Tapered Warfarin or Interrupted Warfarin With Heparin Bridging for Pacemaker or Defibrillator Implantation

Study Overview
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Brief Summary
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Approximately 2 million patients in North America are currently treated with the blood thinner warfarin. These patients have every year more than 200,000 invasive procedures, for which warfarin must be stopped to avoid bleeding complication. To protect the patient against blood clots and stroke while warfarin is stopped, most physicians today order bridging with low-molecular-weight heparin (LMWH). This is another blood thinner and it is injected under the skin during 3 days before the procedure. For implantation of pacemaker or defibrillator (27,000/year in Canada) the bridging routines vary a lot.The common bridging treatment with LMWH for 3 days before pacemaker surgery causes bleeding in the pocket where the pacemaker is placed in about 5%. For comparison, patients not on any blood thinners develop this bleeding in 2% after this surgery. Pocket bleeding may require evacuation of the blood collection and may cause infection. Pocket bleeding is thus a fairly common and clinically important but rarely a dangerous bleeding complication. It is a suitable safety endpoint in a study of bridging of blood thinners. LMWH costs $80-120, for which some patients are not covered. They have to be taught self-injection technique or have a nurse come to their home. The main hypothesis is if patients on blood thinners can be managed more conveniently before and after pacemaker surgery, without injections, without increased risk of pocket bleeding.

Detailed Description
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Patients are recruited from those routinely referred before surgery for adjustment of their blood thinners. Suitable and consenting patients are randomized to one of the two regimens. They will either stop warfarin for 5 days and replace it with injections of LMWH for 3 days before pacemaker or implantable cardioverter defibrillator (ICD) surgery. The other group will have the dose of warfarin reduced to half for 3-6 days before surgery, depending on how thin their blood is. For all patients the degree of blood thinning is checked the day before surgery. If the blood is still to thin, the patient is instructed to take by mouth a dose of vitamin K, provided by us, to reduce the effect of warfarin. After surgery the patients restart warfarin at a double dose for 1 or 2 days to quickly reach the therapeutic effect again. Staff from the Pacemaker or Defibrillator Clinic, unaware of the treatment allocation, examines the patient for bleeding in the implantation pocket before they leave the hospital, and at routine follow-up after 2-3 weeks and 90 days.

Official Title
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An Open-Label Randomized Control Trial of Pre-Operative Low Molecular Weight Heparin Versus Tapered Warfarin as Bridging Therapy for Patients With Implantation of Pacemaker or Defibrillator

Conditions
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Thromboembolism, Hemorrhage, Cardiac Arrhythmias

Intervention / Treatment
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* Drug: Tapered warfarin regimen
* Drug: Bridged regimen Low-molecular-weight heparin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient has been receiving warfarin therapy for at least 1 week and is planned to continue this treatment for at least one month post-procedure The patient will have elective implantation or replacement of a pacemaker or ICD Exclusion Criteria: Age <18 years Previous stroke Stroke risk (CHADS2) score of 0 or 1 in patients with atrial fibrillation as the only indication for anticoagulation Creatinine clearance (CrCl) <30 mL/min Surgery planned for a Monday or a day after a holiday Patient unsuitable for the study as assessed by the investigator (e.g., psychiatric disorder, history of non-compliance) Failure to obtain written consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Bridged regimen<br>Bridged regimen Warfarin therapy is stopped for 5 days before surgery and restarted in the evening of surgery at double the usual dose for two days. Bridging with low-molecular-weight heparin at therapeutic dose is given for 2½ days before surgery. | Drug: Bridged regimen Low-molecular-weight heparin<br>* This intervention is assigned to the active control arm - Bridged regimen<br>* Other names: Low-molecular-weight heparin;|
| Experimental: Tapered warfarin regimen<br>Tapered warfarin regimen Warfarin is given at half the usual maintenance dose for 3-6 days before surgery depending on the INR at the baseline visit. A double dose is given in the evening of surgery. No bridging with LMWH is used. | Drug: Tapered warfarin regimen<br>* This intervention is assigned to the experimental arm - Tapered warfarin regimen<br>* Other names: Half dose warfarin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pocket hematoma | Pocket hematoma is defined as palpable swelling of the pacemaker or defibrillator pocket exceeding the size of the generator. | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major bleeding | Fatal bleeding OR Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome OR Bleeding causing a fall in hemoglobin level of 20 g·L-1 (1.24 mmol·L-1) or more, or leading to transfusion of two or more units of whole blood or red cells. | 1 month | 
| Thromboembolism | Arterial thromboembolism, consisting of one or more of the following: stroke (ischemic or hemorrhagic), transient ischemic attack, systemic embolism to a limb or viscus, thrombosis of a mechanical or native heart valve, or thrombosis of a cardiac chamber. OR Venous thromboembolism that is symptomatic AND for deep vein thrombosis is verified by ultrasound, venography or computed tomography; for pulmonary embolism is verified by ventilation-perfusion lung scan, spiral computed tomography or pulmonary angiography. | 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atrial fibrillation, Mechanical heart valve, Stroke, Venous thromboembolism, Hemorrhage