PAUSE

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Douketis JD, et al. "Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant". JAMA Internal Medicine. 2019. 179(11):1469-1478.
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Clinical Question

In patients with atrial fibrillation on direct oral anticoagulants (DOAC), what proportion of patients experience a major bleed or arterial embolism when following a non-randomized, structured holding pattern?

Bottom Line

In this non-randomized protocol of standard perioperative DOACS holding strategies among adults with AF, few major bleeding and arterial thromboembolism events were observed.

Major Points

Anticoagulation reduces stroke events in AF, but its use is a risk factor for surgical bleeding. DOACs like apixaban, rivaroxaban, and dabigatran are generally simpler for chronic use in AF than warfarin since they don't require INR monitoring or dietary pattern adherence. In the pre-DOAC era, patients would hold their warfarin for a few days and an INR would be measured prior to surgery to confirm that the anticoagulant effects of this agent had worn off. Traditional coagulation assays (eg, INR) do not correspond with the degree of 'blood thinning' from DOACs, and hospital laboratories cannot quickly measure DOAC serum levels on the day of a surgery. For adults with AF, there was little guidance on perioperative holding DOAC holding strategies.

Published in 2019, the Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study enrolled 3,007 patients with AF on a DOAC (apixaban, dabigatran, or rivaroxaban). All patients followed the same perioperative holding strategy, which varied from 1 to 4 days of preoperative holding based upon the specific agent, the surgical bleeding risk, and the patient's creatinine clearance (if on dabigatran). There were few bleeding and arterial thromboembolic events. This cohort provides some guidance on reasonable strategies for perioperative DOAC holding among adults with AF.

Guidelines

As of April 2020, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, prospective cohort, management study
    • Note: this was not a clinical trial.
  • N=3007
    • Apixaban (n=1257)
    • Dabigatran (n=668)
    • Rivaroxaban (n=1082)
  • Setting: 23 sites in Canada, United States, and Europe
  • Enrollment: 2014-2018
  • Follow-up: 30 days
  • Analysis: Intention to treat
  • Primary outcomes: Major bleeding and arterial thromboembolism

Population

Full design details were published elsewhere.[1]

Inclusion Criteria

  • Aged ≥18 years
  • Atrial fibrillation, receiving stroke prevention with apixaban, dabigatran, or rivaroxaban
  • Scheduled elective procedure requiring anticoagulation interruption
  • Able to adhere to interruption protocol

Exclusion Criteria

  • Creatinine Clearance <25ml/min for apixaban or <30ml/min for dabigatran or rivaroxaban
  • Cognitive impairment or psychiatric illness
  • >1 procedure planned in the following 30 days

Baseline Characteristics

From the apixaban group.

  • Demographics: Age 73 years, male sex 64%, white race 96%
  • Anthropometrics: BMI 30 kg/m2
  • Risk scores: CHADS2 score 2.1, CHADS2-VA2Sc 3.5, modified HAS-BLED 2.0
    • Note: HAS-bled omitted labile INR and alcohol use.
  • PMH: HF 19%, hypertension 74%, DM 27%, stroke 8%, TIA 9%, CAD 18%, PAD 1%, bioprosthetic heart valve 3%, mitral valve disease 10%, VTE 6%, active cancer 8%
  • Labs: Hgb 13.4 g/dL, thrombocytopenia (<100) 1%, creatinine 94.1 umol/L, creatinine clearance 78 ml/min
  • Medication use: Lower-dose DOAC 20%, aspirin 12%, P2Y12 inhibitor 1%, P-glycoprotein or CYP3A4 inhibitor or inducer 6%
  • Elective surgery bleeding risk: high 33%, low 66%
  • Anesthesia: general 33%, neuraxial 8%, other 55%

Interventions

  • As this was not a clinical trial, all participants received the same guidance on perioperative management strategies based upon their medication (and renal function if on dabigatran) and the bleeding risk associated with the procedure. Please see the figure on Page 1470 or here for specific perioperative DOAC hold and reinitiation timings.
  • Bleed risk by surgery is presented in eAppendix 1 on PDF page 3 of the supplemental appendix.[2] Details in brief:
    • Low Bleeding Risk surgeries included gastrointestinal procedures (eg, colonoscopy), pacemaker insertions, dental procedures, skin and eye procedures
    • High Bleeding Risk surgeries included any surgery requiring neuraxial anesthesia, major intracranial surgery, major thoracic, vascular, orthopedic and cardiac surgery, major cancer or reconstructive surgery
  • If on apixaban or rivaroxaban (regardless of renal function) or dabigatran with CrCl ≥50 mL/min:
    • If low-bleeding risk procedure, no DOAC 1 day prior and the day of the procedure (approximately 3 DOAC half-lives). Resume DOAC about 24 hours post-op.
    • If high-bleeding risk procedure, no DOAC 2 and 1 days prior and the day of the procedure (approximately 5 DOAC half-lives). Resume DOAC about 48-72 hours post-op.
  • If on dabigatran and CrCl <50ml/min:
    • If low-bleeding risk procedure, no DOAC 2 and 1 days prior and the day of the procedure. Resume DOAC about 24 hours post-op.
    • If high-bleeding risk procedure, no DOAC 4, 3, 2, and 1 day prior and the day of the procedure. Resume DOAC about 48-72 hours post-op.
  • CHADS score did not affect DOAC regiment as no heparin bridging was performed in the study.
  • Those at high VTE risk could receive prophylactic heparin prior to resuming DOAC therapy .

Outcomes

Comparisons are apixaban vs. dabigatran vs. rivaroxaban.

Primary Outcomes

Definitions for these events appear in eAppendix 3, pdf pg 6 of the supplemental appendix.[2]

Major bleeding at 30 days
1.35% (95% CI 0 to 2.00%) vs. 0.9% (0 to 1.73%) vs. 1.85% (0 to 2.65%)
Events by surgical bleeding risk were not primary endpoints and are presented here for simplicity.
Low bleeding risk: 0.59% (0 to 1.20%) vs. 0.91% (0 to 2.01%) vs. 1.27% (0 to 2.17%)
High bleeding risk: 2.96% (0 to 4.68%) vs. 0.88% (0 to 2.62%) vs. 2.95% (0 to 4.76%)
Arterial thromboembolism at 30 days
0.16% (95% CI 0 to 0.48%) vs. 0.6% (0 to 1.33%) vs. 0.37% (0 to 0.82%)

Secondary Outcomes

All-cause mortality
0.25% vs 0.45% vs 0.28%
Myocardial infarction
0.08% vs 0% vs 0%
VTE
DVT: 0.16% vs. 0.15% vs. 0%
PE: 0.32% vs. 0.15% vs. 0.09%
Arterial catheter thrombosis
All of these events were ischemic stroke
0.08% vs. 0.15% vs. 0%
Clinically-relevant non-major bleeding
1.67% vs. 1.95% vs. 2.4%
Minor bleeding
4.3% vs. 5.69% vs. 5.73%

Additional Outcomes

Residual anticoagulant level was <50ng/ml
90.5 vs. 95.1% vs. 96.8%
Residual anticoagulant level was ≥50 ng/mL
High risk procedures: 2.09% vs. 0.55% vs. 0.64%
Low risk procedures: 12.9% vs. 7.1% vs. 4.5%

Criticisms

  • Not a clinical trial.
  • Apixaban and rivaroxaban are also renally-cleared, but their holding patterns were not modified based upon renal function like they were for dabigatran.

Funding

Public and private funding

Further Reading

  1. Douketis JD et al. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study for Patients on a Direct Oral Anticoagulant Who Need an Elective Surgery or Procedure: Design and Rationale. Thromb Haemost 2017. 117:2415-2424.
  2. 2.0 2.1 Supplemental appendix