Ignite Creation Date:
2024-05-05 @ 11:56 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00187408
Status:
COMPLETED
Last Update Posted:
2007-02-27
First Post:
2005-09-13
Brief Title:
The D-KAF Dalteparin in Knee-to-Ankle Fracture Trial
Sponsor:
Sunnybrook Health Sciences Centre
Organization:
Sunnybrook Health Sciences Centre
Study Overview
Official Title:
Clinically-Important Venous Thromboembolism Following Lower Extremity Fractures Epidemiology Prevention
Status:
COMPLETED
Status Verified Date:
2006-02
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:
It is known that patients who fracture their legs sometimes develop blood clots known as deep vein thrombosis in their legs These clots may cause pain and swelling in the leg or they may detach and travel to the lungs producing shortness of breath chest pain and sometimes death Unfortunately it is not known how frequently these complications occur after leg fractures or if the use of a blood thinner medication can effectively and safely prevent these clots Doctors at hospitals across Canada are conducting a study in which patients who have surgery for leg fractures receive either a once-daily injection of a blood thinner known as low molecular weight heparin or a placebo injection for up to 14 days after their fractures Neither the patients nor the doctors know which patient is on the medication and which patient is on placebo All patients receive an ultrasound examination of their legs at 2 weeks after surgery to monitor for deep vein thrombosis In addition all patients are checked for symptoms of leg or lung clots and any side effects of the medication for 3 months If the blood thinner is shown to be effective at reducing this complication and documented to be safe and cost-effective in this setting it will be recommended for use in such patients If on the other hand the frequency of deep vein thrombosis is too low to justify the cost or inconvenience of taking this medication this will also be an important finding
Detailed Description:
RESEARCH QUESTIONS
1 What is the incidence of clinically-important venous thromboembolism VTE following surgically-repaired isolated fractures of the tibia fibula or ankle
2 In patients with surgically-repaired isolated fractures of the tibia fibula or ankle is simple anticoagulant thromboprophylaxis effective safe and cost-effective
BACKGROUND AND RATIONALE
Isolated below-knee fractures are very common injuries seen in all emergency departments and general hospitals Venographic studies suggest that the incidence of overall deep vein thrombosis DVT following such fractures is in the range of 20-50 However the prospective studies that have screened patients with these fractures for DVT are few in number and have methodologic limitations In addition most of the thrombi detected are distal and small and therefore of uncertain clinical significance Although patients with leg fractures are at risk for symptomatic DVT PE and occasionally fatal PE there is a paucity of reliable data about the incidence of and risk factors for the development of clinically-important VTE following contemporary treatment of these fractures
Furthermore data related to thromboprophylaxis in these patients are insufficient to recommend prophylaxis even in patients whose fractures are managed surgically There is considerable variation in the use of prophylaxis for such patients across North America the majority of orthopedic surgeons use no prophylaxis a small proportion use in-hospital prophylaxis only and an even smaller proportion use therapeutic levels of anticoagulation until the patient is fully mobile without a cast The routine use of prophylaxis for patients with below-knee fractures may not be necessary may be associated with adverse effects related to the prophylaxis and may not be cost-effective A methodologically rigorous study is required to address all of the above issues
The D-KAF trial will determine the incidence of and risk factors for clinically-important VTE in patients with isolated fractures of the tibia fibula or ankle who are managed surgically At the same time D-KAF will assess the role if any of routine thromboprophylaxis in such patients The study has the potential to significantly impact on the care of these patients irrespective of whether the result is positive or negative The use of clinically relevant endpoints will be of great importance in the design of future prophylaxis trials in this and other patient groups
OBJECTIVES
Among patients with isolated lower extremity fractures of the tibia fibula or ankle treated surgically to determine
1 The incidence of clinically-important VTE over the first 3 months after injury in patients receiving usual care no thromboprophylaxis
2 The predictors of clinically-important VTE in usual care patients
3 The effectiveness compared to placebo of a LMWH dalteparin given as 5000 U once daily for up to 14 days in the prevention of clinically-important VTE
4 The safety of this prophylaxis regimen with respect to clinically-important bleeding
5 The cost-effectiveness of the active intervention
6 The predictors of prophylaxis failure clinically-important VTE and adverse events
7 The incidence of clinically-important VTE from the time that LMWH is discontinued to week 12 this objective seeks to determine if prophylaxis beyond the first 2 weeks is indicated
STUDY DESIGN
This is a randomized double-blind multi-center comparison of the LMWH dalteparin versus placebo in patients with isolated fractures of the tibia fibula or ankle who undergo surgical repair It will assess the epidemiology of VTE following these injuries and determine the effectiveness safety and cost-effectiveness of dalteparin in preventing clinically important VTE
INTERVENTIONS
All eligible patients who have provided informed consent are randomized to receive
dalteparin 5000 anti-Xa units OR saline placebo given once daily by subcutaneous injection using identical pre-loaded syringes
The first dose of study drug commences as soon as possible after the fracture and always within 72 hours of injury
Non-study anticoagulant prophylaxis and mechanical prophylaxis graduated compression stockings pneumatic compression pumps or venous foot pumps is not allowed Use of aspirin antiplatelet agents and NSAIDS is discouraged unless the indication is for cardiac or stroke prophylaxis the management of arthritis or short-term postoperative analgesia
PATIENT ASSESSMENT
Baseline Assessment
At baseline each patient has
History and physical examination
Completion of baseline case report form which summarizes past medical and surgical history and details of the current injury and its management
CBC INR PTT creatinine
Follow-up Assessments
All inpatients are seen daily to monitor adherence to the protocol as well as symptoms and signs of DVT PE clinically significant bleeding and other adverse events
If discharged prior to 14 days patients are taught to self-administer the study injections at home by a research nurse Patients are called at home every 3 days to ensure compliance with the study medication and to address any questions or concerns related to the study
All patients are seen in follow-up 14 2 days after injury At this visit a focussed history and physical examination is performed and a CBC obtained All patients are screened for proximal DVT using bilateral duplex ultrasound examination
Patients with normal DUS have the study medication discontinued and no further DVT prophylaxis is given for the remainder of the study period
All patients receive a telephone follow up at 6 1 week and 3 months 1 week after randomization to assess their clinical status They are asked specifically about symptoms and signs of DVT and PE hospitalizations and co-intervention administration of anticoagulants
Clinical suspicion of possible DVT or PE during the 3-month study period is investigated in a standardized manner using objective diagnostic tests and pre-specified diagnostic algorithms
All patients who develop objectively confirmed DVT or PE either symptomatic or asymptomatic detected on the day 14 screening ultrasound are treated with full-dose anticoagulation generally LMWH followed by warfarin for at least 3 months
OUTCOME MEASURES
Primary Outcome Clinically important venous thromboembolism in the two study groups This is a composite outcome measure that includes symptomatic DVT symptomatic PE and fatal PE during the 3 months following fracture plus asymptomatic proximal DVT at the end of the prophylaxis phase
Symptomatic DVT is defined as clinically suspected DVT confirmed by positive duplex ultrasound or venography
Symptomatic PE is defined as clinically suspected PE confirmed by high probability VQ scan or positive leg imaging for DVT spiral CT or pulmonary angiogram
Fatal PE as confirmed by autopsy
Asymptomatic proximal DVT by screening ultrasound examination at 14 2 days
Secondary Outcomes
Clinically important VTE during the prophylaxis phase day 1 to discontinuation of study medication - this usually corresponds to the end-of-prophylaxis phase DUS or day 14 2
Clinically important VTE during the post-prophylaxis phase usually day 14 to 3 months
Bleeding modified International Bleeding Classification
Major - defined as overt bleeding that is life threatening or requires surgical intervention the transfusion of 1 or more units of red blood cells or is associated with a drop in hemoglobin of ³ 20 gL or development of hemarthrosis or compartment syndrome
Minor - overt bleeding other than that defined as major Bleeding index This validated measure of bleeding takes into account both change in hematocrit and the amount of blood transfused
Costs associated with the prophylaxis and with the relevant outcomes
ANALYSES
Baseline characteristics of the two study groups will be compared for patients randomized and for those who successfully complete the study using appropriate parametric or nonparametric statistics
Primary analysis will be based on an intention-to-treat principle and will compare the proportion of patients in each group that develop the primary outcome objectively-confirmed clinically-important VTE over the 3 month follow-up period using the Yates-corrected chi-square test of two independent proportions
Secondary analyses will compare the rates of clinically important VTE for the two study phases the prophylaxis phase randomization to day 14 2 and the post-prophylaxis phase day 14 to 3 months
A safety analysis will compare bleeding and other adverse events in the two groups over the prophylaxis phase and the entire study period
Compliance with the assigned intervention will be compared
Cost-effectiveness will be determined prospectively
Predictors of thrombosis in patients with lower extremity fractures from the placebo group and predictors of prophylaxis failures from the active treatment group will be explored using logistic regression analysis although we recognize that the number of events will likely be low The factors to be considered include age gender obesity BMI smoking varicose veins oral contraceptive or hormone replacement use number of risk factors type of fracture method of fracture treatment delay to surgery OR time time after injury to initiation of prophylaxis compliance mobility at the end of the prophylaxis phase and fracture complications including infection reoperation non-union
SAMPLE SIZE ESTIMATION
1 Assumptions used a 005 1-tail power 80 rate of clinically important VTE in the control group 4 risk reduction with prophylaxis 75 yielding a Number Needed to Prophylax 33
2 Assuming a 5 post-randomization attrition rate the estimated sample size will be 350 patients per group a total of 700 patients
3 A formal blinded interim analysis will be performed after 500 patients have completed follow-up
1 What is the incidence of clinically-important venous thromboembolism VTE following surgically-repaired isolated fractures of the tibia fibula or ankle
2 In patients with surgically-repaired isolated fractures of the tibia fibula or ankle is simple anticoagulant thromboprophylaxis effective safe and cost-effective
BACKGROUND AND RATIONALE
Isolated below-knee fractures are very common injuries seen in all emergency departments and general hospitals Venographic studies suggest that the incidence of overall deep vein thrombosis DVT following such fractures is in the range of 20-50 However the prospective studies that have screened patients with these fractures for DVT are few in number and have methodologic limitations In addition most of the thrombi detected are distal and small and therefore of uncertain clinical significance Although patients with leg fractures are at risk for symptomatic DVT PE and occasionally fatal PE there is a paucity of reliable data about the incidence of and risk factors for the development of clinically-important VTE following contemporary treatment of these fractures
Furthermore data related to thromboprophylaxis in these patients are insufficient to recommend prophylaxis even in patients whose fractures are managed surgically There is considerable variation in the use of prophylaxis for such patients across North America the majority of orthopedic surgeons use no prophylaxis a small proportion use in-hospital prophylaxis only and an even smaller proportion use therapeutic levels of anticoagulation until the patient is fully mobile without a cast The routine use of prophylaxis for patients with below-knee fractures may not be necessary may be associated with adverse effects related to the prophylaxis and may not be cost-effective A methodologically rigorous study is required to address all of the above issues
The D-KAF trial will determine the incidence of and risk factors for clinically-important VTE in patients with isolated fractures of the tibia fibula or ankle who are managed surgically At the same time D-KAF will assess the role if any of routine thromboprophylaxis in such patients The study has the potential to significantly impact on the care of these patients irrespective of whether the result is positive or negative The use of clinically relevant endpoints will be of great importance in the design of future prophylaxis trials in this and other patient groups
OBJECTIVES
Among patients with isolated lower extremity fractures of the tibia fibula or ankle treated surgically to determine
1 The incidence of clinically-important VTE over the first 3 months after injury in patients receiving usual care no thromboprophylaxis
2 The predictors of clinically-important VTE in usual care patients
3 The effectiveness compared to placebo of a LMWH dalteparin given as 5000 U once daily for up to 14 days in the prevention of clinically-important VTE
4 The safety of this prophylaxis regimen with respect to clinically-important bleeding
5 The cost-effectiveness of the active intervention
6 The predictors of prophylaxis failure clinically-important VTE and adverse events
7 The incidence of clinically-important VTE from the time that LMWH is discontinued to week 12 this objective seeks to determine if prophylaxis beyond the first 2 weeks is indicated
STUDY DESIGN
This is a randomized double-blind multi-center comparison of the LMWH dalteparin versus placebo in patients with isolated fractures of the tibia fibula or ankle who undergo surgical repair It will assess the epidemiology of VTE following these injuries and determine the effectiveness safety and cost-effectiveness of dalteparin in preventing clinically important VTE
INTERVENTIONS
All eligible patients who have provided informed consent are randomized to receive
dalteparin 5000 anti-Xa units OR saline placebo given once daily by subcutaneous injection using identical pre-loaded syringes
The first dose of study drug commences as soon as possible after the fracture and always within 72 hours of injury
Non-study anticoagulant prophylaxis and mechanical prophylaxis graduated compression stockings pneumatic compression pumps or venous foot pumps is not allowed Use of aspirin antiplatelet agents and NSAIDS is discouraged unless the indication is for cardiac or stroke prophylaxis the management of arthritis or short-term postoperative analgesia
PATIENT ASSESSMENT
Baseline Assessment
At baseline each patient has
History and physical examination
Completion of baseline case report form which summarizes past medical and surgical history and details of the current injury and its management
CBC INR PTT creatinine
Follow-up Assessments
All inpatients are seen daily to monitor adherence to the protocol as well as symptoms and signs of DVT PE clinically significant bleeding and other adverse events
If discharged prior to 14 days patients are taught to self-administer the study injections at home by a research nurse Patients are called at home every 3 days to ensure compliance with the study medication and to address any questions or concerns related to the study
All patients are seen in follow-up 14 2 days after injury At this visit a focussed history and physical examination is performed and a CBC obtained All patients are screened for proximal DVT using bilateral duplex ultrasound examination
Patients with normal DUS have the study medication discontinued and no further DVT prophylaxis is given for the remainder of the study period
All patients receive a telephone follow up at 6 1 week and 3 months 1 week after randomization to assess their clinical status They are asked specifically about symptoms and signs of DVT and PE hospitalizations and co-intervention administration of anticoagulants
Clinical suspicion of possible DVT or PE during the 3-month study period is investigated in a standardized manner using objective diagnostic tests and pre-specified diagnostic algorithms
All patients who develop objectively confirmed DVT or PE either symptomatic or asymptomatic detected on the day 14 screening ultrasound are treated with full-dose anticoagulation generally LMWH followed by warfarin for at least 3 months
OUTCOME MEASURES
Primary Outcome Clinically important venous thromboembolism in the two study groups This is a composite outcome measure that includes symptomatic DVT symptomatic PE and fatal PE during the 3 months following fracture plus asymptomatic proximal DVT at the end of the prophylaxis phase
Symptomatic DVT is defined as clinically suspected DVT confirmed by positive duplex ultrasound or venography
Symptomatic PE is defined as clinically suspected PE confirmed by high probability VQ scan or positive leg imaging for DVT spiral CT or pulmonary angiogram
Fatal PE as confirmed by autopsy
Asymptomatic proximal DVT by screening ultrasound examination at 14 2 days
Secondary Outcomes
Clinically important VTE during the prophylaxis phase day 1 to discontinuation of study medication - this usually corresponds to the end-of-prophylaxis phase DUS or day 14 2
Clinically important VTE during the post-prophylaxis phase usually day 14 to 3 months
Bleeding modified International Bleeding Classification
Major - defined as overt bleeding that is life threatening or requires surgical intervention the transfusion of 1 or more units of red blood cells or is associated with a drop in hemoglobin of ³ 20 gL or development of hemarthrosis or compartment syndrome
Minor - overt bleeding other than that defined as major Bleeding index This validated measure of bleeding takes into account both change in hematocrit and the amount of blood transfused
Costs associated with the prophylaxis and with the relevant outcomes
ANALYSES
Baseline characteristics of the two study groups will be compared for patients randomized and for those who successfully complete the study using appropriate parametric or nonparametric statistics
Primary analysis will be based on an intention-to-treat principle and will compare the proportion of patients in each group that develop the primary outcome objectively-confirmed clinically-important VTE over the 3 month follow-up period using the Yates-corrected chi-square test of two independent proportions
Secondary analyses will compare the rates of clinically important VTE for the two study phases the prophylaxis phase randomization to day 14 2 and the post-prophylaxis phase day 14 to 3 months
A safety analysis will compare bleeding and other adverse events in the two groups over the prophylaxis phase and the entire study period
Compliance with the assigned intervention will be compared
Cost-effectiveness will be determined prospectively
Predictors of thrombosis in patients with lower extremity fractures from the placebo group and predictors of prophylaxis failures from the active treatment group will be explored using logistic regression analysis although we recognize that the number of events will likely be low The factors to be considered include age gender obesity BMI smoking varicose veins oral contraceptive or hormone replacement use number of risk factors type of fracture method of fracture treatment delay to surgery OR time time after injury to initiation of prophylaxis compliance mobility at the end of the prophylaxis phase and fracture complications including infection reoperation non-union
SAMPLE SIZE ESTIMATION
1 Assumptions used a 005 1-tail power 80 rate of clinically important VTE in the control group 4 risk reduction with prophylaxis 75 yielding a Number Needed to Prophylax 33
2 Assuming a 5 post-randomization attrition rate the estimated sample size will be 350 patients per group a total of 700 patients
3 A formal blinded interim analysis will be performed after 500 patients have completed follow-up
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