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

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

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.

Study Overview

• Status: Unknown
• Conditions: Embolic Stroke
• Intervention / Treatment: Drug: Enoxaparin; Drug: Heparin

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• Iran, Islamic Republic of
  • Fars
    • Shiraz, Fars, Iran, Islamic Republic of, 11351-71937
      • Recruiting
      • Nemazi hospital
      • Contact: Reyhane Sedghi, MD; Phone Number: 00989177035783; Email: reihaneh.sedghi@gmail.com
    • Shiraz, Fars, Iran, Islamic Republic of, 7134844119
      • Recruiting
      • Faghihi Hospital
      • Contact: Farnia Feiz, MD; Phone Number: 00989177383403; Email: farniafeiz@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low molecular-weight heparin; 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; 1 mg of enoxaparin per kilogram of body weight subcutaneous every 12 hour; Other Names: clexane (Clexane, Sanofi, Paris)
Active Comparator: unfractionated heparin; 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; 1000 unit per hour continuous intravenous infusion of heparin sodium; 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

Collaborators and Investigators

• Sponsor: Shiraz University of Medical Sciences
• Investigators: Principal Investigator: Afshin Borhani Haghighi, Associate professor, Shiraz University of medical sciences, department of neurology; Study Chair: Farnia Feiz, medical student, Shiraz University of Medical Sciences; Study Chair: Reyhane Sedghi, medical student, Shiraz University of Medical Sciences

Publications and helpful links

General Publications

• Shahpouri MM, Mousavi S, Khorvash F, Mousavi SM, Hoseini T. Anticoagulant therapy for ischemic stroke: A review of literature. J Res Med Sci. 2012 Apr;17(4):396-401.
• Kase CS, Albers GW, Bladin C, Fieschi C, Gabbai AA, O'Riordan W, Pineo GF; PREVAIL Investigators. Neurological outcomes in patients with ischemic stroke receiving enoxaparin or heparin for venous thromboembolism prophylaxis: subanalysis of the Prevention of VTE after Acute Ischemic Stroke with LMWH (PREVAIL) study. Stroke. 2009 Nov;40(11):3532-40. doi: 10.1161/STROKEAHA.109.555003. Epub 2009 Aug 20.
• Algra A, de Schryver EL, van Gijn J, Kappelle LJ, Koudstaal PJ. Oral anticoagulants versus antiplatelet therapy for preventing further vascular events after transient ischaemic attack or minor stroke of presumed arterial origin. Cochrane Database Syst Rev. 2001;(4):CD001342. doi: 10.1002/14651858.CD001342.
• Saxena R, Lewis S, Berge E, Sandercock PA, Koudstaal PJ. Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial. Stroke. 2001 Oct;32(10):2333-7. doi: 10.1161/hs1001.097093.
• Hallevi H, Albright KC, Martin-Schild S, Barreto AD, Savitz SI, Escobar MA, Gonzales NR, Noser EA, Illoh K, Grotta JC. Anticoagulation after cardioembolic stroke: to bridge or not to bridge? Arch Neurol. 2008 Sep;65(9):1169-73. doi: 10.1001/archneur.65.9.noc70105. Epub 2008 Jul 14.
• Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuunemann HJ; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):7S-47S. doi: 10.1378/chest.1412S3. No abstract available. Erratum In: Chest. 2012 Apr;141(4):1129. Dosage error in article text. Chest. 2012 Dec;142(6):1698. Dosage error in article text.
• Fahimi F, Baniasadi S, Behzadnia N. Enoxaparin Utilization Evaluation: An Observational Prospective Study in Medical Inpatients. Iranian Journal of Pharmaceutical Research 2008;7 (1):77-82.
• Kalafut MA, Gandhi R, Kidwell CS, Saver JL. Safety and cost of low-molecular-weight heparin as bridging anticoagulant therapy in subacute cerebral ischemia. Stroke. 2000 Nov;31(11):2563-8. doi: 10.1161/01.str.31.11.2563.
• Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EF; American Heart Association; American Stroke Association Stroke Council; Clinical Cardiology Council; Cardiovascular Radiology and Intervention Council; Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007 May;38(5):1655-711. doi: 10.1161/STROKEAHA.107.181486. Epub 2007 Apr 12. Erratum In: Stroke. 2007 Jun;38(6):e38. Stroke. 2007 Sep;38(9):e96.
• Cohen M, Demers C, Gurfinkel EP, Turpie AG, Fromell GJ, Goodman S, Langer A, Califf RM, Fox KA, Premmereur J, Bigonzi F. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med. 1997 Aug 14;337(7):447-52. doi: 10.1056/NEJM199708143370702.
• Burak CR, Bowen MD, Barron TF. The use of enoxaparin in children with acute, nonhemorrhagic ischemic stroke. Pediatr Neurol. 2003 Oct;29(4):295-8. doi: 10.1016/s0887-8994(03)00270-4.

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Anticipated): February 1, 2016
• Study Completion (Anticipated): September 1, 2016

Study Registration Dates

• First Submitted: January 20, 2014
• First Submitted That Met QC Criteria: June 6, 2014
• First Posted (Estimate): June 9, 2014

Study Record Updates

• Last Update Posted (Estimate): June 9, 2014
• Last Update Submitted That Met QC Criteria: June 6, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: atrial fibrillation; ischemic stroke; bridging therapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Ischemic Stroke; Stroke; Embolic Stroke; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Enoxaparin; Calcium heparin; Enoxaparin sodium
• Other Study ID Numbers: 92-01-01-5667