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Anticoagulant and Fibrinolytic Therapy

5 Contact Hours including 5 Advanced Pharmacology Hours
This peer reviewed course is applicable for the following professions:
Advanced Practice Registered Nurse (APRN), Certified Nurse Practitioner, Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Nursing Student, Registered Nurse (RN)
This course will be updated or discontinued on or before Tuesday, March 26, 2024

Nationally Accredited

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.


Outcomes

This course will provide professional nurses with the information they need to safely and effectively administer anticoagulant and fibrinolytic drugs.

Objectives

After completing this continuing education course, the learner will be able to:

  1. Identify a common indication of the use of warfarin.
  2. Identify a common indication for the use of heparin.
  3. Identify a common indication for the use of fibrinolytic drugs.
  4. Identify two tests that are used to measure coagulation.
  5. Identify the coagulation tests that are used to monitor therapy with heparin and aspirin.
  6. Identify the mechanism of action of aspirin, heparin, the DOACs, and warfarin.
  7. Identify a common adverse effect of aspirin, heparin, the DOACs, and heparin.
  8. Identify drugs used to reverse the anticoagulant effects of heparin and warfarin.
  9. Identify laboratory tests that should be measured before starting anticoagulant therapy.
  10. Identify two major contraindications for fibrinolytic therapy.
CEUFast Inc. and the course planners for this educational activity do not have any relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

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To earn of certificate of completion you have one of two options:
  1. Take test and pass with a score of at least 80%
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Author:    Dana Bartlett (RN, BSN, MA, MA, CSPI)

Introduction

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.

Case Study

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

The clotting process begins with local vasoconstriction of the injured vessels, followed by:

  1. Formation of the platelet plug and;
  2. Activation of the clotting cascade (Kuslos & Fasinu, 2019).

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

Coagulation tests are used to measure the effectiveness of anticoagulant therapy. Commonly used tests include (Zehnder 2019).

Table 1: Commonly Used Coagulation Tests
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 activityCan 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.

Clinical Considerations for Using Anticoagulants

Starting Therapy and Monitoring Therapy

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.

Renal Impairments and Anticoagulants (Aursulesei & Costache, 2019)

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.

Liver Impairment and Anticoagulants

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).

General Considerations

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 the Anticoagulants

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):

  • Estimate the risk of bleeding from the procedure. For example, dental procedures are considered low risk, while coronary artery bypass graft (CABG) surgery is high-risk.
  • Estimate the risk of thromboembolism. Is the patient taking an anticoagulant because their heart rhythm is atrial fibrillation? Does the patient have a mechanical prosthetic heart valve? These situations pose a high risk of thromboembolism development.
  • Determine how long the anticoagulant needs to be discontinued before surgery or an invasive procedure. Examples: Before surgery or an invasive procedure that poses a risk of bleeding, aspirin should be stopped 7-10 days prior; warfarin should be discontinued 5 days prior; dabigatran should be discontinued 2-3 days, and; rivaroxaban should be discontinued 2-3 days before surgery/invasive procedure.
  • Determine if an anticoagulant reversal is available if needed.
  • Assess if bridging therapy is needed. Example: If the patient is taking warfarin and will be having high-risk surgery for bleeding, necessitating that warfarin should be stopped, low-molecular-weight heparin can be started 3 days before the surgery. (Bridging therapy will be discussed in more detail later in the course).
  • Determine when and how to re-start the anticoagulant. For example, Warfarin can be re-started 12-24 hours post-operatively, but full anticoagulation bridging therapy should be considered since it requires 5-10 days.

Reversing the Effects of Anticoagulants

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.

Discontinue the use of the medication

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).

  • Protamine sulfate is used to reverse the effects of heparin (A; Saej & Anderson, 2016)
  • There is no clinically proven and approved antidote or reversal agent for the LMWHs, but protamine sulfate has been used off-label for this purpose, which may be helpful (Tarcia, 2019; Lovenox, 2018)
  • Bleeding or an overdose of dabigatran can be treated with a specific reversal agent, idarucizumab (Billoir, et al., 2018)
  • Bleeding or overdose of the factor X-a inhibitors apixaban or rivaroxaban can be treated with either andexanet alfa or 4-factor PCC (Abdulrehmen et al., 2019); Smith et al., 2019)
  • The use of 4-factor PCCs may be considered for treating excessive coagulation caused by betrixaban or edoxaban (Smith et al., 2019)
  • There are no antidotes/reversal agents for bleeding caused by the other anticoagulants discussed in this module. If the patient is bleeding or clinically unstable, use symptomatic and supportive care

Oral Antiocagulants

Oral Antiplatelet Drugs

Anti-platelet drugs inhibit platelet activation and aggregation.

Aspirin

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):

  • Reduction of the risk of death and stroke in patients who have had an ischemic stroke or a transient ischemic attack.
  • Reduction of cardiovascular mortality in patients having an acute myocardial infarction (MI).
  • Reduction of the risk of death and non-fatal MI in patients who have had an MI or have unstable angina.
  • Reduction of the risk of MI and sudden death in patients who have chronic unstable angina.
  • Aside from its action as an anti-platelet drug, aspirin is commonly used as an analgesic and an antipyretic.

Dose: Aspirin dosing is complex and depends on the clinical situation.

  • Unstable angina/non-ST-segment elevation MI (NSTEMI): 162-325 mg non-enteric aspirin should be given to all patients with unstable angina or an NSTEMI, and a maintenance dose of 81-325 mg should be given indefinitely. If percutaneous coronary intervention (PCI) is planned, the patient should be given aspirin before the procedure: 81 to 325 mg if they are already taking daily aspirin, 325 nonenteric coated if the patient is not already on aspirin therapy. The first dose of aspirin should be chewed; chewing the tablet establishes a blood level faster than being swallowed. After PCI, daily aspirin therapy at 81-325 mg should be continued indefinitely, 81 mg if the patient is also treated with ticagrelor (Amsterdam et al., 2014).
  • STEMI: A 162-325 mg dose of aspirin should be given before PCI and to patients with fibrinolytic therapy; the tablet should be chewed, not swallowed. After PCI and after fibrinolytic therapy, low-dose aspirin therapy, 50-100 mg a day, should be continued indefinitely (Amsterdam et al., 2014).
  • Antiplatelet treatment for the prevention of stroke after TIA or recurrent stroke after an ischemic stroke is critically important, and it is an important part of acute stroke treatment (Barlas et al., 2019; Powers et al., 2018). For treating an acute ischemic stroke or TIA, the dose is 160-300 mg 24-48 hours after onset of the stroke (Powers et al., 2018). Aspirin can be given through a gastrointestinal tube or rectally if the patient cannot swallow. Aspirin is not recommended as an adjunctive therapy within 24 hours of administration of a fibrinolytic agent (Powers et al., 2018).

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).

Aspirin and Dipyridamole (Aggrenox®)

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).

Cilostazol (Pletal®)

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).

Uses:

  • The labeled use of cilostazol is for reducing the symptoms of intermittent claudication, but cilostazol has been used off-label as an option for antiplatelet therapy for the secondary prevention of non-cardioembolic stroke in patients who have a history of non-cardioembolic stroke or TIA (Guyatt et al., 2012; Pletal, 2015).
  • Note: Non-cardioembolic stroke/TIA refers to an embolic neurological injury caused by atrial fibrillation. Cilostazol is also used off-label during PCI if a stent is placed to prevent stent thrombosis and restenosis after a stent has been placed (Guyatt et al., 2012).

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).

Clopidogrel (Plavix®)

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):

  • Clopidogrel is used with aspirin to reduce the risk of death, re-infarction, and stroke in patients with a STEMI.
  • Clopidogrel is used with aspirin to reduce the risk for MI and stroke in patients with a non-ST segment elevation acute coronary syndrome, i.e., unstable angina or NSTEMI.
  • Clopidogrel is used to reduce the rate of MI and stroke in patients who have recently had an MI or a stroke and who have a peripheral atherosclerotic disease.
  • The American College of Chest Physicians recommends 75 mg a day of clopidogrel for the secondary prevention of non-cardioembolic stroke in patients who have had a non-cardioembolic stroke or TIA.

Dose (UpToDate, 2019i):

  • All patients treated with a fibrinolytic should be given clopidogrel. For patients < 75 years of age, the loading dose is 300 mg given as soon as possible; for patients > age 75, the loading dose is 75 mg. In either case, antiplatelet therapy should be continued for ≥ 12 months.
  • For patients undergoing PCI, the dose of clopidogrel depends on when fibrinolysis was done. If fibrinolysis and a loading dose of clopidogrel were given together, simply treat the patient with daily antiplatelet therapy, and the dose of clopidogrel is 75 mg a day for ≥ 12 months.
  • If fibrinolysis was done ≤ 24 hours prior and no loading dose of clopidogrel was given, give 300 mg before PCI and 75 mg once a day after PCI.
  • If fibrinolysis was done > 24 hours ago and a loading dose was not given, give 600 mg of clopidogrel before PCI and 75 mg once a day after PCI.
  • For patients with a non-ST-segment elevation acute coronary syndrome and being treated with medical management, the loading dose is 300 to 600 mg followed by 75 mg a day for ≥ 12 months. (Note: The rationale for continuing aspirin and clopidogrel (and other P2Y12 Inhibitors) for at least a year will be discussed in the section of the module titled Dual Antiplatelet Therapy).
  • For patients with a non-ST-segment elevation acute coronary syndrome and treated with fibrinolysis and PCI, give a loading dose of 600 mg immediately after PCI and 75 mg a day for ≥ 12 months.
  • In all cases, clopidogrel should be given with aspirin and a parenteral anticoagulant, and after the acute phase, all patients should be given clopidogrel and aspirin for ≥ 12 months (UpToDate, 2019i ).
  • Two other antiplatelet drugs, prasugrel, and ticagrelor, may be used instead of clopidogrel during the acute phase or shortly after the acute phase of STEMI, and NSTEMI will be discussed later in the module.
  • 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 (Hao et al., 2018).

Adverse effects: Bleeding.

Special considerations:

  • Clopidogrel is a pro-drug, and the active metabolite is produced by the cytochrome P450 enzyme system, principally by the activity of CYP2C19 (UpToDate, 2019i). Patients who have decreased activity of CYP2C19 will not form a sufficient amount of active metabolite, and platelet aggregation will be decreased (Chi & Wang, 2019). (See the section below, Clopidogrel resistance) Poor metabolizers who also have an acute coronary syndrome or are undergoing PCI and are being treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates than patients with normal CYP2C19 function (US Boxed Warning) (UpToDate, 2019i).
  • Clopidogrel and prasugrel are both antiplatelet drugs. They are classified as thienopyridines and are structurally similar. Cross-reactivity between the two drugs has been reported, and patients sensitive to or allergic to clopidogrel may be sensitive to prasugrel (UpToDate, 2019i).
  • Clopidogrel resistance (Warlo et al., 2019): A significant number of patients given clopidogrel do not achieve the desired anti-platelet effect, a phenomenon syndrome called clopidogrel resistance, non-responsiveness, or high platelet reactivity. The frequency of clopidogrel resistance has been estimated to be approximately 30%, and clopidogrel resistance increases patients’ risk for major adverse cardiac events after PCI.
  • Genetic polymorphisms of the CYP2C19 enzyme that metabolizes clopidogrel are in part responsible for clopidogrel resistance; other contributing factors include (but are not limited to) age > 65, body mass index > 25, diabetes, hypercholesterolemia, hypertension, kidney disease, poor patient compliance with the drug regimen, previous treatment with aspirin, and smoking.
  • There is evidence that genetic testing-guided treatment may help reduce the consequences of clopidogrel resistance. Still, this approach is not universally recommended, and some clinicians increase the dose of clopidogrel or use another P2Y12 receptor blocker ( Tantry et al., 2019).

Prasugrel (Effient®) (O’Gara et al., 2013; UpTo Date, 2019j).

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.

Dose:

  • A loading dose of 60 mg (along with a dose of aspirin) given as early as possible and no later than one hour after PCI is performed. This should be followed by 10 mg once a day for a year, along with a daily dose of aspirin. For patients who weigh less than 60 kg, a lower daily maintenance dose, 5 mg, can be used.
  • Prasugrel should not be given to patients who have a STEMI and have a history of stroke or TIA. Prasugrel, in a 60-mg loading dose, is reasonable once the coronary anatomy is known in patients who did not receive a previous loading dose of clopidogrel at the time of administration of a fibrinolytic agent, but prasugrel should not be given sooner than 24 hours after administration of a fibrin-specific agent or 48 hours after administration of a non-fibrin-specific agent (O’Gara et al., 2013).

Adverse effects: None listed as > 10%.

Special considerations:

  • Thrombotic thrombocytopenic purpura has been reported associated with prasugrel use. US Boxed Warning applies to points 1-4.
  • Do not start therapy with prasugrel in patients who may need urgent CABG surgery.
  • When possible, discontinue prasugrel ≥7 days before any surgery.
  • Prasugrel is generally not recommended in patients ≥75 years of age due to increased risk of fatal and intracranial bleeding and uncertain benefit; use may be considered in high-risk situations.
  • Prasugrel can cause significant and life-threatening bleeding. Prasugrel should not be given to patients who have active bleeding, who have had a stroke or TIA, who have risk factors for bleeding, or who are taking medications that may cause or increase the bleeding. Bleeding should be suspected in a patient who has been given prasugrel and is hypotensive and who has recently undergone coronary angiography, PCI, CABG, or other surgical procedures in the setting of prasugrel. In this situation, prasugrel therapy should be continued if possible because discontinuing use, particularly in the first few weeks after an acute coronary syndrome, increases the risk of subsequent cardiovascular events.
  • The frequency of non-responsiveness/high platelet reactivity with chronic use of prasugrel has been estimated to be 3-15%. Use caution in patients with hepatic or renal impairment and patients > age 75; these patients may be at increased risk for bleeding.

Ticagrelor (Brilinta®) (UpToDate, 2019k)

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.

  • After a loading dose, the onset of platelet inhibition is noticeable after 30 minutes and is almost complete after 2 hours.

Duration of action: Twenty four hours after the maintenance dose is discontinued, platelet inhibition is at approximately 58%.

Uses:

  • Reducing the rate of cardiovascular death, MI, and stroke in patients with acute coronary syndrome or a history of MI.
  • Ticagrelor also reduces the rate of stent thrombosis in patients who have acute coronary syndrome and had a stent placed.

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.

Special considerations:

  • As with clopidogrel, non-responsiveness/high platelet reactivity can occur with ticagrelor.
  • Thrombotic thrombocytopenic purpura has been reported in association with the use of ticagrelor.
  • Brady-arrhythmias and ventricular pauses occurring during use of ticagrelor have been reported, and ticagrelor should be used cautiously in patients who have a second or third-degree AV block, sick sinus syndrome, bradycardia-related syncope if the patient does not have a pacemaker, or if the patient is taking a drug that can cause bradycardia.

US Boxed Warning applies to points 1-5:

  1. Maintenance doses of aspirin > 100 mg reduce the effectiveness of ticagrelor.
  2. Ticagrelor can cause significant, life-threatening bleeding.
  3. The use of ticagrelor is contraindicated in patients who have active bleeding and in patients who have a history of intracranial hemorrhage.
  4. Ticagrelor should not be given to patients who may need urgent CABG surgery or will be having CABG.
  5. Bleeding should be suspected in a patient who has been given ticagrelor and is hypotensive and who has recently undergone coronary angiography, PCI, CABG, or other surgical procedures in the setting of prasugrel. In this situation, ticagrelor therapy should be continued if possible because discontinuing use, increases the risk of subsequent cardiovascular events.

Vorapaxar (Zontivity®) (UpToDate, 2019l)

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.

Uses:

  • Reducing the risk of cardiovascular death, MI, stroke, or the need for urgent coronary revascularization in patients who have a history of MI or peripheral arterial disease and who do not have a history of stroke or TIA.
  • When vorapaxar is added to standard care, studies have shown a significant reduction of the risk of cardiovascular death, MI, recurrent ischemia, and stroke. However, the use of the vorapaxar in this patient population also significantly increased the risk of moderate to several bleeding, especially intracranial hemorrhage.

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.

Oral Antiplatelet Therapy: Clinical Issues

Dual Antiplatelet Thrapy: Acute Coronary Syndromes

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.

High Platelet Resistance

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).

Stroke Prevention

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.

IV Antiplatelet Drugs (UpToDate, 2019m)

Eptifibatide (Integrilin®) (UpToDate, 2019m)

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.

Uses:

  • Treatment of patients with a non-ST-segment elevation acute coronary syndrome (Unstable angina or NSTEMI) is being treated medically or with PCI.
  • Treatment of patients with PCI with or without stent placement.

Dose:

  • Unstable angina/NSTEMI: Eptifibatide is not routinely used for patients with unstable angina or an NSTEMI. These patients are typically treated with aspirin, a PY212 inhibitor, and an IV anticoagulant. However, eptifibatide or another glycoprotein IIB/IIIa receptor antagonist can be used for these patients if PCI is planned and the patient is at high-risk for complications; if the patient has a significant thrombus burden; if the time between administration of the PY212 inhibitor was < 40-45 minutes, or; if prasugrel or ticagrelor was not the PY212 inhibitor.
  • Begin treatment before diagnostic coronary angiography has been done. Give an IV bolus of 180 mcg/kg (Maximum dose 22.6 mg) followed by a continuous IV infusion of 2 mcg/kg/minute (Maximum dose 15 mg/hour). Give a second IV bolus 10 minutes after the first, and the infusion may be continued for up to 18-24 hours after PCI.
  • PCI: Begin treatment before PCI has been done. Give an IV bolus of mcg/kg (Maximum dose 22.6 mg) followed by a continuous IV infusion of 2 mcg/kg/minute (Maximum dose 15 mg/hour). Give a second IV bolus 10 minutes after the first, and the infusion may be continued for up to 2-24 hours after PCI.

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.

  • Acute and significant thrombocytopenia can occur within 24 hours of use. Use with extreme caution if the patient’s platelet count is <100,000/mm3, and if the platelet count falls to< 100,000/mm3, discontinue use of the drug. (Note: Thrombocytopenia and the glycoprotein IIB/IIIa receptor antagonists will be discussed later in this section).

Tirofiban (Aggrastat®) (UpToDate, 2019n)

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.

Dose:

  • Loading dose, 25 mcg/kg administered over 5 minutes or less. Maintenance infusion, 0.15 mcg/kg/minute continued for up to 18 hours.
  • Renal impairment: If the CrCl is ≤60 mL/minute, the IV loading dose should still be 25 mcg/kg administered over ≤5 minutes, but the maintenance infusion dose should be 0.075 mcg/kg/minute continued for up to 18 hours.

Adverse effects: Bleeding.

Special considerations: Use with caution and reduce the dose in patients who have renal impairment.

  • Use extreme caution if the patient has a history of gastrointestinal disease, has a history of hemorrhagic retinopathy, is taking other drugs that affect clotting ability, or has a platelet count < 150,000/mm3.
  • Tirofiban can cause significant thrombocytopenia. If the patient’s platelet count decreases to <90,000 mm3 and if it is confirmed that the patient does not have pseudo-thrombocytopenia, discontinue the drug and heparin if heparin is being used.

Cangrelor (Kengreal®) (UpToDate, 2019o)

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.

IV Antiplatelet Therapy: Clinical Issues

Glycoprotein IIb/IIIa receptor inhibitors: Place in therapy (Velibey et al., 2019).

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:

  1. High risk for stent thrombus
  2. High thrombus burden
  3. Intraprocedural bail-out because of a coronary artery dissection, distal embolus, or hemodynamic instability
  4. The patient has not been given prasugrel or ticagrelor, or the time between administration of a PYs12 inhibitor has been < 30-45 minutes
  5. No reflow or slow reflow
  6. Ongoing ischemia

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.

Vitamin K Antagonists

Warfarin is the only vitamin K antagonist that is available in the US.

Warfarin (UpToDate, 2019p)

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:

  1. inhibits the activity of VKORC1, deleting vitamin K stores
  2. prevents hepatic synthesis of the clotting factors and proteins
  3. reduces the activity of circulating clotting factors and proteins.

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.

Uses:

  • Prophylaxis and treatment of thromboembolic disorders and embolic complications caused by atrial fibrillation or cardiac valve replacement.
  • After an MI, as an adjunct to reduce the risk of systemic embolism that may cause another MI or a stroke.

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:

  • Attaining a level of anticoagulation that will prevent thrombus formation and embolic events
  • Maximizing the amount of time when the patient is in the therapeutic range in order to minimize the amount of time the patient is at risk for thrombus formation and embolic events
  • Avoiding a level of anticoagulation that puts the patient at risk for bleeding

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.

  • Advanced age
  • Alcohol abuse, substance abuse
  • Cancer
  • Diabetes
  • Diet
  • Genetic differences in warfarin metabolism
  • Hepatic impairment
  • Hypertension
  • Kidney disease
  • Labile INR
  • Medications that affect coagulation
  • Prior bleeding events
  • Stroke or TIA

Warfarin: Clinical Issues

Bleeding and Co-Morbidities

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%.

Assessment of Bleeding Risk (Edmiston & Lewis, 2018)

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.

Genetics and Warfarin (Tse et al., 2018; Yang et al., 2019)

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.

Monitoring (Kantito et al., 2018)

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.

Warfarin-drug interactions (UpToDate, 2019q)

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.

  1. Interfering with platelet function: Examples of aspirin and selective serotonin reuptake inhibitors like fluoxetine, paroxetine, and sertraline.
  2. Injury to the gastrointestinal mucosa: Examples include non-steroidal anti-inflammatories such as ibuprofen.
  3. Reduced synthesis of vitamin K: Sulfamethoxazole-trimethoprim.
  4. Interference with warfarin metabolism: Amiodarone, fluconazole, and metronidazole.
  5. Interruption of the vitamin K cycle: Acetaminophen.

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.

Factor Xa inhibitors: New Oral Anticoagulants

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).

Table 5: DOACs Compared to Warfarin
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.

Apixaban (Eliquis®) (UpToDate, 2019r)

Mechanism of action: Direct inhibition of factor Xa.

Onset of action: 3-4 hours.

Duration of action: The half-life is approximately 12 hours.

Uses:

  • Prevention of DVT and PE.
  • Treatment of DVT and PE.
  • Reducing the risk of stroke and systemic embolization in patients who have nonvalvular atrial fibrillation.
  • Prophylaxis for the prevention of postoperative DVT in patients who have had hip or knee replacement.
  • Treatment of PE and to reduce the risk of recurrent PE after initial treatment.

Dose:

  • DVT and PE, 10 mg twice daily for 7 days, then 5 mg twice a day.
  • Nonvalvular atrial fibrillation, 5 mg twice a day. If the patient is ≥ 80 years of age, weighs ≤ 60 kg, or has a serum creatinine of ≥ 1.5 mg/dL, decrease the dose to 2.5 mg twice a day.
  • Post-operative patients, 2.5 mg twice daily. Start therapy 12-24 hours after surgery. The optimum duration of therapy is not known, but the usual course is a minimum of 10-14 days.

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.

Special considerations:

  • Bariatric surgery may decrease the absorption of apixaban.

  • Apixaban is not recommended for patients with a history of thrombosis diagnosed with antiphospholipid syndrome.

  • Premature discontinuation of any oral anticoagulant, including apixaban, increases the risk of thrombotic events without providing alternative anticoagulation.

(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.

Betrixaban (Bevyxxa®) (UpToDate, 2019s)

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.

Special considerations:

  • Epidural or spinal hematomas may occur in patients treated with betrixaban 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 (US Boxed Warning).
  • Drug concentrations of betrixaban can increase as a patient’s renal function worsens, increasing the risk of bleeding.141 If the CrCl is 15-29 mL/minute, the betrixaban dose should be reduced, and the drug should be used with caution.
  • The starting and maintenance dose should be reduced by 50% if the patient takes a p-glycoprotein inhibitor like amiodarone, clarithromycin, ketoconazole, and verapamil.

Edoxaban (Savaysa®) (UpToDate, 2019b)

Mechanism of action: Direct inhibition of factor Xa.

Onset of effects: 1-2 hours.

Duration of action: The half-life is 10-14 hours.

Uses:

  • Treatment of DVT and PE after 5-10 days of initial therapy with a parenteral anticoagulant.
  • Reduction of the risk of stroke and systemic embolism in patients who have nonvalvular atrial fibrillation.

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.

  • CrCl 15-50 mL/minute. The dose should be 30 mg a day.
  • CrCl< 15 mL/minute, use is not recommended.
  • Patients with nonvalvular atrial fibrillation, CrCl > 95 mL/minute, use not recommended. CrCl 51-95 mL/minute, no dosing adjustment is needed. CrCl 15-50 mL/minute, use 30 mg a day. CrCl < 15 mL/minute, use not recommended.

Adverse effects: Bleeding.

Special considerations:

  • Epidural or spinal hematomas may occur in patients treated with edoxaban receiving neuraxial anesthesia or undergoing spinal puncture (US Boxed Warning).
  • Edoxaban should not be used in patients treated for nonvalvular atrial fibrillation and have a creatinine clearance (CrCl) >95 mL/minute. In the ENGAGE AF-TIMI 48 study, patients who had nonvalvular atrial fibrillation, a CrCl >95 mL/minute, and were given edoxaban 60 mg once a day had an increased rate of ischemic stroke compared to patients treated with warfarin. Another anticoagulant should be used (US Boxed Warning).

Rivaroxaban (Xarelto®) (UpToDate, 2019d)

Mechanism of action: Direction inhibition of factor Xa.

Onset of action: 2-4 hours.

Duration of effects: The half-life is 5-9 hours.

Uses:

  • Treatment of DVT and PE.
  • Reducing the risk of stroke and systemic embolic events in patients who have nonvalvular atrial fibrillation.
  • Post-operative prophylaxis of DVT in patients who have had hip or knee replacement.

Dose:

  • Treatment of DVT and PE, 15 mg twice a day for 21 days followed by 20 mg once a day, taken with food.
  • For patients who have nonvalvular atrial fibrillation, the dose is 20 mg a day, taken with the evening meal.
  • Post-operative patients, hip surgery and knee surgery, 10 mg given at least 6-10 hours after surgery or when hemostasis has been attained, followed by 10 mg a day for at least 10-14 days and possibly up to 35 days. The optimum duration of treatment is not known; post-operative patients, knee surgery, 10 mg a day for 12-14 days.

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.

Special considerations:

  • Epidural or spinal hematomas have occurred in patients treated with rivaroxaban receiving neuraxial anesthesia or undergoing spinal puncture (US Boxed Warning) (UpToDate, 2019d).
  • 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 (US Boxed Warning) (UpToDate, 2019d).

DOAC: Clinical Issues

Compliance

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).

Drug Interactions

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.

Laboratory Monitoring

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).

Renal Impairment

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).

Reversal

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.

Parenteral Anticoagulants

Heparin

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

  • Prophylaxis against and treatment for thromboembolic complications associated with atrial fibrillation
  • Prevention of clotting during arterial and cardiac surgery. An anticoagulant during extracorporeal circulation and hemodialysis.

Dose: Doses to prevent clotting during arterial and cardiac surgery, extracorporeal circulation, and hemodialysis will not be covered.

  • Prophylaxis/treatment of thromboembolic disorders. Intermittent SC injections of heparin (or LMWH) are the preferred approach for prophylaxis of thromboembolic disorders (Kline, 2020). A continuous IV infusion of heparin can be used if the patient cannot be treated on an outpatient basis or has a severe renal impairment and cannot be given an LMWH (Goldhaber, 2019).
  • Medical patients: 5000 units given SC every 8-12 hours. Continue use until the patient is fully ambulatory or for the duration of the hospitalization (UpToDate, 2019u).
  • Non-orthopedic surgery, patients with cancer: 5000 units SC given 2 to 4 hours before the procedure, then 5000 units SC every 8 hours. The alternative is 5000 units SC given every 8-12 hours, beginning 24 hours after the procedure. The optimal duration for prophylactic use is not known. Still, it is usually continued for a minimum of 7-10 days, and treatment for up to 4 weeks may be done for patients who have had major abdominal surgery or pelvic surgery (UpToDate, 2019u).
  • Non-orthopedic surgery, patients who do not have cancer: 5000 units SC, given every 8-12 hours. The first dose should be given ≥2 hours before the procedure. The initiation of therapy may also be delayed until after the operation if the patient has a high risk for bleeding. The duration of therapy should be until the patient is fully ambulatory or the risk of VTE has diminished (UpToDate, 2019u).
  • Orthopedic surgery: 5000 units given SC every 8-12 hours; the first dose should be given ≥ 12 hours preoperatively or ≥ postoperatively, once hemostasis has been attained. The optimal treatment duration is unknown, but it is usually continued for a minimum of 10-14 days and occasionally for as long as 35 days (UpToDate, 2019u).
  • Pregnancy: The dosing recommendations for using heparin during pregnancy are based on the bleeding risk, the risk for complications, the trimester, and there are separate prophylactic and therapeutic dosing recommendations. Readers should refer to prescribing information for the details.
  • Prophylaxis against and treatment for thromboembolic complications associated with atrial fibrillation: A bolus dose of 60-80 units/kg given IV, maximum dose of 5000 units. This should be followed by a continuous IV infusion of 12-18 units/kg/hour, a maximum dose of 1000 units/hour. The infusion rate should be adjusted so that the desired level of anticoagulation is maintained.
  • This is a labeled use for heparin, but the 2019 guidelines for the management of atrial fibrillation from the American College of Cardiology/American Heart Association/American Rhythm Society do not mention using heparin for prophylaxis against and treatment for thromboembolic complications associated with atrial fibrillation (January et al., 2019).

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).

Heparin Clinical Issues

Monitoring

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.

Dosing and Dosing Protocols

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

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 degree of thrombocytopenia
  • the timing of thrombocytopenia relative to when heparin was given
  • thrombosis, and
  • other causes of thrombocytopenia

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

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.

Osteoporosis and Fractures

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).

Obesity and Heparin Dosing

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.

Reversal

Protamine is the antidote for excessive coagulation or severe bleeding caused by heparin (UpToDate, 2019u).

Low-Molecular Weight Heparins

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:

  1. A more predictable anticoagulant effect at a given dose than with heparin
  2. Much less risk of heparin resistance, and
  3. Because the anticoagulant response is very predictable, laboratory monitoring is not needed (Weitz, 2018)

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.

Enoxaparin (Lovenox®) (Lovenix, 2018; UpToDate, 2019v)

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.

  • In-patient and out-patient treatment of acute DVT, with or without PE, and used in conjunction with warfarin.
  • Prophylaxis of ischemic complications of unstable angina and non-Q wave MI when used with aspirin.
  • Treatment of patients with acute ST-segment elevation MI and are being medically managed or will subsequently have PCI.

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.

  • DVT prophylaxis, hip or knee replacement surgery: A dose of 30 mg SC given 12-24 hours after surgery, then 30 mg SC once a day for 7-10 days.
  • Medical patients at risk for VTE: 40 mg SC once a day for 6-11 days.
  • In-patient treatment of acute DVT: 1 mg/kg SC every 12 hours or 1.5 mg/kg SC once a day, every day at the same time. Warfarin should be given when appropriate, usually within 72 hours after beginning treatment with enoxaparin. The treatment duration is at least 5 days, and the average duration is 7 days.
  • Out-patient treatment of acute DVT: 1 mg/kg SC every 12 hours. (Note The prescribing information does not recommend treatment duration).
  • Prophylaxis of ischemic complications of unstable angina and non-Q wave MI: 1 mg/kg SC, given every 12 hours, along with aspirin therapy,100-325 mg PO, once a day. Continue treatment until the patient is clinically stable. The minimum treatment duration is 2 days; the average treatment duration is 2-8 days.
  • Treatment of patients with acute STEMI: A single 30 mg bolus given IV and 1 mg/kg dose (Maximum 100 mg for the first two doses) every 12 hours. The first SC dose should be given with the IV bolus doses. If the patient is ≥ 75 years old, do not give an IV bolus dose, the SC dose should be 0.75 mg/kg every 12 hours, and no more than 75 mg should be used for the first two doses.
  • Aspirin, 75 mg-325 mg, should be given once a day unless contraindicated (Rosen, 2018).
  • If enoxaparin is given in conjunction with a thrombolytic, it should be administered 15 minutes before and 30 minutes after the fibrinolytic has been given, and the usual duration of therapy is 8 days or until discharge from the hospital.
  • If the patient is managed with PCI, enoxaparin is not needed again if the last dose of the drug was given < 8 hours before balloon inflation. If the last dose was given > 8 hours before balloon inflation, give 0.3 mg/g IV.

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.

  • DVT prophylaxis in patients who have had abdominal surgery, hip or knee replacement surgery, or medical patients at risk for VTE due to prolonged immobility: 30 mg SC, once a day.
  • In-patient and out-patient treatment of acute DVT: 1 mg/kg SC, once a day.
  • Prophylaxis of ischemic complications of unstable angina and non-Q wave MI: 1 mg/kg SC, once a day.
  • If the patient is < 75 years of age and when enoxaparin is given in conjunction with aspirin, the patient should receive a 30 mg IV bolus and a 1 mg/kg SC dose, followed by 1 mg/kg SC once a day.
  • If the patient is ≥ 75 years of age, no bolus doses should be used, and the patient should be given 1 mg/kg SC once a day.

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.

  • Enoxaparin should be not be given IM, and it should not be substituted on a unit for a unit basis for heparin or another LMWH.
  • Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. This can result in long-term or permanent paralysis. (US Boxed Warning).

Dalteparin (Fragmin®) (UpToDate, 2019v)

Mechanism of action: Inhibition of factor Xa and II.

Onset: 1-2 hours.

Duration: > 12 hours.

Uses (Fragmin, 2019):

  • Prophylaxis of ischemic complications on non-Q-wave MI and unstable angina.
  • Prophylaxis against DVT in patients who have had abdominal surgery, hip or knee replacement surgery, or medical patients at risk for venous thromboembolism due to prolonged immobility.
  • Extended treatment of symptomatic VTE in cancer patients to prevent VTE recurrence.
  • Treatment of symptomatic VTE to reduce the recurrence in pediatric patients 1 month of age and older.

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.

  • DVT prophylaxis, abdominal surgery: 2500 IU SC or 5000 IU SC once a day or 2500 IU SC followed 12 hours later with 2500 IU SC and then 5000 IU SC once a day.
  • DVT prophylaxis, hip or knee replacement surgery: If dalteparin is started post-operatively, give 2500 IU SC at 4-8 hours after the surgery, then 5000 IU SC once a day. Pre-operatively, on the day of surgery, give 2500 IU SC 2 hours before the procedure, 2500 IU SC 4-8 hours after the surgery, and then give 5000 IU SC once a day. Pre-operatively, the night before surgery, give 5000 IU SC and then 5000 IU SC 4-8 hours after the procedure.
  • DVT prophylaxis, medical patients at risk for VTE due to prolonged immobility: 5000 IU SC once a day.
  • Extended treatment of symptomatic VTE in patients who have cancer to prevent the recurrence of VTE: First month, 200 IU/kg SC, once a day. Second-sixth months, 150 IU/kg SC, once a day.

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.

  • Dalteparin should be not be given IM, and it should not be substituted on a unit for a unit basis for heparin or another LMWH.
  • Epidural or spinal hematomas may occur in anticoagulated patients with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture, which can cause long-term or permanent paralysis. (US Boxed Warning).

Low-Molecular Weight Heparins: Clinical Issues

Hepatic Impairment

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).

Renal Impairment

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).

Heparin Induced Thrombocytopenia

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).

Heparin resistance (Saydam et al., 2019)

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).

Monitoring therapy with LMWHs (Ahuja et al., 2018)

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.

Osteoporosis

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).

Reversal (Lauer 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.

Direct Thrombin Inhibitors

Argatroban (Generic) (UpToDate, 2019x)

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.

Uses:

  • Prophylaxis or treatment of thrombosis in adults who have HIT.
  • As an anticoagulant for adults undergoing PCI who have HIT or are at risk of developing HIT.

Dose:

  • For HIT treatment, the dose is 2 mcg/kg/minute. The aPTT should be measured 2 hours after therapy has begun, and the dose should be adjusted (not to exceed 10 mcg/kg/minute) for an aPTT of 1.5-3 times the baseline level, not to exceed 100 seconds.
  • For adults who are undergoing PCI and have or who are at risk for developing HIT, the dose is 25 mcg/kg/minute along with a bolus dose of 350 mcg/kg delivered over 3-5 minutes. The ACT should be measured 5-10 minutes after the bolus dose is given, and the PCI can proceed if the ACT is > 300 seconds.
  • An additional 150 mcg/kg bolus dose should be given, and the infusion rate should be increased to 30 mcg/kg/minute if the ACT is < 300 seconds. Re-check the ACT in 5-10 minutes.
  • If the ACT is > 450 seconds, decrease the infusion rate to 15 mcg/kg/minute and re-check the ACT in 5-10 minutes.
  • When the ACT is between 300-450 seconds, the infusion should be continued for the duration of the PCI procedure. If post-PCI anticoagulation is needed, continue the infusion at a 2 mcg/kg/minute reduced dose.

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.

Bivalirudin (Angiomax®) (UpToDate, 2019y)

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.

  • Who have unstable angina and are undergoing percutaneous transluminal coronary angioplasty (PCTA)
  • Who are undergoing PIC with provisional use of a glycoprotein IIb/IIIa inhibitor
  • Who have or who are at risk for HIT and HIT/thrombosis syndrome (HITTS) and are undergoing PCI

Dose (angiomax, 2016):

  • For patients undergoing PIC or PCTA and who do not have HIT or HITTS, an IV bolus dose of 0.75 mg/kg IV should be given, followed immediately by an IV infusion of 1.75 mg/kg/hour the duration of PIC or PCTA.
  • Five minutes after the bolus dose has been given, the ACT should be measured, and if needed, another bolus dose should be given, 0.3 mg/kg IV.
  • A glycoprotein IIb/IIIa inhibitor should be given if any of the following conditions are present.
    • Abrupt closure
    • Clinical instability
    • Decreased TMI flow (0 to 2) or slow reflow
    • Dissection with decreased flow
    • Distal embolization
    • New or suspected thrombus
    • Persistent residual stenosis
    • Prolonged ischemia
    • Side branch closure
    • Sub-optimal stenting
    • Unplanned stent
  • For patients undergoing PIC and those at risk for HIT or HITTS, the dose is a 0.75 mg/kg bolus given IV. This should be followed by an IV infusion of 1.75 mg/kg/hour for the duration of the procedure.
  • Bivalirudin may be given for up to four hours post-procedure if the treating physician feels needed. If the patient has a STEMI, continue the infusion at 1.75 mg/kg/hour for four hours.
  • After four hours, an additional IV infusion of bivalirudin can be started at 0.2 mg/kg/hour IV for up to 20 hours, if needed.
  • Bivalirudin must be used in conjunction with aspirin, 300 mg to 325 mg, PO, every day.

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.

  • There is an increased risk for thrombus when bivalirudin is used during gamma brachytherapy.
  • Bivalirudin may falsely prolong the INR.

Dabigatran (Pradaxa®, APO-Dabigatran®) (Pradaxa, 2019; UpToDate, 2019z)

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.

Uses:

  • Reducing stroke risk and reducing the risk of systemic embolization in patients who have non-valvular atrial fibrillation.
  • Treatment of DVT and PE in patients who have received a parenteral anticoagulant for 5-10 days.
  • Reducing the risk of DVT and PE in patients previously treated for these pathologies.
  • Prophylaxis against DVT and PE in patients who have had hip replacement surgery.

Dose:

  • Patients with non-valvular atrial fibrillation: 150 mg PO twice a day.
  • Treatment of DVT and PE in patients who have received a parenteral anticoagulant for 5-10 days: 15 mg twice a day.
  • Reducing the risk of DVT and PE in patients who have previously been treated for these pathologies: 150 mg PO, twice a day.
  • Prophylaxis against DVT and PE in patients who have had hip replacement surgery: 110 mg a day PO the first day, 1-4 hours after surgery, then 220 mg PO once a day. The optimal treatment duration is unknown, but dabigatran is usually given after hip replacement surgery for a minimum of 10-14 days and to 35 days post-op.

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.

Special considerations:

  • Dabigatran is contraindicated for patients with a mechanical prosthetic heart valve, and its use is not recommended for valvular heart disease patients.
  • Dabigatran is not recommended for use in patients who have triple-positive antiphospholipid syndrome. Giving these drugs to this patient population has been associated with an increased risk for thromboembolic events.
  • Upon premature discontinuation, the risk of thrombotic events is increased. If dabigatran must be discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider using another anticoagulant during the time of interruption. (US Boxed Warning).
  • Spinal or epidural hematomas may occur with neuraxial anesthesia (epidural or spinal anesthesia) or spinal puncture in anticoagulated patients, resulting in long-term or permanent paralysis. The risk of spinal/epidural hematoma is increased with the use of indwelling epidural catheters, concomitant administration of other drugs that affect hemostasis (e.g., NSAIDs, platelet inhibitors, other anticoagulants) in patients with a history of traumatic or repeated epidural or spinal punctures, or a history of spinal deformity or spinal surgery. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dabigatran is low; however, the optimal timing between the administration of dabigatran and neuraxial procedures is not known. Monitor frequently for signs and symptoms of neurologic impairment (e.g., midline back pain, numbness/weakness of legs, bowel/bladder dysfunction); prompt diagnosis and treatment are necessary. In anticoagulated patients or pharmacologic thromboprophylaxis is anticipated, assess risks versus benefits before neuraxial interventions. (US Boxed Warning).
  • Dabigatran increases the risk of bleeding, and significant bleeding that can cause death can occur. Idarucizumab can reverse the anticoagulant effect of dabigatran, and it should be given to patients who have uncontrolled, life-threatening bleeding caused by dabigatran.

Fibrinolytics

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.

Alteplase (Activase®) (UpToDate, 2019bb)

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.

Uses:

  • Acute ischemic stroke patients present within 3 hours of the onset of symptoms.
  • Massive PE
  • STEMI
  • Alteplase is also used off-label for patients who present within 3 to 4.5 hours after the onset of an acute ischemic stroke. The 2018 American Heart Association/American Stroke Association Guidelines for the Early Management of Patients with Acute Ischemic Stroke recommend the use of alteplase for patients who present within 3 to 4.5 hours after the onset of an acute ischemic stroke or within 3 to 3.5 hours from when the patient was last known to be well (Barlas et al., 2018).

Dose (Activase, 2019):

  • Acute ischemic stroke, used within 3 hours of the onset of symptoms: The total dose is 0.9 mg/kg, the maximum dose no more than 90 mg. Give an initial IV bolus of 10% of the total dose; this should be infused in over 1 minute. The remainder of the dose should be infused in over 60 minutes.
  • Pulmonary embolism: 100 mg IV, infused in over 2 hours.
  • STEMI: The recommended dose is weight-based, and the maximum dose is 100 mg or less. There are two ways to give the drug.
    • Accelerated infusion: For patients who weigh < 67, an initial IV bolus of 15 mg, followed by 50 mg within the first 30 minutes and then 35 mg over the next 60 minutes.
    • For patients who weigh > 67 kg, give an initial IV bolus of 15 mg, followed by 0.75 mg/kg within the next 30 minutes, then 0.5 mg/kg within the next 60 minutes.
    • Three-hour infusion: For patients who weigh < 65 kg, the dose is 100 mg. In the first hour, give 60 mg, with an IV bolus dose of 6-10 mg, and the remainder (50-54 mg) administered within the hour. This is followed by 20 mg over the next hour and 20 mg over the third hour.
  • For patients whose weight < 65 kg, the initial bolus should be 0.075 mg/kg, and 0.675 mg/kg should be infused over the remainder of the first hour. In the second and third hours, infuse 0.25 mg/kg.
  • For patients who weigh ≥ 65 kg, the initial bolus should be 6-10 mg, and 54-50 mg should be infused over the remainder of the first hour. In the second and the third hours, infuse 20 mg.
  • The manufacturer’s prescribing information states that no controlled studies have compared the clinical outcomes of the accelerated infusion versus the three-hour infusion. The 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction recommends using the accelerated infusion. A 2017 systematic review of the literature concluded that the accelerated infusion technique was more effective and associated with less bleeding risk (Chen et al., 2019).ing (Jinatongthai, et al., 2017).
  • Fibrinolytic therapy should be administered within 30 minutes of arrival at the hospital (Chen et al., 2019).
  • The 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction states that fibrinolytic therapy can be administered to patients having a STEMI within 12 hours of the onset of ischemic symptoms (If PCI cannot be performed within 120 minutes of first medical contact). The 2013 ACCF/AHA Guideline also states that using fibrinolytic therapy within 12-24 hours of the onset of symptoms is reasonable for patients having a STEMI if it is clinical or ECG evidence of ongoing ischemia, a large area of the myocardium is at risk, or if the patient is hemodynamically unstable.

Adverse effects:

  • Intracranial hemorrhage. Alteplase: Symptomatic intracranial hemorrhage occurs in 2-8% of patients with an ischemic stroke and is treated with alteplase. The highest risk time appears to be within the first 24 hours after the drug has been given (Chen et al., 2019). Hemopericardium and hemothorax can also occur (Filho & Samuels, 2019; Kelmenson et al., 2015).
  • The risk of intracranial hemorrhage with the use of alteplase to treat ischemic stroke is increased with older age, greater stroke severity, and high baseline glucose, and if the patient has atrial fibrillation, baseline antiplatelet therapy, congestive heart failure, diabetes, hypertension, ischemic heart disease, leukoaraiosis (Abnormal white matter changes), or renal impairment (Yeghi et al., 2017).
  • The incidence risk of intracranial hemorrhage in patients who have a PE and are treated with alteplase has been reported to be 1.5%, and the incidence of major bleeding 9.2%.
  • During clinical trials, the incidence of symptomatic intracranial hemorrhage in patients receiving alteplase as a treatment for STEMI was 0.4-1.7%.

Special considerations - Ischemic stroke:

  • The labeled use of alteplase is within 3 hours of the onset of stroke symptoms. The AHA/ASA concluded that alteplase given within 3 to 4.5 hours after the onset of an acute ischemic stroke or when the patient was last known to be well is effective and should be given (Barlas et al., 2018).
  • Alteplase administration should not be delayed in completing imaging studies, e.g., CT scan or MRI (Barlas et al., 2018).
  • A blood glucose level should be measured before administering alteplase; hypoglycemia and hyperglycemia are stroke mimics (Barlas et al., 2018). The administration of alteplase should not be delayed in preference to obtaining a 12-lead ECG, a CXR, or a baseline serum troponin level (Barlas et al., 2018). Measuring the aPTT, the INR, and the platelet count should not delay the administration of alteplase unless there is a strong reason to suspect that the patient has a coagulopathy (Barlas et al., 2018).
  • Elevated blood pressure may increase the risk of bleeding from alteplase (Barlas et al., 2018). The systolic blood pressure should be < 180 mm Hg and diastolic blood pressure should be < 110 mm Hg before administering alteplase, and alteplase should not be given if the systolic or diastolic blood pressure are not below 180 mm Hg/110 mm Hg, respectively (Barlas et al., 2018). An IV infusion of clevidipine, labetalol, or nicardipine can be used to lower blood pressure; in this situation, hydralazine or enalaprilat are alternate choices.
  • Coagulation tests and measures of fibrinolytic activity are not reliable during treatment with alteplase unless specific adjustments are made in laboratory procedures.

Absolute Contraindications for the Use of Alteplase in Ischemic Stroke (Filho & Samuels, 2019):

  • aPTT > 40 seconds
  • Aortic arch dissection
  • Coagulopathy: INR> 1.7, platelet count < <100 000/mm3, PTT > 15 seconds. (If the patient has no known history of thrombocytopenia, is not taking and oral anticoagulant or heparin, alteplase can be given. If subsequent testing reveals an INR > 1.7, a platelet count < 100,000 mm3, or a PTT > 15 seconds, the alteplase infusion should be discontinued)
  • Elevated blood pressure (systolic >185 mm Hg or diastolic >110 mm Hg)
  • GI bleeding within the past 21 days
  • GI malignancy
  • Glycoprotein IIb/IIIa inhibitors: Current use of these drugs
  • Infective endocarditis
  • Intra-axial intracranial neoplasm
  • Intracranial hemorrhage
  • Intracranial or intraspinal surgery within the past 3 months
  • Ischemic stroke with the past 3 months
  • LMWH: Alteplase should not be administered given if the patient has been given a treatment dose (not a prophylactic dose) of an LMWH in the past 24 hours
  • Severe head trauma within the past 3 months
  • Subarachnoid hemorrhage

Relative Contraindications for the Use of Alteplase in Ischemic Stroke:

  • The effectiveness and safety of administering alteplase in these clinical situations have not been established; consider its use on a case by case basis (Barlas et al., 2018).
  • Acute pericarditis.
  • Arterial puncture at non-compressible site in the past 7 days: The efficacy and safety of using alteplase for a patient who has had an arterial puncture at a non-compressible site in the past 7 days are not known.
  • Cerebral microbleed.
  • Diabetic retinopathy or another ophthalmic hemorrhagic condition.
  • Dural puncture: The use of alteplase can be considered in patients who have had a dural puncture in the past 7 days. Giant unruptured and unsecured intracranial aneurysm.
  • GI or genitourinary bleeding > 21 days before the need for alteplase.
  • Intracranial arterial dissection.
  • Intracranial vascular malformation.
  • Left atrial or ventricular thrombus and an acute ischemic stroke are likely to produce a mild level of disability.
  • Menorrhagia.
  • Major surgery within the past 14 days.
  • Major trauma within the past 14 days (Excluding head trauma; head trauma is an absolute contraindication).
  • Pregnancy.
  • Systemic malignancy.
  • Thrombin Inhibitors or factor Xa inhibitors: Giving alteplase to a patient taking a thrombin inhibitor or a factor Xa inhibitor may be harmful. Alteplase should not be given to these patients unless the aPTT, INR, ecarin clotting time, thrombin time, or factor Xa activity assays are normal or if the patient has not taken a dose in the past 48 hours.

Special considerations – Pulmonary embolism:

  • Alteplase is indicated for treating patients with massive PE who are in shock or hemodynamically unstable (Goldhaber, 2019).
  • Because of a significant risk for bleeding (approximately 10%), alteplase should be given only after the presence of a PE has been confirmed, after determining the absence/presence of contraindications for its use, and after any anticoagulant therapy has been stopped (Goldhaber, 2019).
  • The recommended dose is 100 mg. A lower dose of 50 mg may be as effective as 100 mg (Yeghi et al., 2017). but there is no conclusive evidence that a 50 mg dose decreases the risk of bleeding (Ucar, 2019).

Absolute Contraindications for Alteplase in Pulmonary Embolism (Ucar, 2019):

  • Active bleeding (Excluding menses)
  • Ischemic stroke within the past 3 months
  • Malignant intracranial neoplasm
  • Prior intracranial hemorrhage
  • Significant closed head or facial trauma in the past 3 months
  • Structural cerebral vascular lesion

Relative Contraindications for Alteplase in Pulmonary Embolism:

  • Active peptic ulcer
  • Age > 75 years
  • Current use of an anticoagulant and an INR > 1.7 or a PT > 15 seconds
  • Diabetic retinopathy
  • Internal bleeding within the past 2-4 weeks
  • Ischemic stroke > 3 months before presentation
  • Major surgery within the past 3 weeks
  • Pericarditis or pericardial fluid
  • Pregnancy
  • Recent invasive procedure
  • Systolic blood pressure > 180 mm Hg, diastolic blood pressure > 110 mm Hg
  • Vascular puncture at a non-compressible site

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):

  • Aortic dissection or suspicion of aortic dissection
  • Bleeding (Excluding menses)
  • Ischemic stroke or another cerebrovascular event in the past year
  • Prior cerebrovascular hemorrhage
  • Systolic blood pressure > 180 mm hg, diastolic blood pressure > 110 mm HG

Relative Contraindications for Alteplase in STEMI (Chen, et al., 2019):

  • Active peptic ulcer disease
  • Cardiopulmonary resuscitation, > 10 minutes duration in the past 2 weeks
  • Current use of anticoagulants and INR > 2.0
  • Hemorrhagic ophthalmic condition
  • History of severe hypertension that is not adequately controlled
  • Invasive procedure in the past 2 weeks
  • Pregnancy
  • Surgery in the past 2 weeks

Reteplase (Retavase®) (Retevasae, 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).

Absolute Contraindications:

  • Active bleeding (Except for menses)
  • Bleeding diatheses
  • Intracranial or intraspinal therapy in the past 2 months
  • Ischemic stroke in the past 3 months
  • Malignant intracranial neoplasm, metastatic or primary
  • Prior intracranial hemorrhage
  • Significant closed head trauma or facial trauma in the past 3 months
  • Severe hypertension that does not respond to emergency therapy
  • Structural vascular lesion
  • Suspected aortic dissection

Relative Contraindications:

  • Active peptic ulcer
  • CPR, prolonged or traumatic
  • Dementia
  • Internal bleeding in the past 2-4 weeks
  • Intracranial pathology not covered in the absolute contraindications
  • Major surgery in the past 3 weeks
  • Non-compressible vascular punctures
  • Pregnancy
  • Oral anticoagulant therapy
  • Significant hypertension on presentation: Systolic blood pressure > 180 mm Hg, diastolic blood pressure > 110 mm Hg
  • Stroke in the past 3 months

Tenecteplase (TNKase®) (TNKase, 2020)

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.

Use:

  • Treatment of STEMI by lysis of thrombi in the coronary vasculature.

Dose: The dose is weight-based, and it is administered as a bolus over 5 seconds.

  • <60 kg: 30 mg
  • ≥60 to <70 kg: 35 mg
  • ≥70 to <80 kg: 40 mg
  • ≥80 to <90 kg: 45 mg
  • ≥90 kg: 50 mg

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.

Absolute Contraindications:

  • Active internal bleeding
  • AV malformation
  • Bleeding diathesis
  • Intracranial aneurysm
  • Intracranial or intraspinal surgery in the past 2 months
  • Intracranial neoplasm
  • Severe uncontrolled hypertension

Relative Contraindications:

  • Acute pericarditis
  • Bleeding diathesis
  • Cerebrovascular disease
  • Current use of anticoagulants
  • Diabetic hemorrhagic retinopathy or another hemorrhagic ophthalmic condition
  • Non-compressible
  • Occluded AV cannula at a seriously infected site
  • Pregnancy
  • Recent gastrointestinal or genito-urinary bleeding
  • Recent major surgery
  • Recent trauma
  • Septic thrombophlebitis
  • Severe hepatic dysfunction
  • Subacute bacterial endocarditis
  • Systolic blood pressure > 180 mm Hg, diastolic blood pressure > 110 mg HG
  • Vascular puncture at a non-compressible site

Fibrinolytics: Clinical Issues

Angioedema

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

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).

Effectiveness and Safety

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).

Factor Xa inhibitors: Subcutaneous

Fondaparinux (Arixtra®) (UpToDate, 2019aa)

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.

Uses:

  • Treatment patients who have acute DVT in conjunction with warfarin.
  • Treatment patients who have acute PE in conjunction with warfarin.
  • Prophylactic treatment to prevent venous thromboembolism in patients with abdominal surgery, surgery for a fractured hip, or hip or knee replacement surgery.

Dose:

  • Treatment of patients who have acute DVT or PE, in conjunction with warfarin: < 50 kg, 5 mg SC, once a day. 50-100 kg, 7.5 mg SC, once a day; > 100 kg, 10 mg SC, once a day. The duration of therapy is usually 5 to 9 days, but it can be longer.
  • Prophylactic treatment to prevent venous thromboembolism in patients with abdominal surgery, surgery for a fractured hip, or hip or knee replacement surgery: ≥ 50 kg, 2.5 mg SC, given after hemostasis has been established and no earlier than 6 to 8 hours postoperatively.
  • For non-orthopedic surgery, continue use until the patient is fully ambulatory and the risk of developing VTE has diminished.
  • For orthopedic surgery, fondaparinux is usually given for 10 to 14 days and occasionally for up to 35 days; the optimal therapy duration is unknown.

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.

Special considerations:

  • Fondaparinux is contraindicated if the patient is < 50 kg; if the patient has bacterial endocarditis, severe renal impairment with a CrCl < 30 mL/minute, and if the patient has thrombocytopenia associated with a positive in vitro test for antiplatelet antibody in the presence of fondaparinux.
  • Fondaparinux should not be the only anticoagulant used during PCI because of an increased risk of catheter thrombosis.
  • Thrombocytopenia has occurred after the administration of fondaparinux. Although fondaparinux can be used to treat patients who HIT, there are reports (rare) of HIT being associated with the administration of the drug (Manji et al., 2020).
  • Fondaparinux should not be given to patients who have a positive in vitro test for antiplatelet antibodies in the presence of fondaparinux.
  • Spinal or epidural hematomas that may cause long-term or permanent paralysis may occur with neuraxial anesthesia (epidural or spinal anesthesia) or spinal puncture in patients anticoagulated with LMWH, heparinoids, or fondaparinux. Consider risk versus benefit before spinal procedures; risk is increased by the use of concomitant agents which may alter hemostasis (such as NSAIDs, platelet inhibitors, or other anticoagulants), the use of indwelling epidural catheters, a history of spinal deformity or spinal surgery, as well as a history of traumatic or repeated epidural or spinal punctures. Optimal timing between the administration of fondaparinux and neuraxial procedures is not known. Monitor patients frequently for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary. Consider the benefit and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. US Boxed Warning)

Patient Issues

Adherence to Oral Anticoagulant Therapy

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).:

  • Age < 65
  • Concerns/worries about adverse effects
  • Dissatisfaction about the treatment
  • Emotional distress, e.g., anger, anxiety, and depression about the diagnosis that requires oral anticoagulant therapy
  • Financial cost
  • Information overload
  • Low health literacy
  • Poor level of knowledge about atrial fibrillation and stroke risk
  • Poor level of knowledge about the drugs
  • Time concerns, i.e., fitting the therapy into a life schedule

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.

Diet and Warfarin

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).

Warfarin and Alcohol

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).

Patient Safety

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. 

  1. The signs and symptoms of bleeding.
  2. The need to strictly adhere to the dosing schedule: anticoagulants should be taken on time, doses should not be skipped, and the patient should never be decreased or increased.
  3. It is advisable to wear a medical identification bracelet that indicates the patient has taken an anticoagulant.
  4. Periodic blood testing may be needed to evaluate the therapy's effectiveness and make dose adjustments.
  5. Discuss with the prescriber what physical activities are safe and unsafe and may cause bleeding, e.g., contact sports.
  6. Do not take a new over-the-counter medication or a new supplement without speaking to the prescriber or another health care professional.

Summary

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.

  1. What is drug(s) being used?
  2. Why are they being used?
  3. How do they work?
  4. What clinical signs and symptoms and laboratory studies should be used to monitor the effectiveness of the anticoagulant or fibrinolytic?
  5. What are the common adverse effects?
  6. What are the specific guidelines and rules for administering the anticoagulants to my patients?

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.

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