The time has come for clinicians to turn to novel oral anticoagulant agents for the first-line prevention of stroke and systemic embolism in patients with atrial fibrillation.
Clinicians now have a wider variety of anticoagulation tools at their disposal for the prevention of systemic embolism and stroke in their patients with atrial fibrillation (AF). In addition to the dependable, old standard, warfarin, four FDA-approved oral anticoagulants have been added to their tool belts: dabigatran, rivaroxaban, apixaban, and, most recently, edoxaban.
“The approval of these agents really provides clinicians with a great opportunity,” said Neil Zakai, MD, MSc, associate professor of medicine in the hematology/oncology division at the University of Vermont College of Medicine. “After 50 years of having one anticoagulant, we now have multiple anticoagulants to treat patients at home, increasing flexibility and convenience.”
This increased variety of treatment options has left some clinicians unsure of when it’s best to prescribe these novel oral anticoagulants, or NOACs, and when it’s best to stick with “old reliable,” warfarin.
ASH Clinical News recently spoke with several clinicians familiar with these four novel drugs about how they use these agents in their own practices and their advice for appropriately selecting and treating patients with these anticoagulants.
How Do We Choose?
Compared with warfarin, the four NOACs, also known as target-specific oral anticoagulants, have a faster onset, a shorter half-life, and fewer drug interactions than warfarin. Phase 3 clinical trials have also shown these new agents to be either as effective (in the case of rivaroxaban, edoxaban, and dabigatran 110 mg) or more effective (for apixaban and dabigatran 150 mg) than warfarin in reducing the risk of stroke and systemic embolism in patients with AF.1,2,3,4
“For the last several years, the argument has been about when clinicians should use the new oral anticoagulants. I think that by now the argument should be turned around to ask, ‘What are our reasons for using warfarin?’” said Jack E. Ansell, MD, professor of medicine, Hofstra North Shore/LIJ School of Medicine. “The time has come for the oral anticoagulants to be the first-line therapy based on extensive trials that show that these drugs are as effective and as safe as warfarin. In some cases, they may even be better and safer. And, clearly, they are more convenient.”
Where the choice gets more difficult is in choosing among the four new options, each of which has slightly different characteristics. See the SIDEBAR for more about these agents.
There are currently no head-to-head trials comparing the efficacy and safety of any of these NOACs to each other; each drug was approved based on clinical trials comparing it to warfarin.
“One has to be cautious in comparing outcomes from individual trials and saying one drug is better than the other,” noted Dr. Ansell. “But having said that, clinicians have to do something to aid in decision-making, so I am sure that I, and others, do look at trial results and make some judgments.”
The Right NOAC for the Right Patient
While the availability of the NOACs, in addition to warfarin, opens up several treatment possibilities for patients with AF, but clinicians need particular guidance in special patient populations.
Recent studies have suggested that patients with impaired kidney function may be at an increased risk for bleeding when treated with NOACs, so clinicians need to carefully consider a patient’s renal function when prescribing one of these novel drugs.
This is particularly true in the case of dabigatran, according to Mark A. Crowther, MD, MSc, professor in the Department of Medicine at McMaster University in Ontario, Canada. “Dabigatran is very sensitive to renal function. Patients will need to be monitored a bit more carefully for renal function if they are treated with dabigatran.” A sub-study of the 17,951 patients from the phase 3 RE-LY trial (the basis for dabigatran’s FDA approval) found that rates of stroke or systemic embolism, major intracranial bleeding, all-cause mortality, and net clinical outcome all increased with decreasing renal function (measured by estimated glomerular filtration rate [eGFR]).5 However, the overall rate of stroke and systemic embolism was lower than for warfarin with the use of dabigatran at 150 mg, and similar to warfarin with the 110-mg dose. Prescribing information for dabigatran recommends regular assessment of renal function before and during treatment with dabigatran, as well as a reduced dose (75 mg twice daily) for patients with severe renal impairment (eGFR = 15–30 mL/min).
Similarly, the ROCKET-AF trial of rivaroxaban showed that patients with a creatinine clearance of 30 to 50 mL/min had similar clinical outcomes to patients with normal renal function when the dose was lowered from 20 mg to 15 mg.
Prescribing information for apixaban currently recommends a dose adjustment to 2.5 mg twice daily in patients with moderate renal impairment, but only in patients older than 80 years or weighing less than 60 kg.
The newest approved oral anticoagulant, edoxaban, presents clinicians with a unique issue in the setting of renal impairment. A reduced dose of edoxaban is recommended in patients with a creatinine clearance of 15 to 50 mL/min. However, Dr. Zakai also points out that edoxaban may increase the risk for ischemic stroke even in patients with excellent renal function, because the drug could be excreted from the body too quickly. Therefore, the drug is not recommended in patients with a creatinine clearance greater than 95 mL/min.
“If a patient had borderline renal function, I would likely select apixaban or warfarin compared with the other agents because there is less of an issue with kidney function,” Dr. Zakai said. “Most hospital labs only report when renal function is greater than 60 mL/min; if a patient has clearance greater than 95 mL/min that goes unreported, that could potentially be an issue with edoxaban.”
Calculating Bleeding Risk
Consideration of a patient’s bleeding risk is also necessary when choosing among NOACs. For example, patients given concurrent antiplatelet treatment are at increased risk for major bleeding events and will require close monitoring.
For example, the ATLAS ACS 2 TIMI 51 trial, which tested 2.5-mg and 5-mg rivaroxaban against placebo in 15,526 patients with recent acute coronary syndrome receiving standard antiplatelet therapy, found that the NOAC significantly reduced the risk of the composite endpoint of death from cardiovascular causes, myocardial infarction, or stroke.6 On the other hand, rivaroxaban also increased the risk for major bleeding and intracranial hemorrhage, though there was no increased risk for fatal bleeding.
Body Mass Index
Clinicians may also want to take a patient’s weight into consideration. According to Dr. Crowther, the clinical studies examining the efficacy of these drugs rarely included patients at the extremes of weight. When treating a patient who weighs 250 to 300 pounds, for instance, warfarin may be a better option because it is unknown how efficacious an unmonitored dose of the new agent would be. Similarly, when treating a patient who is underweight, a full dose of the oral anticoagulants may be “over-anticoagulation” and could be associated with a higher risk for bleeding.
“With anybody who falls outside of the norm I would lean toward warfarin because of our ability to monitor it,” Dr. Crowther said.
Working Without the Safety Net of Reversal
Some clinicians may shy away from using these NOACs because of the perceived lack of reversal agents in the event of bleeding. According to Dr. Ansell, though, this may in fact be more of a perception than a reality.
“Among the major atrial fibrillation trials and journal articles published recently, the outcomes of major bleeding episodes between these new agents and those patients on warfarin were the same – if not better – even without a specific reversal agent available,” Dr. Ansell said. “Rates of hospitalization and all-cause mortality as a result of bleeding were about the same or less.”
This perception may be, in part, aided by the plethora of commercials from lawyers advertising class-action lawsuits against the manufacturers of some of these drugs, Dr. Crowther added.
“Everybody knows that anticoagulants cause bleeding. To not use one of these agents because of a perceived inability to reverse them makes no sense,” Dr. Crowther said. “If you look at the research published regarding bleeding risk and mortality risk in patients with a major or life-threatening bleed, the risk of dying was substantially less with the newer drugs than with warfarin – despite the fact that we have a reversal agent for warfarin.”
Even without specific reversal agents, the newer oral anticoagulants all have much shorter half-lives than warfarin, which provide patients and clinicians with other advantages, Dr. Zakai said, particularly when a patient requires a medical procedure.
He offered the following example: “If I had a patient on warfarin who needed to undergo a colonoscopy, I would have to hold warfarin for five days, debate whether to use another anticoagulant during that time, and then debate whether to use an injectable heparin to get the patient back on warfarin. The shorter half-lives of the newer agents mean I can stop medication for a shorter period of time and start back up just after the colonoscopy, making it easier to manage the risks of these patients.”
One of the remaining reasons clinicians may choose to continue using warfarin is cost.
“Warfarin [itself] is inexpensive, but what makes it expensive is the monitoring it requires,” Dr. Zakai said. “Monitoring may be as often as once a month – and there are fees associated with phlebotomy and laboratory work.”
According to Dr. Zakai, the newer drugs all seem to be priced at a point where they are competitive with the approximate cost of warfarin, plus the associated monitoring fees. However, in the real-world setting, the prices do not necessarily work out to be equal. Patients’ out-of-pocket expenses can be affected by their insurance plans, prescriptions plans, and co-pays.
Many factors complicate the ability to calculate overall cost-effectiveness of these drugs – for example, the cost of treating adverse effects of the drugs, or the cost of treating bleeding events that may occur.
“Even the most die-hard warfarin aficionado will acknowledge that these newer agents have a lower risk for intracerebral hemorrhage than warfarin, and hemorrhage is very expensive to manage,” Dr. Crowther said.
Where Does that Leave Us?
Even considering all of this information, the choice of which oral anticoagulant to use will almost always come down to individual patient characteristics, patient preference, and a patient’s likelihood of adhering to the prescribed medication regimen – especially in the case of the new drugs with shorter half-lives.
“Most of us would look at these medications, just like any medication, and say that they have some favorable characteristics and some unfavorable characteristics,” Dr. Crowther said. “Clinicians should take patients’ comorbidities, bleeding risk, renal function, and, perhaps, age into account. It’s also important to pay attention to the package inserts, and make sure that you are complying with the recommendations issued around each drug.”—By Leah Lawrence
- Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med.2009;361:1139-51.
- Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.
- Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.
- Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093-104.
- Hijazi Z, Hohnloser SH, Oldgren J, et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY trialanalysis. Circulation. 2014;129:961-70.
- Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366:9-19.
|NOACs at a Glance|
- FDA approvals: prevention of stroke in patients with AF, treatment of deep-vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5 to 10 days; prevention of recurrent DVT and PE
- Dosage forms and strengths: 75 mg and 150 mg, twice daily
- Mechanism of action: Direct thrombin inhibitor, Factor IIa inhibitor
- Half-life: 12 to 17 hours
- FDA approvals: prevention of stroke in patients with AF; treatment of DVT and PE; prevention of recurrent DVT and PE; prophylaxis of DVT after knee or hip replacement surgery
- Dosage forms and strengths: 10 mg, 15 mg, or 20 mg, once daily
- Mechanism of action: Factor Xa inhibitor
- Half-life: 5 to 9 hours in younger, healthy patients; 11 to 13 hours in older patients
- FDA approvals: prevention of stroke in AF; treatment of DVT and PE; prevention of recurrent DVT and PE; prophylaxis of DVT after knee or hip replacement surgery
- Dosage forms and strengths: 2.5 mg, 5 mg, or 10 mg, twice daily
- Mechanism of action: Factor Xa inhibitor
- Half-life: 12 hours
- FDA approvals: prevention of stroke and systemic embolism in AF; treatment of DVT and PE; treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for 5 to 10 days
- Dosage forms and strengths: 15 mg, 30 mg, and 60 mg, once daily
- Mechanism of action: Factor Xa inhibitor
- Half-life: 10 to 14 hours