This course will provide professional nurses with the information they need to safely and effectively administer anticoagulant and fibrinolytic drugs.
This course will provide professional nurses with the information they need to safely and effectively administer anticoagulant and fibrinolytic drugs.
After completing this continuing education course, the learner will be able to:
Cardiovascular disease is the leading cause of death worldwide and in the United States.1,2 Thrombosis formation 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 who have thrombosis, to prevent thrombosis, and to treat acute complications of thrombosis.3-7
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 attempt to simplify the process of administering anticoagulant and fibrinolytic therapies by discussing the mechanism of action, onset of effects, duration of effects, uses, dosing, adverse effects, and special consideration for each anticoagulant and fibrinolytic.
Clinical issues that require lengthy coverage (e.g., clopidogrel resistance, aspirin discontinuation before surgery, genetics and warfarin prescribing) will be covered in separate sections. With a few exceptions, only labeled uses will be discussed. If information about the onset of effects and duration of effects 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 from the manufacturers’ prescribing information. Dosing adjustments for patients who have 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. Acute coronary syndrome refers to non-ST-segment elevation MI, ST-segment elevation MI, and unstable angina. Venous thromboembolism is abbreviated as VTE.
A 76-year-old male sees his primary care physician because he has been experiencing palpitations for the past 6 weeks. The patient has a past medical history of type 2 diabetes mellitus, hypertension, hypercholesterolemia, and obesity. He is 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 his medical history, the physician determines that the patient has a high risk for developing thromboembolism and an ischemic stroke. To treat these issues, the patient is prescribed a daily dose of aspirin, 325 mg, and 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 of warfarin, so closer than usual monitoring of warfarin 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 that has all the pertinent information about his anticoagulation therapy and to wear a bracelet that identifies him as someone who is taking warfarin.
The clotting process begins with local vasoconstriction of the injured vessels, which is followed by:
The formation of the platelet plug is a two-part process of platelet activation and platelet aggregation.
Platelets are activated when they are exposed to and stimulated by compounds that are produced when there is 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 site of the injury (beginning the formation of the platelet plug), and they release chemical mediators that attract more platelets and initiate the process of platelet aggregation.
Platelet aggregation is the process by which the platelets clump together to complete the formation of the platelet plug. 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 that are synthesized in the liver, proteins C and S, and calcium. The clotting cascade has traditionally been viewed as being comprised of the extrinsic pathway and the intrinsic pathway, both of which lead to the final common pathway. 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 the process of clotting, and how and why coagulation studies are used. However, the extrinsic, intrinsic, and common pathways should be considered as a unified process, activation of clotting factors that eventually convert fibrinogen to fibrin, and fibrin is the mesh that is the “framework” for a thrombus that will stop bleeding - or form a clot that obstructs blood flow to the brain, heart, or other organs.
Coagulation tests are used to measure the effectiveness of anticoagulant therapy. Commonly used tests include.9
Activated clotting time (ACT)
Measures the time it takes for whole blood to clot. The ACT assesses the functioning of the intrinsic and common pathways. Its primary use is to monitor heparin therapy during surgical procedures in which large amounts of heparin are used. In these situations, the high plasma concentration of heparin affects the aPTT and limits its usefulness, and the ACT is used. The normal range of ACT depends on which testing device is used, and it is typically 80-160 seconds.
Activated partial thromboplastin time (aPTT)
Measures the time it takes plasma to clot, and it assesses the functioning of the intrinsic and common pathways. The aPTT is used to monitor heparin therapy and therapy with direct thrombin inhibitors (e.g., argatroban), to evaluate unexplained bleeding, and to diagnose disseminated intravascular coagulation (DIC). The aPTT is not used to monitor low-molecular-weight heparin therapy. The normal range for aPTT is 25-35 seconds.
Anti-factor Xa activity
Can be used to monitor therapy with fondaparinux, low molecular weight heparins, direct thrombin inhibitors, and the new, direct-acting oral anticoagulants (DOACs).
International normalized ratio (INR)
Assesses the functioning of the extrinsic and common pathways. The INR represents the ratio of the patient’s prothrombin time (PT) to a control PT that has been measured using a tissue factor reagent that has a known level of sensitivity and will result in a predictable PT measurement. The patient’s PT is divided by the control PT and the result - the ratio - should be between 0.8 and 1.2. The INR is used to monitor warfarin therapy.
Prothrombin time (PT)
Measures the time it takes plasma to clot, and it assesses the functioning of the extrinsic and common pathways. The normal range for PT is 11-13 seconds. The PT is used to monitor warfarin therapy.
Thrombin time (TT)
Measures the conversion of fibrinogen to fibrin. The normal range of thrombin time will vary, depending on the laboratory and the reagent that is used, but the range is typically 14-19 seconds. Thrombin time is used as an additional diagnostic test in patients who have a prolonged PT and aPTT.
Prior to 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. Dosing of some anticoagulants must be adjusted if the patient has a hepatic or renal impairment. If the patient has severe hepatic or renal impairment, the use of some anticoagulants is contraindicated. Examples are listed below.
Direct-acting anticoagulants: Dosing of dabigatran, edoxaban, and rivaroxaban should be adjusted based on the estimated glomerular filtration rate (eGFR).
Heparin: No dosing adjustment needed.
Low molecular weight heparins (LMWHs): Dosing may need adjustment based on the eGFR.
Warfarin: No dosing adjustment needed.
Dosing of apixaban, argatroban, edoxaban, and rivaroxaban should be decreased, or the drug should not be used if the patient has severe hepatic impairment.11-14
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, hepatic and renal impairment associated with aging and co-morbidities, and drug interactions related to polypharmacy.15-18 The prescribing information for many anticoagulants states that advanced age is a risk factor for bleeding.
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.14”
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 the use of the anticoagulants.19-21 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,22 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.23
Surgery and invasive procedures are problematic for patients who are being treated with an anticoagulant. If the anticoagulant is stopped, the patient can develop thromboembolism, but continuing use to the anticoagulant puts the patient at risk for bleeding.24,25 A reasonable approach to this issue to use a case-by-case assessment that considers the factors listed below.24,25
Therapeutic errors, deliberate overdose, or changes in the patient’s health can cause elevated levels of 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 she/he has elevated coagulation studies and/or evidence of bleeding:
Anti-platelet drugs inhibit platelet activation and aggregation.
Mechanism of action: Aspirin inhibits platelet aggregation and platelet activation by blocking the formation of thromboxane A2.36 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.36
Duration of effects: Aspirin irreversibly inhibits the formation of thromboxane A2 for the life of the platelet, approximately 10 days.36
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.
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.41 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.41-43
These concerns are significant, and the decision to continue, discontinue or initiate aspirin therapy prior to surgery should be done on a case by case basis; for some patients and for some procedures the benefits do not outweigh the risks.42,43
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, and the benefit-risk ratio does not appear to favor its use for the prevention of cardiovascular events.44 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.45 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.46 For patients outside these parameters, USPSTF recommends that aspirin therapy as a preventive measure should be considered on a case by case basis.46
The risk of bleeding from the prophylactic use of aspirin can be significant,44,45 and many patients who might benefit from daily aspirin therapy are those who have a higher risk for bleeding.46
Mechanism of action: Aspirin inhibits platelet aggregation and activity. Dipyridamole inhibits platelet aggregation by inhibiting the activity of adenosine deaminase.47
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.47
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 with caution in patients who are at risk for gastrointestinal bleeding.
If the glomerular filtration rate (GFR) is < 10 mL/minute, avoid use.47 Dipyridamole causes vasodilation, so use with caution if the patient is hypotensive or has coronary artery disease, or if the patient is elderly as orthostatic hypotension may occur.47
Mechanism of action: Cilostazol increases intracellular concentrations of cyclic adenosine monophosphate (cAMP) by inhibiting the activity of phosphodiesterase. Inhibition of phosphodiesterase decreases platelet aggregation.48
Onset of effects: Inhibition of platelet aggregation begins within three hours.49 During chronic therapy, the duration of inhibition of platelet aggregation lasts approximately 96 hours.49
Duration: With chronic administration, platelet function will return to normal in approximately 96 hours.49
Uses: The labeled use of cilostazol is for reducing the symptoms of intermittent claudication,49 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.50
Note: Non-cardioembolic stroke/TIA refers to an embolic neurological injury that is not 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.50
Dose: Off-label, secondary prevention of non-cardioembolic stroke, 100 mg twice a day.
Adverse effects: Headache, abnormal stools, and diarrhea, infection.48,49
Special considerations: Cilostazol is contraindicated with patients with heart failure of any level of severity (US Boxed Warning).48,49
Mechanism of action: Clopidogrel inhibits platelet aggregation by blocking the activity of P2Y12.51 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.51
Duration of effects: Approximately 3-10 days.51,52
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.50
In all cases, clopidogrel should be given with aspirin and a parenteral anticoagulant51, and after the acute phase, all patients should be given clopidogrel and aspirin for ≥ 12 months.51
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; these drugs 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.39,52
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 CYP2C19.51,53 Patients who have decreased activity of CYP2C19 will not form a sufficient amount of active metabolite, and platelet aggregation will be decreased.54 (See the section below, Clopidogrel resistance) Poor metabolizers who also have an acute coronary syndrome or who are undergoing PCI and are being treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates than patients who have normal CYP2C19 function (US Boxed Warning).51
Clopidogrel and prasugrel are both antiplatelet drugs, they are classified as thienopyrdines, and they are structurally similar. Cross-reactivity between the two drugs has been reported, and patients sensitive to or allergic to clopidogrel may be sensitive to or allergic to prasugrel.51
Clopidogrel resistance: A significant number of patients who are given clopidogrel do not achieve the desired anti-platelet effect, a phenomenon syndrome called clopidogrel resistance, non-responsiveness, or high platelet reactivity.53,55 The frequency of clopidogrel resistance has been estimated to be approximately 30%,53,55 and clopidogrel resistance increases patients’ risk for major adverse cardiac events after PCI.55
Genetic polymorphisms of the CYP2C19 enzyme that metabolizes clopidogrel are in part responsible for clopidogrel resistance;53,55 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.53,56
There is evidence that genetic testing-guided treatment may help reduce the consequences of clopidogrel resistance,55 but this approach is not universally recommended57 and some clinicians simply increase the dose of clopidogrel or use another P2Y12 receptor blocker.57
Mechanism of action: Prasugrel inhibits platelet aggregation by blocking the activity of P2Y12.58 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.58
Duration: Normal platelet function returns with 5-9 days after discontinuation of use.58
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.58
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.58,59 For patients who weigh less than 60 kg, a lower daily maintenance dose, 5 mg, can be used.58
Prasugrel should not be given to patients who have a STEMI and have a history of stroke or TIA.59 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.59
Adverse effects: None listed as > 10%.59
Special considerations: Thrombotic thrombocytopenic purpura has been reported in association with the use of prasugrel.58
US Boxed Warning applies to points 1-4.
The frequency of non-responsiveness/high platelet reactivity with chronic use of prasugrel has been estimated to 3-15%.52
Use with caution in patients who have hepatic and/or renal impairment and patients > age 75; these patients may be at increased risk for bleeding.58,60
Mechanism of action: Ticagrelor inhibits platelet aggregation by blocking the activity of P2Y12.61 P2Y12 is a protein on the surface of platelets, and normal functioning of P2Y12 is required for activating platelets, and subsequent platelet aggregation.
Onset of effects: After a loading dose, the onset of platelet inhibition is noticeable after 30 minutes and is almost complete after 2 hours.61
Duration of action: Twenty four hours after the maintenance dose is discontinued, platelet inhibition is at approximately 58%.61
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.61 The maintenance dose should be continued for a least 12 months; after 12 months reduce the dose to 60 mg.61
Adverse effects: Dyspnea.61
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.61
Brady-arrhythmias and ventricular pauses occurring during use of ticagrelor have been reported,61 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.61
US Boxed Warning applies to points 1-5:
Mechanism of action: Vorapaxar inhibits platelet aggregation by antagonizing protease-activated receptor-1 (PAR-1).62
Onset of effects: ≥ 80% inhibition of platelet aggregation after one week of therapy.62
Duration of effects: The decrease of platelet aggregation will be at 50% at 4 weeks after discontinuation of the drug.62
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.62
When vorapaxar is added to standard care, studies have shown a significant reduction of the risk of cardiovascular death, MI, recurrent ischemia, and stroke.63-65 However, the use of the vorapaxar in this patient population also significantly increased the risk of moderate to several bleeding, especially intracranial hemorrhage.63-65
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.62
Adverse effects: Bleeding.62
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).62
Use with caution in patients who have hepatic and/or renal impairment.62
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.66 Aspirin is the cornerstone of dual antiplatelet therapy, and aspirin is used along with cilostazol, clopidogrel, dipyridamole, prasugrel, or ticagrelor, and for their use in dual antiplatelet therapy, each drug has specific indications, benefits and risks.
Cilostazol: The prescribing information for cilostazol lists two off-label uses for the drug: Preventing stent thrombosis after placement of a bare metal or drug-eluting stent, and secondary prevention of non-cardioembolic stroke or TIA.
For the first, the evidence for the effectiveness of cilostazol in preventing stent thrombosis when it is used concurrently with aspirin and clopidogrel is mixed. Some researchers have concluded that this combination is effective, others have not.67,68 The most recent (2014) American Heart Association/American College of Cardiology guidelines for the treatment of 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.37,59
Clopidogrel: Clopidogrel and aspirin can be used for patients who are having a STEMI and are being treated with PCI, prior to the procedure and as long-term therapy to prevent complications.37,65,69 Clopidogrel is effective as long-term dual antiplatelet therapy.70,71 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.65,66,70-72 The incidence of bleeding with clopidogrel is equivalent to that of prasugrel and ticagrelor.69,71,72 Prasugrel and ticagrelor are preferred over clopidogrel for treating patients who are having a STEMI and are being treated with PCI.73
Clopidogrel (given with aspirin) is the preferred platelet inhibitor for patients who are having a STEMI and are being treated with a fibrinolytic,73 and clopidogrel and aspirin reduces the incidence of death, re-infarction, and stroke when used as a long-term dual antiplatelet therapy in these patients.65,74
Dual antiplatelet therapy is recommended for all patients who are having a non-ST-segment elevation acute coronary syndrome,37 and clopidogrel and aspirin have been shown to significantly reduce the risk of death and major cardiac events in this clinical situation.65 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,65,75,76 and they are preferred for treating patients who are having a non-ST-segment elevation acute coronary syndrome.77
Prasugrel versus ticagrelor: Prasugrel is more effective at preventing death, MI, and stroke in patients who have acute coronary syndrome, with or without ST-segment elevation,75 and the risk of bleeding is essentially the same for both drugs.73,75
Duration of dual antiplatelet therapy: 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 from 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.77,78 Dual antiplatelet therapy can be used for years,77 but patients should be routinely assessed for evidence of bleeding and to determine if the benefit-risk ratio of this treatment has changed.77
The problem of high platelet resistance has been addressed by increasing the dose of clopidogrel, 57using prasugrel or ticagrelor,57 or using genotype- or phenotype-guided antiplatelet therapy.55,78 At this time, there is no conclusive evidence that any of these approaches is superior to the others.55,57,78
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.79,80
Cilostazol: Long-term antiplatelet therapy is recommended for secondary prevention of stroke.39,79,80 Cilostazol monotherapy or cilostazol used in combination with aspirin has been shown to be effective at preventing recurrent non-cardioembolic events and superior to aspirin .81,82 Research on cilostazol and stroke prevention has been primarily in Asian populations,80 and the effectiveness of the drug for preventing recurrent non-cardioembolic events in other ethnic groups has not been well studied.
Clopidogrel: 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.39,53 The effectiveness of long-term use of clopidogrel and aspirin versus clopidogrel alone for preventing subsequent stroke has been questioned.,80 But the authors of a recent (2019) meta-analysis concluded that clopidogrel and aspirin are effective at reducing 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.79 The risk for bleeding, however, was significantly higher in patients treated with aspirin and clopidogrel compared to the other groups.79
Aspirin and dipyridamole: Aspirin and dipyridamole are effective for reducing the incidence of ischemic events and serious cardiovascular events in patients who have had a non-cardioembolic stroke,78,80 and the combination is more effective than aspirin alone.80
Mechanism of action: Eptifibatide is a glycoprotein IIB/IIIa receptor antagonist, and binding of the drug to the receptor reversibly prevents platelet aggregation.82
Onset: With an IV bolus the onset of action is immediate, and within 5 minutes there is a > 80% inhibition of platelet aggregation.82
Duration: After stopping an IV infusion, platelet function fully restored within 4 to 8 hours.82
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.82
Special considerations: Use with caution if the patient has impaired renal function.
Acute and significant thrombocytopenia can occur within 24 hours of use.82 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.82 (Note: Thrombocytopenia and the glycoprotein IIB/IIIa receptor antagonists will be discussed later in this section).
Mechanism of action: Tirofiban is a glycoprotein IIB/IIIa receptor antagonist, and binding of the drug to the receptor reversibly prevents platelet aggregation.83
Onset: > 90% platelet inhibition occurs within 10 minutes.83
Duration: Approximately 90% return to normal platelet aggregation 4 to 8 hours after an infusion has been stopped.83
Uses: Tirofiban is approved for decreasing the rate of thrombotic cardiovascular events, death, MI, and refractory ischemia/repeat cardiac procedure in patients who are having unstable angina or an NSTEMI.83
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.83
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.83
Special considerations: Use with caution and reduce the dose in patients who have renal impairment.83
Use with 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/mm3.83
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 use of the drug and of heparin, if heparin is being used.83
Mechanism of action: Cangrelor is a direct-acting PY212 platelet receptor inhibitor that prevents platelet activation and aggregation.84
Onset: Platelet inhibition begins within 2 minutes.84
Duration: After the IV infusion has been stopped, platelet function returns to normal within 1 hour.84
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.84 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.84
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.84
Adverse effects: Hemorrhage.84
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.84
The glycoprotein IIb/IIIa receptor inhibitors were once widely used as antiplatelet therapy before PCI.85 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, and the research results for the effectiveness of glycoprotein IIb/IIIa inhibitors in this situation was more convincing for abciximab - which is no longer available in the United States - than for eptifibatide and tirofiban.72,76 Eptifibatide and tirofiban have been used as a routine adjunct to dual antiplatelet therapy for patients undergoing PIC.86 But the research has shown that using these drugs with dual antiplatelet therapy does not provide an additional benefit,72, 84 and it causes an increased rate of bleeding.86,87 The current recommendations for using eptifibatide and tirofiban are in these circumstance37,59,73,77,84-86:
Thrombocytopenia: Thrombocytopenia occurs in up to 1% of patients receiving eptifibatide88 and 0.1-1.9% of patients receiving tirofiban;89,90 severe thrombocytopenia (platelet count < 20,000 mm3) is unusual, occurring in approximately 0.2% to 1% of all cases.88,91 Thrombocytopenia can occur after the first dose of a glycoprotein IIb/IIIa receptor inhibitor or after previous exposure,88 and recovery is usually within several days.89,90
The mechanism of action that causes this adverse effect is not known or understood: possible explanations are a direct drug effect on the platelets, activation of existing antiplatelet antibodies that were formed after a previous use of the drug, or stimulation of the production of new antiplatelet antibodies.88,91
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: 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.83
These patients will be on long-term treatment with a PY212 receptor inhibitor, and the prescribing information has recommendations for when, in relation to the cangrelor infusion, therapy with these drugs should be started.83 These recommendations are listed below:
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.92 Cangrelor blocks the active metabolite of clopidogrel and prasugrel from binding to the P2Y12 receptor.92 These active metabolites remain in the blood for a short period of time after the drugs are given, so concurrent administration of cangrelor and clopidogrel or prasugrel will decrease their effectiveness.92 Ticagrelor is a direct-acting P2Y12 receptor antagonist, so cangrelor and ticagrelor can be given at the same time.92
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 include the oral anticoagulants apixaban, edoxaban, and rivaroxaban, and fondaparinux, which is given subcutaneously. 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, but in this module, fondaparinux will be considered a factor Xa inhibitor. 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 they are anticoagulants, but there are important differences between warfarin and these drugs: these differences are listed in Table 5.94,97,129-139
The bleeding risk of the DOACs versus warfarin appears to be the same.
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.
Warfarin is inexpensive and widely available.
The DOACs are not approved for anticoagulation therapy in patients who have a prosthetic heart valve.
There are no significant drug-food interaction with the DOACs.
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.
The are hundreds of warfarin-drug interactions; there are comparatively far fewer DOAC-drug interactions.
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.
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.
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.
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.
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.
There is a lot of experience with reversing the effects of warfarin. There is little experience with reversing the effects of the DOACs, and the reversal agents for these drugs can cause serious complications.
Stability of dosing:
Warfarin dosing often requires frequent adjustments;the DOACs do not.
Mechanism of action: Direct inhibition of factor Xa.140
Onset of action: 3-4 hours.140
Duration of action: The half-life is approximately12 hours.140
Hepatic impairment: Moderate impairment (Child-Pugh class B) use with caution. Severe impairment, (Child-Pugh class C), the use of apixaban is contraindicated.140
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.140
Adverse effects: Bleeding.
Special considerations: Bariatric surgery may decrease the absorption of apixiban.140
Apixaban is not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome.140
Premature discontinuation of any oral anticoagulant, including apixaban, without providing alternative anticoagulation, increases the risk of thrombotic events.140 (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.140(US Boxed Warning).
Mechanism of action: Direct inhibition of factor Xa.141
Onset: 2 to 3 hours.141
Duration of action: ≥ 72 hours.141
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.141
Dose: 160 mg once a day for one dose, followed by 80 mg a day for 35-42 days.141
Hepatic impairment: Avoid use in patients who have moderate to severe hepatic impairment.141
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.141
Adverse effects: Bleeding, gastrointestinal complaints, e.g., constipation, diarrhea, and nausea.141
Special considerations: Epidural or spinal hematomas may occur in patients treated with betrixaban 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 (US Boxed Warning).141
Drug concentrations betrixaban can increase as a patient’s renal function worsens, and this can increase the risk of bleeding.141 If the CrCl is 15-29 mL/minute, the dose of betrixaban should be reduced, and the drug should be used with caution.141
The starting and maintenance dose should be reduced by 50% if the patient is taking a p-glycoprotein inhibitor like amiodarone, clarithromycin, ketoconazole, and verapamil.141
Mechanism of action: Direct inhibition of factor Xa.13
Onset of effects: 1-2 hours.13
Duration of action: The half-life is 10-14 hours.13
Dose: 60 mg once daily.13 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.13
Renal impairment: Patients with DVT or PE, CrCl > 51 mL/minute, no dosing adjustment is needed.
Adverse effects: Bleeding.13
Special considerations: Epidural or spinal hematomas may occur in patients treated with edoxaban who are receiving neuraxial anesthesia or undergoing spinal puncture (US Boxed Warning).13
Edoxaban should not be used in patients who are being 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.13 In these patients another anticoagulant should be used (US Boxed Warning).13
Mechanism of action: Direction inhibition of factor Xa.14
Onset of action: 2-4 hours.14
Duration of effects: The half-life is 5-9 hours.14
Hepatic impairment: Moderate to severe impairment, Child-Pugh Class B or C, use is not recommended.14
Renal impairment: DVT and PE: CrCl ≥ 30 mL/minute, no dosage adjustment is needed. CrCl< 30 mL/minute, use should be avoided.14
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.14
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.142
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.14
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 who are receiving neuraxial anesthesia or undergoing spinal puncture (US Boxed Warning).14
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).14
Determining if a patient is correctly taking a DOAC is difficult. An abnormally low or high INR reflects misuse of warfarin, but there is no easily available laboratory test that can determine if a patient has been compliant with the prescribed DOAC therapy.133 This is an important issue because unlike warfarin, missing one or several doses of a DOAC can reduce the amount of time during which the patient is anticoagulated, and this puts the patient at risk for thrombosis.133
Diet: Grapefruit juice is a CYP3A4 inhibitor, and it could increase the serum concentrations of apixaban and rivaroxaban.143,144
Rivaroxaban doses ≥ 15 mg must be taken with food.14
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.144-146
There are far fewer drug-drug interactions involving the newer anticoagulants than with warfarin, and this 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 that concomitant use of strong CYP3A4 or P-glycoprotein inducer is contraindicated or should be avoided.
Note: P-glycoprotein is a transport molecule that is 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 of P-glycoprotein, respectively.
The pharmacokinetics and pharmacodynamics of the DOACs are relatively predictable,133,147-149 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 a patient who needs emergency surgery, determining the patient’s coagulation status and/or measuring a DOAC drug level may be needed.147,148 Common coagulation tests like aPTT, INR, and PT are not predictable or reliable for determining the coagulation status of someone taking a DOAC 133, 147-149 and measuring DOAC drug levels cannot be done quickly. An assessment of the coagulation status of a patient who is taking a DOAC can be done, but 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.133
Preventing stroke and embolic events in patients who have atrial fibrillation 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.150
The prescribing information for each DOAC recommends decreasing the dose for patients who have impaired renal function, presumably because these patients would be at an increased risk for bleeding, but 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.150-152 Subsequent to those trials the FDA approved apixaban, dabigatran, edoxaban, and rivaroxaban (but not betrixaban) for use in patients who have a CrCl as low as 15 mL/minute.150,153 However, recent (2019) literature reviews and meta-analyses of the literature concluded that there is no evidence that the DOACs are effective or safe for patients who have moderate to severe CKD.150-152 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,154,155 especially dabigatran and edoxaban.154 This seemingly conflicting information could be confusing for clinicians, but the lower DOAC doses recommended for patients who have 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.154
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.14,140
There is no antidote for betrixaban and edoxaban.13,14
Warfarin is the only vitamin K antagonist that is available in the US.
Mechanism of action: Warfarin interrupts the synthesis of clotting factors II, VII, IX, and X, and proteins C and S. Synthesis and activation of these clotting factors and proteins requires the reduced form of vitamin K, and reduced vitamin K is produced by the activity of the enzyme vitamin K epoxide reductase complex 1 (VKORC1).
Warfarin is often referred to as a vitamin K antagonist, but warfarin does not actually antagonize vitamin K.
At therapeutic doses, warfarin decreases the functional amount of each vitamin K–dependent coagulation factor by 30%–70%. Warfarin has no effect on the activity of fully γ-carboxylated factors already in the circulation, and these must be cleared before it can produce an anticoagulant effect.
Warfarin does not dissolve an existing thrombus; It prevents new thrombi from forming and prevents the extension of an existing thrombus.93
Onset of effects: A measurable effect of warfarin, reflected by an increase in INR, can be seen within 24-72 hours.93 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 requires 5-7 days of warfarin therapy.93
Duration of effects: Two to 5 days. Warfarin is given orally once a day. IV warfarin is no longer produced.
Warfarin is also used off-label for preventing TIAs in patients who have atrial fibrillation, rheumatic mitral valve disease, or a mechanical prosthetic heart valve.
Dose: Warfarin dosing is a balance between:
Before starting treatment with warfarin, a CBC, INR, aPTT, PT, serum creatinine, and liver function tests should be measured.94 (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 maintenance dose is determined by the INR results,8 and lower and higher starting and maintenance doses are used.94
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.8,93,94 When and how often to measure the INR and what the INR should be will differ from patient to patient, as well.94 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.94,95
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.94 In most cases, an INR of 2-3 is the goal, but for some patients, a higher INR is desired.94
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.96,97 Factors that increase the risk of bleeding from warfarin are listed below. 96-98 Several of these will be discussed in detail in the clinical Issues section.
Alcohol abuse: The relationship between alcohol abuse, warfarin, and the risk of bleeding is complex and not completely understood. Patients who take warfarin and abuse alcohol may have an increased risk of bleeding,93,99 and there are many possible reasons for this. Alcohol abuse causes gastrointestinal bleeding, coagulopathies, and thrombocytopenia.100,101 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 that is above or below the therapeutic range.93,102 Alcohol consumption may have a direct effect on warfarin metabolism, but the nature and severity of this (possible) influence are unclear.93
Diabetes: 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,103,104 and in the CHA2DS2-VASc stroke prediction tool, diabetes is one of the most substantial risk factors for ischemic stroke in patients who have atrial fibrillation.104 Diabetes has been identified as a risk factor for bleeding in patients taking warfarin97 and in diabetics who do not take the drug.105 Diabetes can affect coagulation in many complex ways,103,104 but the issue of diabetes, warfarin, and bleeding appears to be little studied, and it is not clear how much diabetes increases the risk for bleeding in patients who take warfarin.97
Hepatic impairment: Warfarin is primarily metabolized by the liver, and the liver synthesizes clotting factors. Hepatic impairment can decrease the metabolism of warfarin and reduce the synthesis of clotting factors and can affect dosing, INR, and coagulation93,106 and increase a patient’s risk for bleeding.107 In addition, liver disease affects the production of pro-coagulant factors and anticoagulant factors, increasing or decreasing a patient’s clotting ability106,108 and making clotting status variable and unpredictable.108
Hypertension: Hypertension is the most common co-morbidity with atrial fibrillation.109 Hypertension increases the risk of bleeding,109 and warfarin increases the risk of bleeding in hypertensive patients.109,110
Chronic kidney disease: Atrial fibrillation and chronic kidney disease (CKD) are common co-morbidities111 and oral anticoagulation is an established and beneficial therapy for patients with mild to moderate chronic kidney disease.111 However, renal impairment can decrease clotting function and cause a pro-hemorrhagic condition,111 and the risk for bleeding increases as renal function worsens.111,112 In patients who have CKD and take warfarin, the INR is often labile and outside the therapeutic range111 and at least one large study found that in patients with end-stage renal disease (ESRD), warfarin increased the risk for bleeding.112
In addition to an increased risk of bleeding, warfarin can also cause anticoagulant-associated nephropathy.111,112,114 Anticoagulant nephropathy is characterized by acute kidney injury (AKI) and an INR >3 113, it is much more likely to occur in patients who have CKD.111,113 Information on this complication is scarce, but the prevalence of anticoagulant-associated nephropathy has been estimated to be 19%-63%.113
Anticoagulation therapy with warfarin is a balance of 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.115 However, Edmiston et al. (2019) pointed out that bleeding is always a risk with anticoagulation therapy, and in most patients being considered for anticoagulation therapy, the benefits of warfarin clearly 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.115
There can be a 20-fold patient to patient difference in the dose of warfarin needed to attain the therapeutic level of anticoagulation116 and genetics, along with other factors like age and body weight, is 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 of VKORC1 have consistently been associated with, and are to a large degree responsible for, sensitivity to warfarin and the wide dose-response variability of the drug in terms of reaching and maintaining the target INR.106,117 The CYP2C9 genetic polymorphisms reduce 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 that are based on the patient’s CYP2C9 and VKROC1 genetic profile, but using pharmacogenetic information to dose warfarin is not standard practice at this time.94 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.116,117
Time of the INR in the therapeutic range (TTR) is used to determine the effectiveness of warfarin therapy104,118 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,104 and a significant number of bleeding and embolic events (44% and 50%, respectively) occur when the TTR is out of range.97
In the first several days of warfarin therapy, the INR will increase, but because several of the clotting factors whose synthesis is inhibited by warfarin have long half-lives, this early increase in INR does not represent full anticoagulation.106 After a maintenance dose has been established, the INR must be periodically measured, and the schedule and frequency for INR measurements should be determined by the patient’s clinical status and the lability of his/her INR measurements.94 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.94 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.26
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.97,119,120 The American Society of Hematology (ASH) recommendations for at-home testing are26:
Factors that can affect the INR and that may 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.94, 121-126
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.127
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 have a harmful effect on warfarin metabolism, as well.128 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, and many involve commonly prescribed drugs.
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 out the low molecular weight particles. In this module, the term heparin will be used instead of unfractionated heparin.
Mechanism of action: Heparin inactivates thrombin and also the clotting factors IXa, Xa, XIa, and XIIa, and it prevents the conversion of fibrinogen to fibrin.156
Onset: IV, immediate. Subcutaneously, 20-30 minutes.156
Duration: Half-life in 1 to 2 hours.156
Dose: Doses to prevent clotting during arterial and cardiac surgery, extracorporeal circulation, and hemodialysis will not be covered.
Hepatic impairment: No dosing adjustment needed.156
Renal impairment: No dosing adjustment needed.156
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.156
The anticoagulant effect of heparin can be monitored, and the dose adjusted by measuring the aPTT or anti-factor Xa level.160 There is no conclusive evidence that either one is superior to the other.160
The typical goal is an aPTT that is 2-3 times the normal mean.8
There are numerous heparin dosing protocols that are used.161 Many of these are based on clinician preference and experience, and the recommended bolus dose and the duration of therapy and other aspects of heparin can differ from source to source.161 However, the basic goals of heparin therapy are the same, regardless of variances in dosing recommendations, decrease the risk of thromboembolic events and avoid bleeding.
Heparin-induced thrombocytopenia (HIT) is an auto-immune mediated complication of heparin therapy.162-166 It is caused by HIT antibodies that are formed when heparin binds to platelet factor 4 (PF4), a cytokine found inside platelets. The heparin-platelet factor 4 molecule is identified as a xenobiotic by the immune system, and the antigen-antibody reaction causes a decreased platelet count and potentially serious and life-threatening thromboembolic complications.162-166
Heparin-induced thrombocytopenia can be caused by any dose (even after exposure to heparin flushes or to 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.162-165
Heparin-induced thrombocytopenia is uncommon. The incidence of HIT caused by heparin has been reported to be 2.6% to 4.9%;162,163,166 the incidence of HIT caused by LMWH has been reported to be 0.2% to 0.6%.162,163,166
Factors that increase the risk of developing HIT include cancer, female gender, surgical procedures (particularly cardiac and orthopedic), and a bovine source of heparin.163,165,166 However, HIT can happen to any patient who has been given heparin.163,165
The onset of HIT is typically 5-14 days after heparin therapy has begun,162-164 but early-onset and delayed onset HIT can happen.163
Early-onset HIT is caused by exposure to heparin in the prior weeks and months (~100 days) and circulating anti-heparin PF4 antibodies that were formed after the exposure.163 163 It occurs within five days and as early as 24 hours after heparin therapy has begun.163,164
Delayed onset HIT that begins after heparin therapy has been stopped is rare,162,167 and the onset has been reported to be five to 40 days after discontinuation of the drug.163
Heparin-induced thrombocytopenia is characterized by a decrease in platelet count of >50%162,16 and thrombosis.162-166 Bleeding can occur, but it is uncommon.162,165 More than 50% of patients who have HIT will develop a thrombosis.162,164 Arterial and venous thrombosis are possible,163,164 and serious and potentially deadly thromboembolic complications can occur, including limb ischemia with gangrene, myocardial infarction, pulmonary embolism, and stroke.163,165,166
The diagnosis of HIT is made by clinical findings and laboratory testing.162,163 A quick method of forming a provisional diagnosis of HIT is the four Ts assessment163,166,168:
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.158,163 However, this accuracy of this assessment scale is very limited, and it should not be the sole criteria used to make a diagnosis of HIT.166,168
Treatment of HIT involves immediately discontinuing the heparin, assessment for the presence of thrombosis, administration of 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.162 There is some evidence that the DOACs apixaban, edoxaban, rivaroxaban, or dabigatran and fondaparinux may be effective for treating HIT.162,166,169 Heparin should not be given to patients who have had HIT.162
Heparin resistance is defined as administration of a daily dose of heparin ≥ 35,000 units and a sub-therapeutic aPTT or ACT.8,160,170,171 Heparin resistance is caused by an anti-thrombin II deficiency,8,170 and this can be congenital or acquired.8,170,172 Congenital heparin resistance is rare.172,173 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.170,172,173 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.172
Clinicians must differentiate between pseudo-heparin resistance and true heparin resistance.8,171 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.8,171 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.8
Heparin decreases bone formation and increases bone resorption.174,175 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.174,175 These adverse effects have been reported to occur primarily in pregnant women;174,175 this is likely (in part) because when heparin is used for this patient population, it may be given for a relatively long period of time.174,175 The level of risk for adverse bone and skeletal effects caused by heparin in non-pregnant adults has been little studied and is not known.174
There is little published information on heparin dosing for obese patients. The topic is not mentioned in the prescribing information, and it is not clear if total body weight or adjusted body weight should be used to dose heparin for this patient population.170 A recent (2019) study by Ebied et al. found that the time to effective coagulation and the risk of bleeding was similar for both approaches.176
Protamine is the antidote for excessive coagulation and/or severe bleeding caused by heparin.156
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.171 This increases the bioavailability of the LMWHs compared to heparin (90% and 30%, respectively8) and this has three important clinical effects:
Half-life: The half-life of the LMWHs is at least half again longer than heparin, so LMWHs can be dosed intermittently, once or twice a day.160 This is more convenient, and it also allows for patients to self-administer an LMWH at home or for LMWHs to be administered in an out-patient clinic. The longer half-life, however, 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.178
Mechanism of action: Inhibition of factor Xa.179
Onset: The onset of action is approximately 3-5 hours.179
Duration: Approximately 12 hours.179
Aspirin, 75 mg-325 mg, should be given once a day unless contraindicated.175
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.30
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.30
Hepatic impairment: There are no recommendations for dosing adjustments in patients who have hepatic impairment, but this situation has not been studied.30
Renal impairment: For patients who have a CrCl < 30 mL/minute, dosing adjustments are recommended.30 These adjustments are listed below.30
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.179
Enoxaparin should be not be given IM,179 and it should not be substituted on a unit for unit basis for heparin or for another LMWH.179
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.179 This can result in long-term or permanent paralysis.179 (US Boxed Warning).
Mechanism of action: Inhibition of factor Xa and II.180
Onset: 1-2 hours.180
Duration: > 12 hours.180
Hepatic impairment: The prescribing information does not have dosing recommendations for using the drug in patients who have hepatic impairment.180 In patients who have severe hepatic impairment, the drug may accumulate.180
Renal impairment: The prescribing information does not have dosing recommendations for using the drug in patients who have renal impairment.180 However, in the presence of a CrCl < 30 mL/minute, the LMWHs may prolong factor Xa activity and cause bleeding.180 This topic will be discussed later in the Low-Molecular Weight Heparins: Clinical Issues section.
Adverse effects: Bleeding, thrombocytopenia.180
Special considerations: Dalteparin should not be given to a patient who has had HIT or to a patient that has had HIT with thrombosis.181
Dalteparin should be not be given IM,181 and it should not be substituted on a unit for unit basis for heparin or for another LMWH.180,181
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, and this can cause long-term or permanent paralysis.180 (US Boxed Warning).
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), and in this situation, the LMWHs should be used with caution.180 The published literature on this topic is inconclusive. Some authors found that the risk of bleeding from LMWHs was increased in cirrhotic patients,182 others did not,183 and a recent (2019) review article concluded that more research was needed before this question could be answered.184
Dalteparin and enoxaparin are eliminated by the kidneys and 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 who have renal impairment.185 However, the degree to which this occurs is not clear,186,187 and although the evidence is not conclusive, in terms of bleeding, the LMWHs have been found to be safe for use in patients who have end-stage renal disease.186,187
Dalteparin and enoxaparin are called low molecular weight because compared to heparin, they are smaller, short-chain molecules. 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%.162,163,166
Low molecular weight heparins given preoperatively can cause heparin resistance.188 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.”188
Clinical trials of LMWHs did not use the measurement of factor Xa to determine the effectiveness of these drugs,189 and aside from measuring platelet count in patients at risk for HIT,160 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.189 Patients who have renal impairment or who are obese are at risk for bioaccumulation of the drug; the weight of pregnant women changes rapidly, and; the pharmacokinetics of the LMWHs in children are unpredictable.189 In these clinical situations, monitoring factor Xa levels may be helpful.160,189
The risk of developing decreased bone mineral density, fractures, and osteoporosis has usually, but not always, been found to be less for the LMWHs when compared to heparin.174
Administration of protamine is recommended in the case of an overdose or an excessive dose of an LMWH,178,190 usually if the patient has clinically significant bleeding.178 Protamine does not completely or reliably reverse the anticoagulant effects of the LMWHs.180,190-92 However, it has been shown to neutralize the anti-IIa activity of the LMWHs, partially reverse anti-Xa activity, and it can have a hemostatic effect.192 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.180,182
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.193
Onset: The onset of action is immediate.193
Duration: The half-life is 39-51 minutes. In patients who have hepatic impairment, the half-life is 181 minutes.193
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.193
If the ACT is > 450 seconds, decrease the infusion rate to 15 mcg/kg/minute and re-check the ACT in 5-10 minutes.193
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 reduced dose of 2 mcg/kg/minute.193
Hepatic impairment: Argatroban is metabolized by the liver. For patients who have 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 as needed.193,194
Adverse effects: Chest pain, genitourinary tract bleeding, hypotension.193
Special Considerations: Use cautiously if the patient is critically ill or if the patient has heart failure, multiple organ system dysfunction, severe anasarca, or has recently had cardiac surgery.189,190 In these situations, accumulation of the drug and bleeding may occur, and a reduced dose and close monitoring are recommended.193, 194
Mechanism of action: Direct thrombin inhibitor.195
Onset of effects: Immediate.195
Duration of effects: Coagulation times return to normal in approximately 1 hour after the infusion has been discontinued.195
Uses: Bivalirudin is indicated for use as an anticoagulant in patients.196
Bivalirudin may be given for up to four hours post-procedure if the treating physician feels it is needed.192 If the patient has a STEMI, continuing the infusion at 1.75 mg/kg/hour for four hours should be considered.196
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.196
Bivalirudin must be used in conjunction with aspirin, 300 mg to 325 mg, PO, every day.196
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.195
During dialysis, the dose should be decreased to 0.25 mg/kg/hour.195
Adverse effects: Back pain, headache, hypotension, minor hemorrhage, nausea, pain.195
Special considerations: An acute stent thrombosis may occur in patients with a STEMI who are undergoing PCI and who are receiving bivalirudin.196 These patients should remain hospitalized for at least 24 hours after the procedure.196
There is an increased risk for thrombus when bivalirudin is used during gamma brachytherapy.195
Bivalirudin may falsely prolong the INR.197
Mechanism of action: Dabigatran is a pro-drug, and its active metabolite is a direct thrombin inhibitor.198
Onset of effects: The time to peak plasma level is 1 hour.198
Duration: Dabigatran is taken once a day or twice a day. The half-life elimination time is 12-17 hours.198
Renal impairment: Dose reductions of dabigatran are recommended if the patient has renal impairment.198,199 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.198,199
Adverse effects: Bleeding and gastrointestinal distress, e.g., dyspepsia.198
Special considerations: Dabigatran is contraindicated for patients who have a mechanical prosthetic heart valve,198,199 and its use is not recommended for patients who have valvular heart disease.199
Dabigatran is not recommended for use in patients who have triple-positive antiphospholipid syndrome.199 Giving these drugs to this patient population has been associated with an increased risk for thromboembolic events.199
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 the use of another anticoagulant during the time of interruption.199 (US Boxed Warning).
Spinal or epidural hematomas may occur with neuraxial anesthesia (epidural or spinal anesthesia) or spinal puncture in patients who are anticoagulated, and this may result 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 patients who are anticoagulated or pharmacologic thromboprophylaxis is anticipated, assess risks versus benefits prior to neuraxial interventions.198 (US Boxed Warning).
Dabigatran increases the risk of bleeding, and significant bleeding that can cause death can occur.199 Idarucizumab can reverse the anticoagulant effect of dabigatran, and it should be given to patients who have uncontrolled, life-threatening bleeding caused by dabigatran.199
The fibrinolytics alteplase, reteplase, and tenecteplase are used for clot dissolution in patients who are having an acute ischemic stroke, massive PE, or a STEMI.
Effective and safe use of fibrinolytic drugs requires understanding the indications for use, contraindications for use, and administration and monitoring protocols. This is true for any medication, of course, but fibrinolytics are given to patients who are critically ill, and the administration of these drugs and nursing care of the patients receiving them are complex.
Mechanism of action: Alteplase binds to fibrin in a thrombus and converts plasminogen to plasmin. Plasmin is a serine protease that lyses fibrin clots.202
Onset of effects: Immediate.202
Duration of effects: Fibrinolytic activity continues for up to 1 hour after injection.202
Alteplase is also used off-label for patients who present within 3 to 4.5 hours after the onset of an acute ischemic stroke.202 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.39
The manufacturer’s prescribing information states that there are no controlled studies that have compared the clinical outcomes of the accelerated infusion versus the three-hour infusion.203 The 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction recommends using the accelerated infusion,59 and a 2017 systematic review of the literature concluded that the accelerated infusion technique was more effective and was associated with less risk for bleeding.204
Fibrinolytic therapy should be administered within 30 minutes of arrival at the hospital.202,205
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).59 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 there is clinical and/or ECG evidence of ongoing ischemia, a large area of the myocardium is at risk, or if the patient is hemodynamically unstable.59
Adverse effects: Intracranial hemorrhage.202 Alteplase: Symptomatic intracranial hemorrhage occurs in 2-8% of patients who are having an ischemic stroke and are treated with alteplase.203,206-208 The time of highest risk appears to be within the first 24 hours after the drug has been given.206 Hemopericardium and hemothorax can also occur.208,209,210
The risk of intracranial hemorrhage with the use of alteplase to treat ischemic stroke is increased with older age, greater stroke severity, and a 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.207
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%.211
During clinical trials, the incidence of symptomatic intracranial hemorrhage in patients receiving alteplase as a treatment for STEMI was 0.4-1.7%.203
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 from when the patient was last known to be well is effective and should be given.39
The administration of alteplase should not be delayed in preference to completing imaging studies, e.g., CT scan or MRI.39
A blood glucose level should be measured before administering alteplase;39 hypoglycemia and hyperglycemia are stroke mimics.39 The administration of alteplase should not be delayed in preference to obtaining a 12-lead ECG, a CXR, or a baseline serum troponin level.39 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.39
An elevated blood pressure may increase the risk of bleeding from alteplase.39 The systolic blood pressure should be < 180 mm Hg and diastolic blood pressure should be < 110 mm Hg before administering alteplase,39 and alteplase should not be given if the systolic and/or diastolic blood pressure are not below 180 mm Hg/110 mm Hg, respectively.39 An IV infusion of clevidipine, labetalol, or nicardipine can be used to lower blood pressure in this situation39,209 hydralazine or enalaprilat are alternate choices.39,209
Coagulation tests and measures of fibrinolytic activity are not reliable during treatment with alteplase unless specific adjustments are made in laboratory procedures.203
Absolute Contraindications for the Use of Alteplase in Ischemic Stroke:39,202,203,209
Relative Contraindications for the Use of Alteplase in Ischemic Stroke:
The effectiveness and safety of administering alteplase in these clinical situations have not been clearly established; consider its use on a case by case basis.39
Special considerations – Pulmonary embolism:
Alteplase is indicated for treating patients who have a massive PE and who are in shock or are hemodynamically unstable.158,212,213
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.158,212,213
The recommended dose is 100 mg. A lower dose of 50 mg may be as effective as 100 mg,207,208 but there is no conclusive evidence that a 50 mg dose decreases the risk of bleeding.212
Absolute Contraindications for Alteplase in Pulmonary Embolism:212
Relative Contraindications for Alteplase in Pulmonary Embolism:212
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.205
Absolute Contraindications for Alteplase in STEMI:205
Relative Contraindications for Alteplase in STEMI:205
Mechanism of action: Reteplase converts plasminogen to plasmin. Plasmin degrades the fibrin matrix of a thrombus, lysing the clot.214,215
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.214
Uses: Treatment of STEMI.214
Dose: 10 units IV, infused over 2 minutes. This should be followed 30 minutes later by another 10 units.214
Adverse effects: Bleeding (injection site, 49%; genito-urinary, 10%).214 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.216 Elevated blood pressure and age > 70 years increased the risk of intracranial hemorrhage.215
Special Considerations: Coagulation tests and measures of fibrinolytic activity are not reliable during treatment with reteplase unless specific adjustments are made in laboratory procedures.215
Mechanism of action: Tenecteplase binds to fibrin in a thrombus and converts plasminogen to plasmin. Plasmin is a serine protease that lyses fibrin clots.217,218
Onset of effects: Not listed in the prescribing information.
Duration of effects: Tenecteplase has an initial half-life of 20-24 minutes.217
Dose: The dose is weight-based, and it is administered as a bolus over 5 seconds.217,218
Adverse effects: Bleeding, hematoma.217,218 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.211 The incidence of bleeding in the ASSENT-2 trial that required a transfusion was 0.38%.211 Research subsequent to this found a 0.38%-1% incidence of intracranial hemorrhage in STEMI patients;219-200 the incidence for patients > 75 years old was 8.1% but if the dose of tenecteplase as reduced, there were no patients in the age group that developed an intracranial hemorrhage.220
Special considerations: Precipitation may occur when TNKase is administered in an IV line containing dextrose. Dextrose-containing lines should be flushed with a saline-containing solution prior to and following a single bolus administration of TNKase.217,218
Orolingual angioedema has been reported in 0.18% to 8.0% of patients who received alteplase.209,221,222 Most cases are mild and do not require elective intubation.222 Prior use of an ACE inhibitor increases the risk of developing this adverse effect.223,224 A literature search did not locate any cases of angioedema caused by reteplase or tenecteplase.
Cholesterol embolization is a systemic pattern of organ and tissue injury that is caused by atherosclerotic plaque material breaking off from a plaque and lodging in the distal circulation.225 The prescribing information for alteplase, reteplase, and tenecteplase note that cholesterol embolization caused by fibrinolytic therapy is potentially very dangerous but fortunately quite rare.203,214,217 A recent (2019) review article confirmed that cholesterol embolization caused by fibrinolytic therapy is rare,225 and the author noted that it seldom occurs unless the patient who has been treated with a fibrinolytic has also undergone an invasive procedure like angiography.225
As a treatment for STEMI, there does not appear to be significant differences between the fibrinolytics in terms of effectiveness or mortality rate.204,226 Compared to alteplase and reteplase for treating STEMI, tenecteplase has been associated with a lower risk of bleeding.204
Mechanism of action: Inhibits clotting factor Xa.200
Onset of effects: Fondaparinux is rapidly and completely absorbed, and the time to peak plasma is approximately 2 to 3 hours.200
Duration of effects: Fondaparinux is given once a day, and the half-life is approximately 17 to 21 hours.200
For non-orthopedic surgery, continue use until the patient is fully ambulatory, and the risk of developing VTE has diminished.200
For orthopedic surgery, fondaparinux is usually given for 10 to 14 days and occasionally for up to 35 days; the optimal duration of therapy is not known.200
Renal impairment: If the CrCl is 30-50 mL/minute, fondaparinux clearance is approximately 40% of normal, and it should be used cautiously.196 Fondaparinux is contraindicated if the CrCl is < 30 mL/minute.200
Adverse reactions: Anemia, bleeding.200
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.200
Fondaparinux should not be the only anticoagulant used during PCI because of an increased risk of catheter thrombosis.200
Thrombocytopenia has occurred after administration of fondaparinux, and although fondaparinux can be used to treat patients who HIT, there are reports (rare) of HIT being associated with administration of the drug.200,201
Fondaparinux should not be given to patients who have a positive in vitro test for antiplatelet antibodies in the presence of fondaparinux.200
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 prior to 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.200 (US Boxed Warning).
Adherence to the therapy regimen with the oral anticoagulants differs considerably, depending on the patient population, but 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.226 It was hoped that the DOACs would improve patient adherence to oral anticoagulant therapy; some studies have found this to be true, but others have not.226 Factors that may decrease the adherence to oral anticoagulant therapy include226:
Ensuring patient compliance is very important; the risk of death and stroke increases as adherence to the use of the oral anticoagulants decreases.226 Strategies that can increase compliance are a strong caregiver-patient relationship, family involvement, and patient education.226 Monetary rewards, electronic reminders, or visual medication schedules as methods for improving compliance are not recommended by the American Society of Hematology.26
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.227,228 However, there is no evidence that patients who take warfarin need to significantly change their diet vis a vis vitamin K intake,229-231
The use of omega-3 fatty acid supplementation in patients taking warfarin should be done cautiously; the combination may increase the anticoagulant effects of the drug and cause bleeding.232-234
Alcohol may decrease the serum warfarin concentration in people who drink heavily.235 Patients who take warfarin should be advised to limit their alcohol intake to 1-2 servings a day;235 a serving is 12 ounces of beer, 6 ounces of wine, or 1.5 ounces of hard liquor.235
The following points should be discussed when a patient begins warfarin therapy or therapy with any anticoagulant, and there should be periodic reinforcement of this information.
The anticoagulants and the fibrinolytics are highly effective drugs that require quite a bit of knowledge to safely administer. 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, the 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 the anticoagulants, and nurses must know and use them.
Caring for someone who is receiving anticoagulants or fibrinolytics can be relatively simple or be an imposing challenge. Managing this challenge is best done by using an orderly and systematic approach and asking these questions.
You should also remember 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.