Use of Dabigatran Immediately After AF Ablation
In this study, we report our experience with 123 consecutive patients with symptomatic AF referred for catheter ablation for AF treated with dabigitran. The use of dabigatran for postablation anticoagulation was not associated with bleeding or thromboembolic complications and the drug was generally well tolerated. Dabigatran was approved by the US Food and Drug Administration in 2010 to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF. We began using the drug as a postablation anticoagulant as soon as it was available for clinical use. As the first new oral anticoagulant alternative to warfarin for treatment of AF in the last half century, dabigatran will likely play an increasingly important role in the management of patients with AF.
Dabigatran is a highly polar molecule which is not absorbed orally. The prodrug, dabigatran etexilate, is rapidly absorbed in healthy males and converted to dabigatran, the active metabolite. The time to peak plasma concentration is 1.25–1.5 hours in fasting healthy males and 2–4 hours in healthy elderly males and females. Nearly all of the absorbed prodrug is converted to dabigatran and most of the dabigatran is excreted unchanged in the urine. The half-life of dabigatran after multiple dosing is 12–14 hours in healthy elderly subjects. Dabigatran shows linear pharmacokinetics over a wide range of doses with plasma concentration proportional to dose. Drug accumulation is dependent on renal function and dabigatran dosing is based on renal function. Dabigatran is contraindicated in severe renal dysfunction. It has few clinically important drug or food interactions.
Dabigatran is a direct thrombin inhibitor with a high affinity for selective and reversible binding to thrombin. Although steady state dabigatran plasma concentrations are not seen for several days after initiating therapy, the drug's anticoagulant action indicates full antithrombotic effect occurs 2 hours after the initial dose, which remains at 50% of peak effect 12 hours after a dose. Given warfarin's narrow therapeutic window, numerous drug and food interactions, and need for frequent and inconvenient monitoring, all of the phamacologic and pharmacokinetic advantages of dabigatran should improve patient acceptance and compliance.
The onset of dabigatran's antithrombotic action after AF ablation procedures may have some clincially important differences from the above studies based on healthy males, elderly volunteers, or ambulatory patients. In patients undergoing hip surgery, dabigatran absortion is delayed with a median time to peak plasma concentration of 6 hours, with 22% of patients having a delay of >10 hours to peak effect. After hip surgery, some patients had a lower absorbtion than anticipated. To avoid any issues related to poor dabigatran absorption immediately after AF ablation, we chose to cover the patient's anticoagulation needs with enoxaparin immediately postablation and began dabigatran 22 hours after the ablation when the patients were ambulating and eating normally. This 22-hour delay should also minimize the risk of procedure-related bleeding complications that could be exacerbated by dabigatran which can only be immediately reversed by dialysis. Because of the lack of an easy way to reverse dabigatran, we do not recommend continuing it through the procedure.
Dabigatran provides effective anticoagulation for prevention of deep venous thrombosis after hip or knee replacement and for preventing thromboembolic events in patients with nonvalvular AF. Approximately one-quarter of our patients were on dabigatran before their AF ablation and that percentage is increasing rapidly with the acceptance of dabigatran as an anticoagulant for patients with AF. Using our preablation algorithm based on renal function, we did not experience any problems holding the dabigatran before the procedure in terms of thromboembolic events during the brief period off of anticoagulation or excessive bleeding at the time of the procedure. These patients did not require enoxaparin preprocedure. Because our periprocedural incidence of stroke is only 0.24% in over 1,700 AF ablations using the interrupted anticoagulation strategy, we have been reluctant to change to a protocol maintaining an uninterrupted therapeutic warfarin dose before the procedure. Those centers that do continue warfarin anticoagulation up to the time of the procedure may be forced to return to an interrupted protocol as increasing numbers of patients are receiving dabigatran preablation. Failure to interrupt dabigatran preablation could result in the inability to stop bleeding from periprocedural complications because of the lack of an effective method to immediately reverse its anticoagulant effect.
Dabigatran has many properties that make it ideal for stroke prophylaxis in patients after AF ablation. Peak anticoagulant effect occurs within 2 hours, which provides immediate anticoagulation without the need for prolonged enoxaparin bridging. The drug is not metabolized by the hepatic cytochrome P450 enzyme and there are only small differences in pharmacokinetics related to age and gender. This allows the drug to be used in a broad spectrum of AF ablation patients. Dabigatran is devoid of significant drug-drug interaction for the commonly used cardiac drugs such as atorvastatin or antiarrhythmic drugs. Dose adjustments are based on renal function, and we applied simple algorithms based on renal function both for discontinuing the drug before ablation and for choosing a dabigatran dose after AF ablation.
Although we did give our patients 2 doses of subcutaneous enoxaparin within the first 12 hours postprocedure, patients were not discharged on self-injections of enoxaparin. As we gain more experience with dabigatran, it may be possible to begin the drug 10–12 hours postprocedure and avoid the second dose of enoxaparin. The incidence of dabigatran side effects in our study was very simlar to that seen in large clinical trials for stroke prevention in nonvalvular AF patients. Our routine use of a proton-pump inhibitor for 3 weeks after AF ablation may have diminished the incidence of the dyspepsia that has been reported with the use of dabigatran.
Because dabigatran after AF ablation eliminated the need for frequent prothrombin times, it diminished the opportunity for communication with the patient as to their well-being after the procedure. We therefore advised all patients discharged home on dabigatran to call us on a regular basis during the first 30 days after the procedure to report any drug side effects, bleeding, arrhythmia episodes, or other issues.
The lack of bleeding complications, cerebral or noncerebral thromboembolic events, and a minimal side-effect profile, with 97.6% of patients able to remain on the drug, suggests that dabigatran may provide a convenient and acceptable alternative to the use of warfarin for anticoagulation after AF ablation. Although for this study we report only the 30-day incidence of complications, we did not observe any significant bleeding or thromboembolic events, in those patients who remained on dabigatran for periods beyond 30 days. It is likely that once the first 30 days after the procedure have elapsed, the thromboembolic event rates and side effects of dabigatran should be very similar to those seen in other AF patients who took part in major clincal trials for thromboembolic prophylaxis with dabigatran.
This was a retrospective and nonrandomized trial. However, the complete lack of bleeding and thromboembolic events in this case series suggests that a very large randomized trial would be required to determine if dabigatran is better, worse or noninferior to warfarin anticoagulation after AF ablation. During the short time of our study, the preablation use of dabigatran increased markedly among the patients referred for ablation. As such, recruitment into a randomized trial would be difficult if patients had to agree to be randomized back to warfarin versus dabigatran. All of these patients were enrolled at a single, high-volume center with expertise in performing AF ablation and in maximizing procedural safety and our lack of complications may be influenced by operator experience and expertise. It should also be emphasized that very few of our patients had a low GFR; therefore, we had little experience with drug wash out in those patients preablation and the use of the drug in these patients postablation.
Dabigatran seems to provide an effective anticoagulation strategy for preventing thromboembolic events after catheter ablation for AF. In our study, dabigatran was generally well tolerated without thromboembolic or bleeding complications and thus offers an alternative to anticoagulation with warfarin after ablation for AF.
Discussion
In this study, we report our experience with 123 consecutive patients with symptomatic AF referred for catheter ablation for AF treated with dabigitran. The use of dabigatran for postablation anticoagulation was not associated with bleeding or thromboembolic complications and the drug was generally well tolerated. Dabigatran was approved by the US Food and Drug Administration in 2010 to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF. We began using the drug as a postablation anticoagulant as soon as it was available for clinical use. As the first new oral anticoagulant alternative to warfarin for treatment of AF in the last half century, dabigatran will likely play an increasingly important role in the management of patients with AF.
Dabigatran is a highly polar molecule which is not absorbed orally. The prodrug, dabigatran etexilate, is rapidly absorbed in healthy males and converted to dabigatran, the active metabolite. The time to peak plasma concentration is 1.25–1.5 hours in fasting healthy males and 2–4 hours in healthy elderly males and females. Nearly all of the absorbed prodrug is converted to dabigatran and most of the dabigatran is excreted unchanged in the urine. The half-life of dabigatran after multiple dosing is 12–14 hours in healthy elderly subjects. Dabigatran shows linear pharmacokinetics over a wide range of doses with plasma concentration proportional to dose. Drug accumulation is dependent on renal function and dabigatran dosing is based on renal function. Dabigatran is contraindicated in severe renal dysfunction. It has few clinically important drug or food interactions.
Dabigatran is a direct thrombin inhibitor with a high affinity for selective and reversible binding to thrombin. Although steady state dabigatran plasma concentrations are not seen for several days after initiating therapy, the drug's anticoagulant action indicates full antithrombotic effect occurs 2 hours after the initial dose, which remains at 50% of peak effect 12 hours after a dose. Given warfarin's narrow therapeutic window, numerous drug and food interactions, and need for frequent and inconvenient monitoring, all of the phamacologic and pharmacokinetic advantages of dabigatran should improve patient acceptance and compliance.
The onset of dabigatran's antithrombotic action after AF ablation procedures may have some clincially important differences from the above studies based on healthy males, elderly volunteers, or ambulatory patients. In patients undergoing hip surgery, dabigatran absortion is delayed with a median time to peak plasma concentration of 6 hours, with 22% of patients having a delay of >10 hours to peak effect. After hip surgery, some patients had a lower absorbtion than anticipated. To avoid any issues related to poor dabigatran absorption immediately after AF ablation, we chose to cover the patient's anticoagulation needs with enoxaparin immediately postablation and began dabigatran 22 hours after the ablation when the patients were ambulating and eating normally. This 22-hour delay should also minimize the risk of procedure-related bleeding complications that could be exacerbated by dabigatran which can only be immediately reversed by dialysis. Because of the lack of an easy way to reverse dabigatran, we do not recommend continuing it through the procedure.
Dabigatran provides effective anticoagulation for prevention of deep venous thrombosis after hip or knee replacement and for preventing thromboembolic events in patients with nonvalvular AF. Approximately one-quarter of our patients were on dabigatran before their AF ablation and that percentage is increasing rapidly with the acceptance of dabigatran as an anticoagulant for patients with AF. Using our preablation algorithm based on renal function, we did not experience any problems holding the dabigatran before the procedure in terms of thromboembolic events during the brief period off of anticoagulation or excessive bleeding at the time of the procedure. These patients did not require enoxaparin preprocedure. Because our periprocedural incidence of stroke is only 0.24% in over 1,700 AF ablations using the interrupted anticoagulation strategy, we have been reluctant to change to a protocol maintaining an uninterrupted therapeutic warfarin dose before the procedure. Those centers that do continue warfarin anticoagulation up to the time of the procedure may be forced to return to an interrupted protocol as increasing numbers of patients are receiving dabigatran preablation. Failure to interrupt dabigatran preablation could result in the inability to stop bleeding from periprocedural complications because of the lack of an effective method to immediately reverse its anticoagulant effect.
Dabigatran has many properties that make it ideal for stroke prophylaxis in patients after AF ablation. Peak anticoagulant effect occurs within 2 hours, which provides immediate anticoagulation without the need for prolonged enoxaparin bridging. The drug is not metabolized by the hepatic cytochrome P450 enzyme and there are only small differences in pharmacokinetics related to age and gender. This allows the drug to be used in a broad spectrum of AF ablation patients. Dabigatran is devoid of significant drug-drug interaction for the commonly used cardiac drugs such as atorvastatin or antiarrhythmic drugs. Dose adjustments are based on renal function, and we applied simple algorithms based on renal function both for discontinuing the drug before ablation and for choosing a dabigatran dose after AF ablation.
Although we did give our patients 2 doses of subcutaneous enoxaparin within the first 12 hours postprocedure, patients were not discharged on self-injections of enoxaparin. As we gain more experience with dabigatran, it may be possible to begin the drug 10–12 hours postprocedure and avoid the second dose of enoxaparin. The incidence of dabigatran side effects in our study was very simlar to that seen in large clinical trials for stroke prevention in nonvalvular AF patients. Our routine use of a proton-pump inhibitor for 3 weeks after AF ablation may have diminished the incidence of the dyspepsia that has been reported with the use of dabigatran.
Because dabigatran after AF ablation eliminated the need for frequent prothrombin times, it diminished the opportunity for communication with the patient as to their well-being after the procedure. We therefore advised all patients discharged home on dabigatran to call us on a regular basis during the first 30 days after the procedure to report any drug side effects, bleeding, arrhythmia episodes, or other issues.
The lack of bleeding complications, cerebral or noncerebral thromboembolic events, and a minimal side-effect profile, with 97.6% of patients able to remain on the drug, suggests that dabigatran may provide a convenient and acceptable alternative to the use of warfarin for anticoagulation after AF ablation. Although for this study we report only the 30-day incidence of complications, we did not observe any significant bleeding or thromboembolic events, in those patients who remained on dabigatran for periods beyond 30 days. It is likely that once the first 30 days after the procedure have elapsed, the thromboembolic event rates and side effects of dabigatran should be very similar to those seen in other AF patients who took part in major clincal trials for thromboembolic prophylaxis with dabigatran.
Limitations
This was a retrospective and nonrandomized trial. However, the complete lack of bleeding and thromboembolic events in this case series suggests that a very large randomized trial would be required to determine if dabigatran is better, worse or noninferior to warfarin anticoagulation after AF ablation. During the short time of our study, the preablation use of dabigatran increased markedly among the patients referred for ablation. As such, recruitment into a randomized trial would be difficult if patients had to agree to be randomized back to warfarin versus dabigatran. All of these patients were enrolled at a single, high-volume center with expertise in performing AF ablation and in maximizing procedural safety and our lack of complications may be influenced by operator experience and expertise. It should also be emphasized that very few of our patients had a low GFR; therefore, we had little experience with drug wash out in those patients preablation and the use of the drug in these patients postablation.
Conclusions
Dabigatran seems to provide an effective anticoagulation strategy for preventing thromboembolic events after catheter ablation for AF. In our study, dabigatran was generally well tolerated without thromboembolic or bleeding complications and thus offers an alternative to anticoagulation with warfarin after ablation for AF.
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