Patient Description

The patient is a 78-year-old woman with known atrial fibrillation (AF). She has a history of hypertension. She had a myocardial infarction at the age of 73. At that time, she had angiography performed, which showed two-vessel disease. She has a past history of AF with a permanent AF on electrocardiogram (ECG) for the past 5 years. She is currently being managed with ramipril 5 mg daily, metoprolol 25 mg BID, warfarin with an international normalized ratio (INR) between 2.0 and 3.0^* and atorvastatin calcium 20 mg daily. She now presents with recurrent presyncopal spells and a heart rate at rest in the high 40s. Beta-blocker therapy is discontinued but she continues to have episodes of presyncope with heart rates remaining in the high 40s or low 50s and has documented bradycardia of 35 with an episode of presyncope on Holter Monitor. A decision is made to implant a pacemaker.

^*A system established by the World Health Organization and the International Committee on Thrombosis and Hemostasis.

Clinical Decision Point 1: Anticoagulation Therapy Preceding Pacemaker Implantation

Question 1: How should this patient’s anticoagulant therapy be managed at time of implantation?

1. Stop warfarin for 5 days and admit her to the hospital for pacemaker implantation, restarting warfarin 1 to 2 days postoperatively


2. Warfarin should be stopped and she should be bridged with low-molecular-weight heparin for 2 to 3 days, stopping the low-molecular-weight heparin approximately 24 hours before surgery


3. Warfarin does not need to be stopped if the implanter is comfortable with doing procedures in well-controlled warfarin patients


4. All of the above options are reasonable

Discussion

(d) All of the above options are used in current clinical practice. There are no clinical trials that indicate a clear preference for any of these three options.

The management of perioperative anticoagulant therapy in patients with AF presents a challenge for clinicians who need to weigh the competing risks of arterial thromboembolic events (ATEs) with the increased potential for bleeding during or following surgery. The issue is complicated by the potential for increased bleeding in otherwise minor procedures, such as pacemaker insertion, when anticoagulants are used in close proximity to the surgery.¹ Unfortunately, there is a shortage of randomized trials to provide clear guidance in this area, and best practice is based largely on observational studies and expert opinion.

The American College of Chest Physicians (ACCP) recently issued an updated set of guidelines on the perioperative management of antithrombotic therapies.¹ The new guidelines recommend discontinuing vitamin K antagonists approximately 5 days before surgery when discontinuation is required, and reinitiation 12 to 24 hours after surgery when there is adequate hemostasis.¹ The half-life of warfarin is 36 to 42 hours.¹ Thus, discontinuation for approximately 5 days is necessary to normalize the INR, although this rate may be further delayed in some patient subgroups, such as the elderly.^1,2 There have been no randomized trials investigating the timing of preoperative warfarin discontinuation on bleeding outcomes. However, one small randomized study did demonstrate that the mean INR on the day of surgery was significantly lower in patients who discontinued warfarin 5 days prior to surgery with heparin bridging compared with patients who discontinued 1 day before with a 1 mg dose of vitamin K (INR: 1.24 versus 1.61; P <.001).³ At least one study has demonstrated that restarting warfarin 12 to 24 hours following surgery, when hemostasis is adequate, is feasible and safe.⁴

Regarding the use of bridging anticoagulation with heparin (subcutaneous low-molecular-weight or intravenous unfractionated heparin), bridging is suggested following warfarin discontinuation in patients at high risk for thromboembolism, while it is not recommended for patients at low risk.¹ An individualized assessment of risk of ATEs versus bleeding should be made for patients at moderate risk.¹ Numerous studies have evaluated the use of bridging with heparin, reporting a 1% to 2% incidence of perioperative ATEs with subcutaneous low-molecular-weight heparin, and a range between 0% and 5% with unfractionated heparin in high-risk patients.² In moderate-risk patients, the perioperative incidence of ATEs is approximately 1%, regardless of whether bridging is used or not, while the rate is <1% in patients at low risk in the absence of bridging.¹

However, the use of heparin bridging may also increase the potential for other perioperative complications. A retrospective study of 3164 patients who underwent cardiac device surgery found that high-dose heparinization, combined antiplatelet therapy, and low operator experience each predicted for hematoma development.⁵ In addition, postoperative heparinization increased the rate of hematoma formation from 3% to 11% (P <.001) in patients with nonvalvular AF, with no reduction in postoperative ATE. A retrospective case series also reported a significantly higher rate of hematoma formation in high-risk patients who received heparin bridging compared with those who continued warfarin, or low-risk patients who had warfarin held for 4 days prior to surgery (20.7%[bridging] versus 5.0%[warfarin] versus 4.1%[control]; P = .03), with subsequent increases in the duration of hospital stays.⁶ Due to the risks associated with heparin anticoagulation, including an increased risk of perioperative bleeding, the use of this approach should be based on careful consideration of the patient’s risk for both perioperative stroke and bleeding, in addition to individual preferences.⁷

Continuation of warfarin at the time of cardiac device implantation surgery may also be an option for some patients.⁸ Several case series studies have been published demonstrating the feasibility of this approach, including one in which no difference in the complication rate was observed between 37 patients who continued to receive warfarin versus 113 patients who were not anticoagulated, and there were no episodes of clinically significant bleeding.⁹ A second case series that included 47 anticoagulated patients (mean INR 2.3) reported only a single episode of a small hematoma that spontaneously resolved.¹⁰ A large retrospective cohort study that included 470 anticoagulated patients (mean INR 2.6) and 555 controls who underwent cardiac device implantation also reported a similar complication rate between the two patient groups.¹¹ Another large case series of 766 consecutive patients reported no difference in bleeding events between patients undergoing cardiac device surgery who continued warfarin (INR of 2.0–2.5) or who discontinued warfarin (3.7% versus 3.4%; P = .72), although patients with an INR >2.5 were at increased risk (10% versus 3.4%; P = .029).¹² Finally, a small randomized trial recently compared warfarin continuation to interruption (with heparin bridging used only in high-risk patients) in 100 patients referred for cardiac device implantation.¹³ This study reported complications only in the warfarin interruption arm, with no events in the 50 patients who continued on warfarin (P = .056).

Audio Commentary by Stuart Connolly, MD, FRCPC

Case Continues

The electrophysiologist performing the pacemaker implantation is experienced with doing these procedures in patients who continue to receive anticoagulation. He arranges for the INR to come down close to 2.0 and her procedure is performed without incident. The patient has warfarin continued on the day of surgery and her INR remains in the therapeutic range. A few months later, a decision is made to switch this patient to dabigatran therapy at a dose of 150 mg BID. Before starting dabigatran, her creatinine is measured and the creatinine clearance is calculated to be 55 mL/min.

Audio Commentary by Stuart Connolly, MD, FRCPC

Clinical Decision Point 2: Switching from Warfarin to Dabigatran

Question 2: Which of the following strategies should be used when switching a patient from warfarin to dabigatran?

1. Stop warfarin, wait for the INR to come down to the normal range and then start dabigatran


2. Dose-adjust warfarin to an INR of <2.0, then stop warfarin and start dabigatran


3. Start dabigatran, wait 24 hours, and then stop warfarin

Discussion

(a) Dabigatran can be started when the INR is <2.0.¹⁴ Therefore, the INR should be measured and the dose of warfarin adjusted to bring it into the low therapeutic range. Once it reaches that point, warfarin can be stopped and dabigatran started within 12 hours.

Dabigatran is an oral, direct thrombin inhibitor, and the first of the next-generation anticoagulants to be approved for the prevention of stroke in patients with nonvalvular AF. This approval was based on results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, which showed that dabigatran at a dose of 150 mg twice daily significantly reduced the rate of stroke or systemic embolism, with a similar rate of major bleeding, when compared with standard dose-adjusted warfarin.¹⁵

The RE-LY trial included 18,113 patients with AF who were at increased risk for stroke, and compared warfarin with dabigatran at two dose levels.¹⁵ At the higher dose (150 mg twice daily), dabigatran significantly reduced the annual rate of stroke or systemic embolism compared with warfarin (1.11% for dabigatran 150 mg versus 1.69% for warfarin; relative risk [RR] 0.66; 95% confidence interval [CI] 0.53–0.82; P <.001). (Figure 1) Major bleeding rates were similar: 3.36% per year with warfarin versus 3.11% per year with 150 mg dabigatran (RR 0.93; 95% CI 0.81–1.07; P =.31). However, the rate of hemorrhagic stroke was significantly lower with dabigatran 150 mg compared with warfarin (0.10% versus 0.38% per year; RR 0.26; 95% CI 0.14–0.49; P <.001), although the rate of major gastrointestinal bleeding was higher in the dabigatran 150 mg arm (1.51% versus 1.02% per year; RR 1.50; 95% CI 1.19–1.89; P <.001).

The lower dose of dabigatran (110 mg twice daily) was found to be noninferior to warfarin with regard to the annual rate of stroke or embolism (1.53% versus 1.69%; RR 0.91; 95% CI 0.74–1.11; P <.001), but was associated with a significantly lower rate of major bleeding (2.71% versus 3.36% per year; RR 0.80; 95% CI 0.69–0.93; P = .003).¹⁵ Myocardial infarction rates were also increased in patients who received either dose of dabigatran compared with those who received warfarin (110 mg: 0.72% per year, P = .07; 150 mg: 0.74% per year, P = .048 versus warfarin 0.53% per year). The annual rate of death from any cause was 4.13% with warfarin, 3.75% with 110 mg dabigatran (RR 0.91; 95% CI 0.80–1.03; P = .13), and 3.64% with 150 mg dabigatran (RR 0.88; 95% CI 0.77–1.00; P = .051). The only adverse event that was significantly increased with dabigatran was dyspepsia (110 mg: 11.8%; 150 mg: 11.3%) compared with warfarin (5.8%; P <.001 for both comparisons).

Figure 1. RE-LY Trial: Key Results¹⁵

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A second class of new anticoagulants that are being evaluated for prevention of stroke or systemic embolism in patients with nonvalvular AF are the factor Xa inhibitors. The first such agent to receive FDA approval for this use in this patient population was rivaroxaban, based upon results from the ROCKET AF double-blind randomized noninferiority trial.^{16, 17}

The ROCKET AF trial randomized 14,264 patients with nonvalvular AF at increased risk for stroke (mean CHADS₂ score of 3.5) to rivaroxaban (20 mg once daily) or dose-adjusted warfarin.¹⁷ The primary endpoint was stroke or systemic embolism. In the intent-to-treat analysis, the rate of primary events was 2.1% per year in the rivaroxaban arm compared with 2.4% per year for warfarin (hazard ratio [HR] 0.88; 95% CI 0.74–1.03; P <.001 for noninferiority and P = .12 for superiority). (Figure 2) In addition, there was a similar rate of major bleeding between arms: 3.6% per year with rivaroxaban versus 3.4% per year with warfarin (HR 1.04; 95% CI 0.90–1.20; P = .58). However, rivaroxaban was associated with significantly lower rates of intracranial hemorrhage (0.5% versus 0.7%; P = .02) and fatal bleeding (0.2% versus 0.5%, P = .003) compared with warfarin, while major gastrointestinal bleeding rates were higher in the rivaroxaban arm (3.2% versus 2.2%; P <.001). Finally, the annual rate of myocardial infarction was similar between arms (0.9% for rivaroxaban versus 1.1% for warfarin; HR 0.81; P = .12), as was the annual rate of death in the intent-to-treat population (4.5% for rivaroxaban versus 4.9% for warfarin; HR 0.92; P = .15).

Figure 2. ROCKET AF Trial: Key Results¹⁷

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*Intent-to-treat analysis; †noninferiority, P = .12 for superiority.

A second novel oral factor Xa inhibitor, apixaban, is currently undergoing review by the FDA for approval in nonvalvular atrial fibrillation for stroke risk reduction. In the randomized AVERROES trial, apixaban significantly reduced the annual rate of stroke or systemic embolism compared with aspirin, with no difference in major bleeding rates, in patients with nonvalvular AF at risk for stroke who were not candidates for vitamin K antagonist therapy.¹⁸ Apixaban was directly compared with warfarin in 18,201 patients with AF and at least one risk factor for stroke in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in AF (ARISTOTLE) trial.¹⁹ The annual rate of stroke or systemic embolism was significantly lower with apixaban compared with warfarin (1.3% with apixaban versus 1.6% with warfarin; HR 0.79; P <.001 for noninferiority and P = .01 for superiority). (Figure 3) In addition, the annual rate of major bleeding was reduced with apixaban compared with warfarin (2.1% versus 3.1%; HR 0.69; P <.001). Intracranial hemorrhage also occurred significantly less frequently in the apixaban arm (annual rate 0.33% versus 0.80%; HR 0.42; P <.001), while there was no significant difference in gastrointestinal bleeding (0.76% annually with apixaban versus 0.86% with warfarin; HR 0.89; P = .37).The annual rate of myocardial infarction was 0.53% in patients receiving apixaban compared with 0.61% in the warfarin arm (HR 0.88; P = .37). Finally, the annual rate of death from any cause was also significantly lower with apixaban compared with warfarin (3.5% versus 3.9%; HR 0.89; P = .047).

Figure 3. ARISTOTLE Trial: Key Results¹⁷

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*Noninferiority, P = .01 for superiority.

The addition of these new classes of agents increases the options for stroke risk reduction in patients with nonvalvular AF. It is important to be aware of the advantages and disadvantages of all available therapeutic options, and in addition to carefully evaluating individual stroke risk, to discuss the risks and benefits of the different agents with each patient in order to select the optimal approach.

Expert guidelines are just beginning to integrate these new agents into their treatment recommendations. The American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines recently updated their recommendations to include dabigatran as an alternative to warfarin for AF, although switching to dabigatran is not recommended for patients already taking warfarin who have excellent INR control.²⁰ Likewise, the European Society of Cardiology guidelines consider dabigatran an alternative to warfarin in patients with AF for whom oral anticoagulation is an appropriate therapy.²¹ Finally, recently updated guidelines from the ACCP recommend oral anticoagulation for patients with nonrheumatic AF at intermediate or high risk (CHADS2 score ≥1), with a preference for dabigatran over dose-adjusted warfarin.²²  Note that all of these guidelines were developed before the approval of rivaroxaban, and thus future updates will be necessary to keep up with the evolving therapeutic landscape.

Audio Commentary by Stuart Connolly, MD, FRCPC

Case Continues

The patient does well on dabigatran and several months later, she develops increasing angina. Coronary angiography reveals that she now has triple-vessel coronary artery disease. A decision is made for her to undergo elective coronary artery bypass graft surgery.

Clinical Decision Point 3: Management of Dabigatran Prior to Major Surgery

Question 3: How should dabigatran be managed in order to reduce the risk of complications at the time of surgery?

1. Remeasure serum creatinine, estimate creatinine clearance and stop dabigatran. The time period between drug discontinuation and surgery should be based on creatinine clearance.


2. Stop dabigatran 48 hours before surgery and then perform the surgery, restarting dabigatran 1 to 2 days postoperatively.


3. Hold dabigatran for 3 to 4 days before surgery and restart 1 to 2 days postoperatively.

Discussion

(a) Remeasure serum creatinine and estimate creatinine clearance, then discontinue dabigatran for a period of time prior to surgery dependent on degree of renal function. Dabigatran is associated with an increased risk of bleeding, while renal dysfunction causes an increase in its half-life and resultant anticoagulant activity. Therefore, it is recommended that dabigatran be discontinued 1 to 2 days prior to surgery in patients with a creatinine clearance ≥50 mL/min, or 3 to 5 days prior to surgery in patients with a creatinine clearance <50 mL/min.¹⁴ These recommendations are based on the half-life of dabigatran, which is 12 to 17 hours in healthy individuals, but is extended in patients with renal impairment.¹⁴ Clearance of dabigatran occurs primarily through the kidneys (80% renal clearance with intravenous administration). Thus, exposure increases and clearance rate decreases in patients with impairment of renal function, leading to a longer half-life (Figure 4).¹⁴

Figure 4. Impact of Renal Impairment on Dabigatran Half-Life¹⁴

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Abbreviation: CrCl, creatinine clearance (mL/min).

Although this patient had adequate renal function a few months prior to surgery, it is critical to recheck creatinine levels immediately prior to surgery because patients can slip into renal failure without many symptoms. A patient with a creatinine clearance of <30 may require many days of discontinuation of dabigatran before plasma concentrations have returned to a level that is low enough to permit surgery to be performed safely.

Audio Commentary by Stuart Connolly, MD, FRCPC

Conclusion

In conclusion, for minor surgical procedures in patients on warfarin, there are a variety of approaches that can be used for managing drug therapy. These include either discontinuation of the anticoagulant, bridging the patient with low-molecular-weight heparin, or performing the procedure while the patient remains on anticoagulant therapy. Similar recommendations cannot be made for dabigatran or other novel anticoagulants at this time because there is less experience with these drugs. In addition, because dabigatran is subject to 80% renal excretion, the half-life of the drug therefore varies according to creatinine clearance. It is critical to measure the creatinine clearance prior to surgery in order to assess the duration of discontinuation of therapy required.

References

1. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative Management of Antithrombotic Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e326S-350S.


2. Hylek EM, Regan S, Go AS, et al. Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med. 2001;135:393-400.


3. Steib A, Barre J, Mertes M, et al. Can oral vitamin K before elective surgery substitute for preoperative heparin bridging in patients on vitamin K antagonists? J Thromb Haemost. 2010;8:499-503.


4. Douketis JD, Johnson JA , Turpie AG. Low-molecular weight heparin as bridging anticoagulation during interruption of warfarin: assessment of a standardized periprocedural anticoagulation regimen. Arch Intern Med. 2004;164:1319-1326.


5. Wiegand UK, LeJeune D, Boguschewski F et al. Pocket hematoma after pacemaker or implantable cardioverter defibrillator surgery. Chest. 2004;126:1177-1186.


6. Ghanbari H, Feldman D, Schmidt M, et al. Cardiac resynchronization therapy device implantation in patients with therapeutic international normalized ratios. Pacing Clin Electrophysiol. 2010;33:400-406.


7. Dunn A. Perioperative management of oral anticoagulation: when and how to bridge. J Thromb Thrombolysis. 2006;21:85-89 .


8. Tompkins C, Henrikson CA. Optimal strategies for the management of antiplatelet and anticoagulation medications prior to cardiac device implantation. Cardiol J. 2011;18:103-109.


9. Goldstein DJ, Losquadro W, Spotnitz HM. Outpatient pacemaker procedures in orally anticoagulated patients. Pacing Clin Electrophysiol. 1998;21:1730-1734.


10. Al-Khadra AS. Implantation of pacemakers and implantable cardioverter defibrillators in orally anticoagulated patients. Pacing Clin Electrophysiol. 2003;26:511-514.


11. Giudici MC, Paul DL, Bontu P, Barold SS. Pacemaker and implantable cardioverter defibrillator implantation without reversal of warfarin therapy. Pacing Clin Electrophysiol. 2004;27:358-360.


12. Li HK, Chen FC, Rea RF, et al. No increased bleeding events with continuation of oral anticoagulation therapy for patients undergoing cardiac device procedure. Pacing Clin Electrophysiol. 2011;34:868-874.


13. Cheng A, Nazarian S, Brinker JA, et al. Continuation of warfarin during pacemaker or implantable cardioverter-defibrillator implantation: a randomized clinical trial. Heart Rhythm. 2011;8:536-540.


14. Pradaxa^® [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc. 2011.


15. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with AF. N Engl J Med. 2009;361:1139-1151.


16. Xarelto^® [package insert]. Titusville, NJ. Janssen Pharmaceuticals, Inc. 2011.


17. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular AF. N Engl J Med. 2011;365:883-891.


18. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with AF. N Engl J Med. 2011;364:806-817.


19. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with AF. N Engl J Med. 2011;365:981-992.


20. Wann LS, Curstis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with AF (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2011;123:1144-1150.


21. Camm AJ, Kirchof P, Lip GY, et al. Guidelines for the management of AF: the Task Force for the Management of AF of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:2369-2429.


22. You JJ, Singer DE, Howard PA, et al. Antithrombotic Therapy for AF: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141: e531S-75S.