Perioperative anticoagulation management in mechanical heart valves, the PERIOP2 trial

Authors

Taylor Drury, MD, MSc, FRCPC (biography, no disclosures), Poupak Anna Rahmani, MD, PhD, FRCPC (biography and disclosures), and Tony Wan, MD, FRCPC (biography and disclosures).

What I did before

Mechanical heart valves increase a patient’s risk of systemic arterial embolism including stroke, and valve thrombosis, especially if they are not properly anticoagulated. This can be particularly challenging when anticoagulation needs to be held around the time of surgery. Recent studies in patients with atrial fibrillation, especially with CHADS score of 3 or less, have provided evidence that perioperative “bridging” is not beneficial [1]. However, until recently we have had very limited evidence around perioperative bridging for mechanical valves.

The 2012 ACCP (American College of Chest Physicians) perioperative anticoagulation guidelines stratified patients with mechanical heart valves into high, moderate, and low risk based on the estimated annual incidence of thrombotic complications in patients not treated with anticoagulation (Table 1) [2]. These estimates were based on indirect and often outdated studies [3]. The ACCP recommends perioperative bridging anticoagulation for patients at high risk for thromboembolism, no perioperative bridging anticoagulation for patients at low risk, and did not have enough data for a recommendation in patients at moderate risk. However, owing to the paucity of data, the ACCP could not make recommendations on the dosing of anticoagulation used for bridging (i.e. therapeutic vs prophylactic), and as a result, most practitioners employ therapeutic anticoagulation pre- and post-operatively as published in previous studies [1]. Unfortunately, there have been no published updates to these guidelines since 2012, and they continue to direct current clinical practice [4].

Table 1: 2012 ACCP perioperative anticoagulation recommendations for patients with mechanical heart valves

Adapted from the 2012 ACCP perioperative anticoagulation guidelines [2].

TE – thromboembolism; TIA – transient ischemic attack; VKA – vitamin K antagonist

What changed my practice

The PERIOP2 trial, published in June 2021, was a multinational, randomized, double-blind, placebo-controlled trial examining whether no post-operative bridging anticoagulation as compared to post-operative bridging anticoagulation was beneficial in reducing the number of bleeding events and rates of major thromboembolism at 90 days in patients on warfarin who required anticoagulation interruption for a procedure [5]. This study ran between 2007 and 2016, primarily at Canadian centers. Patients with a mechanical heart valve plus or minus concurrent atrial fibrillation, as well as patients with atrial fibrillation and at least one CHADS2 risk factor were included. Patients with multiple mechanical heart valves, a Starr-Edwards valve (caged-ball valve), or a mechanical heart valve plus history of stroke or TIA were excluded. All patients had warfarin stopped 5 days before surgery and received pre-operative therapeutic Dalteparin. Post-operatively, patients were randomized to Dalteparin or placebo injections. Patients randomized to Dalteparin who had a high-risk bleeding procedure received prophylactic Dalteparin (5000 units daily) and those who had a low-risk bleeding procedure received therapeutic Dalteparin (200 units/kg). All patients had warfarin restarted on postoperative day 0. Injections of Dalteparin or placebo were continued for at least 4 days and until INR >1.9. In all, 1471 patients participated, including 305 patients with mechanical heart valves.

Within the mechanical heart valve subgroup, 33% had concurrent atrial fibrillation, 56% had aortic mechanical valve, and 44% had mitral mechanical valve. Of the patients randomized to post-operative Dalteparin, 63% had a high-risk bleeding procedure and thus received only prophylactic Dalteparin. Major thromboembolic events, which included ischemic stroke, TIA, peripheral embolism, myocardial infarction, valve thrombosis, vascular death, and symptomatic acute VTE were low and similar between the no bridging and bridging groups, (1.2% vs 1.0% respectively, p=0.64). Within the mechanical heart valve subgroup, there was one total thromboembolic event (0.3%), a TIA occurring in a patient who received post-operative Dalteparin. Rates of major bleeding were also similar between patients who did not receive post-operative bridging and those who did (2.0% vs. 1.3% respectively, p=0.32), but rates of clinically relevant non-major bleeding were significantly higher in patients who received post-operative bridging (6.1% vs 3.9% respectively, p=0.05). Bleeding rates were not specifically reported in the subgroups of patients who received prophylactic Dalteparin vs therapeutic Dalteparin post-operatively.

What I do now

The PERIOP2 trial represents the largest population of patients with mechanical heart valves studied in the perioperative setting and the first large randomized controlled trial in this field. It addressed patients in all three risk strata from the 2012 ACCP guidelines, with the notable exceptions of patients with caged-ball prostheses and patients with mechanical heart valves and history of stroke or TIA, both in the high-risk stratum.  This study demonstrated that post-operative bridging anticoagulation is not beneficial in reducing rates of major thromboembolism and results in higher rates of bleeding.

Foregoing post-operative bridging anticoagulation entirely in patients with mechanical heart valves, especially those in the moderate to high-risk stratum is a challenging paradigm to overcome as it appears to contrast with the 2012 ACCP guidelines [2], and we recognize that the results of a single study alone are insufficient, in light of the small number of events, even in our own clinical practice.

However, our practice has changed because of this study. As in the PERIOP2 trial, we continue to use full dose therapeutic low molecular weight heparin (LMWH) for bridging in the pre-operative period. However, we now use post-operative prophylactic LMWH as an alternative bridging strategy in patients undergoing high-risk bleeding procedures. In patients at high risk of thromboembolism (including mechanical mitral valve and atrial fibrillation) undergoing a high-risk bleeding procedure, we are now less aggressive in resuming full dose therapeutic anticoagulation, as we feel comfortable using prophylactic LMWH for up to several days post-operatively before resuming therapeutic anticoagulation.

Overall, as the 2012 ACCP guidelines did not specify the dose of anticoagulation required for heparin bridging, this change of practice is not in direct conflict with the guidelines. It is important to note that this change in practice does not apply to patients with mechanical valve and a history of TIA/stroke, a caged ball valve, or those with multiple mechanical valves, as these patients were not included in the PERIOP2 trial.

As a final note, any clinicians in BC wanting to seek advice on perioperative anticoagulation management can call the Thrombosis RACE line (staffed 7 days a week, 8 am to 5 pm) at 604-696-2131 or via the RACEapp+.

References

1. Douketis, JD, Spyropoulos, AC, Kaatz, S, Becker, RC, Caprini, JA, Dunn, AS, Ortel, TL. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373(9):823-833. DOI:1056/NEJMoa1501035. (View).
2. Douketis, JD, Spyropoulos, AC, Spencer, FA, Mayr, M, Jaffer, AK, Eckman, M. H., … & Kunz, R. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2), e326S-e350S. DOI: 10.1378/chest.11-2298. (View).
3. Cannegieter, SC, Rosendaal, FR, & Briet, E. (1994). Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation. 1994;89(2), 635-641. DOI:10.1161/01.CIR.89.2.635. (View).
4. Spyropoulos, AC, Brohi, K, Caprini, J, Samama, CM, Siegal, D, Tafur, A, … & SSC Subcommittee on Perioperative and Critical Care Thrombosis and Haemostasis of the International Society on Thrombosis and Haemostasis. Scientific and Standardization Committee Communication: Guidance document on the periprocedural management of patients on chronic oral anticoagulant therapy: Recommendations for standardized reporting of procedural/surgical bleed risk and patient‐specific thromboembolic risk. Journal of Thrombosis and Haemostasis. J Thromb Haemost. 2019; 17(11), 1966-1972. DOI:10.1111/jth.14598. (View).
5. Kovacs, MJ, Wells, PS, Anderson, DR, Lazo-Langner, A., Kearon, C., Bates, SM, … & Rodger, MA. Postoperative low molecular weight heparin bridging treatment for patients at high risk of arterial thromboembolism (PERIOP2): double blind randomised controlled trial. BMJ. 2021; 373: n1205. DOI:10.1136/bmj.n1205. (View).

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Perioperative anticoagulation management in mechanical heart valves, the PERIOP2 trial

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