Study of the Efficacy, Safety and Tolerability of Low Molecular Weight Heparin vs. Unfractionated Heparin in Stroke

Study Overview
=================
Brief Summary
-----------------
Patients with Atrial fibrillation (AF) make a unique group of ischemic stroke, mostly caused by emboli from the left atrial appendage. Oral anticoagulation (Warfarin) is recommended for prevention of recurrent embolic stroke but it takes several days to reach a therapeutic international normalized ratio (INR : 2.5) so bridging therapy with a short acting intravenous anticoagulant is recommended until therapeutic INR level is reached. A common strategy is to use intravenous unfractionated heparin (UFH) until a standard activated partial thromboplastin time (aPTT) is reached and then initiating warfarin. Another strategy is to use subcutaneous (SQ) injection of a low-molecular-weight heparin (LMWH) eg. Enoxaparin. The investigators will compare LMWH and UFH, focusing on risk of new stroke and mortality rate. METHOD: This study is randomized controlled trial that will be performed in 80 patients ages between 18 and 75 with confirmed acute ischemic stroke purely due to AF who will be hospitalized in Shiraz Medical University affiliated teaching hospitals. Patients will be randomly assigned in two groups. A brain CT will be done to confirm the absence of intracranial hemorrhage and to assess the size of cerebral ischemia. First group will receive 1 mg of enoxaparin (Clexane, Sanofi, Paris) per kilogram of body weight SQ every 12 hour with warfarin 5mg orally everyday and both drugs will be continued until the target INR level (2.5) is reached then clexane will be discontinued. The second group will receive continuous UFH infusion 1000 unit per hour and then the dose will be adjusted to maintain a therapeutic aPTT (two times to baseline) level then warfarin will be started (5 mg everyday). The investigators will follow patients in both groups until target INR will be achieved (2.5) and after that clexane and UFH will be discontinued. Adverse events will be assessed in both groups for three months. Data will be analyzed with Statistical Package for the Social Sciences (SPSS) version 15 and Chi-square statistics. Main outcome of our study will be evaluation of new stroke, mortality, central nervous system (CNS) hemorrhage, major bleeding, drop out and other unwanted side effects in first week and three months after stroke.

Official Title
-----------------
Study of the Efficacy, Safety and Tolerability of Low Molecular Weight Heparin vs. Unfractionated Heparin as Bridging Therapy in Patients With Embolic Stroke Due to Atrial Fibrillation

Conditions
-----------------
Embolic Stroke

Intervention / Treatment
-----------------
* Drug: Enoxaparin
* Drug: Heparin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: confirmed diagnosis of acute ischemic stroke purely due to AF AF confirmed by ECG or 24 hour holter monitoring patients who need initiation of anticoagulation for prevention of recurrent stroke Exclusion Criteria: ages less than 18 or more than 75 no cooperation CNS hemorrhage major bleeding infarction size of more than one third of middle cerebral artery territory National Institutes of Health Stroke Scale (NIHSS) more than 20 hypersensitivity to IV UFH or LMWH no informed consent other causes for stroke except AF pregnancy breast feeding uncontrolled hypertension (BP more than 220/120) renal, hepatic, respiratory or cardiac failure myocardial infarction infectious endocarditis coma vasculitis dissection

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low molecular-weight heparin<br>these patients will receive 1 mg of enoxaparin (clexane) per kilogram of body weight subcutaneous every 12 hour with warfarin 5mg QD and both drugs will be continued until the target INR level (2.5) is reached then clexane will be discontinued. | Drug: Enoxaparin<br>* 1 mg of enoxaparin per kilogram of body weight subcutaneous every 12 hour<br>* Other names: clexane (Clexane, Sanofi, Paris);|
| Active Comparator: unfractionated heparin<br>This group will receive continuous intravenous unfractionated heparin sodium infusion 1000 unit per hour initially and then the dose will be adjusted to maintain a therapeutic aPTT level (two times to baseline) then warfarin will be started (5 mg QD). | Drug: Heparin<br>* 1000 unit per hour continuous intravenous infusion of heparin sodium<br>* Other names: Heparin Sodium (Alborz Darou,Tehran);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| mortality | all death cases are included but only mortality due to cerebrovascular accident are considered. | up to the 3 months of follow-up | 
| ischemic stroke | Ischemic strokes are those that are caused by interruption of the blood supply | up to the 3 months of follow-up | 
| hemorrhagic stroke | hemorrhagic strokes are the ones which result from rupture of a blood vessel or an abnormal vascular structure. | up to the 3 months of follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| symptomatic CNS hemorrhage | Intracranial bleeding occurs when a blood vessel within the skull is ruptured or leaks that causes neurological symptoms. It can result from nontraumatic causes as occurs in hemorrhagic stroke such as a ruptured aneurysm. Anticoagulant therapy can heighten the risk that an intracranial hemorrhage will occur. | up to the 3 months of follow-up | 
| Non-CNS hemorrhage | any bleeding of other sites of body except CNS. | up to the 3 months of follow-up | 
| asymptomatic CNS_hemorrhage | Intracranial bleeding occurs when a blood vessel within the skull is ruptured or leaks that will not cause neurological symptoms. It can result from nontraumatic causes as occurs in hemorrhagic stroke such as a ruptured aneurysm. Anticoagulant therapy can heighten the risk that an intracranial hemorrhage will occur. | up to the 3 months of follow-up | 
| time to reach target INR | the therapeutic INR level for patients on warfarin therapy is between 2.0 to 3.0. | average time 7 to 10 days (it is variable between individuals) | 
| tolerability of drugs | tolerability is how a patient can tolerate heparin and LMWH in terms of side effect and route of administration. | participants will be followed for the duration of hospital stay, an expected average of 1 week | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ischemic stroke, atrial fibrillation, bridging therapy