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The NOACs (Novel Oral Anticoagulants) Have Landed!
Accepted Manuscript The NOACs (Novel Oral Anticoagulants) have landed! Joseph S. Alpert, MD PII:
S0002-9343(14)00666-4
DOI:
10.1016/j.amjmed.2014.07.028
Reference:
AJM 12629
To appear in:
The American Journal of Medicine
Received Date: 22 July 2014 Accepted Date: 22 July 2014
Please cite this article as: Alpert JS, The NOACs (Novel Oral Anticoagulants) have landed!, The American Journal of Medicine (2014), doi: 10.1016/j.amjmed.2014.07.028. 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
The NOACs (Novel Oral Anticoagulants) have landed! Joseph S. Alpert, MD Professor of Medicine, University of Arizona College of Medicine, Tucson, AZ;
RI PT
Editor in Chief, The American Journal of Medicine
Funding: None
SC
COI: None
M AN U
Authorship: The author is solely responsible for the content of this manuscript.
Unless you are practicing medicine on Mars, you have already realized that there is a revolution
TE D
going on in the US and throughout the world in terms of anticoagulant therapy. For many decades, the only anticoagulant available was warfarin, with all of its attendant requirements and prohibitions. I am fond of telling my trainees that I never had a patient thank me for
EP
putting them on warfarin! During the last two years, three new and novel anticoagulants (NOACs) have been approved by the FDA: Dabigatran (Pradaxa), rivaroxaban (Xarelto), and
AC C
apixaban (Eliquis)1-3. There is also a fourth NOAC (edoxaban) working its way through the regulatory pathway4. Dabigatran blocks clotting factor IIa in the clotting cascade, while the other three (rivaroxaban, apixaban, and edoxaban) all block clotting factor Xa. In a number of large randomized, international “gold standard” (double blind) clinical trials, each of these agents has been shown to be as good as, and occasionally in some categories, better than warfarin for stroke prevention in patients with atrial fibrillation, deep venous thrombosis, and
ACCEPTED MANUSCRIPT
pulmonary embolism1-4. Approval by the FDA varies from agent to agent for the different indications but it is likely that in the future, all of these agents will have FDA approval for all of
RI PT
the above indications. The NOACs are much easier to use when compared with warfarin. First of all, frequent
monitoring of clotting parameters is not required and, if done, the results can be confusing. So,
SC
measuring of INR values as is required with warfarin is not indicated. There are no dietary restrictions with these agents and their dosing is quite simple and straightforward. In this issue
M AN U
of the journal, Desai and colleagues have tracked the initiation patterns of 6893 patients who were prescribed an anticoagulant during the time period 2010-20135. The data were obtained from a computer data base of medical and prescription claims of a large health insurer. Given the much simpler clinical protocol associated with a NOAC, it is not surprising that the NOACs
TE D
accounted for 62% of new anticoagulant prescriptions during that time period. Ease of use undoubtedly accounted for this rapid switch from warfarin to a NOAC.
EP
However, as is often the case in clinical medicine, there is no perfect solution to any problem. There are, of course, some negatives associated with the NOACs. Perhaps, the most important
AC C
problem is price. Since these are new agents, their price can be substantial. Desai et al found that 98% of new anticoagulant expense was accounted for by the NOACs. Indeed, the average combined patient and insurer cost during the first 6 months of NOAC use was $900 more than if warfarin had been prescribed. This comes as no surprise since these are new agents and their cost is thus substantially higher than warfarin, which can be purchased in its generic form. I always advise patients receiving a prescription for one of the NOACs to check with their
ACCEPTED MANUSCRIPT
insurance company before handing in the prescription in order to see what their co-payment will be. The range that I have seen is from $30 per month to $140 per month. Often patients
RI PT
with very high co-payment requirements choose to continue or initiate therapy with warfarin. A second issue that is often mentioned with the NOACs is that, at the moment, there is no antidote to reverse their anticoagulant effect in the case of bleeding. In my opinion, this is not
SC
a major issue since all of the NOACs have short half-lives with respect to pharmacological activity, so that discontinuing them results in a return to normal coagulation in a relatively short
M AN U
time, particularly when compared with warfarin. In the large trials, the number of bleeding complications with the NOACs were comparable to those with warfarin, and in some trials, bleeding was less catastrophic than with warfarin, for example, less cerebral hemorrhage1-5. As just noted, the major dreaded complication with all anticoagulants, and the NOACs are no
TE D
exception, is bleeding. This is particularly a problem with elderly patients and individuals who are taking concomitant antiplatelet agents, such as aspirin or clopidogrel. In these situations,
EP
great care should be taken to minimize the risk of hemorrhage. I usually prescribe lower doses of the NOACs in these patients. When using warfarin in these settings, I try to keep the INR at
AC C
the lowest effective value, but as most physicians know, this can be challenging. Given the rapid employment of the NOACs, how do I see anticoagulant therapy in the future? In my opinion, I expect utilization of the NOACs, and there will be more coming, to increase over time, particularly once they become generic. Cost will gradually become less of an issue and new protocols will be devised to minimize, but never eliminate, bleeding risk. One important caveat: The NOACs are apparently less effective in the management of patients with
ACCEPTED MANUSCRIPT
prosthetic heart valves6. In these latter patients, warfarin therapy is the only drug that is effective.
RI PT
Finally, I must state in the interest of full disclosure, that I have been the chair or co-chair for the Data Monitoring Committee (DSM) for two of the large clinical trials involving rivaroxaban, the ROCKET AF and the PIONEER2,7,8. For those of you who do not know what this involves,
SC
here is an explanation. The DSM is a small committee of physicians and biostatisticians who are experts in the field of clinical trials. The DSM examines the data unblinded as it is collected
M AN U
during the trial. The DSM has the power to stop the trial if something very bad (major complications or death associated with the agent being tested) or something very good (marked improvement in a primary end point with the new agent) is happening. That having been said, I have seen no scientific proof as yet that one NOAC is better than another. The
TE D
trials involving the individual NOACs were all somewhat different in their patient selection and drug protocols and, therefore, the results cannot be compared.
EP
One other clinically important finding from recent trials: It is often not necessary to stop warfarin or a NOAC when performing surgical procedures with modest risk for bleeding, for
AC C
example, oral surgery or pacemaker implantation9. One recent trial even demonstrated that warfarin discontinuation with heparin bridging was associated with an increased risk for periprocedural stroke and minor bleeding complications10. As always, I appreciate comments concerning my editorials placed on our AJM blog at amjmed.blogspot.com.
ACCEPTED MANUSCRIPT
Bibliography
RI PT
1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361: 1139-51. doi: 10.1056/NEJMoa0905561. Epub 2009 Aug 30. Erratum in: N Engl J Med. 2010; 363: 1877.
SC
2. Manesh RP, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KAA, Califf RM and the ROCKET AF Steering Committee for the ROCKET AF Investigators. N Engl J Med 2011; 365: 883891.
M AN U
3. Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit C, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FWA, Zhu J, Wallentin L for the ARISTOTLE Committees and Investigators. N Engl J Med 2011; 365: 981-992.
TE D
4. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators: Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013; 369: 2093-104. doi: 10.1056/NEJMoa1310907. Epub 2013 Nov 19.
EP
5. Desai NR, Krumme AA, Schneeweiss S, Shrank WH, Brill G, Pezalla EJ, Spettell CM, Brennan TA, Matlin OS, Avorn J, and Choudhry NK: Patterns of initiation of oral anticoagulants in patients with atrial fibrillation—quality and cost implications. Am J Med: 2014, in press.
AC C
6. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, Blatchford J, Devenny K, Friedman J, Guiver K, Harper R, Khder Y, Lobmeyer MT, Maas H, Voigt JU, Simoons ML, Van de Werf F; RE-ALIGN Investigators: Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013; 369: 1206-14. doi: 10.1056/NEJMoa1300615. Epub 2013 Aug 31. 7. Trial is recruiting: http://clinicaltrials.gov/ct2/results?term=PIONEER+rivaroxaban&Search=Search 8. Ascencio LA, Huang JJ, Alpert JS: Combining antiplatelet and antithrombotic therapy (triple therapy): What are the risks and benefits. Am J Med 2014; 127: 579-585.
ACCEPTED MANUSCRIPT
9. Wahl MJ: Dental surgery and antiplatelet agents: Bleed or die. Am J Med 2014; 127: 260267.
AC C
EP
TE D
M AN U
SC
RI PT
10. Di Biase L, Burkhardt JD, Santangeli P, Mohanty P, Sanchez JE, Horton R, Gallinghouse J, Themistoclakis S, Rosillo, A, Lakkireddy D, Reddy M, Hao S, Hongo R, Beheiry S, Zagrodzky J, Rong B, Mohanty S, Elayi CS, Forleo G, Pelargonio G, Narducci ML, Dello Russo A, Casella M, Fassini G, Tondo C, Schweikert RA, Natale A: Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management. Results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation (COMPARE) randomized trial. Circulation 2014; 129: 2638-2644.
S0002-9343(14)00666-4
DOI:
10.1016/j.amjmed.2014.07.028
Reference:
AJM 12629
To appear in:
The American Journal of Medicine
Received Date: 22 July 2014 Accepted Date: 22 July 2014
Please cite this article as: Alpert JS, The NOACs (Novel Oral Anticoagulants) have landed!, The American Journal of Medicine (2014), doi: 10.1016/j.amjmed.2014.07.028. 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
The NOACs (Novel Oral Anticoagulants) have landed! Joseph S. Alpert, MD Professor of Medicine, University of Arizona College of Medicine, Tucson, AZ;
RI PT
Editor in Chief, The American Journal of Medicine
Funding: None
SC
COI: None
M AN U
Authorship: The author is solely responsible for the content of this manuscript.
Unless you are practicing medicine on Mars, you have already realized that there is a revolution
TE D
going on in the US and throughout the world in terms of anticoagulant therapy. For many decades, the only anticoagulant available was warfarin, with all of its attendant requirements and prohibitions. I am fond of telling my trainees that I never had a patient thank me for
EP
putting them on warfarin! During the last two years, three new and novel anticoagulants (NOACs) have been approved by the FDA: Dabigatran (Pradaxa), rivaroxaban (Xarelto), and
AC C
apixaban (Eliquis)1-3. There is also a fourth NOAC (edoxaban) working its way through the regulatory pathway4. Dabigatran blocks clotting factor IIa in the clotting cascade, while the other three (rivaroxaban, apixaban, and edoxaban) all block clotting factor Xa. In a number of large randomized, international “gold standard” (double blind) clinical trials, each of these agents has been shown to be as good as, and occasionally in some categories, better than warfarin for stroke prevention in patients with atrial fibrillation, deep venous thrombosis, and
ACCEPTED MANUSCRIPT
pulmonary embolism1-4. Approval by the FDA varies from agent to agent for the different indications but it is likely that in the future, all of these agents will have FDA approval for all of
RI PT
the above indications. The NOACs are much easier to use when compared with warfarin. First of all, frequent
monitoring of clotting parameters is not required and, if done, the results can be confusing. So,
SC
measuring of INR values as is required with warfarin is not indicated. There are no dietary restrictions with these agents and their dosing is quite simple and straightforward. In this issue
M AN U
of the journal, Desai and colleagues have tracked the initiation patterns of 6893 patients who were prescribed an anticoagulant during the time period 2010-20135. The data were obtained from a computer data base of medical and prescription claims of a large health insurer. Given the much simpler clinical protocol associated with a NOAC, it is not surprising that the NOACs
TE D
accounted for 62% of new anticoagulant prescriptions during that time period. Ease of use undoubtedly accounted for this rapid switch from warfarin to a NOAC.
EP
However, as is often the case in clinical medicine, there is no perfect solution to any problem. There are, of course, some negatives associated with the NOACs. Perhaps, the most important
AC C
problem is price. Since these are new agents, their price can be substantial. Desai et al found that 98% of new anticoagulant expense was accounted for by the NOACs. Indeed, the average combined patient and insurer cost during the first 6 months of NOAC use was $900 more than if warfarin had been prescribed. This comes as no surprise since these are new agents and their cost is thus substantially higher than warfarin, which can be purchased in its generic form. I always advise patients receiving a prescription for one of the NOACs to check with their
ACCEPTED MANUSCRIPT
insurance company before handing in the prescription in order to see what their co-payment will be. The range that I have seen is from $30 per month to $140 per month. Often patients
RI PT
with very high co-payment requirements choose to continue or initiate therapy with warfarin. A second issue that is often mentioned with the NOACs is that, at the moment, there is no antidote to reverse their anticoagulant effect in the case of bleeding. In my opinion, this is not
SC
a major issue since all of the NOACs have short half-lives with respect to pharmacological activity, so that discontinuing them results in a return to normal coagulation in a relatively short
M AN U
time, particularly when compared with warfarin. In the large trials, the number of bleeding complications with the NOACs were comparable to those with warfarin, and in some trials, bleeding was less catastrophic than with warfarin, for example, less cerebral hemorrhage1-5. As just noted, the major dreaded complication with all anticoagulants, and the NOACs are no
TE D
exception, is bleeding. This is particularly a problem with elderly patients and individuals who are taking concomitant antiplatelet agents, such as aspirin or clopidogrel. In these situations,
EP
great care should be taken to minimize the risk of hemorrhage. I usually prescribe lower doses of the NOACs in these patients. When using warfarin in these settings, I try to keep the INR at
AC C
the lowest effective value, but as most physicians know, this can be challenging. Given the rapid employment of the NOACs, how do I see anticoagulant therapy in the future? In my opinion, I expect utilization of the NOACs, and there will be more coming, to increase over time, particularly once they become generic. Cost will gradually become less of an issue and new protocols will be devised to minimize, but never eliminate, bleeding risk. One important caveat: The NOACs are apparently less effective in the management of patients with
ACCEPTED MANUSCRIPT
prosthetic heart valves6. In these latter patients, warfarin therapy is the only drug that is effective.
RI PT
Finally, I must state in the interest of full disclosure, that I have been the chair or co-chair for the Data Monitoring Committee (DSM) for two of the large clinical trials involving rivaroxaban, the ROCKET AF and the PIONEER2,7,8. For those of you who do not know what this involves,
SC
here is an explanation. The DSM is a small committee of physicians and biostatisticians who are experts in the field of clinical trials. The DSM examines the data unblinded as it is collected
M AN U
during the trial. The DSM has the power to stop the trial if something very bad (major complications or death associated with the agent being tested) or something very good (marked improvement in a primary end point with the new agent) is happening. That having been said, I have seen no scientific proof as yet that one NOAC is better than another. The
TE D
trials involving the individual NOACs were all somewhat different in their patient selection and drug protocols and, therefore, the results cannot be compared.
EP
One other clinically important finding from recent trials: It is often not necessary to stop warfarin or a NOAC when performing surgical procedures with modest risk for bleeding, for
AC C
example, oral surgery or pacemaker implantation9. One recent trial even demonstrated that warfarin discontinuation with heparin bridging was associated with an increased risk for periprocedural stroke and minor bleeding complications10. As always, I appreciate comments concerning my editorials placed on our AJM blog at amjmed.blogspot.com.
ACCEPTED MANUSCRIPT
Bibliography
RI PT
1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361: 1139-51. doi: 10.1056/NEJMoa0905561. Epub 2009 Aug 30. Erratum in: N Engl J Med. 2010; 363: 1877.
SC
2. Manesh RP, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KAA, Califf RM and the ROCKET AF Steering Committee for the ROCKET AF Investigators. N Engl J Med 2011; 365: 883891.
M AN U
3. Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit C, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FWA, Zhu J, Wallentin L for the ARISTOTLE Committees and Investigators. N Engl J Med 2011; 365: 981-992.
TE D
4. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators: Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013; 369: 2093-104. doi: 10.1056/NEJMoa1310907. Epub 2013 Nov 19.
EP
5. Desai NR, Krumme AA, Schneeweiss S, Shrank WH, Brill G, Pezalla EJ, Spettell CM, Brennan TA, Matlin OS, Avorn J, and Choudhry NK: Patterns of initiation of oral anticoagulants in patients with atrial fibrillation—quality and cost implications. Am J Med: 2014, in press.
AC C
6. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, Blatchford J, Devenny K, Friedman J, Guiver K, Harper R, Khder Y, Lobmeyer MT, Maas H, Voigt JU, Simoons ML, Van de Werf F; RE-ALIGN Investigators: Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013; 369: 1206-14. doi: 10.1056/NEJMoa1300615. Epub 2013 Aug 31. 7. Trial is recruiting: http://clinicaltrials.gov/ct2/results?term=PIONEER+rivaroxaban&Search=Search 8. Ascencio LA, Huang JJ, Alpert JS: Combining antiplatelet and antithrombotic therapy (triple therapy): What are the risks and benefits. Am J Med 2014; 127: 579-585.
ACCEPTED MANUSCRIPT
9. Wahl MJ: Dental surgery and antiplatelet agents: Bleed or die. Am J Med 2014; 127: 260267.
AC C
EP
TE D
M AN U
SC
RI PT
10. Di Biase L, Burkhardt JD, Santangeli P, Mohanty P, Sanchez JE, Horton R, Gallinghouse J, Themistoclakis S, Rosillo, A, Lakkireddy D, Reddy M, Hao S, Hongo R, Beheiry S, Zagrodzky J, Rong B, Mohanty S, Elayi CS, Forleo G, Pelargonio G, Narducci ML, Dello Russo A, Casella M, Fassini G, Tondo C, Schweikert RA, Natale A: Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management. Results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation (COMPARE) randomized trial. Circulation 2014; 129: 2638-2644.