PERIOP 2 - A Safety and Effectiveness of LMWH vs Placebo Bridging Therapy for Patients on Long Term Warfarin Requiring Temporary Interruption of Warfarin.

Sponsor

Lawson Health Research Institute (Other)

Overall Status

Unknown status

CT.gov ID

NCT00432796

Collaborator

Canadian Institutes of Health Research (CIHR) (Other), Pfizer (Industry)

1,473

Enrollment

Locations

Arms

168

Duration (Months)

184.1

Patients Per Site

1.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the study is to determine the effectiveness and safety of LMWH postoperative bridging therapy (standard of care) versus postoperative placebo bridging therapy (experimental arm)for patients with mechanical heart valves or atrial fibrillation or atrial flutter who are at high risk for stroke when warfarin is temporarily interrupted for a procedure.

Condition or Disease	Intervention/Treatment	Phase
Stroke	Drug: Dalteparin Other: Placebo	Phase 3

Detailed Description

There are a growing number of patients who receive long-term warfarin therapy for the prevention of arterial thromboembolism. The current approach to the perioperative management of anticoagulation (i.e. "bridging therapy") with low molecular weight heparin (LMWH) is not standardized and has not been assessed by adequate randomized studies. Most clinicians, however, recommend bridging therapy.

We have recently completed a multicentre single arm pilot study of LMWH bridging therapy. This study in 10 centres accrued 224 patients in 10 months. In the pilot study the postoperative thromboembolic event rate was 3.1% and 75% of these occurred in patients who had anticoagulation held due to bleeding.

Design:A prospective multicentre randomized double-blind controlled trial. Patients:

Consecutive eligible and consenting patients from 11 teaching hospitals in Canada. A total of 1773 patients with prosthetic heart valves receiving long-term oral anticoagulation with warfarin or patients with atrial fibrillation/flutter and a major risk factor who require elective non-cardiac surgery or invasive procedure necessitating reversal of their oral anticoagulant therapy.

Treatment Schedule: Consent will be obtained preoperatively but randomization will be performed postoperatively after confirming eligibility.

Preoperative period: In all participants, warfarin therapy will be discontinued five days prior to the procedure. Dalteparin, a LMWH, will be administered at 200 IU/kg sc early in the morning for the three days prior to, but not including the day of, the procedure except on the day prior to surgery the dose will be 100 I.U./kg given 24 hours preoperatively. Warfarin will be resumed the evening of the procedure.

Postoperative period: Dalteparin or placebo will be administered daily (starting the morning after the procedure), provided surgical hemostasis is achieved, and will be continued for at least four days and until the INR is>2.0. Patients considered at high risk for a postoperative major bleed will be given dalteparin or placebo at a dose of 5,000 IU sc daily. Patients who undergo procedures that are considered low risk for bleeding complications will resume dalteparin or placebo at 200 IU/Kg s.c. daily.

Outcomes:The primary outcome will be the frequency of episodes of major thromboembolism over a 90-day follow-up period following the time of randomization. Secondary outcomes will include major bleeding and overall survival.

Relevance: To bridge or not to bridge, is a common clinical question, without randomized trial evidence to guide clinicians. This RCT will answer whether post-operative bridging reduces risk of thromboembolism or causes harm.

Study Design

Study Type:

Interventional

Actual Enrollment :

1473 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

A Double Blind Randomized Control Trial of Post-Operative Low Molecular Weight Heparin Bridging Therapy Versus Placebo Bridging Therapy for Patients Who Are at High Risk for Arterial Thromboembolism (PERIOP 2)

Study Start Date :

Dec 1, 2006

Actual Primary Completion Date :

Mar 1, 2019

Anticipated Study Completion Date :

Dec 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 patients are randomized post-operative to receive either active treatment or placebo. Active treatment is Dalteparin injectable. Patients randomized to active treatment will receive Dalteparin 5,000 iu or 200 iu/kg once daily depending on the type of surgery they have had.	Drug: Dalteparin 5,000 iu or 200 iu/kg depending on the type of surgery injection will be given subcutaneously, once a day for a minimum of 4 days or until the INR is 2.0 Other Names: Fragmin
Experimental: 2 patients will be randomized post-operative to receive either active treatment or placebo	Other: Placebo patients will be randomized post-operative to receive either active treatment or placebo. the placebo will be given as a subcutaneous injection once a day. the amount of the placebo will be equivalent to the active treatment depending on the type of surgery. ie. 5,000 iu or 200 iu/kg

Arm

Intervention/Treatment

Active Comparator: 1

patients are randomized post-operative to receive either active treatment or placebo. Active treatment is Dalteparin injectable. Patients randomized to active treatment will receive Dalteparin 5,000 iu or 200 iu/kg once daily depending on the type of surgery they have had.

Drug: Dalteparin

5,000 iu or 200 iu/kg depending on the type of surgery injection will be given subcutaneously, once a day for a minimum of 4 days or until the INR is 2.0

Other Names:

Fragmin

Experimental: 2

patients will be randomized post-operative to receive either active treatment or placebo

Other: Placebo

patients will be randomized post-operative to receive either active treatment or placebo. the placebo will be given as a subcutaneous injection once a day. the amount of the placebo will be equivalent to the active treatment depending on the type of surgery. ie. 5,000 iu or 200 iu/kg

Outcome Measures

Primary Outcome Measures

major thromboembolism [90 days from randomization]

Secondary Outcome Measures

major bleeding [90 days from randomization]
minor bleeding [90 days from randomization]
a composite of major bleeding and major thromboembolic events [90 days from randomization]
minor thromboembolic events [90 days from randomization]
overall survival. [90 days from randomization]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Informed consent,
Patients aged >18
Patients with prosthetic(mechanical) heart valve
Patients with atrial fibrillation or atrial flutter and a major risk factor (previous TIA or stroke, high blood pressure, diabetes, aged >75, moderate/severe left ventricle dysfunction)
Who are receiving long-term oral anticoagulation and require elective non-cardiac surgery or an invasive procedure with reversal of their anticoagulant therapy.

Exclusion Criteria:

Evidence of active bleeding within last 30 days prior to stopping warfarin.
Platelet count <100 x 109/L.
Spinal or neurosurgery.
Life expectancy less than 3 months.
Calculated creatinine clearance <30 ml/min
Patients requiring cardiac surgery.
Multiple prosthetic(mechanical) valves or Starr-Edwards valve or prosthetic(mechanical) valve with a history of stroke or TIA
History of heparin induced thrombocytopenia (HIT)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	QE II Health Sciences Centre	Halifax	Nova Scotia	Canada	B3H 2Y9
2	Hamilton Health Sciences Corporation-General Hospital	Hamilton	Ontario	Canada	L8L 2X2
3	Hamilton Health Sciences Corporation-McMaster Site	Hamilton	Ontario	Canada	L8N 3Z5
4	Hamilton Health Sciences Corporation-Henderson Site	Hamilton	Ontario	Canada	L8V 1C3
5	Ottawa Hospital-General Campus	Ottawa	Ontario	Canada	K1H 8L6
6	SMBD Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
7	Care Hospital	Hyderabad	Nampally	India	500001
8	Sir Ganga Ram Hospital	New Delhi		India	110060