Anticoagulant and Fibrinolytic Therapy

Prior to starting therapy with an anticoagulant a physical examination and a health history should 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. The laboratory studies, at a minimum, should include a complete blood count (CBC), including platelet count, aPTT, INR, and PT. Liver function tests and test of renal function may also be needed: dosing of some anticoagulants must be adjusted if the patient has renal impairment. 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 intra-cranial 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, intra-muscular (IM) injections, and insertion of nasogastric tubes and urinary catheters should be avoided if possible. Anticoagulants should be used with caution if the patient is > 60 years of age, particularly women as a higher than average incidence of bleeding from anticoagulants has been reported in this patient population. Most of the anticoagulants have a warning in the prescribing information in regards to elderly patients. LexiComp® Vorapaxar (2015) prescribing information states “older patients are generally at higher risk of bleeding… use in the elderly should be undertaken with caution and patients in this age group should be closely monitored for bleeding events.”

Anticoagulant therapy requires constant vigilance and careful monitoring. The prescribing information for many oral anticoagulants contains a U.S. Boxed Warning: “Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation increases the risk of ischemic events.”

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 use of the anticoagulants (Metersky et al, 2015; Piazza et al, 2011). Reinforcing this point, The Institute for Safe Medication Practices (2016) lists warfarin as a drug which has a high risks of causing harm if it is used incorrectly, and includes warfarin in its list of drugs which have a heightened risk of causing significant patient harm when used in error, 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 (LexiComp, Warfarin).

Surgery and invasive procedures are problematic for patients who are being treated with an anticoagulant. If the anticoagulant is stopped the patient can develop a thromboembolism. Continuing the anticoagulant exposes the patient to the risk of bleeding; this would require stopping the anticoagulant - and create a risk for thromboembolism.

Lip et al (2015) recommends a step-by-step approach to this clinical issue:

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

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:

1. Discontinue the medication.
2. In the case of a deliberate overdose, contact the local poison control center (1-800-222-1222). For a supra-therapeutic dose, elevated coagulation studies, or active bleeding, consult a hematologist.
3. Measure and monitor the appropriate laboratory studies. If a factor Xa inhibitor is involved the standard anticoagulation studies are unreliable for monitoring clinical effects (Woo et al, 2013).
4. Administer an antidote or a reversing agent, if one is available and there is a need.
5. Vitamin K is used to reverse the effects of warfarin. The need for vitamin K is determined by the INR and the presence and extent of bleeding (Bungard et al, 2015; Holbrook et al, 2012).
6. Protamine sulfate is used to reverse the effects of heparin (LexiComp, Protamine; Patel et al, 2007).
7. There is no clinically proven and approved antidote or reversal agent for the low-molecular weight heparins, but protamine sulfate has been used off-label for this purpose, as has recombinant activated factor VII. (LexiComp, Protamine sulfate; Byrne et al, 2012).
8. There are no clinically proven and approved antidotes or reversal agents for the factor Xa inhibitors, but there are drugs that have been used in clinical trials and volunteer studies that have been shown to be effective for this purpose (Aronis et al, 2015; Greinacher et al, 2015; Weitz, 2015).
9. There are no antidotes for the other anticoagulants discussed in this module. If the patient is bleeding or clinically unstable, use symptomatic and supportive care. Aspirin overdose can be treated with an IV infusion of sodium bicarbonate and potassium chloride. 

The 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. 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.

Duration of effects: Aspirin irreversibly inhibits the formation of thromboxane A2 for the life of the platelet, approximately 10 days.

Uses: Reduction of risk of death and stroke in patients who have had an ischemic stroke or a transient ischemic attack; reduction of cardiovascular mortality in patients having an acute myocardial infarction (MI); reduction of the risk of death and non-fatal MI in patients who have had an MI or have unstable angina, and; reduction of the risk of MI and sudden death in patients who have chronic unstable angina (LexiComp®, Aspirin; Amsterdam et al, 2014; O’Gara et al, 2014; Jauch et al, 2013; Guyatt et al, 2012). Aside from its action as an anti-platelet drug, aspirin is commonly used as an analgesic and an antipyretic. There are numerous off-label uses for aspirin.

Dose: Aspirin dosing is complex and for ease of understanding, dosing has been listed separately below:

1. Unstable angina/non-ST-segment elevation MI: 162-325 mg should be given to all patients who are having unstable angina or a non-ST-segment elevation MI: a maintenance dose of 81-325 mg should be given indefinitely. If percutaneous coronary intervention (PCI) is planned, the patient should be given aspirin before the procedure, 81 mg if she/he is already taking a daily aspirin, 325 mg if not. After PCI, daily aspirin therapy at 81-325 mg should be continued indefinitely, 81 mg if the patient is also being treated with ticagrelor (Amsterdam et al, 2014).
2. ST-segment MI: A 162-325 mg dose of aspirin should be given before PCI and to patients who are having fibrinolytic therapy. After PCI and after fibrinolytic therapy, aspirin should be continued indefinitely (O’ Gara et al, 2103).
3. The anti-thrombotic effects of aspirin are dependent on a different mechanism of action than the anti-inflammatory and anti-pyretic effects of the drug; therefore, lower doses can be used for this purpose, e.g., 75-150 mg a day. For treatment of an acute ischemic stroke or transient ischemic attack (TIA,) the dose is 160-325 mg within 24-48 hours after onset of the stroke (Jauch, et al, 2013). Aspirin is not recommended as an adjunctive therapy within 24 hours of administration of a fibrinolytic to a patient who has had an acute ischemic stroke (Jauch et al, 2013).
4. For patients who are having an acute ischemic stroke, a 325 mg dose given within 24-48 hours of stroke onset is recommended (Jauch et al, 2013). The administration of aspirin within 24 hours of IV fibrinolysis is not recommended (Jauch et al, 2013).

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, thus increasing the risk of bleeding for this period of time (Eikelboom, et al, 2012). In the POISE-2 study, Devereaux et al (2014) found that continuing aspirin therapy prior to surgery increased the risk for major post-operative bleeding so it would seem that aspirin should be discontinued if the patient will be having surgery.

However, the decision to continue or discontinue aspirin therapy prior to surgery is not a simple one. Gerstein et al (2015) commented on the results of the POISE-2 study and noted, “in patients without a definitive guideline-based indication for aspirin, the drug should likely be held preoperatively in those already receiving it, and it should not be initiated to prevent thrombotic events. However, it is still not possible to conclude whether temporary cessation of aspirin for surgery is warranted in high-risk patients . . . (who are) taking lifelong aspirin for a guideline-based primary or secondary indication.”

Aspirin and primary prevention of cardiovascular events: Aspirin is widely used for secondary prevention of cardiovascular events, but the evidence for its effectiveness as a therapy for primary prevention of cardiovascular events caused by thromboembolism is equivocal. Research has shown that aspirin can, and cannot prevent first MI and stroke (Castro-Torres et al, 2015; Nansseu et al, 2015). Although any level of prevention of MI and/or stroke may seem useful, the benefits and risks must be considered. Research has clearly shown that using aspirin as a primary preventive therapy significantly increases the risk for cerebral, extra-cerebral, and gastrointestinal (GI) bleeding (Nansseu et al, 2015; Wu et al, 2104; Antithrombotic Trialists' et al, 2009).

Aspirin should be prescribed for primary prevention only after considering each patient’s specific needs and clinical conditions (Nansseu et al, 2015; U.S. Preventive Services Task Force, 2014). For example, aspirin would be recommended for men aged 60-69 who had a 10-year risk of coronary heart disease ≥ 9%. At that level of risk, the benefit of preventing cardiovascular disease-related events would exceed the potential harm of a gastrointestinal hemorrhage (U.S. Preventive Services Task Force, 2014).

Table 2 is derived from the U.S. Preventive Services Task Force, The Guide to Clinical Preventive Services 2014, and it illustrates how and for whom aspirin can be used as a primary preventive therapy.

Aspirin mono-therapy has not been shown to prevent stroke in patients who have atrial fibrillation (January et al, 2014).

Mechanism of action: Aspirin inhibits platelet aggregation and activity. Dipyridamole inhibits platelet aggregation by inhibiting the activity of adenosine deaminase

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.

Aspirin and dipyrimadole is used off-label for patients who have symptomatic carotid artery stenosis and to maintain the patency of hemodialysis grafts.

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. Dipyrimadole 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.

Mechanism of action: Cilostazol increases intracellular concentrations of cyclic adenosine monophosphate (cAMP) by inhibiting the activity of phosphodiesterase. Inhibition of phosphodiesterase decreases platelet aggregation.

Onset of effects: 3-6 hours.

Duration: Platelet function will return to normal in approximately 2 days after discontinuing the drug

Uses: The labeled use of cilostazol is for reducing the symptoms of intermittent claudication. The American College of Chest Physicians recommends cilostazolas an antithrombotic therapy for the secondary prevention of non-cardioembolic stroke in patients who have a history of non-cardioembolic stroke or TIA (Guyatt et al, 2012). 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.

Dose: Off-label, secondary prevention of non-cardioembolic stroke, 100 mg twice a day.

Adverse effects: Headache, abnormal stools and diarrhea, infection.

Special considerations: Cilostazol is contraindicated with patients with heart failure of any severity (U. S. Boxed Warning).

Use with caution if the patient has a creatinine clearance (CrCL) < 25 mL/minute.

Mechanism of action: Clopidogrel inhibits platelet aggregation by blocking the activity of P2Y12. P2Y12 is a protein on the surface of platelets and normal functioning of P2Y12 is required for activating platelets and subsequently, aggregation.

Onset of effects:Inhibition of platelet aggregation begins within 2 hours of administration of a loading dose.

Duration of effects:Approximately 7-10 days.

Uses:Reduction of the rate of death, MI, refractory ischemia, or stroke in patients who have unstable angina/non-ST-segment myocardial infarction; ST-segment elevation acute myocardial infarction; recent myocardial infarction, recent stroke, or established peripheral arterial disease(Amsterdam et al, 2014; O’ Garaet al, 2013; Guyattet al, 2012).

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 (Guyatt et al, 2012). The usefulness of clopidogrel as a therapy for patients having an acute ischemic stroke has not been established (Jauch et al, 2013).

Off-label uses include: As adjunctive therapy to support reperfusion during primary PCI; during coronary artery bypass graft surgery; during peripheral artery percutaneous transluminal angioplasty for patients who have symptomatic carotid artery stenosis, and; for patients who have unstable angina/non-ST-elevation MI, are undergoing PCI, and have an aspirin allergy or a significant gastrointestinal intolerance to aspirin.

Dose:For ease of understanding, clopidogreldosing is provided as a numbered list:

1. Unstable angina/non-ST-segment elevation MI: Patients who undergo PCI or are treated with an ischemia-guided regimen should be given a P2Y12 inhibitor. Clopidogrel 300-600 mg as a loading dose followed by 75 mg a day for up to 12 months (Amsterdam et al, 2014).
2. ST-segment elevation MI: If the patient will have PCI, a loading dose of 600 mg should be given as soon as possible or at the time the PCI is done, and 75 mg a day should be given for 1 year if a stent was placed. If fibrinolysis is planned, the patient should be given aspirin and clopidogrel. Patients < 75 years of age should be given 300 mg; > 75 years of age, 75 mg. Post-fibrinolysis aspirin and clopidogrel should be given indefinitely (O’ Gara et al, 2013).
3. 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 (Guyatt et al, 2012).

Adverse effects: Bleeding.

Special considerations:The effectiveness of clopidogrelis dependent on its activation to an active metabolite by the cytochromeP450enzyme system, principally CYP2C19. Patients who have decreased activity of CYP2C19will not form a sufficient amount of this active metabolite and the effect of clopidogrelon platelet aggregation will be decreased. (See the section below, Clopidogrelresistance) Poor metabolizerswho also have acute coronary syndrome or who are undergoing PCI and are being treated with clopidogrelat recommended doses exhibit higher cardiovascular event rates than patients who have normal CYP2C19function (U.S. Boxed Warning).

Cross-reactivity has been reported among clopidogrel and prasugrel, and patients sensitive to or allergic to clopidogrel may be sensitive to or allergic to prasugrel.

Clopidogrel resistance: A significant number of patients who are given clopidogreldo not achieve the desired anti-platelet effect, a syndrome that has been labeled clopidogrelresistance or non-response (Legrandet al, 2015; Oliphantet al, 2015; Braret al, 2011; Gurbelet al, 2007; Catteneo, 2004). Clopidogrelresistance has been observed to occur in as many as 40.0% to 50.2% of patients receiving the drug (Legrandet al, 2015; Price et al, 2011; Gurbelet al, 2007). Also, clopidogrelresistance in patients undergoing percutaneouscoronary intervention (PCI) has been associated with an increased risk for death, MI, and thrombosis of the stent (Samošet al, 2015; Braret al, 2011).

Clopidogrel is a pro-drug that must undergo several metabolic steps to an active metabolite, and pharmacodynamicstudies and clinical experience have shown that there is a wide variability in the response to the drug (Price et al, 2011). Genetic polymorphismsin cytochromeP-450 drug metabolizing enzymes explain some small part of this (Oliphantet al, 2015). Other risk factors such as advanced age, diabetes, hyperuricemia, a high body-mass index, smoking, and poor patient adherence with the drug regimen may also increase the risk for clopidogrelresistance (Guimarãeset al, 2015; Legrandet al, 2015; Wu et al, 2015).

Due to the risk for, and consequences of clopidogrelresistance and the proven efficacy of prasugreland ticagrelorin patients undergoing PCI after an ST-segment MI, consideration should be given for the use of these drugs in this clinical situation instead of clopidogrel(Guimarãeset al, 2015).

Mechanism of action: Prasugrel inhibits platelet aggregation by blocking the activity of P2Y12. P2Y12 is a protein on the surface of platelets and normal functioning of P2Y12 is required for activating platelets, and subsequent aggregation.

Onset of effects: Platelet inhibition begins < 30 minutes after a loading dose.

Duration: Normal platelet function returns with 5-9 days after discontinuation of prasugrel.

Uses: Reducing the rate of thrombotic cardiovascular events in patients who have an acute coronary syndrome that will be managed with PCI.

Off-label use: Patients who have unstable angina/non-ST-elevation myocardial infarction, patients undergoing PCI, and patients that have an aspirin allergy or a significant gastrointestinal intolerance to aspirin.

Dose: For patients who are having an ST-segment elevation MI, a loading dose of 60 mg given as early as possible or at the time PCI is performed. This should be followed by 10 mg once a day for a year (O’ Gara et al, 2013).

Prasugrel should not be given to patients who have an ST-segment elevation MI and have a history of stroke or TIA (O’Gara et al, 2013). Prasugrel, in a 60-mg loading dose, is reasonable once the coronary anatomy is known in patients who did not receive a previous loading dose of clopidogrel at the time of administration of a fibrinolytic agent, but prasugrel should not be given sooner than 24 hours after administration of a fibrin-specific agent or 48 hours after administration of a non-fibrin-specific agent (O’ Gara et al, 2013).

For patients having unstable angina/non-ST-segment elevation MI and are undergoing PCI with stenting, a loading dose of 60 mg should be given. This should be followed by 10 mg once a day for a year (Amsterdam et al, 2014).

Adverse effects: Hypertension, headache, nausea, epistaxis.

Special considerations: Prasugrel can cause significant, sometimes fatal, bleeding (U.S. Boxed Warning).

Do not initiate therapy in patients likely to undergo urgent CABG surgery. When possible, discontinue prasugrel ≥7 days prior to any surgery (U.S. Boxed Warning).

In patients ≥75 years of age, prasugrel is generally not recommended due to increased risk of fatal and intracranial bleeding and uncertain benefit; use may be considered in high-risk situations (U.S. Boxed Warning).

Risk of bleeding is increased in older adults. Prasugrel should not be given to patients who have an ST-segment elevation MI and have a history of stroke or TIA (O’Gara et al, 2013).

Prasugrel should not be given to patients who have an ST-segment elevation MI and have a history of stroke or TIA (O’Gara et al, 2013).

Use with caution in patients who have renal impairment.

Mechanism of action: Ticagrelor inhibits platelet aggregation by blocking the activity of P2Y12. P2Y12 is a protein on the surface of platelets and normal functioning of P2Y12 is required for activating platelets, and subsequent aggregation.

Onset of effects:After a loading dose, the onset of platelet inhibition is noticeable after 30 minutes and is close to complete after 2 hours.

Duration of action:Normal platelet function returns within 3-5 days after discontinuation of the drug.

Uses:Reducing the rate of cardiovascular death, MI, and stroke in patients with an acute coronary syndrome or a history of MI. Ticagreloralso reduces the rate of stent thrombosis in patients who have acute coronary syndrome and had a stent placed.

Off label use: For patients who have unstable angina/non-ST-elevation myocardial infarction if the patient has an aspirin allergy or significant gastrointestinal intolerance to aspirin.

Dose:For patients having a ST-segment elevation MI and will be undergoing PCI, a 180 mg loading dose given as soon as possible, followed by 90 mg twice a day for a year if the patient had a stent placed (O’ Garaet al, 2013).

For patients having unstable angina/non-ST-segment elevation MI, a loading dose of 180 mg followed by 90 mg twice a day. If PCI is performed, a loading dose of 180 mg should be given and if a stent is placed the patient should take 90 mg twice day for a year (Amsterdam et al, 2014).

Adverse effects:Increased uric acid, dyspnea, dyspneaon exertion, major bleeding.

Special considerations:Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelorand should be avoided (U.S. Boxed Warning). Ticagrelorcan cause significant, sometimes fatal, bleeding (U.S. Boxed Warning).

Do not initiate therapy in patients likely to undergo urgent CABG surgery. When possible discontinue ≥7 days prior to any surgery (U.S. Boxed Warning).

Use with caution in patients who have a history of hyperuricemia or gouty arthritis.

Mechanism of action: Vorapaxar inhibits platelet aggregation by antagonizing protease-activated receptor-1 (PAR-1).

Onset of effects: ≥ 80% inhibition of platelet aggregation after one week of therapy.

Duration of effects:The decrease of platelet aggregation will be at 50% at 4 weeks after discontinuation of the drug.

Uses:Reducing the risk of cardiovascular death, MI, stroke, or the need for urgent coronaryrevascularizationin patients who have a history of MI or peripheral arterial disease.

Dose:2.08 mg once a day, used in combination with aspirin orclopidogrel.

Adverse effects:Bleeding.

Special considerations:Do not usevorapaxarin patients with a history of stroke, transient ischemic attack, intracranial hemorrhage, or active pathological bleeding (U.S. Boxed Warning).

Use with caution in patients who have hepatic and/or renal impairment.

Mechanism of action: Abciximab inhibits platelet aggregation by binding to and inhibiting platelet IIb/IIIa receptors.

Onset of effects:Platelet aggregation is reduced to < 20% of baseline within 10 minutes.

Duration of effects:The effect on platelet aggregation last for approximately 72 hours.

Uses:Preventing complications of cardiac ischemia during PCI. Preventing complications of cardiac ischemia in patients who have a non-ST-segment elevation MI or unstable angina that is unresponsive to medical therapy and who will be having PCI within 24 hours.

These drugs are not recommended for patients having an acute ischemic stroke (Jauch et al, 2013).

Dose:PCI, 0.25 mg/kg IV bolus given 10-60 minutes before the start of the procedure. This is followed by a continuous infusion of 0.125 mcg/kg/minute (maximum 10 mcg/minute) for 12 hours. For treating patients who have unstable angina or non-ST-segment elevation MI unresponsive to medical therapy and will have PCI within 24 hours, 0.25 mg/kg IV bolus, followed by 10 mcg/minute for 18-24 hours, concluding 1 hour after PCI.

Adverse effects:ack pain, bleeding, chest pain, headache, nausea.

Special Considerations:Use with caution if the patient is < 75 kg; this increases the risk of bleeding.

These drugs are not recommended for patients having an acute ischemic stroke (Jauch et al, 2013).

Mechanism of action: Eptifibatide inhibits platelet aggregation by binding to and inhibiting platelet IIb/IIIa receptors.

Onset of effects: latelet aggregation is > 80% inhibited within 5 minutes of an IV bolus.

Duration of effects:Platelet function is restored 4-8 hours after discontinuation of the drug.

Uses: reatment of patient who have acute coronary syndrome, including patients who will be managed medically and those undergoing PCI. Eptifibatideis also used for patients undergoing PCI and intracoronarystent placement.

Off label uses includeduring PCI procedure for patients having a ST-segment elevation MI, and during elective PCI for stable ischemic heart disease.

These drugs are not recommended for patients having an acute ischemic stroke (Jauch et al, 2013).

Dose:For patients who have acute coronary syndrome, 180 mcg/kg bolus dose (maximum dose 22.6 mg), followed by a continuous infusion of 2 mcg/kg/minute (maximum infusion of 15 mg/hour). The continuous infusion should be continued until the patient is discharged or CABGsurgery is done.

For patients undergoing PCI, with or without stenting, a 180 mcg/kg bolus dose (maximum dose 22.6 mg), followed by a continuous infusion of 2 mcg/kg/minute (maximum infusion of 15 mg/hour). A second 180 mcg/kg bolus (maximum: 22.6 mg) should be administered 10 minutes after the first bolus, and the infusion should be continued until hospital discharge or for up to 18 to 24 hours, whichever comes first.

Adverse effects:Bleeding.

Special considerations:Use with extreme caution in patients with platelet counts <100,000/mm3 Use with caution if the creatinine clearance is < 50 mLminute. The drug should not be used if the patient has end-stage renal disease.

These drugs are not recommended for patients having an acute ischemic stroke (Jauch et al, 2013).

Mechanism of action: Tirofiban inhibits platelet aggregation by binding to and inhibiting IIb/IIIa receptors.

Onset of effects: > 90% platelet inhibition within 10 minutes administration of a dose.

Duration of effects: Platelet aggregation inhibition reverses when the infusion stops.

Uses:Tirofiban is used to treat patients who have unstable angina or non-ST-segment elevation MI. In this patient populationtirofiban will decrease the rate of death, MI, and refractory ischemia.

These drugs are not recommended for patients having an acute ischemic stroke (Jauch et al, 2013).

Dose: The loading dose is 25 mcg/kg administered over 5 minutes or less. The maintenance infusion is 0.15 mcg/kg/minute. The duration of the infusion varies – 18-24 hours depending on the application.

See Special considerations for dosing in patients who have renal impairment.

Adverse effects: Bleeding.

Special considerations: If the creatinine clearance is≤60mL/minute, the IV loading dose is 25 mcg/kg administered over 5 minutes or less, but the maintenance infusion dose is 0.075 mcg/kg/minute continued for up to 18 hours.

These drugs are not recommended for patients having an acute ischemic stroke (Jauch et al, 2013).

Mechanism of action: Cangrelor is a direct P2Y12 platelet receptor inhibitor that blocks adenosine diphosphate (ADP) - induced platelet activation and aggregation.

Onset of effects:Platelet inhibition is seen within 2 minutes of administration.

Duration of effects:Platelet function is restored 1 hour after the infusion is stopped (LexiComp®, Cangrelor; Sibbinget al, 2015).

Uses: Cangreloris used as an adjunctive therapy for patients undergoing PCI who have not been receiving a P2Y12platelet inhibitor or a glycoproteinIIb/IIIainhibitor. In this patient population, cangrelorwill reduce the rate of MI during the PCI procedure, reduce the need for further revascularization, and reduce stent thrombosis.

Dose:30 mcg/kg IV bolus prior to PCI, This is followed immediately by a 4 mcg/kg/minute infusion. The infusion is continued for at least 2 hours or the duration of the PCI, whichever is longer. Patients should then be started on an oral P2Y12platelet receptor inhibitor: clopidogrel, prasugrel, or ticagrelor.

Adverse effects:Bleeding.

Mechanism of action: Warfarin interrupts the synthesis of clotting factors II, VII, IX, and X, and proteins C and S. Synthesis and activation of these clotting factors and proteins requires the reduced form of vitamin K, and reduced vitamin K is produced by the activity of the enzyme vitamin K epoxide reductase complex 1 (VKORC1).

Warfarin: 1) inhibits the activity of VKORC1, deleting vitamin K stores; 2) prevents hepatic synthesis of the aforementioned clotting factors and proteins, and; 3) reduces the activity of circulating clotting factors and proteins. Warfarin is often referred to as a vitamin K antagonist but warfarin does not actually antagonize vitamin K.

Warfarin does not dissolve existing clots; it prevents new clots from forming.

Onset of effects:A measurable effect ofwarfarin, reflected by an increase inINR, can be seen within 36 of hours of a dose. However, the half-life of some of the clotting factors is 50 hours (e.g., factor II) so complete anti-coagulation and full therapeutic effect requires 5-7 days ofwarfarintherapy (LexiComp®,Warfarin).

Duration of effects:Warfarinis given orally once a day. IVwarfarinis no longer produced.

Uses: The labeled uses ofwarfarinare (LexiComp®,Warfarin; January et al, 2014;Meschiaet al, 2014;O’Garaet al, 2013):

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

Warfarin is also used off-label for preventing TIAs in patients who have atrial fibrillation, rheumatic mitral valve disease, or a mechanical prosthetic heart valve.

Dose: The dose of warfarin is individualized and will depend on the patient’s age, co-morbidities, current medications, nutritional status, risk of bleeding, status as an in-patient or an out-patient, and surgical history (Ageno, et al, 2012). The dose will also depend on why the drug is being used and concomitant use of other anticoagulants. Dosing prediction algorithms for warfarin can be used but these appear to have limits in their accuracy and a clinician’s judgment is still needed for selecting the correct dose (Kasner et al, 2015). Before starting warfarin a CBC, INR, PT, liver function tests, and a serum creatinine should be measured (Hull et al, 11/17/2015).

Patients are given an initial loading dose; this can be from 2-10 mg. This loading dose is given for two days, theINRis measured and a maintenance dose is selected, the goal being anINRthat is between 2-3. This can be difficult to do and maintenance doses can vary from < 2mg to > 10 mg a day (Hull, et al, 11/17/2015). Increasing or decreasing the maintenance dose will depend on the results of the coagulation studies, and the frequency of measuring INR will depend on the patient’s clinical status, the results of prior testing, and how much a dose has been decreased or increased.

In many situations the initial dose is 5-10 mg, orally, once a day. Lower starting doses may be needed if the patient is elderly, or has a high risk of bleeding, congestive heart failure, hepatic impairment, poor nutrition, or hasCYP2C9orVKORC1genetic variations (LexiComp®,Warfarin). Maintenance doses are determined by theINR.

Coagulation studies can be done at specialized clinics, in an outpatient setting, or by the patient at home (Hull et al, 11/17/2105;Heneghanet al, 2012). If the patient is properly trained then home self-monitoring can be safe and effective (Henegahnet al, 2012). If theINRis above or below the desired range the patient should be evaluated for changes in diet, development of an illness, changes in liver function or renal function, the presence of bleeding, non-compliance with the dosing regimen, or use of prescription medications, over-the-counter drugs, or supplements that may interfere withwarfarinmetabolism.

Adverse effects: Bleeding is the most common adverse effect. Reports of the incidence of major bleeding vary considerably, e.g., 2.24% and less to 16%. (Sjögrenet al 2015; Shaw et al, 2015). The incidence ofwarfarin-associatedintracranial bleeding has been reported to be 0.62-0.85% per year (Osakiet al, 2015).

Conditions that increase the risk for warfarin-associated bleeding include (del Campo et al, 2015; Roth et al, 2015; Sandén et al, 2015; Shaw et al, 2015; Efird et al, 2013):

• advanced age
• alcohol and/or substance abuse
• anemia
• cerebrovascular disease
• chronic obstructive pulmonary disease
• congestive heart failure
• heart disease
• history of gastrointestinal bleeding
• hypertension
• malignancy
• new onset atrial fibrillation
• recent percutaneous coronary intervention
• renal insufficiency
• trauma
• concomitant use of aspirin, clopidogrel, and warfarin

Special considerations: Warfarin can cause major or fatal bleeding. Perform regular monitoring of INR on all treated patients. Drugs, dietary changes, and other factors affect INR levels achieved with warfarin therapy. Instruct patients about prevention measures to minimize the risk of bleeding and to report immediately to their health care provider signs and symptoms of bleeding (U.S. Boxed Warning).

Genetics and warfarin: Warfarin is a difficult drug to initiate and maintain. If the dose is too low the patient will not be anti-coagulated and if the dose is too high the risk of bleeding is increased. The risk of thromboembolic events and the risk for hemorrhagic events are greatly increased if the INR is below or above, respectively, the desired therapeutic range (Lane et al, 2007; Okae et al, 2007).

Unfortunately, the therapeutic index of warfarin is very narrow and the effective and safe dose that will produce an INR in the target range varies considerably from patient to patient (Saleh, 2015; Wypasek et al, 2015; Kawai et al, 2014).

Single nucleotide polymorphisms (SNPs) in genes that encode enzymes that affect warfarin pharmacokinetics and pharmacodynamics “contribute substantially to inter-individual variability in warfarin dose requirement. This genetic contribution to predicting warfarin dose is well-established and is most important during the initial weeks of therapy” (Kawai et al, 2014).

It would seem prudent then to perform genetic testing for the enzymes, CYP2C9, CYP4F2, and VKORC1, and in 2007 the Food and Drug Administration (FDA) recommended that manufacturers of warfarin indicate in the prescribing information that lower doses of warfarin be considered for patients who have CYP2C9 and VKROC1 genetic variations. The latest package insert for Coumadin® (2015) states: “CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the initial dose of warfarin” and it provides a dosing algorithm that is based on the results of genetic testing.

Some authors recommend genetic testing if the patient has a risk for bleeding and/or has INR results that are consistently out of range (Shaw et al, 2015). However, although there is strong evidence that CYP2C9 and VKROC1 genotype variations are associated with warfarin-related adverse effects, the contribution of these genetic variations to bleeding events is not well defined (Shaw et al 2015; Kawai et al 2014). There is data that suggests genotype-based dosing will decrease the number of bleeding events caused by warfarin once warfarin therapy is in the maintenance phase and data suggesting that it will not (Shi et al, 2015; Shaw et al 2015). Randomized controlled trials that compared genotype-based dosing and standard dosing have provided mixed results in terms of efficacy and safety (Dahal et al 2015). Pharmacogenetic testing is not universally recommended for use during the initiation phase of warfarin therapy (Hull et al, 11/172015; Guyatt et al 2012). Shaw et al (2015) write “there is insufficient evidence that genotype-guided dosing can decrease the number of adverse events.”

Warfarin resistance:Warfarinresistance has been defined as the inability to bring or maintain theINRinto the desired range when the drug has been given within the normal prescribed doses (Lefrereet al, 1987).Warfarinresistance can be either acquired or hereditary and although the termwarfarinresistance is often used, it is somewhat of a misnomer: resistance towarfarinis not a single entity but can be caused by many factors (Hulse, 1996; Hull et al, 11/17/2015).

Acquiredwarfarinresistance is usually caused by poor patient compliance with the drug regimen (Osinbowaleet al, 2009). Other causes ofwarfarinresistance are drug-drug interactions that interfere with the dose-response towarfarin, decreased absorption or clearance of the drug, hepatic dysfunction, gastrointestinal diseases, and exogenous consumption of vitamin K (Reaveset al, 2013; Kidd et al, 2010;Osinbowaleet al, 2009). There are more drugs that increasewarfarinsensitivity than causewarfarinresistance (Osinbowaleet al 2009).

Warfarin resistance caused by excessive dietary consumption of vitamin K has been reported (Qereshi et al, 1981; O’Reilly et al, 1980). Recent studies have shown a normal intake of vitamin K will not affect INR (Park et al, 2015; Russell et al, 2015; Kim et al, 2010). The foods listed in Table 3 have high vitamin K content and should be avoided by people who are taking warfarin (LexiComp, 11/01/2015).

Most cases of hereditary warfarin resistance are caused by genetic variability; this was previously discussed.

Osinbowale et al (2009) formulated an algorithm for assessing warfarin resistance or possible warfarin resistance: See Table 4.

Warfarin sensitivity: Warfarin sensitivity is caused by Vitamin K deficiency, liver disease, hypoalbuminemia, CYP2C9 enzyme inhibition by drugs such as amiodarone, capecitabine, fluconazole, fluvoxamine, and metronidazole, inherited deficiencies of II, V, VII, and X clotting factors (rare), and CYP2C9 and VKROC1 polymorphisms (Scwher et al, 2013).

Warfarin-drug interactions: There are hundreds of drugs that have been reported to interact with warfarin and increase or decrease its effectiveness. Some of these are documented by a few cases reports and others are well researched and well established, and drug-drug interaction databases may not have information regarding which warfarin-drug interactions are of practical concern.

There are five ways that a drug-drug interaction can change the effectiveness of warfarin and/or increase the risk of bleeding (Juurlink, 2007).

1. Interfering with platelet function: Examples would be clopidogrel (Class D interaction, drug therapy should be modified) and the selective serotonin re-uptake inhibitors (Quinn et al, 2014; Class C interaction, drug therapy should be monitored).
2. Injury to the gastrointestinal mucosa: Examples would include non-steroidal anti-inflammatories such as ibuprofen. (Class D interaction, drug therapy should be modified)
3. Reduced synthesis of vitamin K by intestinal flora: Antibiotics such as sulfamethoxazole-trimethoprim and metronidazole (Daniels et al, 2015; Class D interaction, drug therapy should be modified) and anti-fungals such as fluconazole (Daniels et al, 2015; Class C interaction, drug therapy should be monitored)
4. Interference with warfarin metabolism: Drugs such as amiodarone can inhibit cytochrome P450 enzymes, affect the metabolism of warfarin, and decrease its therapeutic effectiveness (Flaker et al, 2014;Class D interaction, drug therapy should be modified).
5. Interruption of the vitamin K cycle: Acetaminophen (depending on the dose) can interrupt the vitamin K cycle (Class C interaction, drug therapy should be monitored), and Caldeira et al (2015) write that in patients taking a vitamin K antagonist “Acetaminophen is associated with a statistically significant and possible clinically relevant increase in the INR, with a dose dependent relationship. Patients treated concomitantly with VKA and acetaminophen should be monitored more regularly for possible VKA dosage adjustment.”

A helpful way of knowing clinically important drug-warfarin interactions is to remember the ‘8 As’ (Juurlink, 2007):

• Acetaminophen
• antibiotics
• anti-depressants
• antifungals
• anti-platelet agents
• anti-inflammatories
• alternative therapies
• amiodarone

Mechanism of action: Direct inhibition of factor Xa.

Onset of action: 3-4 hours

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

Uses: Prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE); treatment of DVT and PE; reducing the risk of stroke and systemic embolization in patients who have nonvalvular atrial fibrillation, and; prophylaxis of DVT, post-operatively, in patients who have had hip or knee replacement.

Dose: DVT and PE, 10 mg twice day for 7 days; Nonvalvular atrial fibrillation, 5 mg twice a day. If the patient is ≥ 80 years of age, weighs ≤ 60 kg, or has a serum creatinine of ≥ 1.5 mg/dL, decrease the dose to 2.5 mg twice  a day. For post-operative patients the dose is 2.5 mg twice day. Start therapy 12-24 hours after surgery and continue for 35 days (hip replacement) or 12 days (knee replacement.

Adverse effects: Bleeding.

Special considerations: Epidural or spinal hematomas may occur in patients treated with apixaban who are receiving neuraxial anesthesia or undergoing spinal puncture (U.S. Boxed Warning).

Renal function should be evaluated prior to beginning therapy with apixaban and a decrease in dose may be needed if the patient has renal impairment. 

Mechanism of action: Direct inhibition of factor Xa.

Onset of effects:1-2 hours.

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

Uses:Treatment of DVTand PE after 5-10 days of initial therapy with a parenteralanticoagulant. Reduction of the risk of stroke and systemic embolism in patients who have nonvalvularatrial fibrillation.

Dose: 60 mg once day. See the Special considerations section for more dosing information.

Adverse effects:Bleeding.

Special considerations:Epidural or spinal hematomasmay occur in patients treated with edoxabanwho are receiving neuraxialanesthesia or undergoing spinal puncture (U.S. Boxed Warning).

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, nonvalvular atrial fibrillation patients with CrCl >95 mL/minute had an increased rate of ischemic stroke with edoxaban 60 mg once daily compared to patients treated with warfarin. In these patients another anticoagulant should be used (U.S. Boxed Warning).

For patients being treated for DVT or PE, the dose will need to be decreased if the creatinine clearance is 15-50 ml/minute and the drug should not be used if the creatinine clearance is < 15 ml/minute.

If the patient weighs ≤ 60 kg the dose should be 30 mg once a day.

Mechanism of action: Direction inhibition of factor Xa.

Onset of action: 2-4 hours.

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

Uses: Treatment of DVT and PE; reducing the risk of stroke and systemic embolization in patients who have nonvalvular atrial fibrillation, and; prophylaxis of DVT, post-operatively, in patients who have had hip or knee replacement.

Dose: Treatment of DVT and PE, 15 mg twice a day for 21 days followed by 20 mg once a day. For patients who have nonvalvular atrial fibrillation, the dose is 20 mg a day, taken with the evening meal. Post-operative patients, hip surgery, 10 mg a day for 35 days; post-operative patients, knee surgery, 10 mg a day for 12-14 days.

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 (U.S. Boxed Warning).

Dosage adjustments will be needed for patients who have renal impairment.

Heparin is a naturally occurring molecule but commercially produced heparin is derived from 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 by doing so, prevents the conversion of fibrinogen to fibrin. Heparin also inhibits the activity of the clotting factors IX, X, XI, and XII.

Indications for use: Prophylaxis and treatment of thromboembolic disorders.

Off-label uses that are commonly recommended by the American College of Cardiology Foundation/American Heart Association are: anticoagulation during PCI; for patients having a ST-segment elevation MI and are receiving fibrinolytic therapy, and; for patients who are having unstable angina or a non-ST-segment elevation MI.

Other off-label uses include treatment of acute DVT of the legs and upper extremities; treatment of superficial vein thrombosis; non-bacterial thrombotic endocarditis and systemic emboli or PE; cerebral venous sinus thrombosis; patients who have atrial fibrillation and are undergoing cardioversion, and; acute arterial emboli or thrombosis.

Onset of action: IV, immediate. Subcutaneously, 20-30 minutes.

Duration of effects: The duration of effects is dependent on the dose; the higher the dose the longer the anti-coagulant effect.

Dose: A baseline aPTT is measured prior to starting heparin therapy. Heparin is dosed in units (U), and the dose depends on the patient’s weight (typically the primary consideration), the clinical indication and if a subcutaneous injection, intermittent infusion, or continuous infusion is used.

Loading doses are often used with the IV infusions. Dosing calculators for continuous IV infusions are based on patient weight are used to determine the initial dose and dosing adjustments are made, depending on the aPTT results. A complete blood count including platelet count and aPTT should be routinely measured during heparin therapy.

Intermittent dosing of heparin for the prophylaxis of thromboembolism is typically 5000 units every 8-12 hours.

Doses for the off-label uses will be discussed in a following part of this section.

Adverse effects: Bleeding, heparin-induced thrombocytopenia (The latter is discussed later in this section).

Off-label use - PCI and heparin: The American College of Cardiology Foundation/American Heart Association recommends some form of anticoagulation during PCI (Levine et al, 2011).

If the patient has received anticoagulant therapy prior to the procedure and an IV glycoprotein inhibitor will be used, give an additional 2000 - 5000 units to achieve an activated clotting time of 200-250 seconds. If an IV glycoprotein inhibitor will not be used, give an additional 2000 - 5000 units of heparin to achieve an ACT of 250-350 seconds, depending on the measuring device that is used (Levine et al, 2011).

If the patient has not received anticoagulant therapy prior to the procedure and an IV glycoprotein inhibitor will be used, give a 50 - 70 unit/kg bolus of heparin to achieve an ACT of 200-250 seconds. If an IV glycoprotein inhibitor will not be used, give a 70 -100 units/kg bolus of heparin to achieve an activated clotting time of 200-350 seconds, depending on the measuring device that is used (Levine et al, 2011).

O’Gara et al (2013) recommend heparin with boluses as needed to maintain therapeutic ACT, taking into account whether or not a glycoprotein inhibitor has been used.

Off-label use - Unstable angina/non-ST-segment elevation MI: A loading dose of 60 U/kg (maximum 4000 U) and an initial infusion of 12 U/kg/h (maximum 1000 U/h), adjusted using a standardized nomogram. Check aPTT every 4 to 6 hours for a target of 1.5 to 2 times the upper limit of control (50 to 70 seconds). Optimal duration of therapy is unknown. The recommended duration is 48 hours or until percutaneous coronary intervention is performed (Amsterdam et al, 2014).

Off-label use - ST-segment elevation MI - an adjunct to fibrinolysis: Initial bolus of 60 U/kg (maximum: 4000 units), then 12 U/kg/hour (maximum: 1000 U/hour) as a continuous infusion. Check aPTT every 4 to 6 hours; adjust to a target of 1.5 to 2 times the upper limit of control (50 to 70 seconds). Continue for a minimum of 48 hours, and preferably for the duration of hospitalization (up to 8 days) or until revascularization (if performed) (O’Gara, 2013).

Off-label use - Atrial fibrillation/flutter and cardioversion: Patients who have atrial fibrillation or atrial flutter of < 48 hours duration and have a high risk of stroke should be given heparin as soon as possible before or after cardioversion (January et al, 2014). The need for post-cardioversion anticoagulation is based on the patient’s stroke risk (January et al, 2014).

Bridging therapy: Patients on warfarin therapy who are undergoing a procedure that requires the drug to be stopped have traditionally been treated with heparin during the relatively brief discontinuation of warfarin, a technique called bridging therapy.

Bridging therapy is intended to decrease the risk for thromboembolic events and death, and it is still used and recommended, based on patient risk factor (January et al 2014). However, its value and effectiveness are being questioned. Rose et al (2015) opined that > 90% of patients on warfarin therapy should not receive bridging anticoagulation unless there were unusual circumstances and a strong justification. Rechenmacher et al (2015) write that “physicians should carefully consider both the need for oral anticoagulation interruption and the practice of routine bridging when anticoagulation interruption is indicated.” Rechenmacher et al also wrote that “for most patients it produces excessive bleeding, longer length of hospital stay, and other significant morbidities, while providing no clear prevention of TE.”

Heparin-induced thrombocytopenia: Heparin-induced thrombocytopenia (HIT) is an immune-system mediated complication of heparin therapy that decreases platelet count and can cause thrombosis. Heparin-induced thrombocytopenia can be caused by any dose (even after exposure to heparin flush or a heparin-coated catheter), any dosing schedule, after a single exposure to heparin, or with any route of administration of the drug (Coutre, 08/10/2015). The incidence of HIT has been reported to be from 1-5% of patients receiving heparin (Coutre, 08/10/2015; Greinacher, 2015).Risk factors for the development of HIT include the use of un-fractionated heparin (as opposed to low molecular weight heparin); female gender, and; use of heparin for a surgical procedure rather than a medical reason (Coutre, 08/10/2015).

Heparin-induced thrombocytopenia usually begins 5-10 days after heparin therapy has been started, but HIT can begin within 24 hours of heparin administration if the patient has previously been treated with heparin and has circulating antibodies (which can persist for 2-3 months), and HIT can occur after heparin therapy has been stopped (Greinacher, 2015; Coutre, 08/10/2015). The most common clinical featured of HIT is thrombocytopenia, which is typically > 50% of baseline (Coutre, 08/10/2015; Greinacher, 2015).

Quickly and correctly recognizing HIT is very important. Heparin-induced thrombocytopenia rarely causes bleeding but thrombotic complications such as myocardial infarction, pulmonary embolism, stroke, and arterial and venous thrombosis are common complications of HIT (Coutre, 08/10/2015; Greinacher, 2015).

Heparin-induced thrombocytopenia is diagnosed by using the 4T’s score: thrombocytopenia; timing of thrombocytopenia; thrombosis or other sequelae, and; other causes of thrombocytopenia have been rules out. Each of the four T’s is given a score and HIT is present if the score is above a certain point (Cuker et al, 2012; Lo et al, 2006).

Treatment of HIT involves immediately stopping heparin therapy; immediate anti-coagulation with argatroban, danaparoid, fondaparinux, or bivalirudin (danaparoid is not available in the US), and; life time avoidance of heparin (Coutre, 09/03/2015; Greinacher, 2015).

A vitamin K antagonist should not be given until the platelet count has increased to > 150,000 for two consecutive days; warfarin decreases the level of protein C and can cause venous limb gangrene (Greinacher, 2015).

The low-molecular weight (LMW) heparins are derived from heparin; they are called low-molecular weight because their molecular weight is less than that of heparin.

The specific features, differences, advantages, and disadvantages of the LMW heparins when compared to heparin are summarized in Table 6 (Hull et al, 10/29/2015).

Each LMW heparin has specific biochemical and pharmacologic properties and they are not interchangeable.

Mechanism of action: Inhibits factor IIa and Xa.

Onset: Anti Xa activity begins within 1-2 hours

Duration of effects: > 12 hours.

Uses: Prevention of DVT in selected patients who are having abdominal surgery; is patients who are having hip surgery; patients who are immobile because of an acute illness; patients who have cancer and are at risk for DVT and PE, and; prevention of ischemic complications in patients who are having a non-Q-wave myocardial infarction. 

Off-label uses include bridging therapy for patients who have a mechanical prosthetic heart valve and are undergoing surgery or an invasive procedure, and prevention of recurrent venous thromboembolism during pregnancy.

Doses: Dalteparin is given subcutaneously. The dose is 2500-5000 units prior to surgery. The timing of the dose, the duration of therapy and the dose depend on the clinical application; the usual duration is 5-10 days post-operatively. When used for patients who have a non-Q-wave MI or patients who have cancer, dalteparin is dosed based on weight.

Adverse effects: Bleeding, pain at the injection site.

Special considerations: Epidural or spinal hematomas may occur in patients who are anticoagulated with LMW heparins or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture (U.S. Boxed Warning).

The half-life of dalteparin is increased in patients who have chronic renal failure. Dalteparin should be used with caution in patients who have severe hepatic impairment.

Mechanism of action: Inhibition of anti-thrombin III and clotting factor Xa.  

Onset of effects: Peak effect on anti-thrombin and factor Xa is 2-5 hours.

Duration of effects: Approximately 12 hours.

Uses: Acute coronary syndromes, acute treatment of DVT, and DVT prophylaxis. Enoxaparin is used off-label as an adjunctive treatment during PCI and as a bridging therapy.

Dose: Enoxaparin is given subcutaneously. Dosing depends on the clinical situation and is summarized in Table 7.

Adverse effects: Bleeding.

Special considerations: Epidural or spinal hematomas may occur in patients who are anticoagulated with LMW heparins or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture (U.S. Boxed Warning).

Use with caution in patients with renal failure; dosage adjustment needed if the patient’s creatinine clearance is <30 mL/minute.

The safety and effectiveness of enoxaparin have not been established in patients who are obese (> BMI > 30 kg/m2).

Men who weigh < 57 kg and women who weigh < 45 kg may have an increased risk of bleeding from enoxaparin. 

Mechanism of action: Direct and reversible inhibition of thrombin, preventing the activation of the clotting factors V, VIII, and XIII, activation of protein C, and platelet aggregation.

Onset of action: Immediate

Duration of action: The half-life is 39-51 minutes.

Uses: Prophylaxis or treatment of thrombosis in adults who have HIT. Argatroban is also used as an anticoagulant for adults who are undergoing PCI and who have HIT or at risk of developing HIT.

Off-label uses: Maintaining extracorporeal circuit patency of continuous renal replacement therapy (CRRT) in critically-ill patients with HIT.

Doses: For the treatment of HIT the dose is 2 mcg/kg/minute. The aPTT should be measured 2 hours after therapy has begun and the dose should be adjusted (not to exceed 10 mcg/kg/minute) for an aPTT of 1.5-3 times the baseline level, not to exceed 100 seconds. Patients who are critically ill or obese may need dosing adjustments.

For adults who are undergoing PCI and have or are at risk for developing HIT, the dose is 25 mcg/kg/minute along with a bolus dose of 350 mcg/kg delivered over 3-5 minutes. The ACT should be measured 5-10 minutes after the bolus dose is given and the PCI can proceed if the ACT is > 300 seconds. An additional bolus dose should be given or the infusion rate should be decreased if the ACT is < 300 seconds or > 450 seconds, respectively. Once the ACT is between 300-450 seconds the infusion should be continued for the duration of the PCI procedure. If post-PCI anticoagulation, if required, continue the infusion at a reduced dose of 2 mcg/kg/minute.

Adverse effects: Bleeding, chest pain, hematuria, hypotension.

Special considerations: Use with caution in patients who have hepatic impairment.

Mechanism of action:Direct thrombin inhibitor.

Onset of effects: Immediate.

Duration of effects: Coagulation times return to normal in approximately 1 hour after the infusion has been discontinued.

Uses: Labeled uses: As an anticoagulant used in conjunction with aspirin, for patients who have unstable angina and are undergoing PCI or percutaneous transluminal coronary angioplasty (PCTA) with a provisional glycoprotein inhibitor. Used as an anticoagulant, in conjunction with aspirin, for patients undergoing PCI who have, or at risk for having, HIT.

Off-label- Treating patients who are undergoing cardiac surgery who have HIT; HIT complicated by thrombosis; patients who have a ST-segment elevation MI and are undergoing PCI and are receiving a glycoprotein inhibitor and; patients who have unstable angina or non-ST-segment elevation MI who are undergoing early invasive treatment and are receiving a glycoprotein inhibitor. (O’ Gara et al, 2103; Amsterdam et al, 2014)

Dose:Patients who do not have HIT and are undergoing PCI or PCTA: Start with a 0.75 mg/kg IV bolus followed by 1.75 mg/kg/hour. Measure the ACT 5 minutes after the bolus dose. If needed, give another bolus dose of 0.3 mg/kg. The infusion should be continued for the duration of the procedure. After the PCI/PCTA has been completed, the infusion can be continued for 4 hours. After that point, the infusion can be continued for 20 hours at a rate of 0.2 mg/kg/hour, if needed.

Patients who have HIT and are undergoing PCI or PCTA: Start with a 0.75 mg/kg IV bolus. Follow the bolus with a 1.75 mg/kg/hour IV infusion for the duration of the procedure. After the PCI/PCTA has been completed, the infusion can be continued for 4 hours. After that point, the infusion can be continued at 0.2 mg/kg/hour for 20 hours, if needed.

Off-label dosing- Unstable angina/non-ST-segment elevation MI, patient undergoing PCI - Bivalirudin is considered to be useful as an anticoagulant in this clinical situation, with or without prior treatment with heparin. The loading dose is 0.25 mg/kg/hour. This is continued until diagnostic angiography or PIC is performed, and only with provisional use of a glycoprotein inhibitor and dual anti-platelet therapy (Amsterdam et al, 2014).

ST-segment elevation MI, patient undergoing PCI and is receiving a glycoprotein inhibitor - 0.75 mg/kg bolus then 1.75 mg/kg/hour, with or without heparin. An additional 0.3 mg/kg bolus can be given. Reduce infusion to 1 mg/kg/hour if the patient’s creatinine clearance is < 30 ml/minute.

If the patient has a high risk of bleeding, it is reasonable to use bivalirudin alone rather than heparin and a glycoprotein inhibitor. .

Adverse effects: Bleeding, headache, hypotension, nausea, pain.

Special considerations: Use with caution in patients who have renal impairment.

Mechanism of action: Dabigatran is a pro-drug and its active metabolite is a direct thrombin inhibitor.

Onset of effects: The peak effect occurs within 2 hours

Duration of action: Hemostasis occurs 12 hours after the drug has been stopped (Roca et al, 2015).

Uses: Prevention and treatment of DVT and PE; Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Doses: 150 mg, orally, twice a day. If dabigatran is used for prevention/treatment of DVT/PE, the patient should first receive oral anti-coagulation for 5-10 days.

Adverse effects: Bleeding, dyspepsia, gastritis-like symptoms.

Special considerations: The patient’s renal function should be assessed prior to and during therapy with dabigatran, and a review of interactions of dabigatran and other currently used medications should be done.

Mechanism of action: Direct thrombin inhibition.

Onset of effects: The time to peak plasma level is 1-3 hours.

Duration of effects: Desirudin is given twice a day.

Uses: Prophylaxis of DVT in patients undergoing hip replacement surgery.

Dose: 15 mg subcutaneously every 12 hours. The average duration of use has been 9-12 days. If the aPTT is > 2 times control, interrupt therapy with the drug  and resume desirudin at a reduced dose when the aPTT is < 2 times the control.  If the patient has renal impairment the dose should be decreased, depending on creatinine clearance level.

Adverse effects: Bleeding.

Special considerations: When neuraxial anesthesia or spinal puncture is used, patients anticoagulated or scheduled to be anticoagulated with desirudin may be at risk of developing an epidural or spinal hematoma; this can result in long-term or permanent paralysis. This risk may be increased by the use of indwelling spinal catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as non-steroidal anti-inflammatory drugs, platelet inhibitors, or other anticoagulants (U.S. Boxed Warning).

If the patient’s creatinine clearance is < 31 mL/minute or ≥ to 31-60 mL/minute, dosing adjustments will need to be made; the dose should be decreased.

Mechanism of action: Inhibits clotting factor Xa.

Onset of effects: Peak effect of Xa inhibition is in 4-5 hours.

Duration of effects: The half-life is approximately 25 hours and the drug is given twice a day.

Uses: Labeled uses are treatment of acute DVT, in conjunction with warfarin; treatment of acute PE, in conjunction with warfarin, and; prophylaxis for DVT in patients having abdominal, hip, or knee surgery, and for patients who have had a hip fracture.

Fondaparinux is used off-label for patients who are having unstable angina, non-ST segment and ST-segment elevation MI; acute symptomatic superficial venous thrombosis; DVT prophylaxis in patients who have HIT; acute thrombosis in patients who have a history of HIT; venous thromboembolism prophylaxis in general surgery.

Dose: Fondaparinux is given subcutaneously.

For DVT prophylaxis in adults ≥ 50 kg, 2.5 mg once a day. Fondaparinux should not be given any earlier than 6-8 hours post-operatively. Do not give fondaparinux to patients who weigh < 50 kg.

For acute treatment of DVT or PE, 5 mg once a day for patients < 50 kg; 7.5 mg once a day for patients between 50-100 kg, and; 10 mg once a day for patients > 100 kg. Warfarin should be started on the first or second day of fondaparinux therapy and continue fondaparinux until the INR is ≥ 2 for at least 24 hours.

For initial therapy of patients having unstable angina/non-ST-segment elevation MI, 2.5 mg a day for the duration of hospitalization or until PCI is performed (Amsterdam et al, 2014).

For patients who are having a ST-segment elevation MI and are undergoing fibrinolysis, fondaparinux administered as an initial intravenous dose, followed in 24 hours by once a day injections, if the estimated creatinine clearance is greater than 30 mL/min, for the duration of the hospitalization for up to 8 days or until revascularization (O’ Gara et al, 2013).

Adverse effects: Anemia, bleeding.

Special considerations: Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins, heparinoids, or fondaparinux and are receiving neuraxial anesthesia or undergoing spinal puncture (U.S. Boxed Warning).

If the patient’s creatinine clearance is 30-50 ml/minute, use with caution, and do not use fondaparinux if the creatinine clearance is < 30 ml/minute.

Fondaparinux is contraindicated if the patient weighs < 50 kg and it is used as prophylactic therapy. If the patient weighs < 50 kg but fondaparinux is not being prescribed prophylactically, use with caution.

Fondaparinux should not be used as the only anticoagulant during primary PCI because of the risk of catheter thrombosis (O’ Gara et al, 2013).

Discontinue fondaparinux 24 hours before CABG and use heparin instead.

Mechanism of action: Alteplase binds to fibrin in a thrombus and converts plasminogen to plasmin. Plasmin is a serine protease that lyses fibrin clots.

Onset of effects: Immediate.

Duration of effects: Fibrinolytic activity continues for up to 1 hour after injection.

Uses: Acute ischemic stroke, acute, massive PE, ST-segment elevation MI.

There are numerous off-label uses for alteplase. Perhaps the most important off-label use is administering alteplase to a patient 3-4.5 hours after the onset of an acute ischemic stroke; this will be discussed in the Special considerations section.

Dose:

1. Acute ischemic stroke, used within 3 hours of the onset of symptoms. The total dose is 0.9 mg/kg, the maximum dose is 90 mg. Patients ≤100 kg: Load with 0.09 mg/kg (10% of 0.9 mg/kg dose) as an IV bolus over 1 minute, followed by 0.81 mg/kg (90% of 0.9 mg/kg dose) as a continuous infusion over 60 minutes. Patients >100 kg: Load with 9 mg (10% of 90 mg) as an IV bolus over 1 minute, followed by 81 mg (90% of 90 mg) as a continuous infusion over 60 minutes
2. Pulmonary embolism: 100 mg over 2 hours
3. ST-segment elevation MI, accelerated regimen (weight-based, O’Gara et al, 2013):ts >67 kg: Total dose: 100 mg over 1.5 hours; administered as a 15 mg IV bolus over 1 to 2 minutes followed by infusions of 50 mg over 30 minutes, then 35 mg over 1 hour. Maximum total dose: 100 mg. Patients ≤67 kg: Infuse 15 mg IV bolus over 1 to 2 minutes followed by infusions of 0.75 mg/kg (not to exceed 50 mg) over 30 minutes then 0.5 mg/kg (not to exceed 35 mg) over 1 hour. Maximum total dose: 100 mg.? se can be given to the patient who is having ST-segment elevation MI and who has ischemic symptoms within 12 hours of arrival, or has evidence of ongoing ischemia 12 to 24 hours after symptom onset and there is a large area amount of myocardium at risk or the patient is hemodynamically unstable (O’ Gara et al, 2013). /ol>

   Adverse effects: Bleeding: Clinical trials have shown an incidence of bleeding of 5-7% (Samuels, 2015).

   Orolingual angioedema has been reported to occur in 0.2-5.1% of patients who are receiving alteplase for treatment of an acute ischemic stroke (Correia et al, 2015; Madden et al, 2015). Severe reactions that compromise the airway are possible, but orolingual angioedema is usually mild and self-limiting, and it is empirically treated with IV diphenhydramine, methylprednisolone, and ranitidine. (Samuels, 2015; Jauch, et al, 2013)

   Special considerations: Incompatible with bivalirudin, dobutamine, heparin, and morphine; may be incompatible with dopamine and nitroglycerin. Alteplase should be given through a dedicated IV catheter.

   The use of alteplase in patients taking direct thrombin inhibitors or direct factor Xa inhibitors may be harmful and is not recommended unless laboratory tests such as aPTT, INR, platelet count, ecarin clotting time (ECT), TT, or direct factor Xa activity assays are normal, or the patient has not received a dose of these drugs for >2 days (assuming normal renal function).

   Extended timing, 3-4.5 hours after stroke symptom onset: Giving alteplase at a point 3-4.5 hours after onset of stroke symptoms may be effective for certain patients (Jauch et al, 2013; Hacke et al, 2008). Inclusion criteria for this late administration of alteplase are 1) diagnosis of ischemic stroke causing measurable neurological deficit, and; 2) onset of symptoms within 3 to 4.5 hours before beginning treatment. Administration of alteplase 3-4.5 hours after onset would be contraindicated if the patient is > 80 years of age; has a severe stroke with a National Institutes of Health Stroke Scale (NIHSS) stroke score > 25; is taking an anticoagulant, regardless of the INR result, or; has a history of diabetes or prior stroke (Jauch et al, 2013).

   Stroke mimics: There are many clinical conditions that can mimic an acute ischemic stroke, including but not limited to drug overdose, hypoglycemia, and migraine headache with aura (Jauch et al, 2013). If the patient has a stroke mimic that is misdiagnosed and he/she receives fibrinolytic therapy the risk of serious complications appears to be relatively low (Spokoyny et al, 2014; Chang et al, 2012; Chernyshev et al, 2010).

   Alteplase and the patient having an acute ischemic stroke: Administering alteplase to a patient who is having an acute ischemic stroke requires a thorough knowledge of protocol.

   1. Timing: Alteplase should be given as soon as possible, preferably within 60 minutes of arrival at a health care facility (Jauch et al, 2013). The labeled recommendation is that alteplase should only be given ≤ three hours from the onset of symptoms.
   2. There are many laboratory and diagnostic tests that should be done for the patient who will be given alteplase, but only glucose measurement is required prior to administration of alteplase. Jaruch et al (2013) write fibrinolytic therapy should not be delayed while awaiting the results of the PT, aPTT, or platelet count unless a bleeding abnormality or thrombocytopenia is suspected, the patient has been taking warfarin and heparin, or anticoagulation use is uncertain.”
   3. The blood pressure must be at or below 185 mm Hg systolic and 110 mm Hg diastolic before starting alteplase.
   4. Urgent anticoagulation is not recommended and starting anticoagulation with 24 hours of using alteplase is not recommended (Jauch et al, 2013).
   5. Aspirin and other anti-platelet drugs should not be given within the first 24 hours after administration of alteplase.
   6. Contraindications and relative contraindications for the use of alteplase are listed in Tables 8 and 9 (Samuels, 2015).

   Table 8: Contraindications for the Use of Alteplaseg>

   Significant head trauma or prior stroke in previous 3 months Symptoms of subarachnoid hemorrhage Arterial puncture at non-compressible site in the past 7 days History of previous intracranial hemorrhage Intracranial neoplasm, arteriovenous malformation, or aneurysm Recent intracranial or intraspinal surgery Elevated blood pressure (systolic >185 mm Hg or diastolic >110 mm Hg) Active internal bleeding Acute bleeding diathesis Platelet count <100 000/mm3 Heparin received within 48 hours, resulting in an aPTT greater than the upper limit of normal Current use of anticoagulant and an INR >1.7 or PT >15 seconds Current use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated laboratory tests of NR, platelet count, and ECT, TT, or factor Xa activity assays Blood glucose concentration < 50 mg/dL Multi-lobar brain infarction seen on CT scan

   Table 9: Relative Contraindications for the Use of Alteplase

   Admit the patient to an intensive care or stroke unit Patient assessment should be done every 15 minutes during the alteplase infusion closely for signs of intracranial hemorrhage and angioedema If the patient develops severe headache, acute hypertension, nausea, or vomiting or has a worsening neurological examination, discontinue the infusion and do an emergent CT scan Measure blood pressure and perform neurological assessments every 15 minutes during and after the infusion for 2 hours, then every 30 minutes for 6 hours, then hourly until 24 hours after the infusion has finished Intra-arterial catheters, in-dwelling urinary catheters, and nasogastric tubes should not be placed if the patient can be safely managed without them Obtain a follow-up CT or MRI scan at 24 hours after the alteplase infusion and before starting anticoagulants or antiplatelet agents

   Fibrinolytic therapy and ST-segment elevation MI

   Alteplase has a labeled use for the treatment of ST-segment MI. Tenecteplase appears to be equally effective and has a lower rate of non-cerebral bleeding events, but it does not have a labeled use for this purpose (Gibson et al, 2015).

   Alteplase should be given within 30 minutes of arrival at the hospital.

   If the time from first medical contact to PCI will be > 120 minutes, fibrinolytic therapy with alteplase should be given.

   Fibrinolytic therapy should be considered if the patient has evidence of a ST-segment MI, she/he has had ischemic symptoms within the previous 12 hours and the time to PCI is > 120 minutes.

   Antiplatelet therapy and anticoagulant therapy should be administered along with fibrinolytic therapy (O’ Gara et al, 2013). Aspirin and clopidogrel should be given, and enoxaparin, fondaparinux, or heparin can be used. The anticoagulant therapy should be continued for a minimum of 48 hours and preferably for the duration of hospitalization, up to 8 days, or until revascularization has occurred (O’ Gara et al, 2013).

   Table 11 Anti-platelet and Anticoagulant Dosing with Fibrinolytic Therapy and ST-Segment Elevation MI

   325 mg aspirin, 300 mg clopidogrel (75 mg if the patient is ≥ 75 years of age) Heparin, adjust the dose to attain an aPTT 1.5-2 times the control. Enoxaparin, an IV bolus (dose based on age, weight, and creatinine clearance) followed in 15 minutes by subcutaneous injections. Fondaparinux, IV loading dose followed in 24 hours by subcutaneous injections if the creatinine clearance is > 30 mL/minute.

   Absolute contraindications to fibrinolytic therapy in the patient who is having an ST-segment MI include active bleeding or bleeding diathesis, significant closed-head or facial trauma with 3 months, previous intracranial hemorrhage, ischemic stroke within 3 months, a structural cerebral vascular lesion, malignant intracranial neoplasm, or suspected aortic dissection (Gibson et al, 2015).

   Relative contraindications to fibrinolytic therapy in the patient who is having an ST-segment MI include chronic hypertension or poorly controlled hypertension, dementia or another intracranial pathology, ischemic stroke more than 3 months previously, prolonged (> 10 minutes) or traumatic cardiopulmonary resuscitation, or major surgery < 3 weeks prior (Gibson et al, 2015).

Mechanism of action: Tenecteplase binds to fibrin in a thrombus and converts plasminogen to plasmin. Plasmin is a serine protease that lyses fibrin clots.

Onset of effects:

Durations of effects:

Use: ST-segment elevation MI, lysis of thrombi in the coronary vascular.

Off label use, acute ischemic stroke; there is some evidence that tenecteplase can be useful for treatment of acute ischemic stroke (Huang et al, 2015; Logallo et al, 2015).

Dose: The dose is based on weight and should be administered as a bolus over 5 seconds.

Adverse effects: Bleeding, hematoma.

Special considerations: Precipitation may occur when TNKase is administered in an IV line containing dextrose. Dextrose-containing lines should be flushedwith a saline-containing solution prior to and following single bolusadministration of TNKase.