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Navigating the anticoagulant landscape in 2017

Cleveland Clinic Journal of Medicine. 2017 October;84(10):768-778 | 10.3949/ccjm.84gr.17005
October 2, 2017|Cleveland Clinic Journal of Medicine
James D. Douketis, MD, FRCP(C), FACP, FCCP
Author and Disclosure Information

James D. Douketis, MD, FRCP(C), FACP, FCCP
Professor of Medicine, McMaster University, Hamilton, ON, Canada; Chair, American College of Physicians Practice Guidelines in Perioperative Management of Antithrombotic Therapy

Address: James D. Douketis, MD, St Joseph’s Healthcare Hamilton, Room F-544, 50 Charlton Ave E, Hamilton, ON, Canada L8N 4A6; jdouket@mcmaster.ca

This article is based on an edited transcript from a Heart and Vascular Institute Grand Rounds presentation at Cleveland Clinic. It was approved by the author but not peer-reviewed.

ABSTRACT

Several questions remain regarding anticoagulant management: What is the best strategy for managing acute venous thromboembolism? How should patients on a direct oral anticoagulant or on warfarin be managed when they need elective surgery? When is heparin bridging necessary? 

KEY POINTS

  • Venous thromboembolism has a myriad of clinical presentations, warranting a holistic management approach that incorporates multiple antithrombotic management strategies.
  • A direct oral anticoagulant is an acceptable treatment option in patients with submassive venous thromboembolism, whereas catheter-directed thrombolysis should be considered in patients with iliofemoral deep vein thrombosis, and low-molecular-weight heparin in patients with cancer-associated thrombosis.
  • Perioperative management of direct oral anticoagulants should be based on the pharmacokinetic properties of the drug, the patient’s renal function, and the risk of bleeding posed by the surgery or procedure. 
  • Perioperative heparin bridging can be avoided in most patients who have atrial fibrillation or venous thromboembolism, but should be considered in most patients with a mechanical heart valve.

Is bridging needed during interruption of a direct oral anticoagulant?

There are no randomized, controlled trials of bridging vs no bridging in patients taking direct oral anticoagulants. Substudies exist of patients taking these drugs for atrial fibrillation who had treatment interrupted for procedures, but the studies did not randomize bridging vs no bridging, nor were bridging regimens standardized. Three of the four atrial fibrillation trials had a blinded design (warfarin vs direct oral anticoagulants), making perioperative management difficult, as physicians did not know the pharmacokinetics of the drugs their patients were taking.22–24

We used the database from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial22 to evaluate bridging in patients taking either warfarin or dabigatran. With an open-label study design (the blinding was only for the 110 mg and 150 mg dabigatran doses), clinicians were aware of whether patients were receiving warfarin or dabigatran, thereby facilitating perioperative management. Among dabigatran-treated patients, those who were bridged had significantly more major bleeding than those not bridged (6.5% vs 1.8%, P < .001), with no difference between the groups for stroke or systemic embolism. Although it is not a randomized controlled trial, it does provide evidence that bridging may not be advisable for patients taking a direct oral anticoagulant.

The 2017 American College of Cardiology guidelines25 conclude that parenteral bridging is not indicated for direct oral anticoagulants. Although this is not based on strong evidence, the guidance appears reasonable according to the evidence at hand.

The 2017 American Heart Association Guidelines16 recommend a somewhat complex approach based on periprocedural bleeding risk and thromboembolic risk.

How long to interrupt direct oral anticoagulants?

Table 4 shows a simplified approach to interrupting direct oral anticoagulants that we use in Canada. The approach takes into account the type of surgery and kidney function for patients taking dabigatran, a drug that depends more on renal clearance than the other direct oral anticoagulants do.26

Evidence for this approach comes from a prospective cohort study27 of 541 patients being treated with dabigatran who were having an elective surgery or invasive procedure. Patients received standard perioperative management, with the timing of the last dabigatran dose before the procedure (24 hours, 48 hours, or 96 hours) based on the bleeding risk of surgery and the patient’s creatinine clearance. Dabigatran was resumed 24 to 72 hours after the procedure. No heparin bridging was done. Patients were followed for up to 30 days postoperatively. The results were favorable with few complications: one transient ischemic attack (0.2%), 10 major bleeding episodes (1.8%), and 28 minor bleeding episodes (5.2%).

A subgroup of 181 patients in this study28 had a plasma sample drawn just before surgery, allowing the investigators to assess the level of coagulation factors after dabigatran interruption. Results were as follows:

  • 93% had a normal prothrombin time 
  • 80% had a normal activated partial thromboplastin time
  • 33% had a normal thrombin time
  • 81% had a normal dilute thrombin time.

The dilute thrombin time is considered the most reliable test of the anticoagulant effect of dabigatran but is not widely available. The activated partial thromboplastin time can provide a more widely used coagulation test to assess (in a less precise manner) whether there is an anticoagulant effect of dabigatran present, and more sensitive activated partial thromboplastin time assays can be used to better detect any residual dabigatran effect.

Dabigatran levels were also measured. Although 66% of patients had low drug levels just before surgery, the others still had substantial dabigatran on board. The fact that bleeding event rates were so low in this study despite the presence of dabigatran in many patients raises the question of whether having some drug on board is a good predictor of bleeding risk.

An interruption protocol with a longer interruption interval—12 to 14 hours longer than in the previous study (3 days for high-bleed risk procedures, 2 days for low-bleed risk procedures)—brought the activated partial thromboplastin time and dilute thrombin time to normal levels for 100% of patients with the protocol for high-bleeding-risk surgery. This study was based on small numbers and its interruption strategy needs further investigation.29

Case 3 continued

Based on the current empiric evidence, we recommend interrupting direct oral anticoagulants for 2 days (or approximately a 60-hour interval between the last dose and surgery) for this 75-year-old woman who is taking apixaban (Table 5). This interruption interval corresponds to 5 elimination half-lives for apixaban, which should result in little to no residual anticoagulant and will facilitate major surgery and, if indicated, neuraxial anesthesia.

The PAUSE study (NCT02228798), a multicenter, prospective cohort study, is designed to establish a safe, standardized protocol for the perioperative management of patients with atrial fibrillation taking dabigatran, rivaroxaban, or apixaban and will include 3,300 patients.

PATIENTS WITH A CORONARY STENT WHO NEED SURGERY

Case 4: A woman with a stent facing surgery

A 70-year-old woman needs breast cancer resection. She has coronary artery disease and had a drug-eluting stent placed 5 months ago after elective cardiac catheterization. She also has hypertension, obesity, and type 2 diabetes. Her medications include an angiotensin II receptor blocker, hydrochlorothiazide, insulin, and an oral hypoglycemic. She is also taking aspirin 81 mg daily and ticagrelor (a P2Y12 receptor antagonist) 90 mg twice daily.

Her cardiologist is concerned that stopping antiplatelet therapy could trigger acute stent thrombosis, which has a 50% or higher mortality rate.

Should she stop taking aspirin before surgery? What about the ticagrelor?

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