BMJ June 09, 2021

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

Michael J Kovacs, Philip S Wells, David R Anderson, Alejandro Lazo-Langner, Clive Kearon, Shannon M Bates, et al.

Bottom Line

In patients with atrial fibrillation or mechanical heart valves requiring temporary interruption of warfarin, postoperative bridging with dalteparin did not reduce major thromboembolism but increased clinically relevant non-major bleeding compared to placebo.

Key Findings

1. The rate of major thromboembolism within 90 days was 1.0% (8/820) in the dalteparin bridging group versus 1.2% (8/650) in the placebo group (P=0.64, risk difference -0.3%, 95% CI -1.3 to 0.8).

2. Major bleeding occurred in 1.3% (11/820) of the dalteparin group and 2.0% (13/650) of the placebo group (P=0.32, risk difference -0.7%, 95% CI -2.0 to 0.7).

3. Clinically relevant non-major bleeding (CRNMB) was significantly more frequent in the postoperative dalteparin bridging group compared to the placebo group (6.1% vs 3.9%, P=0.05).

Study Design

Design

RCT

Double-Blind

Sample

1,471

Patients

Duration

90 days

Median

Setting

Multicenter, Canada and India

Population Adults ≥18 years on chronic warfarin therapy for atrial fibrillation or mechanical heart valves who required temporary interruption of anticoagulation for a planned procedure.

Intervention Postoperative bridging with subcutaneous dalteparin (administered at a prophylactic or therapeutic dose based on procedural bleeding risk) until INR >1.9.

Comparator Postoperative placebo administered until INR >1.9.

Outcome Major thromboembolism (composite of stroke, TIA, proximal DVT, PE, MI, peripheral embolism, or vascular death) at 90 days.

Study Limitations

• The trial excluded patients at the absolute highest risk for thrombosis, such as those with older-generation caged-ball (Starr-Edwards) valves, multiple mechanical valves, or a history of stroke/TIA in the presence of a mechanical valve.

• Because the protocol mandated that all participants receive preoperative bridging with dalteparin, the study specifically evaluated the safety of omitting postoperative bridging rather than avoiding bridging entirely.

• The overall event rate for major thromboembolism was lower than initially expected, which could impact statistical power, although the consistent lack of benefit strongly supports the primary findings.

• Recruitment took over 9 years, and there was an unexpected imbalance in randomization allocation (821 vs 650) due to block size visibility at some sites, though baseline characteristics remained well-matched.

Clinical Significance

The PERIOP2 trial demonstrates that postoperative low molecular weight heparin bridging does not confer a thromboembolic protective benefit for patients with atrial fibrillation or mechanical heart valves undergoing procedures, but does increase the risk of clinically relevant non-major bleeding. These findings provide robust randomized data challenging the historical standard of care, supporting the resumption of warfarin without postoperative bridging in these patient populations.

Historical Context

For decades, perioperative bridging with heparin or LMWH was standard practice for patients on warfarin who were considered at high risk of thromboembolism, based largely on expert consensus and the physiological rationale to minimize time without anticoagulation. The landmark BRIDGE trial (2015) challenged this practice by demonstrating that omitting bridging entirely was safe in atrial fibrillation patients, but that trial explicitly excluded those with mechanical heart valves. PERIOP2 was a highly anticipated trial because it included mechanical heart valve patients (approximately 21% of the cohort) and specifically isolated the risks and benefits of the postoperative bridging phase, further solidifying the shift toward simplified, non-bridged perioperative management.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Why is bridging therapy traditionally considered for patients with mechanical heart valves or atrial fibrillation when pausing warfarin for surgery, and how does the mechanism of LMWH differ from warfarin?

Key Response

Tests foundational knowledge of the coagulation cascade. Warfarin inhibits vitamin K dependent factors II, VII, IX, X, Proteins C and S with a long half-life, whereas LMWH enhances antithrombin III primarily against Factor Xa with a shorter half-life. Bridging was theoretically designed to minimize the time patients spend subtherapeutic.

Resident

Based on the PERIOP2 trial results, how should you manage a patient with a mechanical aortic valve who is on warfarin and scheduled for an elective hernia repair regarding their postoperative anticoagulation?

Key Response

Applies trial findings directly to clinical management. Residents must recognize that postoperatively, starting an LMWH bridge increases clinically relevant bleeding without significantly reducing thromboembolic events. Therefore, resuming warfarin alone without an LMWH bridge is the evidence-based approach.

Fellow

The PERIOP2 trial included patients with both atrial fibrillation and mechanical heart valves. How does the inclusion of mechanical valve patients in this trial advance our understanding beyond the BRIDGE trial, and what are the specific sub-group considerations for mitral versus aortic mechanical valves?

Key Response

The BRIDGE trial excluded mechanical heart valves, focusing only on AF. Fellows must understand this critical difference and evaluate whether the PERIOP2 trial was adequately powered to definitively rule out bridging benefits in the highest-risk subgroup: patients with mechanical mitral valves.

Attending

How do the findings of PERIOP2 change the risk-benefit conversation we have with our surgical colleagues when coordinating postoperative anticoagulation, specifically regarding the long-standing dogma of perioperative rebound hypercoagulability?

Key Response

Focuses on interdisciplinary communication and changing deeply ingrained practice. Attendings must use this evidence to reassure surgeons and proceduralists that omitting postoperative LMWH bridging does not increase thromboembolic risk but significantly protects their surgical field from iatrogenic bleeding complications.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The PERIOP2 trial struggled with slow enrollment and lower-than-anticipated thromboembolic event rates. From a statistical and methodological standpoint, how does this affect the study's power to conclude a lack of efficacy for dalteparin, and what alternative trial designs could mitigate this in surgical populations?

Key Response

Critiques the study's statistical power. Low event rates and premature termination risk a Type II error regarding the efficacy endpoint (thromboembolism prevention). A PhD should consider how this limitation affects the confidence interval of the hazard ratio and explore adaptive trial designs or registry-based randomized trials.

Journal Editor

As a peer reviewer, how would you evaluate the decision by the PERIOP2 authors to use a composite safety outcome of major bleeding and clinically relevant non-major bleeding, and does this composite potentially inflate the perception of harm?

Key Response

Editors must scrutinize composite endpoints. Combining major and non-major bleeding increases event rates and statistical power, but reviewers must ensure that the harm signal is not driven entirely by minor, easily manageable events while obscuring the true, potentially low rate of devastating major bleeding.

Guideline Committee

Given that ACC/AHA and CHEST guidelines have historically recommended bridging for high-risk mechanical heart valves (e.g., mitral valves), how should the PERIOP2 data be incorporated to modify these specific recommendations, and what Level of Evidence does this trial provide?

Key Response

Guideline committees must weigh this new RCT against historical consensus. Since PERIOP2 showed increased bleeding without thromboembolic benefit, committees must decide if this Level B-R evidence is sufficient to downgrade the recommendation for post-op bridging in mechanical valves from a Class IIa to a Class III (Harm).

Clinical Landscape

Noteworthy Related Trials

2013

RE-ALIGN Trial

n = 252 · NEJM

Tested

Dabigatran

Population

Patients with mechanical heart valves

Comparator

Warfarin

Endpoint

Trough dabigatran levels, thromboembolism, and major bleeding

Key result: Dabigatran use in patients with mechanical heart valves led to increased rates of thromboembolic and bleeding complications compared to warfarin, causing early trial termination.

2013

BRUISE CONTROL Trial

n = 681 · NEJM

Tested

Continued warfarin (no bridging)

Population

Patients with moderate-to-high thromboembolic risk undergoing pacemaker or ICD implantation

Comparator

Interrupted warfarin with heparin bridging

Endpoint

Clinically significant device-pocket hematoma

Key result: Continuing warfarin significantly reduced the risk of device-pocket hematomas compared to interrupting warfarin and bridging with heparin.

2015

BRIDGE Trial

n = 1,884 · NEJM

Tested

Placebo (no bridging)

Population

Patients with atrial fibrillation undergoing elective surgery or invasive procedure

Comparator

Bridging with low-molecular-weight heparin (dalteparin)

Endpoint

Arterial thromboembolism and major bleeding at 30 days

Key result: Forgoing bridging was noninferior to bridging with LMWH for preventing arterial thromboembolism and resulted in a significantly lower risk of major bleeding.

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