STROKE IS A LEADING CAUSE of long-term disability and is the fifth leading cause of death in the United States (Benjamin et al., 2017). Approximately 795,000 people in the United States experience a new or recurrent stroke each year, with approximately 133,000 stroke-related deaths (Benjamin et al., 2017). The estimated annual direct medical cost of stroke in the United States is approximately $18 billion; the estimated annual total cost is approximately $34 billion, including direct costs such as health care services and medications and indirect costs such as lost productivity (Benjamin et al., 2017). In a population-based study of patients who survived 30 days after a first-ever stroke, approximately one third remained disabled, with one in seven patients requiring permanent institutional care (Hankey, Jamrozik, Broadhurst, Forbes, & Anderson, 2002).
The most common type of stroke is acute ischemic stroke (AIS), which accounts for 87% of all strokes (Benjamin et al., 2017). Ischemic stroke is caused by a blood clot or blockage in a cerebral artery that interrupts blood flow to the brain, resulting in neurological dysfunction (Sacco et al., 2013). Alteplase is a recombinant human tissue plasminogen activator approved for management of AIS (“Activase (alteplase),” 2017). Alteplase causes fibrin degradation and thrombolysis by binding to fibrin in a thrombus and stimulating fibrin-bound plasminogen to active plasmin (“Activase (alteplase),” 2017). In clinical trials, patients who received alteplase within 3 hr of stroke onset were more likely to have minimal or no disability as well as improved Barthel Index, modified Rankin Scale, Glasgow Outcome Scale, and National Institutes of Health Stroke Scale scores at 3 months compared with those who received placebo (Lees et al., 2010; National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995). The American Heart Association (AHA)/American Stroke Association (ASA) guidelines for early management of patients with AIS recommend administration of intravenous alteplase within 0–4.5 hr after onset of ischemic stroke in eligible patients (Powers et al., 2018). In 2016, the AHA/ASA published an advisory statement on the scientific rationale behind the inclusion and exclusion criteria for intravenous alteplase treatment of AIS and administration of alteplase within 3–4.5 hr after stroke onset (Demaerschalk et al., 2016). Eligibility criteria are similar to what is advised in the U.S. Food and Drug Administration (FDA) label, with the following additional exclusion criteria: patients older than 80 years, those receiving oral anticoagulants regardless of international normalized ratio, those with a baseline National Institutes of Health Stroke Scale score more than 25, those with imaging evidence of ischemic injury involving more than one third of the middle cerebral artery territory, and those with a history of both stroke and diabetes mellitus (Demaerschalk et al., 2016).
Alteplase is the first FDA-approved recombinant human tissue plasminogen activator that is also indicated for treatment of acute myocardial infarction (AMI) and acute massive pulmonary embolism (PE) (“Activase (alteplase),” 2017). Other recombinant tissue plasminogen activators have since been approved for AMI, including the modified recombinant human tissue plasminogen activators tenecteplase (“TNKase (tenecteplase),” 2017) and reteplase (“Retavase (reteplase),” 2017). Recent clinical studies have demonstrated comparable efficacy and safety of tenecteplase and alteplase in patients with mild AIS (Huang et al., 2015; Logallo et al., 2017). Neither tenecteplase nor reteplase is FDA approved for use in AIS; however, the AHA/ASA guidelines recommend that tenecteplase may be considered as an alternative to alteplase in patients with minor neurological impairment and no major intracranial occlusion, even though tenecteplase has not been proven to be superior or noninferior to alteplase (Powers et al., 2018).
Between 2000 and 2014, the FDA received 21 reports of medication errors involving alteplase and tenecteplase (Tu, 2015). Reports of accidental substitution of reteplase for alteplase have also been documented (Scott & Davis, 2001). In patients with AIS, wrongful administration of tenecteplase or reteplase instead of alteplase results in failure to treat patients using a drug with known effectiveness and the potential for overdose, particularly with respect to tenecteplase (Institute for Safe Medication Practices [ISMP], 2015). Tenecteplase overdose may increase the risk of intracranial hemorrhage, retroperitoneal bleeding, extended hospitalization, and death (ISMP, 2015; Tu, 2015). The objective of this review is to compare the clinical features of alteplase, tenecteplase, and reteplase and to provide steps to reduce medication errors in administration of alteplase for AIS.
INDICATION, MODE OF ADMINISTRATION, AND DOSING
Alteplase is the only tissue plasminogen activator approved for AIS after excluding intracranial hemorrhage. Neither tenecteplase nor reteplase is approved for treatment of AIS or PE. Alteplase is administered by intravenous infusion, with dose and infusion time dependent on the indication; dosing for AIS and AMI is also based on patient weight (see Table 1; “Activase (alteplase),” 2017). In patients with AMI, alteplase should be administered as soon as possible after symptom onset by one of two administration regimens (see Figure 1; “Activase (alteplase),” 2017). The clinical outcomes of alteplase administration by accelerated or 3-hr infusion in patients with AMI have not been compared in controlled clinical studies.
Table 1. -
Overview of plasminogen tissue activators
||Mode of administration
||Timing of administration
|Activase (alteplase, 2017)
|IV infusion, with dose and infusion time dependent on indication
||For AIS, as soon as possible but within 4.5 hr of onset of symptomsb
For AMI, as soon as possible after onset of symptoms by one of two administration regimens
For PE, as soon as possible after onset of symptoms
|For AIS, 0.9 mg/kg (90 mg or less total dose) infused over 60 min, with 10% of total dose administered as initial bolus over 1 min
For AMI, refer to for dosing regimens
For PE, 100 mg administered over 2 hr
|TNKase (tenecteplase, 2017)
||Single IV bolus over 5 s
||As soon as possible after onset of symptoms
||30 mg for patients less than 60 kg
35 mg for patients 60 kg or more to less than 70 kg
40 mg for patients 70 kg or more to less than 80 kg
45 mg for patients 80 kg or more to less than 90 kg
50 mg for patients 90 kg or more
|Retavase (reteplase, 2017)
||IV bolus injection over 2 min
||As soon as possible after onset of symptoms
||Two 10-unit (17.4 mg) bolus injections, each administered over 2 min
Second injection should be administered 30 min after the first injection
Note. AIS = acute ischemic stroke; AMI = acute myocardial infarction; IV = intravenous; PE = pulmonary embolism.
aManagement of AMI, including reduction of mortality and incidence of heart failure and lysis of acute massive PE, defined as embolism obstructing blood flow to a lobe or multiple lung segments or embolism accompanied by unstable hemodynamics (e.g., failure to maintain blood pressure without supportive measures).
bThis is the guideline recommendation per the American Heart Association and the American Stroke Association.
cManagement of AMI, including reduction of mortality associated with AMI.
dTreatment of ST-elevation AMI to reduce risk of death and heart failure.
For AMI, tenecteplase is given as a single intravenous bolus for 5 s (“TNKase (tenecteplase),” 2017), with the recommended dose based on patient weight (“TNKase (tenecteplase),” 2017). The maximum recommended dose for alteplase (90 mg; “Activase (alteplase),” 2017) in AIS is higher than the maximum labeled dose for tenecteplase (50 mg; “TNKase (tenecteplase),” 2017); thus, tenecteplase overdose may occur if a patient inadvertently receives tenecteplase instead of alteplase using the alteplase weight-based dosing regimen (i.e., administering tenecteplase at the alteplase dose would be almost double the highest recommended tenecteplase dose).
Reteplase is administered by intravenous bolus injection as two 10-unit doses 30 min apart, which should be started quickly after onset of AMI symptoms (“Retavase (reteplase),” 2017). Accidentally administering 100 units of reteplase instead of alteplase would be less likely to occur than accidentally administering 100 mg of tenecteplase, given that the reteplase and alteplase dosing units are different and the reteplase vial size (each vial contains 10 units = 34.8 mg) would require 2.9 vials to be administered for a single-bolus injection.
Alteplase is provided as a preservative-free, sterile, lyophilized powder in 50-mg vials with a vacuum or 100-mg vials without a vacuum (see Table 1). To make the solution for injection, each vial is packaged with a 50- or 100-ml vial, respectively, of sterile water USP; 100-mg vials are also accompanied by a transfer device for reconstitution and a clear plastic hanger to facilitate infusion from the vial. After reconstitution, each vial will contain alteplase 1 mg/ml; if necessary, the alteplase solution can be further diluted with an equivalent amount of 0.9% sterile saline injection, USP, or 5% dextrose injection, USP.
Tenecteplase is provided as a preservative-free, sterile, lyophilized powder in 50-mg vials under partial vacuum, with a 10-ml vial of sterile water for making the solution for injection, USP, a 10-ml syringe with Twinpak dual-cannula device (Becton Dickinson, Franklin Lakes, NJ) for reconstitution and administration, and three alcohol preparation pads (see Table 1). Tenecteplase should be administered as a reconstituted 5-mg/ml solution.
Reteplase is supplied in a full- or half-kit configuration with preservative-free, sterile, lyophilized powder in 10-unit vials without a vacuum with components for reconstitution and delivery (see Table 1). The full kit contains the components for a single dosing regimen (i.e., two 10-unit bolus injections), including two 10-unit vials of reteplase, two 10-ml prefilled syringes of sterile water for injection, USP, two syringe plungers, two 10-ml graduated syringes, and two sterile reconstitution spikes, whereas each half kit contains one of each component. After reconstitution, each reteplase vial contains 10 ml of reteplase 1 unit/ml (i.e., one 10-unit bolus injection) plus a small amount of extra solution to ensure sufficient drug for administration.
A primary contributing factor to tissue plasminogen activator drug errors is use of the abbreviation “TPA” (ISMP, 2015; Scott & Davis, 2001; Tu, 2015). “TPA” (or “tPA”) is the abbreviation commonly used for “tissue plasminogen activator.” However, health care professionals often use “TPA” to refer specifically to alteplase because it was the first FDA-approved recombinant human tissue plasminogen activator; in addition, alteplase is often referred to as “TPA” in published literature. Because “TPA” is the abbreviation used for the drug class that encompasses all tissue plasminogen activators, use of “TPA” in written or verbal prescriptions may lead to confusion regarding the intended agent. In addition, health care professionals may refer to tenecteplase as “TNK,” an abbreviation of the tenecteplase brand name TNKase (Genentech, Inc., South San Francisco, CA); however, “TNK” has been frequently confused with “TPA,” further increasing the potential for medication error (Tu, 2015). “TPA,” “tPA,” and “TNK” are listed in the ISMP list of error-prone abbreviations, symbols, and dose designations and the list of high-alert medications in acute care settings (ISMP, 2018a,2018b).
Both the FDA and the ISMP recommend using full brand or generic names for the approved tissue plasminogen activators in prescriptions, order sets, treatment protocols, and published literature (see Table 2; ISMP, 2015; Tu, 2015). The abbreviation “TPA” should not be used for written prescriptions or verbal orders for alteplase. Similarly, the abbreviation “TNK” should not be used to prescribe tenecteplase; the full brand name TNKase or full generic name tenecteplase should be used in written prescriptions and verbal orders. The ISMP also recommends including the indication on written prescriptions (ISMP, 2015). Because alteplase is the only tissue plasminogen activator approved for management of AIS and PE, including the indication may help reduce confusion in prescriptions for patients with these conditions. Separate order sets can be established for each indication (i.e., AIS, AMI, and PE). In addition, hospital pharmacy formularies could be limited to one fibrinolytic agent if possible. If more than one agent is available, using a pocket in an automated dispensing machine that is sized to fit only one treatment dose of a fibrinolytic could be a possibility. Similarly, for institutions that use smart pumps for dosing, the indication can be used for correct selection.
Table 2. -
Strategies for preventing medication errors when administering alteplase, tenecteplase
, or reteplase
|Use of abbreviations: Confusion with “TPA” vs. “TNK” vs. “tPA”
||Use full brand or generic names for approved tissue plasminogen activators in prescriptions, order sets, treatment protocols, and published literature
Use “look-alike–sound-alike” medication lists to raise awareness of confusing medication names, including bolded tall man letters to draw attention to dissimilarities and additional warning labels
||Include indication on prescription
||Establish separate order sets for each indication (i.e., AIS, AMI, and PE)
For hospitals with computerized physician order entry systems, discourage written orders
||Limit hospital formulary to one fibrinolytic agent if possible
|Smart pumps for dosing
||Include indication on pumps
||Entering order and bar code scanning before drug administration, if door-to-needle times will not be compromised
Use stroke boxes that contain alteplase and other materials needed for alteplase administration
Perform brief “time-out” immediately before drug administration that includes patient name, drug name, dose, and indication
Request that a second provider verify correct dose, drug, and indication
Use a consistent clinical staff to administer alteplase in AIS
|Automated dispensing machines
||Activate alert to ensure that correct drug is being acquired
Include indication with drug name in display
If more than one is available, use pocket that is sized to fit only one fibrinolytic
|Regular review of medication errors
||Review information about medication safety risks that have occurred in organizations outside your facility, and take action to prevent similar errors
Establish a primary contact within your organization who is responsible for coordinating this review to determine appropriate actions and document decisions accordingly
Note. AIS = acute ischemic stroke; AMI = acute myocardial infarction; PE = pulmonary embolism; TNK = tenecteplase; tPA = tissue plasminogen activator.
Both the FDA and the ISMP require participating hospitals to have “look-alike–sound-alike” medication lists to raise awareness of confusing medication names. They recommend using bolded tall man letters to draw attention to dissimilarities with look-alike names (e.g., predniSONE vs. prednisoLONE; ISMP, 2018c). Additional warning labels could be included to alert staff to look-alike or sound-alike drugs, particularly in hospitals that have limited technology. For hospitals with computerized physician order entry systems, written orders could be discouraged in general to prevent confusion. If door-to-needle times will not be compromised, entering an order and bar code scanning the medication before administration can be considered. If the medication is stored in an automated dispensing machine, an alert can be activated to ensure that the correct medication is being acquired.
Other factors contributing to drug errors among tissue plasminogen activators may include similar settings of use, such as emergency departments and critical care areas; approval of alteplase, tenecteplase, and reteplase for treatment of AMI; inadequate knowledge of or experience with multiple tissue plasminogen activators; lack of understanding of the differences among tissue plasminogen activators; stocking of a single tissue plasminogen activator for cardiac use in emergency departments; and/or use of automated drug-dispensing systems that may or may not recognize “TPA” or “tPA” (Cohen & Smetzer, 2015; ISMP, 2015; Scott & Davis, 2001). Additional steps to reduce errors may include revision of stroke treatment protocols to reduce the chance of drug substitutions, increased physician and staff education on the differences among tissue plasminogen activators, and addition of alerts in electronic prescriber order entry systems or automated medication-dispensing systems to ensure selection of the correct agent (Cohen & Smetzer, 2015; ISMP, 2015; Scott & Davis, 2001). Several strategies to prevent medication errors are summarized in Table 2.
Three tissue plasminogen activators are FDA approved for treatment of AMI: alteplase, tenecteplase, and reteplase; among these, only alteplase is also approved for management of AIS. Because of different indications and dosing regimens among these tissue plasminogen activators, accidental administration of tenecteplase or reteplase instead of alteplase in patients with AIS can result in failure to administer the most effective treatment and increase the risk of overdose. To avoid confusion and reduce the likelihood of errors, full brand or generic names should be used in written prescriptions, verbal orders, and publications and the abbreviations “TPA” and “TNK” should be avoided. Additional steps to reduce wrongful administration of tissue plasminogen activators include increased physician and staff education and use of alerts in electronic prescriber order entry systems or automated medication-dispensing systems.
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