Accepted Manuscript New Oral Anticoagulants- what the cardiothoracic surgeon needs to know Tsuyoshi Kaneko , MD Maroun Yammine , MD Sary F. Aranki , MD PII:
S0022-5223(14)00672-2
DOI:
10.1016/j.jtcvs.2014.05.060
Reference:
YMTC 8644
To appear in:
The Journal of Thoracic and Cardiovascular Surgery
Received Date: 24 March 2014 Revised Date:
18 May 2014
Accepted Date: 22 May 2014
Please cite this article as: Kaneko T, Yammine M, Aranki SF, New Oral Anticoagulants- what the cardiothoracic surgeon needs to know, The Journal of Thoracic and Cardiovascular Surgery (2014), doi: 10.1016/j.jtcvs.2014.05.060. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Prepared for JTCVS
RI PT
New Oral Anticoagulants- what the cardiothoracic surgeon needs to know Tsuyoshi Kaneko MD, Maroun Yammine MD, Sary F Aranki MD
SC
Division of Cardiac Surgery
Address for correspondence: Sary F Aranki, MD
TE D
75 Francis St.
M AN U
Brigham and Women’s Hospital, Boston, Massachusetts
Boston MA
EP
Tel: 617-738-0921
AC C
Email: [email protected]
Word Count: 3078
Page 1
ACCEPTED MANUSCRIPT Prepared for JTCVS Ultra-mini Abstract New oral anticoagulants such as direct thrombin inhibitor and Factor Xa inhibitor are rapidly gaining
RI PT
wide acceptance as credible alternative to vitamin K antagonist given its shortcomings. Consequently more cardiothoracic surgeons will encounter patients on these new drugs. We offer a comprehensive
AC C
EP
TE D
M AN U
SC
review of the pharmaco-profile and clinical evidence for their use.
Page 2
ACCEPTED MANUSCRIPT Prepared for JTCVS Introduction Oral anticoagulation for cardiothoracic patients has traditionally been synonymous with warfarn. The
RI PT
recent introduction of new oral anticoagulants (NOACs) targeting factor Xa or thrombin represents a new approach for anticoagulation. Cardiothoracic surgeons need to familiarize themselves with these agents as more preoperative patients will be on NOACs and strategies for discontinuation prior to surgery with or without bridging becomes paramount. The rapid onset of action, wide therapeutic index,
SC
and a steady therapeutic state without the need for monitoring makes these new agents more attractive
M AN U
than warfarin for these indications.
Currently available NOACs are dabigatran etexilate (Pradaxa®, Boehringer Ingelheim, Ridgefield CT), rivaroxaban (Xarelto®, Bayer HealthCare AG, Leverkusen, Germany), apixaban (Eliquis® , Bristol-Myers Squibb, New York NY) and edoxaban (Savaysa®, Daiichi Sankyo, Tokyo, Japan, not approved in the United States). We will review the pharmaco-profile, clinical evidence for safety and efficacy, current
TE D
approved indications, and strategies to guide in the perioperative management of the patients on NOAC.
EP
Traditional Oral Anticoagulant- Warfarin
Warfarin was approved for human use in 1954, and has been the mainstay oral anticoagulant in clinical
AC C
practice ever since until recently. Warfarin inhibits vitamin K-dependant synthesis of calcium-dependant clotting factors and the regulatory protein C and S. Multiple food-drug and drug-drug interactions with other medications and food complicates the use of warfarin. (Table 1 and appendix) Narrow therapeutic index with frequent monitoring is a burden of therapy for frequent dose adjustment, and the long halflife of warfarin (approximately 60 hrs) requires several days to restore the therapeutic anticoagultion level following interruption.
Page 3
ACCEPTED MANUSCRIPT Prepared for JTCVS One major advantage compared to NOACs is reversibility. In emergency setting, warfarin can be reversed with fresh frozen plasma and patients can undergo safe procedure. Vitamin K provides excess cofactor for ongoing coagulation factor carboxylation in the setting of irreversible inhibition by warfarin,
RI PT
and therefore requires synthesis of new coagulation factors in order to have an effect. For additional information on warfarin, see online material.
M AN U
Use of warfarin in cardiothoracic surgery
SC
These limitations led to development of NOACs targeting Factor Xa or thrombin (Factor IIa).
We reviewed the use of warfarin after cardiac surgery at the Brigham and Women’s Hospital. In 2011, out of 1257 cardiac cases performed, 586 patients (46.6%) were discharged on warfarin. Similarly in 2012, out of 1234 cardiac cases performed, 557 patients (45.1%) were discharged on warfarin. These
TE D
data included all patients who were on warfarin, hence both patients who were on preoperatively and
EP
started new postoperatively were counted.
Pharmacokinetic/Pharmacodynamic profile of oral anticoagulants
Table 1.
AC C
The characteristics of dabigatran, rivaroxaban, apixaban and edoxaban are compared with warfarin in
Dabigatran
Dabigatran etexilate is a direct thrombin inhibitor and comes in the form of prodrug with bioavailability of 7.2%.1 It is converted to active form dabigatran in the liver. It directly blocks the active site and prevents conversion of fibrinogen into fibrin. Half life of dabigatran is about 13 hours in healthy Page 4
ACCEPTED MANUSCRIPT Prepared for JTCVS individual, and is cleared by kidneys (renal excretion 80%). Renal function needs to be monitored in patients with renal insufficiency, since poor renal function can impair renal excretion and prolong the effect of anticoagulation. Dose adjustment is done accordingly based on the creatinine clearance. (table
RI PT
1) Interaction with permability glycoprotein (p-gp) inhibitors such as quinidine, ketoconazole, and verapamil can increase plasma concentration by reducing the clearance of dabigatran etexilate.2 This is more significant in renal failure patients, and patients with severe renal impairment (Creatinine
SC
clearance 50ml/min), last dose should be given 3 days before surgery. 48-60 hours of interruption will lead to
TE D
minimal anticoagulant effect of
S0022-5223(14)00672-2
DOI:
10.1016/j.jtcvs.2014.05.060
Reference:
YMTC 8644
To appear in:
The Journal of Thoracic and Cardiovascular Surgery
Received Date: 24 March 2014 Revised Date:
18 May 2014
Accepted Date: 22 May 2014
Please cite this article as: Kaneko T, Yammine M, Aranki SF, New Oral Anticoagulants- what the cardiothoracic surgeon needs to know, The Journal of Thoracic and Cardiovascular Surgery (2014), doi: 10.1016/j.jtcvs.2014.05.060. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Prepared for JTCVS
RI PT
New Oral Anticoagulants- what the cardiothoracic surgeon needs to know Tsuyoshi Kaneko MD, Maroun Yammine MD, Sary F Aranki MD
SC
Division of Cardiac Surgery
Address for correspondence: Sary F Aranki, MD
TE D
75 Francis St.
M AN U
Brigham and Women’s Hospital, Boston, Massachusetts
Boston MA
EP
Tel: 617-738-0921
AC C
Email: [email protected]
Word Count: 3078
Page 1
ACCEPTED MANUSCRIPT Prepared for JTCVS Ultra-mini Abstract New oral anticoagulants such as direct thrombin inhibitor and Factor Xa inhibitor are rapidly gaining
RI PT
wide acceptance as credible alternative to vitamin K antagonist given its shortcomings. Consequently more cardiothoracic surgeons will encounter patients on these new drugs. We offer a comprehensive
AC C
EP
TE D
M AN U
SC
review of the pharmaco-profile and clinical evidence for their use.
Page 2
ACCEPTED MANUSCRIPT Prepared for JTCVS Introduction Oral anticoagulation for cardiothoracic patients has traditionally been synonymous with warfarn. The
RI PT
recent introduction of new oral anticoagulants (NOACs) targeting factor Xa or thrombin represents a new approach for anticoagulation. Cardiothoracic surgeons need to familiarize themselves with these agents as more preoperative patients will be on NOACs and strategies for discontinuation prior to surgery with or without bridging becomes paramount. The rapid onset of action, wide therapeutic index,
SC
and a steady therapeutic state without the need for monitoring makes these new agents more attractive
M AN U
than warfarin for these indications.
Currently available NOACs are dabigatran etexilate (Pradaxa®, Boehringer Ingelheim, Ridgefield CT), rivaroxaban (Xarelto®, Bayer HealthCare AG, Leverkusen, Germany), apixaban (Eliquis® , Bristol-Myers Squibb, New York NY) and edoxaban (Savaysa®, Daiichi Sankyo, Tokyo, Japan, not approved in the United States). We will review the pharmaco-profile, clinical evidence for safety and efficacy, current
TE D
approved indications, and strategies to guide in the perioperative management of the patients on NOAC.
EP
Traditional Oral Anticoagulant- Warfarin
Warfarin was approved for human use in 1954, and has been the mainstay oral anticoagulant in clinical
AC C
practice ever since until recently. Warfarin inhibits vitamin K-dependant synthesis of calcium-dependant clotting factors and the regulatory protein C and S. Multiple food-drug and drug-drug interactions with other medications and food complicates the use of warfarin. (Table 1 and appendix) Narrow therapeutic index with frequent monitoring is a burden of therapy for frequent dose adjustment, and the long halflife of warfarin (approximately 60 hrs) requires several days to restore the therapeutic anticoagultion level following interruption.
Page 3
ACCEPTED MANUSCRIPT Prepared for JTCVS One major advantage compared to NOACs is reversibility. In emergency setting, warfarin can be reversed with fresh frozen plasma and patients can undergo safe procedure. Vitamin K provides excess cofactor for ongoing coagulation factor carboxylation in the setting of irreversible inhibition by warfarin,
RI PT
and therefore requires synthesis of new coagulation factors in order to have an effect. For additional information on warfarin, see online material.
M AN U
Use of warfarin in cardiothoracic surgery
SC
These limitations led to development of NOACs targeting Factor Xa or thrombin (Factor IIa).
We reviewed the use of warfarin after cardiac surgery at the Brigham and Women’s Hospital. In 2011, out of 1257 cardiac cases performed, 586 patients (46.6%) were discharged on warfarin. Similarly in 2012, out of 1234 cardiac cases performed, 557 patients (45.1%) were discharged on warfarin. These
TE D
data included all patients who were on warfarin, hence both patients who were on preoperatively and
EP
started new postoperatively were counted.
Pharmacokinetic/Pharmacodynamic profile of oral anticoagulants
Table 1.
AC C
The characteristics of dabigatran, rivaroxaban, apixaban and edoxaban are compared with warfarin in
Dabigatran
Dabigatran etexilate is a direct thrombin inhibitor and comes in the form of prodrug with bioavailability of 7.2%.1 It is converted to active form dabigatran in the liver. It directly blocks the active site and prevents conversion of fibrinogen into fibrin. Half life of dabigatran is about 13 hours in healthy Page 4
ACCEPTED MANUSCRIPT Prepared for JTCVS individual, and is cleared by kidneys (renal excretion 80%). Renal function needs to be monitored in patients with renal insufficiency, since poor renal function can impair renal excretion and prolong the effect of anticoagulation. Dose adjustment is done accordingly based on the creatinine clearance. (table
RI PT
1) Interaction with permability glycoprotein (p-gp) inhibitors such as quinidine, ketoconazole, and verapamil can increase plasma concentration by reducing the clearance of dabigatran etexilate.2 This is more significant in renal failure patients, and patients with severe renal impairment (Creatinine
SC
clearance 50ml/min), last dose should be given 3 days before surgery. 48-60 hours of interruption will lead to
TE D
minimal anticoagulant effect of
