patients in the noninvasive vascular lab Emergency Department primary care office and inpatient care units at Brigham and Womens Hospital often summon our Group for consultation Our Group will under these circumstances describe this protocol If the referring physician and the patient agrees these patients will be approached for enrollment by physician investigators from the research team
We will study 40 patients with symptomatic DVT or PE confirmed by ultrasound or chest computed tomography respectively and treat them with once daily enoxaparin as a bridge to warfarin In this case-control series we will match 2 historical controls by age and gender to every case Controls who received twice daily enoxaparin as a bridge to warfarin for acute venous thromboembolism will be matched from a retrospective study of previously hospitalized patients Additional characteristics of matched control group will include prior DVT or PE cancer heart disease and pulmonary disease
All patients enrolled in the study will receive enoxaparin 15mgkgday as a bridge to warfarin using at least 4 outpatient doses of enoxaparin and overlapping enoxaparin and warfarin for at least 4 days
Study Procedures
Enrollment Eligible patients with confirmed DVT andor PE who are stable for outpatient treatment will be approached for enrollment
Following enrollment patients will be started on enoxaparin 15mgkgday as a bridge to warfarin Patients will receive overlapping once daily enoxaparin and warfarin for at least 4 days
After enrollment patients will be started on warfarin 75 mg daily Initial INR will be checked on day 3 after starting warfarin Thereafter INR will be checked daily from day 4 to day 7 and until INR is 20 for 2 consecutive days Enoxaparin will be discontinued after a minimum of 4 days and after 2 consecutive values 20 Once enoxaparin is discontinued patients will continue oral warfarin alone All INR tests can be done at any hospital including Brigham and Womens or at a lab that is closer to patients home
Study investigators will perform anticoagulation management after discharge for 30 days with an initial office follow-up visit between days 7 and 13 and a final office visit between days 27 and 33 This will include clinical assessment and blood testing of renal function and international normalized ratio INR Each study visit will take up to 1 hour Each blood test will require 5 ml of patients blood
At the conclusion of the 30-day trial responsibility for anticoagulation including the decision about its duration will revert to the Primary Care Physician
Biostatistical Analysis
The sample size of 40 patients serves to assess the feasibility and safety of once daily enoxaparin therapy as a bridge to warfarin for outpatient treatment of acute DVT andor PE
A composite endpoint of death recurrent venous thromboembolism and major hemorrhage will be assessed at 30 days Comparisons are made on an intention-to-treat basis Separate analyses will also be performed on each individual endpoint
The statistical analysis plan will include specific exploratory subgroup analyses DVT without PE PE without DVT and combined DVT plus PE
The statistical analysis will be by intention to treat In other words once a patient is recruited that patient will be analyzed regardless of protocol violations and regardless of missing data No patient will be excluded from the analyses because of protocol violations missing data or any other reason
Chi-squared testing will be used for statistical analysis For cells with 5 or fewer patients the Fishers Exact Test will be used
Efficacy and safety will be statistically evaluated in a composite endpoint This composite endpoint will include Death recurrent venous thromboembolism and major hemorrhage at 30 days Separate analyses will also be performed on each individual endpoint
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None