Safety concerns of antithrombotic agents
The primary safety concern for any antithrombotic agent is major bleeding. Major bleeding may be classified as fatal bleeds, hemorrhagic stroke, intraocular bleeds, and gastrointestinal bleeds. In general, however, all of these bleeding events combined occur infrequently (~2% to 4% per year) for both warfarin and the newer agents.7 Based on data from the clinical trials, hemorrhagic strokes occur approximately 0.10% to 0.47% per year, which was less likely in patients who have received the newer agents in the clinical trials (0.10% to 0.26%/year).7
Patients who are at highest risk for bleeding should be identified in advance of starting antithrombotic therapy. For example, certain risk factors for bleeding are also absolute or relative contraindications to starting therapy at all. These include the following: a history of bleeding (greatest risk factor for bleeding) or a predisposition for bleeding, abnormal liver or kidney disease, uncontrolled hypertension, concomitant drug or alcohol use, reduced platelet count/function, excessive fall risk, and malignancy.12,13 Other risk factors for bleeding, however, are also risk factors for having a stroke (prior history of stroke, age of over 65 years, and a history of hypertension).12,13 For example, research has shown that the higher a patients' CHADS2 score is and the older a patient is, the higher the likelihood there is of bleeding.14 This situation creates a challenge for the clinician as to whether to start antithrombotic therapy. However, it is important for the clinician to keep in mind, when considering risk-benefit ratios, the likelihood of stroke is greater than the likelihood of bleeding in many patients with AF. Thus, the clinician should openly discuss the risks/benefits of antithrombotic therapy with each individual patient to determine the best treatment plan for stroke prevention.5,7
Management of bleeding
Management of bleeding needs to be taken into consideration in advance of starting any chronic antithrombotic therapy. Warfarin has a specific antidote (vitamin K).11 However, at this time, none of the newer agents have specific antidotes.
Dabigatran is partially dialyzable, but the data are limited.8 However, the other two new agents are not expected to be dialyzable. The use of activated charcoal to reduce absorption of rivaroxaban and apixaban may be considered for cases of overdosage.9,10 Furthermore, “universal antidotes” for factor Xa inhibitors (rivaroxaban and abixaban) are currently in phase 2 drug development studies.16
A temporary discontinuation of therapy for the new agents may suffice for management of minor bleeds due to the relatively short half-life (ranging from 2 to 4 hours). If discontinued, approximately half of the medication will be out of the body within a few hours.
Beyond the use of an antidote (for warfarin), treatment for major bleeding with warfarin includes: stopping the agent, applying direct pressure to the bleeding site (if the site is compressible), and administering I.V. fluids and blood products as needed (fresh frozen plasma 2 to 4 units, red blood cells, prothrombin complex concentrate, and/or activated Factor VII).11 Management of major bleeding for the newer agents, however, is less well established. The use of procoagulant reversal agents (prothrombin complex concentrate, activated prothrombin complex, or recombinant Factor VIIa) may be helpful, but data are limited, as these have not been evaluated in clinical studies.15
In general, as with any medication that has the potential to increase the risk of bleeding, all patients should be made aware of signs and symptoms of bleeding (unusual bleeding from nose or gums, heavier than normal menstrual bleeding, red or brown urine, red or black colored stools, hemoptysis, vomiting blood or coffee ground emesis, or unusual bruising or discoloration on the skin).8–11 If the patient experiences any of these signs or symptoms, especially if severe, they should notify their healthcare provider immediately or seek medical attention right away.
Specific patient education for newer agents. Because of the relatively short half-life of the new antithrombotic agents, it is very important for patients to not miss a dose, therefore, leaving them unprotected for stroke prevention. It is also important to instruct patients not to stop their medications abruptly, due to the increased risk of stroke (as a result of subtherapeutic drug levels). If they anticipate stopping the medication, they should consult with their healthcare provider first.
Patients should be advised not to double up on doses in the event of a missed dose. In the case of dabigatran, if the patient realizes that they missed a dose soon after the “usual” time they take the medication, they may take the missed dose as long as they can space the next dose out by at least 6 hours.8 The packet insert for apixaban, the other twice-daily medication, recommends taking the missed dose as soon as possible on the same day.10 As with dabigatran, apixaban should not be doubled to make up for the missed dose.8,10
It is important to remind patients taking dabigatran to not to open, cut, or crush the capsules. If the pellets are taken without the capsule shield, the oral bioavailability is increased by 75%, which would place the patient at an increased risk of bleeding.8 Therefore, patients must be able to swallow the capsules if prescribed dabigatran. In addition, due to the possibility of degradation, the capsules should not be taken out of the pill container or blister pack until they are ready to swallow the capsule.8 This means medication boxes for ease of administration should not be prefilled by others due to the possible degradation of the capsules. Patients should also be advised to use all the capsules within 4 months of opening the bottle.8
Rivaroxaban may be crushed and taken with a small amount of applesauce followed by food for patients who are unable to swallow the tablet whole.9 For those with a nasogastric tube or a gastric feeding tube, after confirming tube placement, the tablet may be crushed and mixed with water and administered via the tube.9
Drug-food and drug-drug interactions
There are many drug-drug and drug-food interactions associated with warfarin. Fewer of these interactions exist with the newer antithrombotic agents. The only known food interaction with a newer agent involves rivaroxaban (15 or 20 mg doses). This agent should be given with food (the evening meal) to maximize the bioavailability of the drug.9 The other two newer agents may be taken with or without food.8,10
Some important drug-drug interactions with the newer agents exist, specifically with CYP3A4 and P-glycoprotein (P-gp) transporter inhibitors and inducers. The packet inserts for the newer agents provide specific drug-drug interactions for each of the medications.8–10 For example, for rivaroxaban and apixaban (the factor Xa inhibitors), inducers of CYP3A4 and P-gp are known to decrease the exposure to the medication, thus, increasing the risk of stroke; therefore, concomitant use should be avoided.9,10 These agents, as listed on the packet inserts, include rifampin, carbamazepine, phenytoin, and St. John's wort. The packet insert for dabigatran, the other new antithrombotic agent, specifies that coadministration with rifampin should also be avoided.8
Likewise, strong inhibitors of CYP3A4 and P-gp may increase the risk of bleeding when given concurrently with the newer agents. Examples of these agents include ketoconazole, itraconazole, ritonavir, and clarithromycin. If concurrently administered with apixaban, a lower dose should be prescribed (2.5 mg twice daily).10 Likewise, the dose of dabigatran should be decreased (75 mg twice daily) if given to patients with moderate renal impairment (CrCl of 30 to 50 mL/min) and if given with dronedarone or systemic ketoconazole.8 Concurrent administration of any of these agents with rivaroxaban, however, should be avoided all together.9
Finally, as with warfarin, any of the new antithrombotic agents taken concurrently with other agents that alter coagulation (aspirin, antiplatelet agents, chronic nonsteroidal anti-inflammatory drug use, heparin, and fibrinolytics) can increase the risk of bleeding.8–11
Discontinuation of therapy for surgery or other procedures
In general, the newer antithrombotic agents should be stopped within 24 to 48 hours of elective surgery. All three agents should be discontinued at least 48 hours prior to elective surgery or invasive procedures that have a moderate-to-high risk of clinically significant bleeding.8–10 Longer drug-free intervals (3 to 5 days) should be considered for patients who have an altered CrCl (CrCl less than 50 mL/min).8–10 However, the surgeon should be consulted to discuss specific patient situations.
For elective surgery or invasive procedures that carry a low risk for bleeding, the medications should be stopped 24 hours prior to surgery.8–10 After surgery, the medications should be resumed when hemostasis is obtained to avoid an extensive drug-free interval, which places the patient at risk for stroke. Most dental procedures may be performed safely on full-dose medications. However, advise patients to give the dentist the list of their current medications prior to the procedure.
Implications for advance practice registered nurses
NPs and other advance practice registered nurses should consider the risks and benefits when deciding which therapy to prescribe for stroke prophylaxis in patients with nonvalvular AF. The newer antithrombotic agents offer several advantages over warfarin and are more efficacious in preventing stroke and systemic emboli as compared to warfarin in addition to a reduction in mortality.7,17 The newer agents are associated with a lower likelihood of having a hemorrhagic stroke (by 40% to 70%), intracranial hemorrhage (~50%), and less major bleeding as compared to warfarin.7,17 The newer agents have a more rapid onset of action, a shorter half-life, and are more convenient to prescribe (no dose adjustments or need for international normalized ratio [INR] monitoring).7,17,18
There are, however, disadvantages to having patients take the newer agents as compared to warfarin. Newer medications are typically associated with a substantial increase in cost as compared to medications off patent. In addition, the newer medications do not have a specific antidote (whereas warfarin does). Another downside to the newer agents is that they have a much shorter half-life as compared to warfarin, so if a patient inadvertently misses a dose, they are much more likely to have a stroke as compared to missing a dose of warfarin.8–10,17,18 In addition, some patients who have been on warfarin for an extended period of time do not want to “let go” of the lab monitoring. Finally, as with any new class of medications that have obtained FDA approval, some adverse reactions may not be reported until the medications have been on the market for a longer period of time.
When to use which agents. In general, the most important take-home message for preventing stroke in patients with nonvalvular AF is to treat them with any antithrombotic therapy if they have a CHADS2 score of 1 or more, unless contraindicated. Beyond this general rule, there are a few other tips for deciding which agent to place patients on.
When treating patients who are not managing well on warfarin, the consensus is to switch them to an alternative agent, as per the prescribing information of the newer agent. This can be done once the INR is less than 2.0 for dabigatran and apixaban, and less than 3.0 for rivaroxaban.8–10
When treating patients who are on warfarin and doing well, there are two schools of thought. Some experts advise to leave them alone if they are in the therapeutic range most of the time, and they are not experiencing any adverse reactions.7 Other experts say to convert all of those (who can afford it) to the newer agents due to the increased efficacy and safety profile.7
When treating a third group of patients, those naive to any type of antithrombotic therapy, there are also two schools of thought. Some experts say put any patient who can afford it on the newer agents; others say it does not matter which agent is used as long as they are on some type of stroke prophylaxis7,17; therefore, it is important to discuss the pros and cons of each type of therapy with the patient and their family.
When deciding which of the newer agents to choose, indirect comparisons provide insight into subtle, but unique advantages for each of the three medications.7,17,18 Dabigatran has the best efficacy (for stroke prevention) as compared to the other two agents.7,17 Apixaban has the best safety profile (less bleeding).7,17 Rivaroxaban provides more convenient dosing: once a day as opposed to twice daily with the other two agents. Finally, for patients with CKD, rivaroxaban and apixaban have less renal excretion as compared to dabigatran.
Optimize patient outcomes
NPs should be knowledgeable about how to risk stratify patients with AF to determine who needs stroke prophylaxis. For those patients who need therapy, there are new treatment options that are available. NPs need to weigh the pros and cons of using new therapy versus conventional treatment with warfarin in order to optimize patient outcomes.
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8. Pradaxa®[package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; Revised April 2013.
9. Xarelto®[package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; Revised March 2013.
10. Eliquis®[package insert]. Princeton, NJ: Bristol-Myers Squibb Pharma Co.; Issued December 2012.
11. Coumadin®[package insert]. Princeton, NJ: Bristol-Myers Squibb Co.; Revised October 2011.
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14. Gomes T, Mamdani MM, Holbrook AM, Paterson JM, Hellings C, Juurlink DN. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ
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Keywords:© 2013 Lippincott Williams & Wilkins
anticoagulation; atrial fibrillation; oral antithrombotic agents; stroke prevention