IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read Hepatorenal syndrome: Progressive renal failure in patients with cirrhosis; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to www.aapa.org and searching for keyword JAAPA post-tests. All others may complete and submit the post-test online at no charge at www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.

KEY POINTS

■ Clinicians may choose to monitor INR more frequently, for example, in high-risk patients on multiple agents with known warfarin 
interactions, in patients with a history of unstable INR response, during exacerbations of comorbid conditions, and while adjusting 
codosage, but all patients should have their INR checked at least once every 4 weeks.


■ Routine monitoring of patients taking dabigatran is not required. In the event of bleeding, rapid reversal may not be required consid­ering that the drug's therapeutic effect begins to diminish within 24 hours after the latest dose.


■ Advantages of warfarin over dabigatran include lower cost, once-daily dosing, more extensive indications and broader investigation across cardiovascular and cerebrovascular diagnoses, availability of established guidelines for use, and clarity of dosing for patients with severe renal impairment.


■ Advantages of dabigatran over warfarin include reduced need for and expense of laboratory monitoring, simplified dosage calculation and adjustment, greater predictability of dose response, fewer drug interactions, and rapid achievement of therapeutic concentrations.


Anticoagulation is commonly used for the prophylaxis and treatment of venous thrombosis and pulmonary embolism, as well as for the prevention of thromboembolism related to heart arrhythmias and valvular disorders. Current anticoagulant therapies include oral and parenteral agents that affect various elements of the coagulation cascade. Patients most commonly treated with oral anticoagulation therapy are those with persistent or paroxysmal atrial fibrillation (AF) who are at high risk for thromboembolic events, such as stroke. Atrial fibrillation affects roughly 2.5 million persons in North America and is the primary cause of cardioembolic stroke.1,2 


 

Vitamin K antagonists have been the mainstay of oral anticoagulation for more than half a century. Warfarin (Coumadin, Jantoven, generics) is the most commonly used vitamin K antagonist, consistently ranking among the most frequently prescribed drugs in the United States. Warfarin has a narrow margin for safety, a widely variable dose-response relationship, and numerous food and drug interactions. The relative complexity in prescribing and monitoring this therapy is likely an important contributor to underprescribing for patients at high risk of cardioembolic stroke.3 When warfarin is prescribed and used responsibly, however, the benefits have clearly been shown to outweigh risk. Net treatment benefit is greatest in patients with history of previous stroke, those older than 85 years, and others with high stroke risk.4 The American College of Chest Physicians (ACCP) has developed a systematic, evidence-based approach to anticoagulation within its practice guidelines Antithrombotic and Thrombolytic Therapy.5 


After many years without orally administered alternatives to warfarin, emerging anticoagulant therapies now include direct thrombin inhibitors and factor Xa inhibitors. Reported advantages of these therapies include reduced burden of frequent therapeutic laboratory monitoring, simplified dosing, and fewer clinically significant drug-drug interactions.6 Dabigatran (Pradaxa) is the first oral direct thrombin inhibitor to be approved by the FDA and is currently indicated for prophylaxis of stroke and systemic embolism in patients with nonvalvular AF. 


VITAMIN K ANTAGONIST: WARFARIN


Warfarin is indicated for prophylaxis and treatment of venous thrombosis and pulmonary embolism; thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement; and risk of death, recurrent MI, and thromboembolic events, such as stroke or systemic embolization after MI.7 Warfarin is an oral anticoagulant that acts through inhibition of vitamin K-dependent coagulation factors (ie, factors II, VII, IX, and X).7 


Considerations before prescribing Warfarin has a narrow margin for safety. Therefore, careful consideration of safety is essential when identifying appropriate patients, determining dosing and monitoring plans, and educating patients or caregivers. Contraindications are presented in Table 1. A variety of precautions exist, and long-term therapy with warfarin requires significant commitment to monitoring by patient and prescriber. Patients who are most vulnerable to drug-induced injury from warfarin include those with poor nutritional status, hepatic disorders, decreased intestinal absorption, diabetes, renal impairment, or anemia.8,9 Warfarin metabolism is also subject to genetic mutations. Screening tests are available to assess several recognized polymorphisms, specifically in the genes coding for VKORC1 and CYP2CP enzymes. The high cost of these tests currently limits use, but these assays may be particularly useful in Asian American and African American populations based on their higher susceptibility to the sensitive or resistant genotype.8 


Prescribing and monitoring Dosing of warfarin is guided by laboratory measures of clotting, namely prothrombin 
time (PT) or international normalized ratio (INR). Thera­peutic goals differ by indication as presented in Table 2. The onset of anticoagulant effects of warfarin is delayed; thus patients with acute conditions, such as deep venous thrombosis or pulmonary embolism, should receive concurrent parenteral anticoagulation. In this case, warfarin may generally be initiated on the same day as parenteral therapy. Parenteral therapy is discontinued no sooner than 5 days and only if INR is 2.0 or higher for 24 hours. The ACCP provides more information about bridging these therapies within published guidelines.8 


The ACCP recommends that starting doses be based on patient characteristics (see Table 3).8 Loading doses greater than 10 mg per day are not generally recommended because of an association with excessive anticoagulation and risk of major hemorrhage.8 The starting dose should be continued for 2 to 3 days before therapeutic monitoring with PT/INR is performed. This delay is based on the half-lives of the coagulation factors inhibited by warfarin.8 A variety of tools exist to guide prescribers in adjusting warfarin doses to attain therapeutic goal. In their 2003 paper comparing starting doses of warfarin, Kovacs and colleagues provided examples of dosing regimens.10 The standard for laboratory monitoring is an office- or laboratory-based INR; however, prescribers should be aware that home monitoring products are now available, approved by the FDA, and covered by numerous health insurance plans, including Medicare. Existing research suggests that for selected patients, home-based testing has the ability to increase time in target therapeutic range, patient satisfaction, and quality of life.11


Clinicians may choose to monitor INR more frequently, for example, in high-risk patients on multiple agents with known warfarin interactions, in patients with a history of unstable INR response, during exacerbations of comorbid conditions, and while adjusting dosage; but all patients should have their INR checked at least once every 4 weeks.8 Some patients will not tolerate dosing and may incur supra­therapeutic INRs or bleeding. In the case of an emergency, vitamin K and/or fresh frozen plasma can be used to antagonize or reverse the effects of warfarin.8 Warfarin should be discontinued if bleeding risks outweigh potential antico­agulation benefits or in the event of significant bleeding. Table 4 describes dose adjustments for suboptimal INR levels or the onset of significant bleeding. Additionally, ACCP guidelines offer specific recommendations for discontinuing warfarin or when bridging is necessary prior to surgical procedures.12


Safety Bleeding is the major adverse reaction with warfarin. Several models for predicting bleeding risk, including the Outpatient Bleeding Risk Index and HEMORR2HAGES, have been developed and can be helpful for risk stratification.9 Clinical studies found the annual risk of major bleeds to be 0.3% to 0.5% and of intracranial hemorrhages (ICHs) to be 0.2% in patients who were closely monitored on warfarin when compared with controls.9 Intensity of treatment was found to be the most powerful predictor of ICH.9 In general, patients who have been on long-term established therapy have lower rates of major bleeding.8,9 Rare but potentially serious side effects include anaphylaxis, "purple toe" syndrome, tissue necrosis, and limb gangrene.7 


Drug interactions are pervasive with warfarin and occur through a variety of different mechanisms.8,9 Given the broad array of potential drug-drug and drug-food interactions, providers should consult a reference or pharmacist for assistance in screening before initially prescribing warfarin or when treatments are added or discontinued for patients currently on warfarin. Some of the most commonly cited interacting agents are presented in Table 5, but this list is not all-inclusive. Patients should be educated about key food and drug interactions and encouraged to consult with their provider or a pharmacist before beginning OTC medications, dietary supplements, or vitamins. Particular attention should be given to educating patients about foods and supplements containing moderate to high levels of vitamin K, as consistency of dietary vitamin K intake will improve the provider's ability to maintain the therapeutic target. Multiple sources provide comprehensive lists of food and drug interactions with warfarin.8,13


Cost Warfarin is available in several generic formulations for less than $10 per month.14 Associated costs of therapy include laboratory monitoring with PT/INR, which costs approximately $30 per test, along with additional expenses related to office visits for medication management.15 


DIRECT THROMBIN INHIBITOR: DABIGATRAN


Dabigatran is currently indicated for prevention of stroke and systemic embolism in patients with nonvalvular AF.16 By inhibiting thrombin (factor IIa), dabigatran prevents the activation of fibrinogen to fibrin, thereby preventing the stabilization of clots.16 


Considerations before prescribing Contraindications to the use of dabigatran include active bleeding and serious hypersensitivity reaction.16 The major risk associated with dabigatran is hemorrhage. This risk is compounded with the concomitant use of antiplatelet agents or other anticoagulants and during invasive procedures. Signs and symptoms of blood loss should be regularly assessed and dabigatran discontinued immediately in patients with active pathologic bleeding. Therapy should be resumed as soon as safely possible after bleeding resolves. Dabigatran is classified as Pregnancy Category C. Whether it crosses the placenta or is excreted in breast milk is unknown. Until further data are available, exercise caution when administering dabigatran to a nursing or pregnant woman. Safety has not been established in pediatric patients. Patients 75 years or older may be at slightly greater risk of major bleeding, but at present, no special dose adjustments are recommended for this population.16 


Prescribing and monitoring Dabigatran is available in 75- and 150-mg tablets. Dose adjustment is necessary for patients with moderate to severe renal impairment.16 Dosing instructions based on creatinine clearance (CrCl) are presented in Table 6. Patients should be advised to swallow dabigatran whole, as breaking or crushing capsules increases bioavailability and bleeding risk.16 Patients should never take a double dose of dabigatran. A missed dose may be taken if less than 6 hours has elapsed since the scheduled time; otherwise the patient should wait until the next dose is due.16 Recommendations for converting between dabigatran, parenteral anticoagulants, and warfarin are presented in Table 7. In preparation for invasive procedures or surgery that requires discontinuation of anticoagulation, dabigatran should be stopped 1 to 2 days prior to the procedure if the CrCl is 50 mL/min or greater and 3 to 5 days prior to the procedure if the CrCl is less than 50 mL/min.16


Routine monitoring is not required. In the event of bleeding, rapid reversal may not be required considering that the drug's therapeutic effect begins to diminish within 24 hours after the latest dose. Although supporting evidence is limited, 60% of the drug may be eliminated over 2 to 3 hours with dialysis.16 During a hemorrhagic emergency, the transfusion of fresh frozen plasma or RBCs may be considered.16 


Safety Common adverse reactions include dyspepsia, abdominal pain, and gastritis.16 Severe bleeding (GI hemorrhage or otherwise) and serious hypersensitivity are less common but possible. GI symptoms may be explained by the medication's tartaric acid core, as low pH is necessary to increase absorption.17 Drug-drug interactions are primarily mediated through effects of P-glycoprotein (Pgp) inducers and inhibitors. P-glycoproteins are transporters that play a key role in drug bioavailability. Dabigatran may be affected by medications that act as Pgp inducers (eg, rifampin, St. John's wort, carbamazepine) or Pgp inhibitors (eg, verapamil). Simultaneous use of inducers can decrease effects of dabigatran, whereas inhibitors may increase its effects.16 Screening for specific drug interactions is advised.


Cost A 1-month supply of 150-mg tablets costs approximately $246.18 Clinicians should be aware that coverage for dabigatran by many insurance companies is subject to preauthorization.


DISCUSSION


Clinicians and patients now have a choice when selecting an oral anticoagulant regimen. FDA approval of dabigatran was based on the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, which randomized more than 18,000 patients and compared the use of warfarin and dabigatran in patients with nonvalvular atrial fibrillation.17 A subgroup analysis of RE-LY presented at the American College of Cardiology 2011 Scientific Sessions reports that dabigatran 150 mg twice daily is as safe and effective as warfarin in patients with permanent, persistent, and paroxysmal atrial fibrillation.


The results from RE-LY also demonstrated that a 150-mg dose of dabigatran was superior to warfarin in terms of overall stroke and systemic embolism prevention. In particular, the rates of hemorrhagic stroke and intracranial bleeding were notably lower with dabigatran. Rates of major hemorrhage were similar when comparing the two medications, except for GI bleeding, which was more common with dabigatran. Most GI toxicities were more common with dabigatran, especially dyspepsia. Considering that ximelagatran (Exanta), a previously studied direct thrombin inhibitor, failed to earn FDA approval because of hepatotoxicity, clinicians may have concerns about dabigatran's effects on liver function. RE-LY, however, did not demonstrate significant differences in liver function (ie, AST or ALT levels greater than three times the upper limit of normal) or the occurrence of hepatobiliary disorders between dabigatran and warfarin. RE-LY results also created initial concern that dabigatran offered less protection against MI than warfarin, but revised data have challenged those claims. Table 8 presents a summary of select outcomes studied in the trial.17,19 


Advantages of warfarin over dabigatran include lower cost, once-daily dosing, more extensive indications and broader investigation across cardiovascular and cerebrovascular diagnoses, availability of established guidelines for use, and clarity of dosing for patients with severe renal impairment. Advantages of dabigatran over warfarin include reduced need for and expense of laboratory monitoring, simplified dosage calculation and adjustment, greater predictability of dose response, fewer drug interactions, and rapid achievement of therapeutic concentrations. Clinicians should consider safety, tolerability, efficacy, price and simplicity of use when deciding which drug to initiate. 


Dabigatran's entry into the market as the first oral direct thrombin inhibitor is expected to herald entry of other alternative anticoagulants. Specifically, the "-xabans" are a novel group of oral direct factor Xa inhibitors currently being studied. Rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Lixiana) are among the most promising agents. Rivaroxaban gained FDA approval in 2011 as a once-daily oral tablet indicated for the prophylaxis of deep venous thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. Additional comparative trials among available oral anticoagulants are needed to describe relative advantages or disadvantages and assist clinicians in making prescribing choices. jaapa


Mary McArthur, Elise Dzintars, and Brock Phillips were students in the PA program at Wake Forest University School of Medicine, Winston-Salem, North Carolina, when this manuscript was written. Reamer Bushardt is professor and chair of the Department of Physician Assistant Studies at Wake Forest University School of Medicine. The authors have indicated no relationships to disclose relating to the content of this article.



IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read Hepatorenal syndrome: Progressive renal failure in patients with cirrhosis; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to www.aapa.org and searching for keyword JAAPA post-tests. All others may complete and submit the post-test online at no charge at www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.

REFERENCES


1. Clinical and Scientific Affairs Council of the AAPA. Atrial fibrillation: more help for the most common arrhythmia. JAAPA. 2007;20(5):18-21.


2. Ferro JM. Cardioembolic stroke: an update. Lancet Neurol. 2003;2(3):177-188.


3. Zimetbaum PJ, Thosani A, Yu HT, et al. Are atrial fibrillation patients receiving warfarin in accordance with stroke risk? Am J Med. 2010;123(5):446-453.


4. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009;151(5):297-305. 


5. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):546S-592S.


6. Dabigatran etexilate (Pradaxa)—a new oral anticoagulant. Med LettDrugsTher. 2010;52(1351):89-90.


7. Coumadin [package insert]. http://packageinserts.bms.com/pi/pi_coumadin.pdf. Updated 
January 2010. Accessed October 24, 2011.


8. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):160S-198S.


9. Schulman S, Beyth RJ, Kearon C, et al. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6) suppl:257S-298S.


10. Kovacs MJ, Rodger M, Wells P, et al. Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. Ann Intern Med. 2003;138(9):714-719.


11. Matchar DB, Jacobson A, Dolor R, et al. Effect of home testing of international normalized ratio on clinical events. New Engl J Med. 2010;363(17):1608-1620.


12. Douketis JD, Berger PB, Dunn AS, et al. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):299S-339S.


13. Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165(10):1095-1106.


14. Epocrates Online. Warfarin (generic/pricing). https://online.epocrates.com/noFrame/showPage.
do?method=drugs&MonographId=548&ActiveSectionId=6. Accessed October 4, 2011.


15. Anderson RJ. Cost analysis of a managed care decentralized outpatient pharmacy anticoagulation service. J Manag Care Pharm. 2004;10(2):159-165.


16. Pradaxa [package insert]. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf. Updated August 2011. Accessed October 4, 2011.


17. Connolly SJ, Ezekowitz MD, Yusuf F, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151.


18. Pradaxa. Drugstore.com Web site. http://www.drugstore.com/pradaxa/bottle-60-150mg-
capsules/qxn00597013554. Accessed October 4, 2011.


19. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363(19):1875-1876.


20. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):454S-545S.


21. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism; American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S.


22. Becker RC, Meade TW, Berger PB, et al. The primary and secondary prevention of coronary 
artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):776S-814S.


23. Salem DN, O'Gara PT, Madias C, et al. Valvular and structural heart disease: American College 
of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;
133(6 suppl):593S-629S.


24. Ebell MH. A systematic approach to managing warfarin doses. Fam Pract Manag. 2005;12(5):
77, 79-80, 83.



IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read Hepatorenal syndrome: Progressive renal failure in patients with cirrhosis; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to www.aapa.org and searching for keyword JAAPA post-tests. All others may complete and submit the post-test online at no charge at www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.