Postoperative low molecular weight heparin bridging treatment for patients at high risk of arterial thromboembolism (PERIOP2): double blind randomised controlled trial

Abstract Objective To determine the efficacy and safety of dalteparin postoperative bridging treatment versus placebo for patients with atrial fibrillation or mechanical heart valves when warfarin is temporarily interrupted for a planned procedure. Design Prospective, double blind, randomised controlled trial. Setting 10 thrombosis research sites in Canada and India between February 2007 and March 2016. Participants 1471 patients aged 18 years or older with atrial fibrillation or mechanical heart valves who required temporary interruption of warfarin for a procedure. Intervention Random assignment to dalteparin (n=821; one patient withdrew consent immediately after randomisation) or placebo (n=650) after the procedure. Main outcome measures Major thromboembolism (stroke, transient ischaemic attack, proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, peripheral embolism, or vascular death) and major bleeding according to the International Society on Thrombosis and Haemostasis criteria within 90 days of the procedure. Results The rate of major thromboembolism within 90 days was 1.2% (eight events in 650 patients) for placebo and 1.0% (eight events in 820 patients) for dalteparin (P=0.64, risk difference −0.3%, 95% confidence interval −1.3 to 0.8). The rate of major bleeding was 2.0% (13 events in 650 patients) for placebo and 1.3% (11 events in 820 patients) for dalteparin (P=0.32, risk difference −0.7, 95% confidence interval −2.0 to 0.7). The results were consistent for the atrial fibrillation and mechanical heart valves groups. Conclusions In patients with atrial fibrillation or mechanical heart valves who had warfarin interrupted for a procedure, no significant benefit was found for postoperative dalteparin bridging to prevent major thromboembolism. Trial registration Clinicaltrials.gov NCT00432796 .

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Double Blind Randomized Control Trial of Postoperative Low Molecular Weight Heparin Bridging Therapy for Patients Who Are at High Risk for Arterial Thromboembolism (PERIOP 2)

Blood ◽

10.1182/blood-2018-99-109964 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 424-424 ◽

Cited By ~ 4

Author(s):

Michael J. Kovacs ◽

Marc Rodger ◽

Philip S. Wells ◽

Shannon M. Bates ◽

Clive Kearon ◽

...

Keyword(s):

Atrial Fibrillation ◽

Major Bleeding ◽

Research Funding ◽

Heart Valves ◽

Mechanical Valve ◽

Mechanical Heart Valves ◽

Bridging Therapy ◽

Double Blind ◽

Post Procedure ◽

History Of

Abstract Background It remains uncertain if patients with atrial fibrillation or mechanical heart valves requiring interruption of warfarin for procedures benefit from post-procedure anticoagulant bridging therapy. Methods In order to determine the efficacy and safety of postoperative LMWH bridging, we conducted a multicenter randomized double-blind controlled trial of patients with atrial fibrillation or a mechanical heart valve who require interruption of warfarin for a planned procedure. We excluded patients with active bleeding within 30 days, platelet count <100 x10⁹/L, spinal, cardiac or neurosurgery, life expectancy <3months, creatinine clearance <30ml/min, multiple mechanical valves or a Starr-Edwards valve, mechanical valve with history of stroke or TIA, or a history of heparin induced thrombocytopenia. The last dose of warfarin was given 6 days prior to the procedure. All patients received pre-procedure bridging therapy with dalteparin 200 IU per kilogram (max 18,000 IU) subcutaneously in the morning day-3 and day-2 then dalteparin 100 IU per kilogram (max 18,000 IU) subcutaneously 24 hours pre-procedure. Warfarin was resumed in the evening of the procedure at twice the usual dose for the first two days and then titrated according to INR. After the procedure (same day or next day), when hemostasis had been achieved, patients were randomized to receive dalteparin or placebo for at least 4 days and until the INR was greater than 1.9. Randomization was stratified by presence of a mechanical valve, by the post-procedure risk for major bleeding, and by centre. For patients at high risk for post-procedure major bleeding, dalteparin or placebo was administered at a fixed daily dose of 5000 IU. For patients at low risk for post-procedure major bleeding, dalteparin or placebo was administered at a daily dose of 200 IU per kilogram (max 18,000 IU). The primary analysis was a comparison of the proportion of patients who had major thromboembolism (stroke, proximal DVT, PE, MI, peripheral embolism) over 90 days by Chi-squared test according to the intention to treat principle. Secondary outcomes were major bleeding, all cause mortality and a composite outcome of major thromboembolism and major bleeding. Results Starting in October 2006 we randomized a total of 1471 patients of whom 1167 had atrial fibrillation (without mechanical heart valves) and 304 had mechanical valves (99 also had atrial fibrillation). Last follow up was completed in May 2016. Baseline characteristics were similar between the LMWH and the placebo groups (see Table 1). Due to a randomization program system error at two centres more atrial fibrillation patients were randomized to dalteparin rather than to placebo. Major thromboembolism occurred in 6/820 (0.71%) dalteparin patients and 7/650 (1.11%) placebo patients. Major post-procedure bleeding occurred in 12 (1.46%) dalteparin patients and 16 (2.46%) placebo patients. Findings were similar in patients with atrial fibrillation alone and in patients with mechanical heart valves (with or without atrial fibrillation) (Table 2). Conclusions In patients with atrial fibrillation and/or mechanical heart valves who had warfarin interrupted for a procedure there was no benefit from post-procedure LMWH bridging. Disclosures Kovacs: Bayer: Research Funding; Daiichi Sankyo Pharma Development: Research Funding. Wells:Janssen: Honoraria; Sanofi: Honoraria; BMS: Honoraria, Research Funding; Bayer: Honoraria. Schulman:Boehringer-Ingelheim: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Sanofi: Honoraria; Bayer: Honoraria.

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