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

Stroke Clinical Trial

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00432796
• Other study ID #: R-06-267
• Secondary ID: NRA6300019
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: December 2006
• Est. completion date: December 2020

Study information

• Verified date: February 2020
• Source: Lawson Health Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1473
• Est. completion date: December 2020
• Est. primary completion date: March 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Informed consent,

2. Patients aged >18

3. Patients with prosthetic(mechanical) heart valve

4. 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)

5. 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:

1. Evidence of active bleeding within last 30 days prior to stopping warfarin.

2. Platelet count <100 x 109/L.

3. Spinal or neurosurgery.

4. Life expectancy less than 3 months.

5. Calculated creatinine clearance <30 ml/min

6. Patients requiring cardiac surgery.

7. Multiple prosthetic(mechanical) valves or Starr-Edwards valve or prosthetic(mechanical) valve with a history of stroke or TIA

8. History of heparin induced thrombocytopenia (HIT)

Related Conditions & MeSH terms

• Stroke
• Thromboembolism

Intervention

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:
• 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

Locations

Country	Name	City	State
Canada	QE II Health Sciences Centre	Halifax	Nova Scotia
Canada	Hamilton Health Sciences Corporation-General Hospital	Hamilton	Ontario
Canada	Hamilton Health Sciences Corporation-Henderson Site	Hamilton	Ontario
Canada	Hamilton Health Sciences Corporation-McMaster Site	Hamilton	Ontario
Canada	SMBD Jewish General Hospital	Montreal	Quebec
Canada	Ottawa Hospital-General Campus	Ottawa	Ontario
India	Care Hospital	Hyderabad	Nampally
India	Sir Ganga Ram Hospital	New Delhi

Sponsors (3)

Lead Sponsor	Collaborator
Lawson Health Research Institute	Canadian Institutes of Health Research (CIHR), Pfizer

Countries where clinical trial is conducted

Canada,  India, 

References & Publications (45)

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* Note: There are 45 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	major thromboembolism		90 days from randomization
Secondary	major bleeding		90 days from randomization
Secondary	minor bleeding		90 days from randomization
Secondary	a composite of major bleeding and major thromboembolic events		90 days from randomization
Secondary	minor thromboembolic events		90 days from randomization
Secondary	overall survival.		90 days from randomization