This course will provide professional nurses with the information they need to safely and effectively administer anticoagulant and fibrinolytic drugs.
CEUFast, Inc. is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center's Commission on Accreditation. ANCC Provider number #P0274.
This course will provide professional nurses with the information they need to safely and effectively administer anticoagulant and fibrinolytic drugs.
After completing this continuing education course, the learner will be able to:
Cardiovascular disease is the leading cause of death worldwide and in the United States (Jameson et al., 2018). Thrombosis is the basic underlying pathology of cardiovascular diseases like atherosclerosis, stroke, and thromboembolism. Anticoagulants and fibrinolytics are the primary pharmacologic therapy used to treat patients with thrombosis, prevent thrombosis, and treat acute complications (Kuslos & Fasinu, 2019).
Treating patients with anticoagulant and fibrinolytic drugs can be complicated. There are multiple medications available, each drug affects a different part of the clotting process, and serious side effects are possible. This course will simplify administering anticoagulant and fibrinolytic therapies by discussing the mechanism of action, the onset of effects, duration of effects, uses, dosing, adverse effects, and special consideration for each anticoagulant fibrinolytic.
Clinical issues that require lengthy coverage (e.g., clopidogrel resistance, aspirin discontinuation before surgery, genetics, and warfarin prescribing) will be covered separately. With a few exceptions, only labeled uses will be discussed. If information about the onset of effects and duration of a drug is not provided, it is not available from drug reference sources or prescribing information. Adverse effects that occur in > 10% of patients will be discussed. Unless otherwise specified, drug information in the module is from LexiComp®, a commonly used drug information database, and the manufacturers’ prescribing information. Dosing adjustments for patients with hepatic or renal impairment who are elderly or obese will be provided if they are mentioned in Lexicomp® or the prescribing information. Pharmacokinetic information will be provided when it is available.
The term acute coronary syndrome will be used on occasion. The acute coronary syndrome refers to non-ST-segment elevation MI, ST-segment elevation MI, and unstable angina. Venous thromboembolism is abbreviated as VTE.
A 76-year-old male sees his primary care physician because he has been experiencing palpitations for the past 6 weeks. The patient has a past medical history of type 2 diabetes mellitus, hypertension, hypercholesterolemia, and obesity. He has currently prescribed lisinopril, metformin, and simvastatin. A 12-lead ECG reveals that the patient’s heart rhythm is atrial fibrillation; in previous ECGs, his heart was in a normal sinus rhythm. The patient’s hepatic and renal function is normal, and his complete blood count (CBC), platelet count, activated partial thromboplastin time (aPTT), international normalized ratio (INR), and prothrombin time (PT) are all normal.
Because of his age and medical history, the physician determines that the patient has a high risk of developing thromboembolism and an ischemic stroke. To treat these issues, the patient is prescribed a daily dose of aspirin, 325 mg, a starting dose of warfarin, 2 mg once a day, and a beta-blocker for treatment of atrial fibrillation. He will continue taking metformin and lisinopril as before. The combination of simvastatin and warfarin may require a lower dose, so closer than usual. Warfarin monitoring will be done. The patient is given instructions for safe use of warfarin, including information on adverse effects, diet, the importance of strict adherence to the drug regimen, safety issues, self-monitoring for bleeding, and the need for periodic measurement of INR.
After two days of taking warfarin, the patient’s INR is 1.8, and he has no evidence of adverse effects, so the dose is increased to 3 mg once a day. After two days of taking 3 mg a day, the patient’s INR is 2.2. The physician decides not to increase the dose, and two weeks later, the patient’s INR is 2.3. It is decided to continue with the current dose. The patient is advised to have his INR measured once a week for the next 4 weeks, and the education instructions are reinforced. The patient is also advised to carry a card containing all the pertinent information about his anticoagulation therapy and wear a bracelet identifying him as someone taking warfarin.
The clotting process begins with local vasoconstriction of the injured vessels, followed by:
The platelet plug formation is a two-part platelet activation and platelet aggregation process.
Platelets are activated when exposed to and stimulated by compounds produced with a vascular injury. These factors include (but are not limited to) glycoproteins, collagen in the wall of an injured blood vessel, thrombin, P2Y1 and P2Y12, and adenosine diphosphate (ADP). Activated platelets adhere to the injury site (beginning the platelet plug formation). They release chemical mediators that attract more platelets and initiate the process of platelet aggregation.
Platelet aggregation is how the platelets clump together to complete the platelet plug formation. Platelet aggregation is initiated and sustained by serotonin, thrombin, thromboxane A2, and glycoproteins IIb and IIIa.
The clotting cascade is very complex, and it requires the presence of activated clotting factors synthesized in the liver, proteins C and S, and calcium. The clotting cascade has traditionally been viewed as comprised of the extrinsic and intrinsic pathways, leading to the final common pathways. This way of viewing the clotting process is useful for explaining specific mechanisms of action of the anticoagulants, explaining the roles of each of the clotting factors in clotting, and how and why coagulation studies are used. However, the extrinsic, intrinsic, and common pathways should be considered as a unified process, activation of clotting factors that eventually convert fibrinogen to fibrin, and fibrin is the mesh that is the “framework” for a thrombus that will stop bleeding or form a clot that obstructs blood flow to the brain, heart, or other organs.
Coagulation tests are used to measure the effectiveness of anticoagulant therapy. Commonly used tests include (Zehnder 2019).
|Activated clotting time (ACT)||Measures the time it takes for whole blood to clot. The ACT assesses the functioning of the intrinsic and common pathways. Its primary use is to monitor heparin therapy during surgical procedures in which large amounts of heparin are used. In these situations, the high plasma concentration of heparin affects the aPTT and limits its usefulness, and the ACT is used. The normal range of ACT depends on which testing device is used, and it is typically 80-160 seconds.|
|Activated partial thromboplastin time (aPTT)||Measures the time it takes plasma to clot, and it assesses the functioning of the intrinsic and common pathways. The aPTT is used to monitor heparin therapy and therapy with direct thrombin inhibitors (e.g., argatroban), to evaluate unexplained bleeding, and to diagnose disseminated intravascular coagulation (DIC). The aPTT is not used to monitor low-molecular-weight heparin therapy. The normal range for aPTT is 25-35 seconds.|
|Anti-factor Xa activity||Can be used to monitor therapy with fondaparinux, low molecular weight heparins, direct thrombin inhibitors, and the new, direct-acting oral anticoagulants (DOACs).|
|International normalized ratio (INR)||Assesses the functioning of the extrinsic and common pathways. The INR represents the ratio of the patient’s prothrombin time (PT) to a control PT that has been measured using a tissue factor reagent that has a known level of sensitivity and will result in a predictable PT measurement. The patient’s PT is divided by the control PT and the result - the ratio - should be between 0.8 and 1.2. The INR is used to monitor warfarin therapy.|
|Prothrombin time (PT)||Measures the time it takes plasma to clot, and it assesses the functioning of the extrinsic and common pathways. The normal range for PT is 11-13 seconds. The PT is used to monitor warfarin therapy.|
|Thrombin time (TT)||Measures the conversion of fibrinogen to fibrin. The normal range of thrombin time will vary, depending on the laboratory and the reagent that is used, but the range is typically 14-19 seconds. Thrombin time is used as an additional diagnostic test in patients who have a prolonged PT and aPTT.|
Before starting therapy with an anticoagulant, a physical examination and a health history should be done, a medication profile (including the use of over-the-counter drugs, supplements, and natural products) should be completed, and laboratory studies should be performed. At a minimum, the laboratory studies should include a complete blood count (CBC), including platelet count, aPTT, INR, and PT. Liver function tests and tests of renal function may also be needed. The dosing of some anticoagulants must be adjusted if the patient has a hepatic or renal impairment. Or, if the patient has severe hepatic or renal impairment, the use of some anticoagulants is contraindicated. Examples are listed below.
Direct-acting anticoagulants: Dosing of dabigatran, edoxaban, and rivaroxaban should be adjusted based on the estimated glomerular filtration rate (eGFR).
Heparin: No dosing adjustment needed.
Low molecular weight heparins (LMWHs): Dosing may need adjustment based on the eGFR.
Warfarin: No dosing adjustment needed.
Dosing of apixaban, argatroban, edoxaban, and rivaroxaban should be decreased, or the drug should not be used if the patient has a severe hepatic impairment (UptoDate, 2019a, 2019b, 2019c, 2019d).
The need for pharmacogenetic testing to determine a patient’s ability or inability to metabolize anticoagulants should be determined on a case-by-case basis. (This issue will be discussed in more detail in the section on warfarin)
During anticoagulant therapy, the patient should be closely monitored for signs and symptoms of bleeding. Bleeding can be minor, or there can be severe gastrointestinal, genito-urinary, pericardial, retro-peritoneal, and intracranial hemorrhage. Coagulation studies are ordered on as needed basis.
Patient education should include information about adherence to the medication regimen, diet, exercise, discussing the use of over-the-counter medications and supplements with a pharmacist or the prescriber, safety issues, and self-monitoring for signs/symptoms of bleeding.
If the patient is being treated with an anticoagulant, invasive procedures such as insertion of arterial and venous catheters, arterial and venous punctures, intramuscular (IM) injections, and insertion of nasogastric tubes and urinary catheters should be avoided if possible.
Using anticoagulants in elderly patients can be complex and involves considerations of benefits (prevention of thrombus formation and thromboembolic events) versus risks, i.e., bleeding, bleeding from an injury suffered from a fall, the hepatic and renal impairment associated with aging and co-morbidities, and drug interactions related to polypharmacy (Caballari, 2018). The prescribing information for many anticoagulants states that advanced age is a risk factor for bleeding.
Anticoagulant therapy requires constant vigilance and careful monitoring. The prescribing information for many oral anticoagulants contains a US Boxed Warning: “Premature discontinuation of any oral anticoagulant, including rivaroxaban, increases the risk of thrombotic events. If anticoagulation with rivaroxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant (UpTo Date, 2019d).
Nurses must understand and use the anticoagulant administration practices particular to their practice and place of employment. These drugs require close attention to administer safely and effectively as medication errors and adverse effects are not uncommon with anticoagulants (Barr, 2019). Reinforcing this point, The Institute for Safe Medication Practices (2016) lists anticoagulants as high-alert medications, capable of causing serious harm when they are used incorrectly and The Joint Commission on Accreditation of Healthcare Organizations requires healthcare organizations to have a process in place to reduce the risk of anticoagulant-associated patient harm (ISMP, 2019; TJC, 2018).
Surgery and invasive procedures are problematic for patients treated with an anticoagulant. If the anticoagulant is stopped, the patient can develop thromboembolism, but continuous use of the anticoagulant puts the patient at risk for bleeding (Douketis et al., 2019: Douketis, 2019). A reasonable approach to this issue is to use a case-by-case assessment that considers the factors listed below (Douketis et al., 2019: Douketis, 2019):
Therapeutic errors, deliberate overdose, or changes in the patient’s health can cause elevated anticoagulants and serious bleeding. If the patient on an anticoagulant has been given or has taken a supra-therapeutic dose, has taken an overdose, or if they have elevated coagulation studies or evidence of bleeding.
In the case of a deliberate overdose, contact the local poison control center (1-800-222-1222). Consult a hematologist for a supra-therapeutic dose, elevated coagulation studies, or active bleeding.
Measure and monitor the appropriate laboratory studies. Standard coagulation studies are not useful in assessing the level of anticoagulation from the direct-acting anticoagulants (Witt et al., 2018).
Administer an antidote or a reversing agent if one is available and there is a need.
Vitamin K is used to reverse the effects of warfarin. The need for vitamin K is determined by the INR and the presence and extent of bleeding. The American College of Chest Physicians and the American College of Hematology have published guidelines for treating patients with elevated INR or bleeding caused by warfarin (UpToDate, 2019e).
Anti-platelet drugs inhibit platelet activation and aggregation.
Mechanism of action: Aspirin inhibits platelet aggregation and platelet activation by blocking the formation of thromboxane A2 (UpToDate, 2019f). Thromboxane A2 is a signaling molecule that is synthesized in platelets. It is released when there is a vascular injury, and it initiates a complex series of actions that activate platelets and consequently platelet aggregation.
Onset of effects: Non-enteric, 1 hour. If a non-enteric tablet is chewed the onset of effect is approximately 20 minutes (UpToDate, 2019f).
Duration of effects: Aspirin irreversibly inhibits the formation of thromboxane A2 for the life of the platelet, approximately 10 days(UpToDate, 2019f).
Uses (UpToDate, 2019f):
Dose: Aspirin dosing is complex and depends on the clinical situation.
Adverse effects: Gastrointestinal distress, bleeding, tinnitus.
Special considerations: Use with caution in patients at risk for gastrointestinal bleeding.
Aspirin and surgery: The effect of aspirin on platelet activation and aggregation lasts approximately 10 days (Kapil et al., 2017). Continuing aspirin during the perioperative phase may reduce the risk of post-operative thromboembolic or cardiovascular events, but it may increase the risk of intraoperative bleeding (Kapil et al., 2017). These concerns are significant, and the decision to continue, discontinue or initiate aspirin therapy before surgery should be done on a case by case basis; for some patients and some procedures, the benefits do not outweigh the risks (Biccard et al., 2018; Muluk, 2019).
Aspirin and primary prevention of cardiovascular events and stroke:
A recent (2019) meta-analysis concluded that aspirin therapy does not reduce cardiovascular mortality or all-cause mortality. The benefit-risk ratio does not appear to favor its use to prevent cardiovascular disease events (Gelbenegger et al., 2019). The American College of Cardiology/American Heart Association states that low-dose aspirin therapy, 75-100 mg a day, can be considered for preventing atherosclerotic cardiovascular disease (ASCVD) in patients aged 40-70 who have a high risk for ASCVD and a low risk for bleeding (Arnett, 2019).
The United States Preventive Services Task Force (USPSTF) recommends aspirin therapy as a measure for preventing cardiovascular disease and colorectal cancer in adults aged 50 to 59 who have a 10-year risk of ASCVD >10%, who are not at risk for bleeding, who have a life expectancy of at least 10 years, and who are willing to take low-dose aspirin for at least 10 years (USPS, 2019). USPSTF recommends that aspirin therapy as a preventive measure for patients outside these parameters be considered on a case-by-case basis (USPS, 2019).
The risk of bleeding from the prophylactic use of aspirin can be significant, and many patients who might benefit from daily aspirin therapy are those who have a higher risk for bleeding (USPS, 2019).
Mechanism of action: Aspirin inhibits platelet aggregation and activity. Dipyridamole inhibits platelet aggregation by inhibiting adenosine deaminase activity (UpToDate, 2019g).
Onset of effects: See the section on aspirin. Pharmacokinetic information about dipyridamole as it applies to anticoagulation is not available.
Duration: See the section on aspirin. Pharmacokinetic information about dipyridamole as it applies to anticoagulation is not available.
Uses: Reducing the risk of stroke in patients who have had a transient ischemic attack or a thrombotic stroke (UpToDate, 2019g).
Dose: The brand name is Aggrenox®. Aggrenox® contains 25 mg of aspirin and 200 mg of extended-release dipyridamole; the dose is one capsule twice a day.
Adverse effects: Headache, abdominal pain and dyspepsia, nausea, and diarrhea.
Special considerations: Use caution in patients at risk for gastrointestinal bleeding. Avoid use if the glomerular filtration rate (GFR) is < 10 mL/minute. Dipyridamole causes vasodilation, so use caution if the patient is hypotensive or has coronary artery disease, or if the patient is elderly as orthostatic hypotension may occur (UpToDate, 2019g).
Mechanism of action: Mechanism of action: Cilostazol increases intracellular concentrations of cyclic adenosine monophosphate (cAMP) by inhibiting phosphodiesterase activity. Inhibition of phosphodiesterase decreases platelet aggregation (UpToDate, 2019h).
Onset of effects: Inhibition of platelet aggregation begins within three hours. During chronic therapy, the duration of inhibition of platelet aggregation, lasts approximately 96 hours (Pletal, 2015).
Duration: With chronic administration, platelet function will return to normal in approximately 96 hours (Pletal, 2015).
Dose: Off-label, secondary prevention of non-cardioembolic stroke, 100 mg twice a day.
Adverse effects: Headache, abnormal stools, diarrhea, infection (Guyatt et al., 2012; Pletal, 2015).
Special considerations: Cilostazol is contraindicated with patients with heart failure of any severity level (US Boxed Warning) (Guyatt et al., 2012; Pletal, 2015).
Mechanism of action: Clopidogrel inhibits platelet aggregation by blocking the activity of P2Y12. P2Y12 is a protein on the surface of platelets, and normal functioning of P2Y12 is required for activating platelets and subsequently, platelet aggregation.
Onset of effects: Inhibition of platelet aggregation begins within 2 hours of administration of a loading dose (UpToDate, 2019i).
Duration of effects: Approximately 3-10 days (UpToDate, 2019i).
Uses (UpToDate, 2019i):
Dose (UpToDate, 2019i):
Adverse effects: Bleeding.
Mechanism of action: Prasugrel inhibits platelet aggregation by blocking the activity of P2Y12. P2Y12 is a protein on the surface of platelets, and normal functioning of P2Y12 is required for activating platelets and subsequently platelet aggregation.
Onset of effects: Platelet inhibition begins < 30 minutes after a loading dose.
Duration: Normal platelet function returns with 5-9 days after discontinuation of use.
Uses: Reducing the rate of thrombotic cardiovascular events, including stent thrombosis, in patients who have an acute coronary syndrome that will be managed with PCI; unstable angina, NSTEMI, and STEMI.
Adverse effects: None listed as > 10%.
Mechanism of action: Ticagrelor inhibits platelet aggregation by blocking the activity of P2Y12. P2Y12 is a protein on the surface of platelets, and the normal functioning of P2Y12 is required for activating platelets and subsequent platelet aggregation.
Duration of action: Twenty four hours after the maintenance dose is discontinued, platelet inhibition is at approximately 58%.
Dose: For patients having a non-ST-segment elevation acute coronary syndrome or STEMI, use a loading dose of 180 mg (along with a dose of aspirin) and follow this with a 90 mg daily maintenance dose (along with low-dose aspirin) 12 hours after the loading dose. The maintenance dose should be continued for a least 12 months; after 12 months reduce the dose to 60 mg.
Adverse effects: Dyspnea.
US Boxed Warning applies to points 1-5:
Mechanism of action: Vorapaxar inhibits platelet aggregation by antagonizing protease-activated receptor-1 (PAR-1).
Onset of effects: ≥ 80% inhibition of platelet aggregation after one week of therapy.
Duration of effects: The decrease of platelet aggregation will be at 50% at 4 weeks after discontinuation of the drug.
Dose: 2.08 PO mg once a day, used in combination with aspirin or clopidogrel. Vorapaxar should not be used as monotherapy, and there is no clinical experience using vorapaxar with antiplatelet drugs other than aspirin or clopidogrel.
Adverse effects: Bleeding.
Special considerations: Do not use vorapaxar in patients with a history of stroke, transient ischemic attack, intracranial hemorrhage, or active pathological bleeding (US Boxed Warning).
Use with caution in patients who have hepatic and/or renal impairment.
Dual antiplatelet therapy with aspirin and a PY212 inhibitor is a critically important treatment for preventing thrombosis, ischemic events, stent thrombosis, and other complications in patients who are having/have had an acute coronary syndrome. Aspirin is the cornerstone of dual antiplatelet therapy, and aspirin is used along with cilostazol, clopidogrel, dipyridamole, prasugrel, or ticagrelor. For their use in dual antiplatelet therapy, each drug has specific indications, benefits and risks (Notarangelo et al., 2018).
Cilostazol: The prescribing information for cilostazol lists two off-label uses for the drug: Preventing stent thrombosis after placing a bare metal or drug-eluting stent and secondary prevention of secondary prevention non-cardioembolic stroke or TIA.
For the first, the evidence for the effectiveness of cilostazol in preventing stent thrombosis when used concurrently with aspirin and clopidogrel is mixed. Some researchers have concluded that this combination is effective. Others have not (Huang, 2018). The most recent (2014) American Heart.
Association/American College of Cardiology guidelines for treating non-ST-segment acute coronary syndromes and the most recent (2013) American College of Cardiology Foundation/American Heart Association guidelines for the treatment of STEMI do not mention its use.
Clopidogrel: Clopidogrel and aspirin can be used for patients with a STEMI and treated with PCI before the procedure and as long-term therapy to prevent complications (Qlier et al., 2018). Clopidogrel is effective as long-term dual antiplatelet therapy (Wang et al., 2018). However, clopidogrel is a pro-drug, so its onset of action is comparably slower. Clopidogrel resistance is common and compared to prasugrel and ticagrelor. It is less effective at preventing cardiovascular death, ischemic events, MI, and stroke than prasugrel or ticagrelor. The incidence of bleeding with clopidogrel is equivalent to that of prasugrel and ticagrelor. Prasugrel and ticagrelor are preferred over clopidogrel for treating patients with a STEMI and are treated with PCI (Berwanger et al., 2019).
Clopidogrel (given with aspirin) is the preferred platelet inhibitor for patients with a STEMI and treated with a fibrinolytic. Clopidogrel and aspirin reduce the incidence of death, re-infarction, and stroke when used as a long-term dual antiplatelet therapy in these patients (Schupke et al., 2019).
Dual antiplatelet therapy is recommended for all patients with a non-ST-segment elevation acute coronary syndrome. Clopidogrel and aspirin have been shown to significantly reduce the risk of death and major cardiac events in this clinical situation. Prasugrel and ticagrelor have a more rapid onset, a greater level of platelet inhibition, they appear to be more effective at preventing major adverse cardiac events (prasugrel), death, MI, and stroke (ticagrelor) than clopidogrel, and they are preferred for treating patients who are having a non-ST-segment elevation acute coronary syndrome (Kheiri et al., 2019).
Prasugrel versus ticagrelor: Prasugrel is more effective at preventing death, MI, and stroke in patients with acute coronary syndrome, with or without ST-segment elevation, and the risk of bleeding is essentially the same for both drugs (Berwanger et al., 2019).
Duration of dual antiplatelet therapy (Kheiri et al., 2019): Authoritative sources and drug prescribing information recommend that the duration of dual antiplatelet therapy should be at least 12 months. This recommendation is based on clinical experience and research studies that showed that 12 months of dual antiplatelet therapy was superior to six months for preventing stent thrombosis, MI, stroke, and other complications. Dual antiplatelet therapy can be used for years. Still, patients should be routinely assessed for bleeding evidence and determine if the benefit-risk ratio of this treatment has changed.
The problem of high platelet resistance has been addressed by increasing the dose of clopidogrel, using prasugrel or ticagrelor, or using genotype- or phenotype-guided antiplatelet therapy. At this time, there is no conclusive evidence that any of these approaches is superior to the others (Claassens et al., 2019).
People who have had a stroke have a high risk for a subsequent stroke and other ischemic events, e.g., MI, and long-term antiplatelet therapy can prevent these complications (Greving et al., 2019).
Cilostazol (Greving et al., 2019): Long-term antiplatelet therapy is recommended for secondary prevention of stroke. Cilostazol monotherapy or cilostazol used in combination with aspirin effectively prevents recurrent non-cardioembolic events and is superior to aspirin. Research on cilostazol and stroke prevention has been primarily in Asian populations, and the effectiveness of the drug for preventing recurrent non-cardioembolic events in other ethnic groups has not been well studied.
Clopidogrel (Cuccharia & Messe, 2019): Clopidogrel and aspirin, started within 24 hours and given for 21 days to patients who have had a minor ischemic stroke or a TIA, has been shown to reduce the risk for subsequent stroke for 90 days. The effectiveness of long-term use of clopidogrel and aspirin versus clopidogrel alone for preventing subsequent stroke has been questioned. But the authors of a recent (2019) meta-analysis concluded that clopidogrel and aspirin effectively reduce the incidence of ischemic events and serious cardiovascular events in patients who have had a non-cardioembolic stroke, and it is as effective at doing so as clopidogrel alone, aspirin alone, and aspirin-dipyridamole. However, the risk for bleeding was significantly higher in patients treated with aspirin and clopidogrel compared to the other groups.
Aspirin and dipyridamole (Cuccharia & Messe, 2019): Aspirin and dipyridamole effectively reduce the incidence of ischemic events and serious cardiovascular events in patients who have had a non-cardioembolic stroke, and the combination is more effective than aspirin alone.
Mechanism of action: Eptifibatide is a glycoprotein IIB/IIIa receptor antagonist, and binding the drug to the receptor reversibly prevents platelet aggregation.
Onset: With an IV bolus, the onset of action is immediate, and within 5 minutes, there is a > 80% inhibition of platelet aggregation.
Duration: After stopping an IV infusion, platelet function is fully restored within 4 to 8 hours.
Adverse effects: Hemorrhage: Risk factors for bleeding include concomitant use of drugs that can cause bleeding, a history of bleeding disorders, older age, and weight < 70 kg.
Special considerations: Use with caution if the patient has impaired renal function.
Mechanism of action: Tirofiban is a glycoprotein IIB/IIIa receptor antagonist, and binding the drug to the receptor reversibly prevents platelet aggregation.
Onset: > 90% platelet inhibition occurs within 10 minutes.
Duration: Approximately 90% return to normal platelet aggregation 4 to 8 hours after an infusion has been stopped.
Uses: Tirofiban is approved for decreasing the rate of thrombotic cardiovascular events, death, MI, and refractory ischemia/repeat the cardiac procedure in patients with unstable angina or an NSTEMI.
Adverse effects: Bleeding.
Special considerations: Use with caution and reduce the dose in patients who have renal impairment.
Mechanism of action: Cangrelor is a direct-acting PY212 platelet receptor inhibitor that prevents platelet activation and aggregation.
Onset: Platelet inhibition begins within 2 minutes.
Duration: After the IV infusion has been stopped, platelet function returns to normal within 1 hour.
Uses: Cangrelor is approved for use as an adjunct during PCI to reduce the risk of periprocedural MI, reduce the need for repeat coronary revascularization, and minimize the risk of stent thrombosis. Cangrelor is intended to be used for patients who have not been treated with a P2Y12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor.
Dose: An IV bolus of 30 mcg/kg before PCI, followed immediately by a continuous IV infusion of 4 mcg/kg/minute for at least 2 hours or for the duration of the PCI, whichever is longest.
Adverse effects: Hemorrhage.
Special considerations: If clopidogrel or prasugrel are administered before the cangrelor infusion is discontinued, no antiplatelet effect will occur until the next dose is administered. Do not administer clopidogrel or prasugrel until after the cangrelor infusion is discontinued.
Warfarin is the only vitamin K antagonist that is available in the US.
Mechanism of action: Warfarin interrupts the synthesis of clotting factors II, VII, IX, and X, and proteins C and S. Synthesis and activation of these clotting factors and proteins requires the reduced form of vitamin K, and reduced vitamin K is produced by the activity of the enzyme vitamin K epoxide reductase complex 1 (VKORC1).
Warfarin is often referred to as a vitamin K antagonist, but warfarin does not actually antagonize vitamin K.
At therapeutic doses, warfarin decreases the functional amount of each vitamin K–dependent coagulation factor by 30%–70%. Warfarin has no effect on the activity of fully γ-carboxylated factors already in the circulation, and these must be cleared before it can produce an anticoagulant effect.
Warfarin does not dissolve an existing thrombus; It prevents new thrombi from forming and prevents the extension of an existing thrombus.
Onset of effects: A measurable effect of warfarin, reflected by an increase in INR, can be seen within 24-72 hours. However, the half-life of some of the clotting factors is quite long, e.g., 60-72 hours for factor II, so complete anti-coagulation and full therapeutic effect require 5-7 days of warfarin therapy.
Duration of effects: Two to 5 days.
Warfarin is given orally once a day. IV warfarin is no longer produced.
Warfarin is also used off-label for preventing TIAs in patients who have atrial fibrillation, rheumatic mitral valve disease, or a mechanical prosthetic heart valve.
Dose: Warfarin dosing is a balance between:
Before starting treatment with warfarin, a CBC, INR, aPTT, PT, serum creatinine, and liver function tests should be measured. (Note: The effect of hepatic and renal function on warfarin will be discussed later in this section).
The usual dose of warfarin is 2-5 mg a day during the initiation phase of 2-4 days, followed by 1-10 mg a day during the maintenance phase. The INR results determine the maintenance dose, and lower and higher starting and maintenance doses are used (Hull et al., 2019).
Warfarin dosing and INR monitoring are very individualized. An effective and safe dose depends on many factors, including age, bleeding history, co-morbidities, diet, drug interactions, genetic variability that affects the patient’s response to the drug, and the INR results. When and how often to measure the INR and what the INR should be will differ from patient to patient. Dosing algorithms are available, and they can be effective for starting and maintaining warfarin therapy and maximizing the time the patient is within the therapeutic range (Hull et al., 2019).
A typical approach is to measure the INR after the second day of taking warfarin and to decrease/increase the dose after that as needed. In most cases, an INR of 2-3 is the goal, but a higher INR is desired (Hull et al., 2019).
Adverse effects: Bleeding is the most common adverse effect. The risk for major bleeding, i.e., gastrointestinal, intracranial, and spinal, has been estimated to be from 0-2% a year. Factors that increase the risk of bleeding from warfarin are listed below. Several of these will be discussed in detail in the clinical Issues section.
Alcohol abuse: The relationship between alcohol abuse, warfarin, and the risk of bleeding is complex and not completely understood. Patients who take warfarin and abuse alcohol may have an increased risk of bleeding, and there are many possible reasons for this (Roth et al., 2015). Alcohol abuse causes gastrointestinal bleeding, coagulopathies, and thrombocytopenia (Schuckit, 2019). Patients who abuse alcohol are more likely to have a nutrient-poor diet or be malnourished, and they are more likely to have an INR above or below the therapeutic range. Alcohol consumption may directly affect warfarin metabolism, but the nature and severity of this (possible) influence are unclear.
Diabetes (Pomero, 2019; Yamagishi, 2019): Patients who have diabetes often need anticoagulation therapy. Diabetes significantly increases the risk of developing diseases like atrial fibrillation that cause thrombus formation and embolic events. In the CHA2DS2-VASc stroke prediction tool, diabetes is one of the most substantial risk factors for ischemic stroke patients with atrial fibrillation. Diabetes has been identified as a risk factor for bleeding in patients taking warfarin and in people with diabetes who do not take the drug. Diabetes can affect coagulation in many complex ways. Still, the issue of diabetes, warfarin, and bleeding appear to be little studied, and it is not clear how much diabetes increases the risk for bleeding in patients who take warfarin.
Hepatic impairment (Hull, 2019): The liver primarily metabolizes Warfarin, and the liver synthesizes clotting factors. Hepatic impairment can decrease the metabolism of warfarin and reduce the synthesis of clotting factors, affect dosing, INR, and coagulation, and increase a patient’s risk for bleeding. In addition, the liver disease affects the production of pro-coagulant factors and anticoagulant factors, increasing or decreasing a patient’s clotting ability and making clotting status variable and unpredictable.
Hypertension (Park et al., 2019): Hypertension is the most common co-morbidity with atrial fibrillation. Hypertension increases the risk of bleeding, and warfarin increases the risk of bleeding in hypertensive patients.
Chronic kidney disease (Chang et al., 2018; Kumare et al., 2019): Atrial fibrillation and chronic kidney disease (CKD) are common co-morbidities, and oral anticoagulation is an established and beneficial therapy for patients with mild to moderate chronic kidney disease. However, renal impairment can decrease clotting function and cause a pro-hemorrhagic condition, and the risk for bleeding increases as renal function worsens. In patients who have CKD and take warfarin, the INR is often labile and outside the therapeutic range, and at least one large study found that warfarin increased in patients with end-stage renal disease (ESRD) risk for bleeding.
In addition to an increased risk of bleeding, warfarin can also cause anticoagulant-associated nephropathy. Anticoagulant nephropathy is characterized by acute kidney injury (AKI) and an INR >3. It is much more likely to occur in patients who have CKD. Information on this complication is scarce, but the prevalence of anticoagulant-associated nephropathy has been estimated to be 19%-63%.
Anticoagulation therapy with warfarin balances the benefits of anticoagulation and the risk of bleeding. Scoring systems like CHA2DS2-VASc and HAS-BLED can be used to determine if the patient needs anticoagulation and to predict a patient’s risk for bleeding, respectively. However, Edmiston et al. (2019) pointed out that bleeding is always a risk with anticoagulation therapy. In most patients being considered for anticoagulation therapy, the benefits of warfarin outweigh the risks. The author also noted that predictive scoring systems (There are many others aside from CHA2DS2-VASc and HAS-BLED) should be used primarily to identify patients who need closer monitoring, not to exclude patients from warfarin anticoagulation therapy.
There can be a 20-fold patient-to-patient difference in the dose of warfarin needed to attain the therapeutic level of anticoagulation. Genetics and other factors like age and body weight are a reason for this effect. The anticoagulant effect of warfarin is mediated by its inhibitory action on vitamin K epoxide reductase subunit 1 (VKORC1) and metabolism of the more pharmacologically active isomer of warfarin, the S-isomer, is primarily by the CYP2C9 enzyme. Genetic polymorphisms of CYP2C9 and VKORC1 have consistently been associated with, and are largely responsible for, sensitivity to warfarin and the wide dose-response variability of the drug in terms of reaching and maintaining the target INR. The CYP2C9 genetic polymorphisms reduce the metabolism and inactivation of the S-isomer of warfarin. The VKORC1 polymorphism increases the sensitivity of VKROC1 to warfarin, and patients who have these genetic variants should require a comparatively low dose of warfarin.
The prescribing information for warfarin has dosing recommendations based on the patient’s CYP2C9 and VKROC1 genetic profile, but using pharmacogenetic information to dose warfarin is not standard practice. Years of research on genotype-based warfarin dosing protocols have not produced consistent and conclusive evidence for their benefits or that they are superior to standard warfarin dosing protocols.
Time of the INR in the therapeutic range (TTR) is used to determine the effectiveness of warfarin therapy, and maintaining the desired TTR of >70% is very important. For example, a 10% decrease in TTR has been associated with a 10% increase in embolic events and stroke. A significant number of bleeding and embolic events (44% and 50%, respectively) occur when the TTR is out of range.
In the first several days of warfarin therapy, the INR will increase. Still, because several clotting factors whose synthesis is inhibited by warfarin have long half-lives, this early increase in INR does not represent full anticoagulation. After a maintenance dose has been established. The INR must be periodically measured. The schedule and frequency for INR measurements should be determined by the patient’s clinical status and the lability of their INR measurements. Measuring INR is usually done every day for hospitalized patients; for patients in the community who have had several weeks during which the INR has been stable, an INR measurement every 4 weeks is usually sufficient. The American Society of Hematology recommends measuring the INR every 6 to 12 weeks if the patient’s INR has been stable and measuring the INR every 4 weeks or less if a dosing adjustment has been made because the INR was out of range.
INR measurement can be done by a clinician, in a coagulation clinic, or at home by the patient. Evidence has shown that if the patient has the skills to perform at-home testing and, if needed, dosing adjustments, at-home INR measuring is effective, safe, and superior for maintaining the desired TTR. The American
Society of Hematology (ASH) recommendations for at-home testing are:
For patients receiving maintenance VKA therapy for the treatment of VTE, the ASH guideline panel suggests using home point-of-care INR testing (patient self-testing [PST]) over any other INR testing approach except patient self-management (PSM) (see recommendation 4) in suitable patients (those who have demonstrated competency to perform PST and who can afford this option).”
For patients receiving maintenance VKA therapy for the treatment of VTE, the ASH guideline panel recommends using point-of-care INR testing by the patient at home and self-adjustment of VKA dose (PSM) over any other management approach, including PST in suitable patients (those who have demonstrated competency to perform PSM and who can afford this option).
Factors that can affect the INR and cause poor control include age > 75, co-morbidities, e.g., heart failure and renal impairment, drug-drug interactions, dietary vitamin K intake, poor adherence to the medication regimen (common with patients taking warfarin), illnesses, and genetic influences.
There are five basic ways that a warfarin-drug interaction can affect the INR, increase the risk of bleeding, and change the pharmacokinetics of warfarin.
There are hundreds of warfarin-drug interactions - the Lexicomp® database lists 266 - and commonly used over-the-counter supplements like green tea, ginseng, and saw palmetto can potentially harm warfarin metabolism well. The mechanisms of action that underpin many warfarin-drug interactions are not well understood, and the evidence that any specific warfarin-drug interaction is clinically significant is, at times, sparse and conflicting. However, the important point is that there are numerous warfarin-drug interactions, including commonly prescribed drugs.
Before PCI, the glycoprotein IIb/IIIa receptor inhibitors were once widely used as antiplatelet therapy. However, the evidence for their effectiveness was done before aspirin/PY212 therapy was in common use, before the stronger PY212 inhibitors prasugrel and ticagrelor were available. The research results for glycoprotein IIb/IIIa inhibitors' effectiveness in this situation were more convincing for abciximab - which is no longer available in the United States - than for eptifibatide and tirofiban.
Eptifibatide and tirofiban have been used as a routine adjunct to dual antiplatelet therapy for patients undergoing PIC. But the research has shown that using these drugs with dual antiplatelet therapy does not provide an additional benefit, and it causes an increased rate of bleeding. The current recommendations for using eptifibatide and tirofiban are in this circumstance:
Thrombocytopenia (Bahatia et al., 2017): Thrombocytopenia occurs in up to 1% of patients receiving eptifibatide and 0.1-1.9% of patients receiving tirofiban; severe thrombocytopenia (platelet count < 20,000 mm3) is unusual, occurring in approximately 0.2% to 1% of all cases. Thrombocytopenia can occur after the first dose of a glycoprotein IIb/IIIa receptor inhibitor or after previous exposure, and recovery is usually within several days.
The mechanism of action that causes this adverse effect is unknown or unknown; possible explanations are a direct drug effect on the platelets. This activation of existing antiplatelet antibodies was formed after previous drug use or stimulation of the production of new antiplatelet antibodies.
Treatment involves discontinuing the use of the drug and ruling out other causes like heparin-induced thrombocytopenia, pseudo-thrombocytopenia, and thrombotic thrombocytopenia purpura caused by clopidogrel or prasugrel.
Cangrelor (UpToDate, 2019m): Transitioning from the infusion to a PY212 inhibitor.
Cangrelor is used as an adjunct during PCI to reduce the risk of periprocedural MI, decrease the need for repeat coronary revascularization, decrease the risk of stent thrombosis in patients who have not been treated with a P2Y12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor.
These patients will be on long-term treatment with a PY212 receptor inhibitor. The prescribing information has recommendations for when, concerning the cangrelor infusion, therapy with these drugs should be started. These recommendations are listed below.
Give 600 mg of clopidogrel immediately after the cangrelor infusion has been stopped. Do not give clopidogrel before the infusion has been stopped.
Give 60 mg of prasugrel immediately after the cangrelor infusion has been stopped. Do not give prasugrel before the infusion has been stopped.
Give 180 mg of ticagrelor at any time during the cangrelor infusion or immediately after the infusion has been stopped.
There are several reasons why this approach is used. After a cangrelor infusion has been stopped, platelet function is restored to normal within 1 hour, and these patients need platelet aggregation inhibition. Cangrelor blocks the active metabolite of clopidogrel and prasugrel from binding to the P2Y12 receptor. These active metabolites remain in the blood for a short time after the drugs are given, so concurrent administration of cangrelor and clopidogrel or prasugrel will decrease their effectiveness. Ticagrelor is a direct-acting P2Y12 receptor antagonist, so cangrelor and ticagrelor can be given simultaneously.
Factor Xa is the “link” between the intrinsic and extrinsic coagulation pathways and the common pathway. Factor Xa converts prothrombin to thrombin. The factor Xa inhibitors, given subcutaneously, include the oral anticoagulants apixaban, edoxaban, rivaroxaban, and fondaparinux. Apixaban, edoxaban, and rivaroxaban are typically referred to as direct-acting oral anticoagulants (DOACs).
Dabigatran is often included in discussions of the new oral anticoagulants, but it is a direct thrombin inhibitor, and dabigatran will be covered in a separate section.
Fondaparinux is, at times, classified as a heparinoid as it shares some similarities with the low-molecular-weight heparins. Still, fondaparinux will be considered a factor Xa inhibitor in this module. Fondaparinux is given subcutaneously and will be discussed in the parenteral anticoagulants section.
These drugs are often called the new oral anticoagulants because they are used in place of warfarin. They are relatively new and anticoagulants, but there are important differences between warfarin and these drugs: these differences are listed in Table 5 (Aloi et al., 2019).
|Bleeding risk:||The bleeding risk of the DOACs versus warfarin appears to be the same.|
|Clinical use:||Warfarin has been used for decades and the clinical issues of its use are well known and well described. There is much less clinical experience with the DOACs and more unanswered questions about their use.|
|Cost:||Warfarin is inexpensive and widely available.|
|Heart valves:||The DOACs are not approved for anticoagulation therapy in patients who have a prosthetic heart valve.|
|Diet:||There are no significant drug-food interaction with the DOACs.|
|Dosing:||Warfarin is taken once a day. Several of the DOACs need to be taken twice a day and this may decrease patient compliance with the therapy regimen.|
|Drug interactions:||The are hundreds of warfarin-drug interactions; there are comparatively far fewer DOAC-drug interactions.|
|Effectiveness:||The DOACs are at least as effective as warfarin at preventing stroke and embolic events and they may be more effective than warfarin at preventing stroke and embolic events.|
|Mechanism of action:||The DOACs are direct inhibitors of clotting factors. Warfarin inhibits the synthesis of clotting factors.|
|Missed doses:||Because of the short duration of action and short half-life of the DOACs, missing one or several doses of a DOAC has more potential to put the patient at risk for harm than a missed dose of warfarin.|
|Monitoring:||Therapy with warfarin requires frequent monitoring of the INR, and the INR can be used to measure the effectiveness of anticoagulation. There is no requirement for laboratory monitoring with the DOACs, but there are no easy and widely available laboratory tests that can be used to monitor the effectiveness of the anticoagulation of these drugs.|
|Onset and duration:||The onset of the anticoagulant effects of warfarin takes several days to begin, and the anticoagulant effects of warfarin continue for several days after the patient stops taking it. The onset of effects of the DOACs is within hours.|
|Obesity:||In patients who are obese or morbidly obese, it appears that the DOACs and warfarin are equally safe and effective, but there is much less clinical experience with the DOACs in these patient populations.|
|Renal:||The renal excretion of the DOACs and warfarin are distinctly different, and this may affect the benefit-risk profile of the DOACs versus warfarin in patients who have impaired renal function (Note): This issue will be discussed later in this section). There is also evidence that the DOACs are less likely than warfarin to cause renal damage.|
|Reversal:||There is a lot of experience with reversing the effects of warfarin. There is little experience with reversing the effects of the DOACs, and the reversal agents for these drugs can cause serious complications.|
|Stability of dosing:||Warfarin dosing often requires frequent adjustments;the DOACs do not.|
Mechanism of action: Direct inhibition of factor Xa.
Onset of action: 3-4 hours.
Duration of action: The half-life is approximately 12 hours.
Hepatic impairment: Moderate impairment (Child-Pugh class B) use with caution. Severe impairment, (Child-Pugh class C), the use of apixaban is contraindicated.
Renal impairment: The prescribing information does not have recommendations for dosing adjustments in patients who have renal impairment. However, patients who had a creatinine of 2.5 mg/dL or CrCl <25 mL/minute were not included in clinical trials of apixaban. Approximately 27% of the parent drug is renally excreted, and exposure to apixaban is increased as real function declines.
Adverse effects: Bleeding.
Bariatric surgery may decrease the absorption of apixaban.
Apixaban is not recommended for patients with a history of thrombosis diagnosed with antiphospholipid syndrome.
(US Boxed Warning)
Epidural or spinal hematomas may occur in patients treated with apixaban who are receiving neuraxial anesthesia or undergoing spinal puncture. The risk of these events may be increased using in-dwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures.
Mechanism of action: Direct inhibition of factor Xa.
Onset: 2 to 3 hours.
Duration of action: ≥ 72 hours.
Uses: Preventing VTE in adults who are hospitalized for an acute medical illness and who are at risk for a thromboembolic complication due to moderate or severe activity restriction or other risk factors.
Dose: 160 mg once a day for one dose, followed by 80 mg a day for 35-42 days.
Hepatic impairment: Avoid use in patients who have moderate to severe hepatic impairment.
Renal impairment: CrCl > 30 mL/minute, no dosing adjustment is needed. If the CrCl is ≥15 to <30 mL/minute, begin with 80 mg on the first day and follow that with 40 mg once a day for 35-42 days.
Adverse effects: Bleeding, gastrointestinal complaints, e.g., constipation, diarrhea, and nausea.
Mechanism of action: Direct inhibition of factor Xa.
Onset of effects: 1-2 hours.
Duration of action: The half-life is 10-14 hours.
Dose: 60 mg once daily. See the Special considerations section for more dosing information.
Hepatic impairment: Moderate to severe impairment, Child-Pugh Class B or C, use is not recommended.
Renal impairment: No dosing adjustment is needed in patients with DVT or PE, CrCl > 51 mL/minute.
Adverse effects: Bleeding.
Mechanism of action: Direction inhibition of factor Xa.
Onset of action: 2-4 hours.
Duration of effects: The half-life is 5-9 hours.
Hepatic impairment: Moderate to severe impairment, Child-Pugh Class B or C, use is not recommended.
Renal impairment: DVT and PE: CrCl ≥ 30 mL/minute, no dosage adjustment is needed. CrCl< 30 mL/minute, use should be avoided(UpToDate, 2019d).
Renal impairment, non-valvular atrial fibrillation: CrCl > 50 mL/minute, no dosing adjustment is needed. CrCl 15-50 mL/minute, the dose should be 15 mg a day, taken with food. If the patient develops renal failure, stop the use of the drug.
The prescribing information for Xarelto® does not have a specific dosing recommendation for patients who have a CrCl < 15 mL/minute, but it does mention that a daily dose of 15 mg in patients whose CrCl is < 15 mL/minute should produce a serum concentration similar to patients who have only moderate renal impairment (Janssen, 2019).
Renal impairment, prophylaxis after hip and knee surgery: CrCl > 50 mL/minute, no dosing adjustment is needed. CrCl 30-50 mL/minute, no dosing adjustment is needed, but the drug should be used with caution, and use should be stopped if the patient develops renal failure. If the CrCl is < 30, avoid use (UpToDate, 2019d).
Adverse effects: Bleeding. The risk of bleeding is especially high for patients who have DVT or a PE.
Determining if a patient is correctly taking a DOAC is difficult. An abnormally low or high INR reflects misuse of warfarin. Still, no easily available laboratory test can determine if a patient has been compliant with the prescribed DOAC therapy (Leung, 2019). This is an important issue because, unlike warfarin, missing one or several doses of a DOAC can reduce the time the patient is anticoagulated, putting the patient at risk for thrombosis (Leung, 2019).
Diet: Grapefruit juice is a CYP3A4 inhibitor, and it could increase the serum concentrations of apixaban and rivaroxaban (UpToDate, 2019t). Rivaroxaban doses ≥ 15 mg must be taken with food (UpToDate, 2019d).
Concomitant use of DOACs and drugs that induce or inhibit CYP3A4 and affect the activity of permeability-glycoprotein (p-glycoprotein), including (but not limited to) antiretrovirals, antiarrhythmics, and some antipsychotics and macrolides, has been reported to increase the serum level of the DOACs, cause bleeding, and reduce their therapeutic effectiveness (Vazquez, 2018).
There are far fewer drug-drug interactions involving the newer anticoagulants than with warfarin, which is a comparative advantage of the DOACs. But the clinical implications of these interactions with the DOACS - when and in whom they occur, how serious they are - have not been clearly outlined. Significant effects from the drug-drug interactions have been reported, and the prescribing information for apixaban, edoxaban, and rivaroxaban state concomitant use of strong CYP3A4 or P-glycoprotein inducer is contraindicated or should be avoided.
Note: P-glycoprotein is a transport molecule in the gut, the blood-brain barrier, and other areas. One of the functions of P-glycoprotein is to transport drug molecules across cell membranes or prevent their movement across cell membranes, and inhibition and induction of P-glycoprotein activity can increase and decrease blood levels of drugs that are substrates P-glycoprotein, respectively.
The pharmacokinetics and pharmacodynamics of the DOACs are relatively predictable, so each DOAC is prescribed as a fixed dose, and laboratory monitoring during DOAC therapy is not needed. But in some clinical situations, e.g., a patient who has taken an overdose of a DOAC or needs emergency surgery, determining the patient’s coagulation status or measuring a DOAC drug level may be needed. Common coagulation tests like aPTT, INR, and PT are not predictable or reliable for determining the coagulation status of someone taking a DOAC, and measuring DOAC drug levels cannot be done quickly. An assessment of a patient's coagulation status taking a DOAC can be done. Still, the appropriate tests are specific to each drug, they may not be widely available, and they require expertise to interpret the results. Example: For a patient who is taking dabigatran, the ecarin clotting time is most useful, but some laboratories cannot perform it, and the aPTT can be used (with some limits) to assess the coagulation status of a patient taking dabigatran but not in a patient taking a factor Xa inhibitor (Leung, 2019).
Preventing stroke and embolic events in atrial fibrillation patients is a primary use of the DOACs. Atrial fibrillation and CKD are common co-morbidities, and this presents a difficult clinical challenge: patients who have atrial fibrillation and CKD have a very high risk for stroke, and decreased renal function/CKD significantly increases the risk for bleeding (Ha et al., 2019).
The prescribing information for each DOAC recommends decreasing the dose for patients with impaired renal function, presumably because these patients would be at an increased risk for bleeding. Still, the initial clinical trials of the DOACs did not include patients who had a CrCl < 30 mL/minute, patients who had ESRD, or patients who needed hemodialysis (Ha et al., 2019). After those trials, the FDA approved apixaban, dabigatran, edoxaban, and rivaroxaban (but not betrixaban) for use in patients with a CrCl as low as 15 mL/minute (Ha et al., 2019).
However, recent (2019) literature reviews and meta-analyses concluded that there is no evidence that the DOACs are effective or safe for patients who have moderate to severe CKD. In addition, the oral DOACs are renally excreted (Apixaban 25%; dabigatran 80-85%; edoxaban 35%; rivaroxaban 35%), and renal impairment may increase blood levels of the DOACs, especially dabigatran and edoxaban (Hu, 2018). This seemingly conflicting information could be confusing for clinicians. Still, the lower DOAC doses recommended for patients with impaired renal function are based on research studies that showed that the decreased dose was safe and resulted in acceptable blood levels of the drug (Hu, 2018).
Andexanet alfa binds to apixaban and rivaroxaban, and it has a labeled use as an antidote for reversing the anticoagulant effects of apixaban and rivaroxaban (UpToDate, 2019r). There is no antidote for betrixaban and edoxaban.
Heparin is a naturally occurring molecule, but commercially produced heparin is derived from the intestinal mucosal tissues of pigs and cattle.
Heparin does not break down emboli and thrombi, but it prevents their extension and prevents new ones from forming.
Heparin is often referred to as unfractionated heparin to distinguish it from the low-molecular-weight heparins. The term unfractionated means that heparin has not been broken down fractionated to separate the low molecular weight particles. In this module, heparin will be used instead of unfractionated heparin.
Mechanism of action: Mechanism of action: Heparin inactivates thrombin and the clotting factors IXa, Xa, XIa, and XIIa, and it prevents the conversion of fibrinogen to fibrin (UpToDate, 2019u).
Onset: IV, immediate. Subcutaneously, 20-30 minutes (UpToDate, 2019u).
Duration: Half-life in 1 to 2 hours (UpToDate, 2019u).
Labeled uses (UpToDate, 2019u):
Prophylaxis against and treatment for thromboembolic disorders
Dose: Doses to prevent clotting during arterial and cardiac surgery, extracorporeal circulation, and hemodialysis will not be covered.
Hepatic impairment: No dosing adjustment needed.
Renal impairment: No dosing adjustment needed.
Adverse effects: Thrombocytopenia (Discussed in detail in the Heparin: Clinical Issues section).
Special considerations: Heparin is contraindicated in patients who have severe thrombocytopenia, a history of heparin-induced thrombocytopenia (HIT), a history of HIT with thrombosis (HITT), or active, uncontrolled bleeding (UpToDate, 2018).
The anticoagulant effect of heparin can be monitored, and the dose adjusted by measuring the aPTT or anti-factor Xa level. There is no conclusive evidence that either one is superior to the other (Hull et al., 2019). The typical goal is an aPTT 2-3 times the normal mean.
Numerous heparin dosing protocols are used (Marlar et al., 2017). Many of these are based on clinician preference and experience. The recommended bolus dose, therapy duration, and other aspects of heparin can differ from source to source (Marlar et al., 2017). However, the basic goals of heparin therapy are the same, regardless of variances in dosing recommendations, decrease the risk of thromboembolic events and avoid bleeding.
Heparin-induced thrombocytopenia (HIT) is an auto-immune-mediated heparin therapy complication (Leavitt & Minichiello, 2020). It is caused by HIT antibodies that are formed when heparin binds to platelet factor 4 (PF4), a cytokine found inside platelets. The immune system identifies the heparin-platelet factor 4 molecule as a xenobiotic. The antigen-antibody reaction causes a decreased platelet count and potentially serious and life-threatening thromboembolic complications (Leavitt & Minichiello, 2020).
Heparin-induced thrombocytopenia can be caused by any dose (even after exposure to heparin flushes or a heparin-coated catheter), any dosing schedule, after a single exposure to heparin, with any route of administration of the drug, and after administration of unfractionated and LMWHs (Leavitt & Minichiello, 2020).
Heparin-induced thrombocytopenia is uncommon. The incidence of HIT caused by heparin has been reported to be 2.6% to 4.9%; the incidence of HIT caused by LMWH has been reported to be 0.2% to 0.6% (Leavitt & Minichiello, 2020).
Factors that increase the risk of developing HIT include cancer, female gender, surgical procedures (particularly cardiac and orthopedic), and a bovine source of heparin. However, HIT can happen to any patient who has been given heparin (Coutre & Crowther, 219).
The onset of HIT is typically 5-14 days after heparin therapy has begun, but early-onset and delayed onset HIT can happen (Coutre & Crowther, 219).
Early-onset HIT is caused by exposure to heparin in the prior weeks and months (~100 days) and circulating anti-heparin PF4 antibodies formed after the exposure (Coutre & Crowther, 2019). It occurs within five days and as early as 24 hours after heparin therapy has begun (Coutre & Crowther, 219).
Delayed onset HIT that begins after heparin therapy has been stopped is rare, and the onset has been reported to be five to 40 days after discontinuation of the drug (Coutre & Crowther, 219).
Heparin-induced thrombocytopenia is characterized by a decrease in platelet count of >50% and thrombosis. Bleeding can occur, but it is uncommon (Leavitt & Minichiello, 2020). More than 50% of HIT patients will develop a thrombosis (Leavitt & Minichiello, 2020). Arterial and venous thrombosis are possible, and serious and potentially deadly thromboembolic complications can occur, including limb ischemia with gangrene, myocardial infarction, pulmonary embolism, and stroke (Coutre & Crowther, 219).
Clinical findings and laboratory testing make the diagnosis of HIT. A quick method of forming a provisional diagnosis of HIT is the four Ts assessment (Coutre & Crowther, 219):
The four Ts assessment can be used before the results of laboratory tests are available, and if the four Ts assessment score is high, treatment for HIT may be considered (Goldhaber, 2019). However, the accuracy of this assessment scale is very limited, and it should not be the sole criteria used to make a diagnosis of HIT (Tran & Tran, 2018).
HIT treatment involves immediately discontinuing the heparin, assessing the presence of thrombosis, administering a direct thrombin inhibitor (argatroban or bivalirudin), and when the platelet count has normalized, begin treatment with warfarin and continue this for at least 30 days. There is some evidence that the DOACs apixaban, edoxaban, rivaroxaban, dabigatran, and fondaparinux may effectively treat HIT (Leavitt & Minichiello, 2020). Heparin should not be given to patients who have had HIT (Leavitt & Minichiello, 2020).
Heparin resistance is defined as administering a daily dose of heparin ≥ 35,000 units and a sub-therapeutic aPTT or ACT (Durrani et al., 2018). An anti-thrombin II deficiency causes heparin resistance, congenital or acquired (Coutre & Crowther, 2019). Congenital heparin resistance is rare (Tsikouras, 2018). Acquired heparin resistance can be caused by asparaginase therapy, cirrhosis, coronary bypass surgery, disseminated intravascular coagulation (DIC), extracorporeal membrane oxygenation (ECMO), hemodialysis, nephrotic syndrome, pregnancy, sepsis, surgery, and trauma (Coutre & Crowther, 2019). In some of these conditions, heparin resistance is rare, but in others, it is common; heparin resistance has been reported to occur in up to 22% of patients undergoing coronary bypass surgery (Tsikouras, 2018).
Clinicians must differentiate between pseudo-heparin resistance and true heparin resistance (Downie et al., 2019). True heparin resistance is a failure of the heparin dose to achieve anticoagulation and a sub-therapeutic aPTT; pseudo-heparin resistance is a sub-therapeutic aPTT, but the patient is anticoagulated (Downie et al., 2019). Measuring the aPTT and an anti-factor Xa level from the same blood sample will differentiate between the two; if the patient has true heparin resistance, both the aPTT and the anti-factor Xa level will be sub-therapeutic.
Heparin decreases bone formation and increases bone resorption (Signorelli et al., 2019). Drug information sources, the prescribing information for heparin, and published articles warn that long-term use, e.g., > six months, has been associated with osteoporosis, decreased bone density ( > 10% loss of BMD has been reported), and fractures. These adverse effects have been reported to occur primarily in pregnant women; this is likely (in part) because when heparin is used for this patient population, it may be given for a relatively long time (Signorelli et al., 2019). The level of risk for adverse bone and skeletal effects caused by heparin in non-pregnant adults has been little studied and is unknown (Signorelli et al., 2019).
There is little published information on heparin dosing for obese patients. The topic is not mentioned in the prescribing information. It is unclear whether total body weight or adjusted body weight should be used to dose heparin for this patient population (Coutre & Crowther, 2019). A recent (2019) study by Ebied et al. found that the time to effective coagulation and the risk of bleeding were similar for both approaches.
Protamine is the antidote for excessive coagulation or severe bleeding caused by heparin (UpToDate, 2019u).
The low molecular weight heparins are fragments of heparin that have been separated from the heparin molecule, and the LMWHs have approximately one-third the weight of heparin. The LMWHs and heparin are used for many of the same clinical conditions, but there are important differences between the two drugs. These differences are listed below; some will be discussed in more detail later in this section.
Bioavailability: The LMWHs bind to thrombin much more avidly than heparin, and they bind less avidly to endothelial cells, heparin-binding plasma proteins, and macrophages than unfractionated heparin (Downie et al., 2019). This increases the bioavailability of the LMWHs compared to heparin (90% and 30%, respectively), and this has three important clinical effects:
Half-life: The half-life of the LMWHs is at least half again longer than heparin so that LMWHs can be dosed intermittently, once or twice a day (Hull et al., 2019). This is more convenient, and it also allows patients to self-administer an LMWH at home or for LMWHs to be administered in an out-patient clinic. However, the longer half-life can be problematic if the anticoagulant effect of an LMWH becomes excessive.
Heparin-induced thrombocytopenia: HIT occurs much less frequently with the LMWHs than with heparin.
Onset of action: The onset of action of the LMWHs is much slower than that of heparin.
Osteoporosis: Lower incidence of osteoporosis with LMWHs than with heparin.160
Renal clearance: Heparin is not eliminated by the kidneys, but renal clearance is the primary route of excretion of the LMWHs.
Reversal: The anticoagulant effects of heparin can be quickly reversed with protamine sulfate. Protamine sulfate only partially reverses the anticoagulant effects of the LMWHs and its effectiveness for this purpose is unpredictable.
Mechanism of action: Inhibition of factor Xa.
Onset: The onset of action is approximately 3-5 hours.
Duration: Approximately 12 hours.
Uses: Prophylaxis against DVT in patients who have had abdominal surgery, hip or knee replacement surgery, or medical patients at risk for VTE due to prolonged immobility.
Dose: DVT prophylaxis, abdominal surgery: An initial dose of 20 mg SC should be given two hours before surgery, and then 40 mg SC once a day after surgery with a duration of 7-10 days.
Hepatic impairment: There are no recommendations for dosing adjustments in patients who have hepatic impairment, but this situation has not been studied.
Renal impairment: Dosing adjustments are recommended for patients with a CrCl < 30 mL/minute. These adjustments are listed below.
Adverse effects: Anemia, hemorrhage.
Special considerations: Enoxaparin should not be given to a patient who has had HIT in the past 100 days or to someone who has circulating HIT antibodies.
Mechanism of action: Inhibition of factor Xa and II.
Onset: 1-2 hours.
Duration: > 12 hours.
Uses (Fragmin, 2019):
Dose (Fragmin, 2019): Prophylaxis of ischemic complications in patients with non-Q-wave MI and unstable angina: 120 IU/kg SC every 12 hours, with aspirin.
Hepatic impairment: The prescribing information does not have dosing recommendations for using the drug in hepatic impairment patients. In patients who have a severe hepatic impairment, the drug may accumulate.
Renal impairment: The prescribing information does not have dosing recommendations for using the drug in renal impairment patients. However, in the presence of a CrCl < 30 mL/minute, the LMWHs may prolong factor Xa activity and cause bleeding. This topic will be discussed later in the Low-Molecular-Weight Heparins: Clinical Issues section.
Adverse effects (Fragmin, 2019): Bleeding, thrombocytopenia
Special considerations: Dalteparin should not be given to a patient who has had HIT or to a patient with HIT with thrombosis.
The prescribing information for Lovenox® and Fragmin® does not discuss the use of these drugs in patients who have hepatic impairment. The Lexapro® drug information database states that the LMWHs may accumulate in patients who have hepatic impairment (Presumably increasing the risk for bleeding). In this situation, the LMWHs should be used with caution (UpToDate 2019w). The published literature on this topic is inconclusive. Some authors found that the risk of bleeding from LMWHs was increased in cirrhotic patients others did not, and a recent (2019) review article concluded that more research was needed before this question could be answered (Summers et al., 2019).
The kidneys eliminate Dalteparin and enoxaparin to prevent bioaccumulation and decrease the risk of bleeding. It is recommended to reduce the dose of these drugs in patients who have severe renal impairment, i.e., CrCl <30 mL/minute.
The LMWHs can accumulate in patients with renal impairment (Karaoui et al., 2019). However, the degree to which this occurs is not clear, and although the evidence is not conclusive in terms of bleeding, the LMWHs are safe for use in patients with an end-stage renal disease (Pai et al., 2018).
Dalteparin and enoxaparin are low molecular weight because they are smaller, short-chain molecules than heparin. This property makes the LMWHs less likely to bind to the LMWH-platelet factor 4 complex, and the incidence of HIT caused by LMWHs has been reported to be 0.2% to 0.6% (Leavitt & Minichiello, 2020).
Low molecular weight heparins given preoperatively can cause heparin resistance. A recent (2019) study found that 20.9% of patients given LMWH pre-operatively developed heparin resistance, and the authors noted that the overall incidence of intraoperative HR was 20.9% (n=29), which was similar to that of other studies (Saydam et al., 2019).
Clinical trials of LMWHs did not use the measurement of factor Xa to determine the effectiveness of these drugs. Aside from measuring platelet count in patients at risk for HIT, routine laboratory monitoring is not needed or typically used during therapy with the LMWHs. Exceptions to this would be patients who have renal impairment, patients who are obese, pregnant women, and pediatric patients. Patients who have renal impairment or are obese are at risk for bioaccumulation of the drug; the weight of pregnant women changes rapidly. The pharmacokinetics of the LMWHs in children are unpredictable. In these clinical situations, monitoring factor Xa levels may be helpful.
The risk of developing decreased bone mineral density, fractures, and osteoporosis has usually, but not always, been less for the LMWHs when compared to heparin (Signorelli et al., 2019).
Administration of protamine is recommended in the case of an overdose or an excessive dose of an LMWH, usually if the patient has clinically significant bleeding. Protamine does not completely or reliably reverse the anticoagulant effects of the LMWHs. However, it has been shown to neutralize the anti-IIa activity of the LMWHs, partially reverse anti-Xa activity, and have a hemostatic effect. The prescribing information for Fragmin® and Lovenox® have dosing instructions for using protamine as a reversal agent in case of overdose or an excessive dose of these drugs.
Mechanism of action: Argatroban is a direct, reversible thrombin inhibitor that prevents the activation of the clotting factors V, VIII, and XIII, activation of protein C, and platelet aggregation.
Onset: The onset of action is immediate.
Duration: The half-life is 39-51 minutes. In patients who have hepatic impairment, the half-life is 181 minutes.
Hepatic impairment: Argatroban is metabolized by the liver. For patients with moderate to severe hepatic impairment, Child-Pugh class B and C, respectively, the dose should be reduced to 0.5 mcg/kg/minute. The aPTT should be closely monitored, and the dose adjusted needed.
Adverse effects: Chest pain, genitourinary tract bleeding, hypotension.
Special Considerations: Use cautiously if the patient is critically ill or if the patient has heart failure, multiple organ system dysfunctions, severe anasarca, or has recently had cardiac surgery. Drug accumulation and bleeding may occur in these situations, and a reduced dose and close monitoring are recommended.
Mechanism of action: Direct thrombin inhibitor.
Onset of effects: Immediate.
Duration of effects: Coagulation times return to normal in approximately 1 hour after the infusion has been discontinued.
Uses: Bivalirudin is indicated for use as an anticoagulant in patients.
Dose (angiomax, 2016):
Renal Impairment: Clearance of bivalirudin is decreased in patients who have renal impairment. If the CrCl is < 30 mL/minute, the dose should be decreased to 1 mg/kg/hour.
During dialysis, the dose should be decreased to 0.25 mg/kg/hour.
Adverse effects: Back pain, headache, hypotension, minor hemorrhage, nausea, pain.
Special considerations: An acute stent thrombosis may occur in patients with a STEMI undergoing PCI and receiving bivalirudin. These patients should remain hospitalized for at least 24 hours after the procedure.
Mechanism of action: Dabigatran is a pro-drug, and its active metabolite is a direct thrombin inhibitor.
Onset of effects: The time to peak plasma level is 1 hour.
Duration: Dabigatran is taken once a day or twice a day. The half-life elimination time is 12-17 hours.
Renal impairment: Dose reductions of dabigatran are recommended if the patient has renal impairment., For the sake of brevity, the dosing recommendations for dabigatran in patients who have renal impairment will not be included; they are long, complex, and specific to the degree of impairment and to the reason dabigatran is being used.
Adverse effects: Bleeding and gastrointestinal distress, e.g., dyspepsia.
The fibrinolytics alteplase, reteplase, and tenecteplase are used for clot dissolution in patients with an acute ischemic stroke, massive PE, or a STEMI.
Effective and safe use of fibrinolytic drugs requires understanding the indications for use, contraindications, and administration and monitoring protocols. This is true for any medication, of course. Still, fibrinolytics are given to critically ill patients, and the administration of these drugs and nursing care of the patients receiving them are complex.
Mechanism of action: Alteplase binds to fibrin in a thrombus and converts plasminogen to plasmin. Plasmin is a serine protease that lyses fibrin clots.
Onset of effects: Immediate.
Duration of effects: Fibrinolytic activity continues for up to 1 hour after injection.
Dose (Activase, 2019):
Special considerations - Ischemic stroke:
Absolute Contraindications for the Use of Alteplase in Ischemic Stroke (Filho & Samuels, 2019):
Relative Contraindications for the Use of Alteplase in Ischemic Stroke:
Special considerations – Pulmonary embolism:
Absolute Contraindications for Alteplase in Pulmonary Embolism (Ucar, 2019):
Relative Contraindications for Alteplase in Pulmonary Embolism:
Special Considerations- STEMI:
Patients who are having a STEMI and are being given alteplase should also be started on antiplatelet therapy with aspirin and clopidogrel and anticoagulant therapy with heparin or an LMWH.
Absolute Contraindications for Alteplase in STEMI (Chen, et al., 2019):
Relative Contraindications for Alteplase in STEMI (Chen, et al., 2019):
Mechanism of action: Reteplase converts plasminogen to plasmin. Plasmin degrades the fibrin matrix of a thrombus, lysing the clot.
Onset: 30-90 minutes.
Duration: The half-life of reteplase is 13-16 minutes, and the mean fibrinogen level returns to baseline level by 48 hours.
Uses: Treatment of STEMI.
Dose: 10 units IV, infused over 2 minutes. This should be followed 30 minutes later by another 10 units.
Adverse effects: Bleeding (injection site, 49%; genito-urinary, 10%). The three clinical trials that were used to evaluate the efficacy and safety of reteplase reported that the incidence of intracranial hemorrhage was 0.8%-1.2%, the incidence of gastrointestinal bleeding was 1.8%-9%, genito-urinary bleeding 0.9%-10%, and bleeding that required a transfusion occurred in 12.4% of all patients (Retevase, 2020). Elevated blood pressure and age > 70 years increased the risk of intracranial hemorrhage (UpToDate, 2015).
Special Considerations: Coagulation tests and measures of fibrinolytic activity are not reliable during treatment with reteplase unless specific adjustments are made in laboratory procedures (UpToDate, 2015).
Mechanism of action: Tenecteplase binds to fibrin in a thrombus and converts plasminogen to plasmin. Plasmin is a serine protease that lyses fibrin clots.
Onset of effects: Not listed in the prescribing information.
Duration of effects: Tenecteplase has an initial half-life of 20-24 minutes.
Dose: The dose is weight-based, and it is administered as a bolus over 5 seconds.
Adverse effects: Bleeding, hematoma. The prescribing information for tenecteplase notes that during the ASSENT-2 clinical trial, 0.9% of patients having a STEMI who were treated with tenecteplase had an intracranial hemorrhage. The incidence of bleeding in the ASSENT-2 trial that required a transfusion was 0.38%. Research after this found a 0.38%-1% incidence of intracranial hemorrhage in STEMI patients; the incidence for patients > 75 years old was 8.1%, but if the dose of tenecteplase was reduced, there were no patients in the age group that developed an intracranial hemorrhage.
Special considerations: When TNKase is administered in an IV line containing dextrose, Precipitation may occur. Dextrose-containing lines should be flushed with a saline-containing solution before and following a single bolus administration of TNKase.
Orolingual angioedema has been reported in 0.18% to 8.0% of patients who received alteplase (Filho & Samuels, 2019). Most cases are mild and do not require elective intubation (Shirazy et al., 2019). Prior use of an ACE inhibitor increases the risk of developing this adverse effect (Sczepanski & Bazvk, 2018). A literature search did not locate any cases of angioedema caused by reteplase or tenecteplase.
Cholesterol embolization is a systemic organ and tissue injury caused by atherosclerotic plaque material breaking off from a plaque and lodging in the distal circulation (Oxkok, 2019). The prescribing information for alteplase, reteplase, and tenecteplase note that cholesterol embolization caused by fibrinolytic therapy is potentially very dangerous but fortunately quite rare. A recent (2019) review article confirmed that cholesterol embolization caused by fibrinolytic therapy is rare. The author noted that it seldom occurs unless the patient treated with a fibrinolytic has also undergone an invasive procedure like angiography (Oxkok, 2019).
As a treatment for STEMI, there does not appear to be significant differences between the fibrinolytics in terms of effectiveness or mortality rate (Jinatongthai et al., 2017). Compared to alteplase and reteplase for treating STEMI, tenecteplase has been associated with a lower risk of bleeding (Jinatongthai et al., 2017).
Mechanism of action: Inhibits clotting factor Xa.
Onset of effects: Fondaparinux is rapidly and completely absorbed, and the time to peak plasma is approximately 2 to 3 hours.
Duration of effects: Fondaparinux is given once a day, and the half-life is approximately 17 to 21 hours.
Renal impairment: If the CrCl is 30-50 mL/minute, fondaparinux clearance is approximately 40% of normal, and it should be used cautiously. Fondaparinux is contraindicated if the CrCl is < 30 mL/minute.
Adverse reactions: Anemia, bleeding.
Adherence to the therapy regimen with the oral anticoagulants differs considerably, depending on the patient population. However, in many places, e.g., the United States, fewer than one-half of all patients were still taking warfarin two years after it was first prescribed for them (Lowres et al., 2019). It was hoped that the DOACs would improve patient adherence to oral anticoagulant therapy; some studies have found this true, but others have not (Lowres et al., 2019). Factors that may decrease the adherence to oral anticoagulant therapy include (Lowres et al., 2019).:
Ensuring patient compliance is very important; the risk of death and stroke increases as adherence to the use of the oral anticoagulants decreases (Lowres et al., 2019). Strategies to increase compliance are a strong caregiver-patient relationship, family involvement, and patient education (Lowres et al., 2019). Monetary rewards, electronic reminders, or visual medication schedules as methods for improving compliance are not recommended by the American Society of Hematology.
Patients who take warfarin have often been advised to be careful about consuming too much or too little dietary vitamin K. Certainly, dietary consumption of excessively large amounts of vitamin K or a vitamin K deficiency can adversely change the effectiveness of warfarin and the INR. However, there is no evidence that patients who take warfarin need to significantly change their diet vis-a-vis vitamin K intake (Violi et al., 2016).
The use of omega-3 fatty acid supplementation in patients taking warfarin should be done cautiously; the combination may increase the drug's anticoagulant effects and cause bleeding (UpToDate, 2019).
Alcohol may decrease the serum warfarin concentration in people who drink heavily (UpToDate, 2020b). Patients who take warfarin should be advised to limit their alcohol intake to 1-2 servings a day; a serving is 12 ounces of beer, 6 ounces of wine, or 1.5 ounces of hard liquor (UpToDate, 2020b).
The following points should be discussed when a patient begins warfarin therapy or therapy with an anticoagulant, and there should be periodic reinforcement of this information.
Anticoagulants and fibrinolytics are highly effective drugs that require quite a bit of knowledge to administer safely. The mechanisms of action are varied and complex. The patients are often critically ill or, at least, have significant chronic medical problems. And using the anticoagulants and the fibrinolytics requires constant clinical (and many times) laboratory monitoring as these drugs can cause serious adverse effects. In addition, anticoagulants are very widely used, and medication errors, at times resulting in serious adverse effects, are unfortunately common with these drugs. In response to this clinical problem, health care facilities have guidelines and rules for administering anticoagulants, and nurses must know and use them.
Caring for someone receiving anticoagulants or fibrinolytics can be relatively simple or an imposing challenge. Managing this challenge is best done by using an orderly and systematic approach and asking these questions.
It would help if you also remembered that despite the differences in the mechanism of actions, doses, indications for use, monitoring factors, and adverse effects, the anticoagulants and fibrinolytic have many similarities: risk for bleeding, need for frequent close clinical monitoring, and; possibility for serious adverse effects.
CEUFast, Inc. is committed to furthering diversity, equity, and inclusion (DEI). While reflecting on this course content, CEUFast, Inc. would like you to consider your individual perspective and question your own biases. Remember, implicit bias is a form of bias that impacts our practice as healthcare professionals. Implicit bias occurs when we have automatic prejudices, judgments, and/or a general attitude towards a person or a group of people based on associated stereotypes we have formed over time. These automatic thoughts occur without our conscious knowledge and without our intentional desire to discriminate. The concern with implicit bias is that this can impact our actions and decisions with our workplace leadership, colleagues, and even our patients. While it is our universal goal to treat everyone equally, our implicit biases can influence our interactions, assessments, communication, prioritization, and decision-making concerning patients, which can ultimately adversely impact health outcomes. It is important to keep this in mind in order to intentionally work to self-identify our own risk areas where our implicit biases might influence our behaviors. Together, we can cease perpetuating stereotypes and remind each other to remain mindful to help avoid reacting according to biases that are contrary to our conscious beliefs and values.