Author: Lauren Koscal, PharmD Candidate 2019, St. Louis College of PharmacyMentor: Emily Cooke, PharmD, BCPS, Barnes-Jewish Hospital – St. Louis
Antibiotics are among the most commonly prescribed medications, with a high prevalence of utilization by pregnant women.1 Due to the potential for both maternal and fetal side effects, it is imperative to balance both safety and efficacy of antibiotics in these patients. Guidelines recommend utilization of antibiotics only when the indication is present and there is a clear benefit to treatment.2 Untreated infections, specifically urinary tract infections, present serious complications including progression to pyelonephritis, pre-term labor, low birth weight, acute respiratory distress syndrome and sepsis.1 In 2014, the CDC reported the most frequently dispensed antibiotics in the United States during the first trimester of pregnancy were nitrofurantoin (34.7%), ciprofloxacin (10.5%), cephalexin (10.3%), and sulfamethoxazole-trimethoprim (SMZ-TMP) (7.6%).3 Despite frequent use, there are limitations and debate surrounding the evidence recommending use of these antibiotics.
Literature supports the use of penicillins, cephalosporins, and erythromycin in pregnant women based on the low potential for fetal and maternal consequences.2 Generally, serum levels of antibiotics are lower in pregnancy as a result of increased renal clearance and expanded maternal intravascular volume, reducing potential exposure to the fetus.1 In contrast, it is known that tetracyclines should be avoided after the 16th week of pregnancy due to reported incidences of fetal tooth discoloration, dose related hepatotoxicity, and inhibition of bone growth in the second and third trimesters.4 Safety data and recommendations surrounding other antibiotics in this patient population are not as clear.
Controversy still exists regarding the safety of both SMZ-TMP and nitrofurantoin during pregnancy. The National Birth Defects Prevention Study conducted in 2009 was the first major publication to associate SMZ-TMP and nitrofurantoin with several birth defects.The authors analyzed 13,155 women who had pregnancies affected by at least one major birth defect and concluded that nitrofurantoin use led to an increased prevalence of several fetal birth defects including hypoplastic left heart syndrome, ophthalmic malformations, atrial septal defects, and cleft lip. Additionally, SMZ-TMP use was associated with the greatest number of birth defects including anencephaly, left-sided heart defects, choanal atresia, transverse limb deficiency, and diaphragmatic hernia.5 Despite statistically significant data, applicability is limited based upon study design. First, study participants were provided questionnaires up to 24 months after birth contributing to potential recall bias. Secondly, antibiotic regimen, co-morbidities, and other concurrent medications were not recorded. Finally, concurrent infection could have contributed to the birth defects seen in this study. Thus, the decision to avoid use of SMZ-TMP and nitrofurantoin during pregnancy based on this study alone is questionable.
Sulfamethoxazole-TrimethoprimSMZ-TMP is composed of sulfamethoxazole, which inhibits dihydropteroate synthase, and trimethoprim, an inhibitor of dihydrofolate reductase. These two drugs synergistically reduce folate synthesis in microorganisms leading to its bactericidal activity. SMZ-TMP crosses the placenta presenting the potential for fetal adverse events.6 The 2001 Hungarian Case-Control Surveillance Study targeted 38,151 women within three months postpartum with reported congenital abnormalities. The results showed a statistically significant increase in incidence of neural tube defects (0.8%), cleft lip/palate (0.6%), and urinary tract abnormalities (0.7%) associated with SMZ-TMP use in the first month of pregnancy and cardiovascular abnormalities (0.5%) in the second to third months.7 It is important to note that the observed prevalence of these abnormalities are comparable to those in the general United States population: neural tube defects (0.15%), cleft lip/palate (0.06%), genitourinary abnormalities (0.86%), and cardiovascular abnormalities (1.1%).8 A limitation of this study is the potential for the patient’s underlying infection and concomitant medication exposures during pregnancy to contribute to the observed fetal complications. Hansen and colleagues tackled this controversy by comparing fetal outcomes in patients administered SMZ-TMP versus penicillins, cephalosporins, or no antibiotic exposures. Recall bias was eliminated through the use of medical record review and pharmacy dispensing data and confounding was mitigated through randomized matching of exposure groups based on indication, age, and health plan. The authors compared outcomes in 20,064 patients and found no statistically significant associations with SMZ-TMP use and congenital abnormalities during the first trimester of pregnancy, including the previously observed differences with cleft lip/palate, club foot, urinary system, and cardiovascular abnormalities. 9 Overall, current evidence indicates that treatment with SMZ-TMP in the first trimester of pregnancy is safe in patients with a confirmed infection.
NitrofurantoinNitrofurantoin is the most frequently prescribed antibiotic during the first trimester of pregnancy, despite discrepancies in the evidence that support its safety. It is utilized primarily for the treatment of urinary tract infections and damages bacterial DNA through its conversion to reactive intermediates that attack ribosomal proteins, DNA, and other macromolecules within the cell. Nitrofurantoin rapidly crosses the placenta; however, it does so in low concentrations and readily disappears from the fetal circulation.10 Kallen and colleagues described an association between nitrofurantoin and increased risk for cardiac deficits; however, differences may have been due to confounding factors.11 Nordeng and colleagues utilized the Medical Birth Registry of Norway and a prescription database to look at differences in outcomes between nitrofurantoin, pivmecillinam, and no antibiotic. There was no observed increased risk of low birth weight, pre-term delivery, survival, or congenital abnormalities with nitrofurantoin use, although minor malformation were not assessed.12 Additionally, Goldberg and colleagues conducted a systematic review of 32 studies in a qualitative synthesis and eight studies in quantitative synthesis that analyzed nitrofurantoin use during the first trimester. Even with the inclusion of the 2009 National Birth Defects Prevention Study, the investigators did not find a statistically significant association between nitrofurantoin and craniosynostosis, oral cleft, or cardiovascular defects. Although assessment of the cohort studies showed no difference in major malformations with nitrofurantoin use, there was a statistically significant increase in major malformations within the three case-control studies.13 Synthesis of the data regarding nitrofurantoin indicates use is safe during all trimesters of pregnancy, but caution could be taken during the first trimester.
ConclusionDespite mixed evidence, the 2011 American College of Obstetricians and Gynecologists (ACOG) guidelines report SMZ-TMP and nitrofurantoin are safe to use in the second and third trimesters of pregnancy. They also permit utilization in the first trimester if there are no alternative options for the patient.2 Due to the ethical issues associated with randomized controlled trials, decisions must be extrapolated from limited observational studies that contain several limitations and flaws in study design. Although studies have reported statistically significant increases in birth defects associated with SMZ-TMP and nitrofurantoin exposure, overall prevalence of these congenital abnormalities are low compared to outcomes associated with untreated infections. The current body of evidence supports use of these antibiotics for the shortest effective duration in patients with an appropriate indication at any point during pregnancy. Health care professionals should use clinical judgment when initiating SMZ-TMP and nitrofurantoin during the first trimester of pregnancy if other options are available; however, as the above evidence indicates, practitioners can feel comfortable utilizing these agents in this patient population.
Authors: Rahima Hussien, PharmD Candidate 2019, UMKC School of PharmacyEric Wombwell, PharmD, UMKC School of Pharmacy
Ureaplasma is a small, self-replicating bacteria that belongs to the class of bacteria called Mollicutes or more frequently referred to by the term “atypical bacteria”.1 This group of bacteria, including Ureaplasma, are considered atypical due to their absence of cell wall. Similar organisms without cell wall include Chlamydia spps., Mycoplasma spps., and Legionella spps. The absence of a cell wall makes it difficult to identify the presence of these bacteria using normal laboratories procedures. Gram staining procedures are dependent on the presence of a cell wall for identification and culturing requires complex nutrition media. Therefore, they are not observed in routine clinical practice.
The genitourinary presence of Ureaplasma spps. has been reported in 40-80% of asymptomatic sexually active women.2 It is broadly considered a colonizing bacteria with limited inflammatory activity. Despite not routinely causing infection, Ureaplasma spps. are known contributors to male urethritis, epididymitis, and prostatitis, as well as, cystitis, pyelonephritis, and bacterial vaginitis in women.3,4 An association with several other diseases has been observed but causation is questionable based on the evidence. For instance, an association for pathogenesis in immunocompromised populations specifically premature infants and adults with hypogammaglobulinemia has been observed. In the neonatal population it has been associated with severe infections, primarily pulmonary complications like pneumonia.5,6 Finally, there are reported associations between the genitourinary presence of Ureaplasma during pregnancy and negative perinatal outcomes such as miscarriage, stillbirth, preterm delivery, wound infection post-cesarean, and postpartum bacteremia and fever. 7-9
Ureaplasma spps. are more common in females compared to males. Other risk factors for ureaplasma include increased sexual partners, increased sexual activities, low socioeconomic status, and immunocompromised patients.1,10-11 Ureaplasma is transmitted by sexual contact, directly from mothers to infants during birth or during pregnancy, and directly from transplant tissue.11,12
There are no distinguishing symptoms specific to Ureaplasma spps. According to Horner et al, Ureaplasma detection was associated more often in patients that have developed chronic nongonococcal urethritis 30 to 92 days after treatment with signs and symptoms.13 Additive suspicion may include patients with multiple sexual partners. A culture and PCR is recommended for diagnosis using swabs from urethral, semen, urine, cervix, or vagina to detect Ureaplasma.14 Culture require more sophisticated methods including complex nutrition media and most hospitals and labs may not be prepared to culture these organisms. PCR assay is the most sensitive method to detect Ureaplasma, but frequently lack specificity due to colonization of specimen sites with multiple organisms. Due to the difficulty in identification most patients, in which suspicion is present, receive empiric treatment.
In addition, the lack of cell wall eliminates antimicrobial treatments which target cell wall such as beta-lactams. Ureaplasma is susceptible to antimicrobials that inhibit protein syntheses such as macrolides (azithromycin) and tetracyclines (doxycycline); and agents that inhibit DNA replication (fluoroquinolone). Most treatment resources recommend either doxycycline or azithromycin at normal recommend doses and durations based on site of infection for empiric treatment. A randomized controlled trial evaluated the activity of azithromycin and doxycycline in various atypical pathogens in 606 men ≥ 16 years with nongonococcal urethritis.15 Overall response rates were 80% (CI, 74%-85%) receiving azithromycin and 76% (CI, 70%-82%) receiving doxycycline, no difference observed (P = 0.40). Similar response rates were noted in the Ureaplasma indentified cases, 75% vs 70%, no statistical difference observed (P = 0.50).
Definitive diagnosis of Ureaplasma is difficult due to lack of differentiating symptomatology and limited available and reliable testing methods. In patients concerning for Ureaplasma empiric treatment with doxycycline and azithromycin as an alternative is appropriate. However, patients found to be colonized without clinical symptoms do not require treatment.
Authors: Jung Clayton, PharmD Candidate 2019, St. Louis College of PharmacyRebecca Nolen, PharmD, BCPS, AAHIVP, SSM Health St. Mary’s Hospital - St. Louis
Fluoroquinolones are among the most prescribed antibiotics, with a broad spectrum of activity against Gram negative organisms, some Gram-positive organisms, and sometimes Pseudomonas. These properties of fluoroquinolones combined with convenient dosing frequencies, good oral absorption, and low cost have contributed to their overutilization in clinical practice as well as the emergence of resistant strains.1
Over the years, fluoroquinolones have been associated with several adverse events of varying severities and incidence rates. In some cases, tolerability concerns have led to the withdrawal of select fluoroquinolones from the market. The most common adverse events involve the gastrointestinal tract (nausea, diarrhea) and the central nervous system (CNS) (headache, dizziness), which are usually mild and tolerable. Severe adverse events involving the endocrine system, musculoskeletal system, cardiovascular system, renal system, and the CNS have been more commonly associated with fluoroquinolones than with other antimicrobial classes.2 Because the risk of these serious adverse events generally outweighs the benefit for patients with uncomplicated infections, the FDA advises that fluoroquinolones be reserved for patients with no alternative treatment options. Some appropriate indications for fluoroquinolones include bloodstream infections (oral option), osteomyelitis (oral option), anthrax, Yersinia pestis infection, treatment of organisms that are not susceptible to other antibiotics, or if the patient has anaphylaxis to cephalosporins. This article addresses the risks associated with fluoroquinolones and potential alternative agents (if susceptible).
Risks associated with Fluoroquinolones Hypoglycemia3(Most recent FDA update 07/2018)Recently, the Food and Drug Administration (FDA) conducted a safety review based on postmarketing adverse event reports found in the FDA Adverse Event Reporting System (FAERS) database and published medical literature. This review found reports of life-threatening hypoglycemia, leading to updated warnings in the prescribing information for the fluoroquinolone class. In a FAERS search from 1987 and 2017, 67 reports of fluoroquinolone-associated hypoglycemic coma were found, including 13 deaths and 9 events leading to permanent disability. Most affected patients had hypoglycemia risk factors, including diabetes, old age, renal insufficiency, and concomitant use of hypoglycemic drugs. The FDA determined that the serious risks associated with the use of fluoroquinolones for uncomplicated infections generally outweigh the benefits and recommends against using fluoroquinolones to treat these infections in patients with alternate treatment options.
CNS Effects3(Most recent FDA update 07/2018)An FDA safety review of psychiatric adverse events related to fluoroquinolones found that drug labels did not adequately warn of all potential side effects. In addition to the previously listed side effects of nervousness, agitation, and disorientation, the FDA now requires manufacturers to include three new adverse effects: disturbance in attention, memory impairment, and delirium.
Tendinopathy/Tendon Rupture(Most recent FDA update 10/2008)Fluoroquinolones have long been associated with tendinopathy, particularly Achilles tendon rupture, with the earliest published case-report dating back to 1983.4 Since then, evidence of fluoroquinolone-associated tendinopathy has been increasing.5 As of 2008, the FDA has required black box warnings for all fluoroquinolones indicating an increased risk of tendon rupture. Fluoroquinolones are an independent risk factor for developing tendinopathy, but concomitant risk factors such as age greater than 60 years, corticosteroid therapy, renal failure, diabetes mellitus, and a history of tendinopathy exacerbate the risk.6,7 Excessive loading of tendons during vigorous physical training have been cited as the main pathologic stimuli inducing tendinopathy.8 Vigorous exercise puts a patient at risk of developing tendinopathy which can then be exacerbated by fluoroquinolones. To avoid debilitating tendinopathy, prescribers should avoid using fluoroquinolones in athletes and other patients with a history of vigorous physical activity.9
Peripheral Neuropathy10(Most recent FDA update 08/2013)Peripheral neuropathy is an identified risk of fluoroquinolones and has been listed on all drug labels for systemic fluoroquinolones since 2004. Following a FAERS review showing a continued association of fluoroquinolone use and disabling peripheral neuropathy between 2003 and 2012, the FDA required updates to the labels for all fluoroquinolones to describe the potential for irreversible peripheral neuropathy. According to the review, the onset of nerve damage rapidly followed the initiation of fluoroquinolone therapy, often within a few days, and in some cases persisted for more than a year after the medication was discontinued. A study published in 2014 found that current users of fluoroquinolones were at higher risk of developing peripheral neuropathy, and that the risk was greater for patients who were fluoroquinolone naive (RR = 2.07; 95% CI 1.56 to 2.74).11
Myasthenia gravis12(Most recent FDA update 02/2011)Antibacterials are the drugs most implicated as triggers of acute myasthenia gravis exacerbation. Fluoroquinolones specifically exhibit neuromuscular blockade, which is a pathophysiological mechanism for drug-induced exacerbations of myasthenia gravis. The FAERS search conducted in 2011 identified 37 unique cases of acute exacerbation following systemic fluoroquinolone exposure, including 19 patients experiencing dyspnea, 11 requiring ventilatory support, and 2 deaths. Onset of exacerbations were rapid, with a median onset of one day following fluoroquinolone exposure. Recurrent myasthenia gravis exacerbation was seen in some patients who were reintroduced to fluoroquinolones.
(Most recent FDA update 05/2017)Fluoroquinolones have been shown to induce degradation and reduce de novo production of collagen,13 which is heavily involved in keeping an intact extracellular matrix of the aorta. The pathophysiology of aortic aneurysm is known to involve excessive breakdown of the matrix. A retrospective cohort study published in January 2018 found an increased risk of aortic aneurysm or dissection with fluoroquinolones within a 60-day risk period (HR 1.66; 95% CI 1.12 to 2.46).14 Those findings are supported by a recent case-crossover study published in September 2018 where the overall 60-day risk was found to be increased with fluoroquinolone exposure (OR 2.52; 95% CI 1.44 to 4.44).15
QTc Prolongation2,16Fluoroquinolones have been long associated with QT prolongation due to inhibition of cardiac voltage-gated potassium channels encoded by the KCNH2 gene. QT prolongation is associated with an increased risk of Torsades de Pointes (TdP). All fluoroquinolones inhibit this channel; however the magnitude of prolongation varies. It has been shown that the risk of QT prolongation (and consequently the risk of TdP) is relative to the fluoroquinolone dose and serum AUCs. The average QT prolongation associated with fluoroquinolones has little effect against normal QT interval, but the risk of developing TdP is greater in a patient with pre-existing QT interval prolongation due to hypokalemia, hypomagnesemia, heart failure, arrhythmia, or other medications.17
Clostridium difficile-associated diarrheaAntibiotic treatment is a major risk factor for C. difficile-associated diarrhea (CDAD). All systemic antibiotics have been known to increase the risk of CDAD by disrupting the normal intestinal flora. Fluoroquinolones in particular have been associated with higher rates of CDAD. In a retrospective cohort study of CDAD cases in Quebec from 2003 to 2004, fluoroquinolones were reported to be the antibiotic class with the highest risk of inducing CDAD (AHR = 3.44; 95% CI 2.65 to 4.47).18 Increased risk of CDAD with fluoroquinolones is explained by a genomic analysis of C. diff indicating that the bacterium lacks genes for topoisomerase IV which is one of the target sites of fluoroquinolones.19,20 A highly virulent strain of C. diff referred to as NAP1/B1/027 demonstrates high-level fluoroquinolone resistance as a result of a single amino acid substitution in the DNA gyrase subunit. In a study conducted in Quebec and Ontario, researchers found the NAP1 strain present in 62.7% of CDAD patients and in 36.1% of colonized patients.2
Author: Jackie Harris, PharmD, BCPSR&E Foundation Chair/St. Louis College of Pharmacy/Christian Hospital Northeast
UMKC, St. Louis College of Pharmacy, and MSHP are co-hosting a reception at the ASHP Midyear Clinical Meeting on Monday December 3rd at the Marriott Anaheim from 6-8pm. Please plan to attend the Missouri reception to meet with friends and colleagues from across the state and to hear updates from each of the host organizations. Awards will be presented to two students from UMKC and two students from St. Louis College of Pharmacy who won their local Clinical Skills Competition at their colleges earlier this fall. These students will represent their respective colleges by competing in the ASHP Clinical Skills Competition at the ASHP Midyear Clinical Meeting on Saturday December 1st. The MSHP R&E provides the $150 award for each of the students to offset their travel cost to the competition.
This year the MSHP R&E will be providing free drink tickets for donations made to the R&E Foundation. These donations go directly to providing support to these awards as well as the Best Practice Award, Garrison Award, Best Resident Project, and poster awards presented during the MSHP Spring Meeting. For every $25 donation made to the MSHP R&E prior to the reception, you will be given a ticket for a free drink at the reception. Please go to the MSHP website to make your donation today to benefit students and to receive a beverage to enjoy as you catch up with friends at the Missouri Reception. Donations will also be accepted onsite, but save some time and donate online. We can't wait to see you at the reception!
Author: Sarah Cox, PharmD, MSMSHP Public Policy Chair/Assistant Professor, UMKC School of Pharmacy at MU
MSHP sends representatives to ASHP Legislative Day and ASHP Policy Week each year. This year’s attendee’s included Roy Guharoy, Kat Miller, Lynn Eschenbacher, and Laura Butkievich. These important events allow ASHP members to promote pharmacy-related issues to legislators and lead to the development of policies that ASHP supports as an organization.
Legislative Day topics that were highlighted on Capitol Hill this year include:
ASHP Policy Week focused on the following major issues:
MSHP legislative priorities for Missouri align perfectly with the initiatives ASHP supports on the national level. These include advancing policies for the pharmacy technician workforce and expanding pharmacist responsibilities.
Authors: Ashley Evans, PharmD, BCACP
MSHP Membership Chair/Mercy Hospital – Springfield, MO
Sarah Cook, PharmD, BCPS
MSHP Newsletter Chair/SSM Health St. Joseph Hospital – St. Charles
The Membership and Newsletter Committees are pleased to share some of the results from the 2018 MSHP Annual Survey. This was the first year that the membership and newsletter surveys were combined. There was an excellent response this year with 102 members answering the survey.
Reasons for Being InvolvedNetworking was again selected by respondents as the primary reason for involvement in MSHP.
Top three reasons for being involved in MSHP:
Meetings, CE, and leadership opportunities were also frequently ranked by responders as top three membership benefits.
Organization ActivitiesOverall, responders felt that MSHP is doing a good job fulfilling most organization activities.
Most important MSHP activities per responders:
MSHP activities which the organization is best fulfilling:
Newsletter ContentApproximately 65% of responders read the newsletter ≥75% of the time.
Top three types of articles read:
The top ranked topics of interest for featured clinical articles were grouped together and designated for particular issues in 2019 (see end of the newsletter for further information). Precepting and Transitions of Care also ranked high on the list, and the committee will be soliciting submissions for these topics with a goal of having at least two articles regarding each in 2019.
Top Priorities for Coming Year:
Top Areas for Improvement:
The majority of members are responsible for paying their own dues and feel they receive a good value for their membership dues.
We want to thank all the members that took the time to fill out the survey. These results will be used during the next strategic planning meeting to guide organization initiatives.
We are excited about all the changes that have been happening within MSHP over the past year and look forward to continuing to improve your membership experience!
Overview and Management of Local Anesthetic Systemic Toxicity (LAST) Based on Updated 2017/18 ASRA Practice Guidelines
Author: Alexander Spillars, Pharm.D. Candidate 2019, St. Louis College of PharmacyPreceptor: Rachel C. Wolfe, Pharm.D, BCCCP
OverviewLocal anesthetic therapy has become an increasingly utilized component of multimodal analgesia.1 Potential benefits include decreasing opioid exposure, decreasing postoperative nausea and vomiting, improving patient satisfaction, decreasing hospital length of stay, improving the quality of recovery from surgery, and reducing the risk of chronic postoperative pain.2 Despite the potential benefits, administration of local anesthetics can lead to a rare and potentially fatal event known as local anesthetic systemic toxicity (LAST). Organ systems affected by LAST include the cardiovascular system and/or central nervous system (CNS). The treatment, management, and prevention of LAST is multifactorial and involves multiple pharmacological interventions with lipid emulsion administration as the cornerstone of therapy.
IncidenceThe reported incidence of LAST and its major complications (i.e. seizures and cardiac arrest) is low with data being derived from registry studies, administrative databases, and case reports/case series.3 In 2017, Mörwald et al4 examined the incidence of LAST using an administrative database, surrogate markers, and the International Classification of Disease Codes in nearly 238,500 patients receiving a peripheral nerve block for total joint arthroplasty at over 400 hospitals between 2006 and 2014. The overall incidence of LAST, as defined by the occurrence of cardiac arrest, seizure and/or the administration of lipid emulsion on the day of surgery, was 1.8 per 1000 patients. During the 9-year study period, the overall incidence of LAST trended down, from 8.2 per 1000 in 2006 to 2.5 per 1000 in 2014. Advances in localization techniques, such as ultrasound guided blocks, and implementation of safety steps that reduce intravascular injection of local anesthetics is thought to contribute to this decline. In comparison to administrative databases, a recent review (2018) of clinical registries by Gitman and Barrington claimed a reported incidence of LAST to be 0.3 per 1000 peripheral nerve blocks.5 Though the frequency of LAST is low based on these studies, each institution or clinic utilizing local anesthetics must be prepared to manage such an event, should it occur.
Pharmacology and Pharmacokinetics of Local AnestheticsAll local anesthetics have the potential to cause LAST and it can occur with any route of administration. Pharmacologically, these agents exert their primary effect by blocking voltage-gated sodium channels at the alpha-subunit inside the channel, preventing sodium influx, depolarization, and action potential generation. Blocking this conduction prevents pain transmission from neuronal cells to the cerebral cortex, ultimately producing analgesia and anesthesia.6 Cardiac toxicity occurs when local anesthetics inhibit sodium channels in the myocardium leading to conduction disturbances, ventricular arrhythmias, contractile dysfunction, and ultimately cardiac arrest.7, 8 Neurotoxicity occurs when local anesthetics bind to thalamocortical neurons in the brain. This leads to altered mental status, paresthesia, visual changes, muscle twitching, and seizures.9
The toxicities associated with LAST may present in various ways based on the physiochemical, pharmacokinetic, and pharmacological properties of the local anesthetics. Physiochemical properties such as pKa, lipophilicity, and protein binding contribute to individual pharmacokinetic differences and toxicities among the clinically used agents. A lower pKa indicates a greater proportion of the drug exists in the uncharged state at physiological pH allowing for more drug transfer across the lipophilic cellular membrane to the effector site, which impacts onset time. Lipophilicity correlates to potency. Increased potency of local anesthetics correlates with increased cardiac toxicity, as higher lipophilicity allows for better lipid bilayer penetration to the target receptor. For example, bupivacaine is considered a more potent local anesthetic (higher lipophilicity) versus lidocaine and is therefore more cardiotoxic. Finally, a higher affinity for protein binding decreases the circulating levels of free local anesthetic translating to an increased duration of action (Table 1).10
Clinical PresentationSystemic toxicity from local anesthetic overdose often occurs due to accidental intravascular injection, absorption from a tissue depot, or administration of repeated doses of local anesthetics without balanced elimination. Symptoms of local anesthetic toxicity classically emerge as a progression of adverse effects. Classical symptoms appear as CNS excitement (i.e. prodromal symptoms) followed by seizures then CNS depression. Symptoms then progress to the cardiovascular system, initially presenting as cardiac excitability or depression then leading to arrhythmias and cardiac arrest (Table 2).2, 3 Clinical presentations of LAST do not always follow the classical symptom progression as described above and instead target exclusively either the cardiovascular system or the CNS.
A review of systemic toxicity cases over a 30-year period published by Di Gregorio et al12 revealed that 60% of cases were classic in terms of rapid onset presenting with CNS signs/symptoms followed by cardiovascular signs/symptoms (as outlined in Table 2). Gitman and Barrington5 found that the most common presenting symptom of local anesthetic toxicity was seizures, occurring in 53% and 61% of case reports and registries, respectively. This was followed by combined cardiovascular and CNS symptoms, and lastly by isolated cardiovascular symptoms. Overall, the clinical presentation of LAST is highly variable and should be suspected whenever physiologic changes occur after local anesthetic administration. Heightened vigilance is crucial to detecting toxicity.
Prevention3The American Society of Regional Anesthesia (ASRA) practice advisory guidelines recommends specific strategies and techniques in order to prevent the occurrence of LAST during local anesthetic administration3, these include:
Prevention techniques and active vigilance should always be performed while administering local anesthetics as toxicity could develop, requiring proper treatment and management.
Treatment and Management3, 13Updates from the 2017/18 ASRA practice advisory guidelines recommend the use of IV lipid emulsion therapy as the cornerstone of LAST treatment. The precise mechanism of lipid emulsion therapy in LAST is not fully understood. Current research believes that it acts as a carrier to remove local anesthetic from high blood flow organs that are sensitive to local anesthetics, such as the heart and brain. The complex is then redistributed to organs that store and detoxify the drug, such as the muscle and liver.14 This is known as the “shuttling effect” as positively charged, fat-soluble local anesthetic molecules bind to negatively charged lipid particles.
Updates from the 2017/18 ASRA practice advisory guidelines recommend discontinuing the local anesthetic at the first sign of LAST, managing the airway (to prevent hypoxia, hypercapnia, and acidosis), and then administering lipid emulsion therapy as follows:
The pharmacological treatment of LAST is different from other cardiac arrest scenarios and following ACLS recommendations are not warranted. If cardiac arrest occurs the following recommendations should be utilized per ASRA:
If seizures develop, priority should be placed on initiating lipid emulsion therapy which results in the shuttling of local anesthetic away from the thalamocortical neurons. In addition to lipid emulsion therapy, ASRA guidelines recommends treatment with benzodiazepines. If seizures persist despite benzodiazepine therapy, then administering small doses of propofol is acceptable. Though large doses of propofol should be avoided, as this can further depress cardiac function. Monitoring should occur 4 to 6 hours post-treatment in a patient with a significant cardiovascular event and 2 hours if the event is limited to CNS symptoms that resolve quickly.
SummaryThough LAST is an overall rare event, it can occur after administration of any local anesthetic via any route and can result in potentially fatal cardiac and CNS toxicities. Healthcare practitioners should be aware of the additive nature of these agents, as local anesthetic are often administered to the same patient by different clinicians. Additionally, the use of local anesthetic continuous infusions as part of multimodal analgesic regimens predispose patients to the development of toxicity. Prevention of LAST through proper anesthetic techniques and monitoring of the patient during and after completion of local anesthetic therapy for physiologic and/or hemodynamic changes is key to prompt recognition and treatment of LAST. Lipid emulsion rescue should be readily available in settings in which local anesthetics are utilized to avoid potential fatal events. Pharmacists can assist in updating protocols, electronic medical records, and infusion pump libraries in accordance with the new lipid emulsion dosing in the updated 2017/18 ASRA guidelines to aid in the prevention, treatment, and management of LAST.
Andexanet Alfa: A Novel Reversal Agent for Factor Xa InhibitorsAuthor: Christopher Kimes, Pharmacy Student, University of Kansas School of PharmacyPreceptor: Amy Sipe, PharmD, Kansas City VA Medical Center
BackgroundIn recent years, direct acting oral anticoagulants (DOACs) have been gaining increased utilization due to fewer drug and food interactions and less frequent blood monitoring required than the traditional anticoagulant of choice, warfarin. However, like warfarin, DOACs still possess a risk for acute major bleeds.
Portola Pharmaceuticals’ andexanet alfa (Andexxa®) has recently garnered significant attention for being the first FDA-approved reversal agent for the factor Xa (fXa) inhibitor class of DOACs.1 Given the limited real-world experience in the use of this drug, this overview may serve as useful source for providers to feel more comfortable with its use in practice.
Pharmacology/Mechanism of Action2,3fXa inhibitors produce anticoagulant effects by inhibiting the serine active site of fXa, which is responsible for the conversion of prothrombin into activate thrombin during secondary hemostasis. Direct fXa inhibitors (apixaban, rivaroxaban, edoxaban, betrixaban) act by directly inhibiting the serine active site. Indirect fXa inhibitors (fondaparinux, enoxaparin) act by changing the structure of antithrombin III, which makes it more effective at binding and inhibiting the serine active site (Figure 1).
Figure 1. Interaction of Andexanet Alfa with Drugs and Proteins Involved in the Regulation of fXa Activity.
Andexanet reverses the effects of fXa inhibitors by sequestering these drugs away from fXa, allowing fXa to convert prothrombin into thrombin (Figure 1). Andexanet accomplishes this because it is a modified human fXa protein that acts as a decoy for fXa inhibitors. An important part of andexanet’s design was the removal of the procoagulant properties of fXa (Figure 2). During clinical trials, andexanet was found to possess a procoagulant effect that would potentially increase the risk of thromboembolic events in patients, however, the consequences of this property on clinical outcomes have not been fully studied.3
Figure 2. Comparison of Andexanet Alfa with Factor Xa
IndicationCurrently, andexanet is FDA-approved for the reversal of anticoagulant effects in the event of life-threatening or uncontrolled bleeding for patients on either apixaban or rivaroxaban therapy.1,4 This indication was based largely on the results of the phase III ANNEXA trials, in which test subjects were given only apixaban or rivaroxaban prior to reversal by andexanet.5 Consequently, the FDA did not approve labeling of andexanet as a reversal agent for all fXa inhibitors. Although other fXa inhibitors had been used in animal studies and phase II trials, the FDA cited differences in pharmacokinetic, pharmacodynamic, and in-vivo/ex-vivo properties between anticoagulants as a reason for limiting andexanet use to agents studied in the phase III trials.3
Andexanet received breakthrough designation from the FDA, which accelerated approval based on phase III trials using healthy volunteers and surrogate biomarker as primary efficacy endpoint. The clinical efficacy of andexanet is currently being studied through the prospective, open-label, single-group Phase IV ANNEXA-4 trial.6 Researchers intend to determine the hemostatic efficacy of andexanet in patients suffering an acute major bleed within 18 hours of taking a fXa inhibitor. To assess efficacy, the researchers have established a rating system to classify hemostasis. Given that institutions and providers may disagree with what constitutes excellent or good hemostasis, a review of this rating system is prudent prior to consideration of andexanet use (Table 1).
Table 1. Rating system for assessing hemostatic efficacy utilized in the ANNEXA-4 trial.
Based on this rating system, preliminary data from the phase IV trial indicates an 83% efficacy of achieving excellent or good hemostasis for patients of all bleed types.7 However, most patients suffered from intracerebral (61%) or gastrointestinal (27%) bleeds. Although this satisfies the FDA’s desire for the manufacturer to study the effects of andexanet in patients suffering from an intracerebral hemorrhage,1 it limits the efficacy and safety data for other types of bleeds.
Dosage and AdministrationThe current FDA recommended dosing guidelines were ascertained during the phase II trials and confirmed in the phase III trials. The phase II trials found that the decline in the anti-fXa activity caused by andexanet was correlated to the decline in plasma concentration of the fXa inhibitor.2 This is consistent with andexanet’s mechanism of action. Therefore, the optimal dose of andexanet is dependent upon the steady-state concentration and the volume of distribution of the fXa inhibitor.8 This led to the adoption of using a high dose regimen or low dose regimen of andexanet based on the expected plasma concentration of the fXa inhibitor (Table 2).
Table 2. Andexanet regimens developed in clinical trials and approved for use by the FDA4
Phase III trials proved that andexanet could significantly reverse the anti-fXa activity of apixaban and rivaroxaban. Andexanet showed reduced anti-fXa activity by -94% in apixaban subjects compared to -21% for placebo and by -92% for rivaroxaban subjects compared to -18% for placebo5 (Graph 1). The reduction in anti-fXa activity only took 2-5 minutes after completion of bolus infusion to reach its nadir. This reversal effect was only maintained for the duration of the infusion. Therefore, a continuous infusion after the bolus administration is necessary to maintain a sustained reduction in anti-fXa activity.
Graph 1. Anti-fXa activity of subjects over time during phase III trials. Graph 1 displays the anti-fXa activity of patients with steady state concentrations of apixaban from the phase III trials receiving either (A1) IV bolus of andexanet alone, (A2) IV bolus followed by a continuous IV infusion of andexanet, and (P) placebo. As the graph demonstrates, anti-fXa activity rapidly returns to placebo levels after cessation of andexanet infusion.
Based on efficacy data from phase III trials, FDA labeling recommends that andexanet alfa be given as an initial IV bolus followed by a 120-minute continuous IV infusion4 (Figure 3). None of the clinical trials measured the effectiveness or safety of multidose administration or infusion administration beyond 2 hours, therefore, no efficacy or safety data exists for situations requiring infusions over that 2-hour period
Figure 3. Algorithm based on FDA package insert for andexanet4
SafetyCurrent data from the phase IV trial indicate that 11% of patients suffer a thromboembolic event, while 12% died within 30 days of receiving andexanet. Citing these events and the unexpected ability of andexanet to inhibit TFPI, the FDA issued a Black Box Warning that andexanet was associated with arterial and venous thromboembolic events, ischemic events (including myocardial infarction and ischemic stroke), cardiac arrest, and sudden death.3 The FDA advises that patients given andexanet are monitored for these conditions and that patients should resume anticoagulant therapy as soon as medically appropriate.
There is limited efficacy or safety data for certain patient populations due to the design of the clinical trials. The Phase III trials were performed using only healthy test subjects. The phase IV trials excluded patients who possessed certain medical conditions or were on certain drug therapies.6 The FDA package insert takes into consideration a certain number of these exclusions, however, it does not describe all exclusions in detail. Therefore, it is important for institutions and providers to be familiar with the medical conditions that were excluded from these trials when considering andexanet use (Table 3).
Table 3. Exclusion Criteria for the ANNEXA-4 Trial
Product Availability and Cost4Andexanet is produced from Chinese hamster ovary cells by two biotechnology companies: CMC Biologics (Copenhagen, Denmark) and Lonza (Visp, Switzerland). Concerns with manufacturing capacity and an inability to produce adequate drug quantities was a factor that prevented andexanet from gaining FDA approval in 2016.2 These concerns were addressed in subsequent reviews, however, andexanet will be produced in very limited quantities. Therefore, only a select number of medical facilities (ranging from as low as 10 to as much as 50) will carry this medication.9,10 The manufacturer has stated that andexanet will most likely be limited to medical facilities that participated in ANNEXA-4 trials. There is a possibility that a select few level 1 trauma centers and comprehensive stroke centers will be able to receive this product.9
Andexanet is produced as 100 mg lyophilized powder in single-use vials. It is sold in a package of four vials. The current estimated cost for a single package of four 100mg vials is $11,000.11 At this price point, a low and high dose andexanet regimen will cost $24,750 and $49,500, respectively.
Comparison to Other Available TreatmentsDespite andexanet’s niche role as the first FDA-approved reversal agent for fXa inhibitors, bleeding caused by fXa inhibitors have previously been controlled through other pharmacological agents.12,13 While the procedure for treating bleeds varies by institution, the two most commonly recommended agents include four-factor prothrombin complex concentrates (4FPCC) and activated charcoal. A table containing information on the drug properties, FDA indications, off-label use, current recommend dosing, and research data on these two products are presented below to serve as a reference.14
Table 4. Information on off-label treatments for major bleeds caused by fXa inhibitors.15-22
Despite accelerated approval by the FDA, andexanet remains undergoing scrutiny, as the ANNEXA-4 trial is still underway with no final results or completion. Furthermore, the FDA felt that andexanet’s ability as a reversal agent for fXa inhibitors would be best suited for treating intracranial hemorrhages. Consequently, it has mandated the manufacturer to conduct a postmarketing study to determine the hemostatic efficacy and safety of andexanet on patients suffering from intracranial hemorrhages to be completed by October 31, 2022.
Andexanet alfa garnered significant attention for its novelty. For many, the approval suggested a new era in which life-threatening bleeds caused by fXa inhibitors could be easily reversed with an antidote. However, an overview of andexanet’s drug design, indication, dosing regimen, safety data, and manufacturing logistics seems to paint a more complex picture. Furthermore, ever increasing research data on the off-label use of more easily accessible products may diminish the enthusiasm for the drug. Institutions and practitioners may need to consider these issues when they are reviewing andexanet for use in their patients.
Direct-Acting Oral Anticoagulants (DOACs) use in Patients with Chronic Kidney Disease
Authors: Kaily Kurzweil, Pharm.D. Candidate UMKC School of Pharmacy and Andrew Smith, Pharm.D., FCCP, BCPS, UMKC School of Pharmacy
BackgroundSince the approval of the first direct-acting oral anticoagulant (DOAC), dabigatran in 2010, the management of oral anticoagulation in patients has significantly changed. In the years following its approval, four more agents were approved as well: rivaroxaban, apixaban, edoxaban, and betrixaban.1-5 The introduction of these drugs into practice provides an alternative to warfarin, which has historically been the only option for oral anticoagulation in patients. Where warfarin requires monitoring every 2-4 weeks and frequent regimen modifications, the DOACs do not have any monitoring requirements and rarely require dose adjustments.1-5 The DOACs also have notably less interactions with diet and other medications or supplements. These qualities make the DOACs a more patient and provider-friendly option to those requiring anticoagulation.
The populations that predominantly benefit from the DOACs are patients at risk for a venous thromboembolism (VTE) and those diagnosed with nonvalvular atrial fibrillation (AF) for the prevention of stroke and systemic embolism.1-5 Patients that concurrently have a diagnosis of chronic kidney disease (CKD) or end stage renal disease (ESRD) are a high-risk population that has largely been excluded from the potential benefits of the DOACs due to limited data regarding use in patients with poor renal function. It has been established that patients with CKD have increased likelihood of developing AF, believed to be due to poor kidney function. Patients who develop AF with CKD are five times more likely to suffer from a stroke which often leads to mortality in these patients.6
In an effort to assess the use of DOACs in patients with impaired renal function, many post-marketing studies and analyses have been completed. This article examines new evidence supporting dosing strategies for renal insufficiency in rivaroxaban and apixaban, as pharmacokinetically these agents are more reasonable for use in kidney impairment due to decreased renal clearance in comparison to the other agents in the class.1-4 Due to the newness of betrixaban to the market, there is not enough comparative data to include it in this assessment.5
Clinical Trial Review
The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial was the study that established rivaroxaban’s efficacy in patients with atrial fibrillation. Rivaroxaban was shown to be non-inferior to dose-adjusted warfarin in terms of prevention of stroke and systemic embolism. Major and non-major clinically relevant bleeding rates were similar in both arms, rivaroxaban did show less frequent cases of intracranial hemorrhage, critical bleeding, and fatal bleeding.7 The ROCKET-AF trial did show that the rivaroxaban group had more gastrointestinal bleeding, but post-market studies have not confirmed this.8 The initial safety and efficacy of rivaroxaban was only assessed and approved in patients with a creatinine clearance (CrCl) of 30 ml/min or greater, including a dose reduction to 15mg daily for patients with CrCl between 30-49 ml/min.7 After post-market sub-studies of patients with renal impairment the 15mg daily dose was approved for patients with a CrCl of 15 ml/min or greater.8 In a sub-analysis of patients with a CrCl < 50 ml/min both groups had comparable rates of stroke or systemic embolism as well as major and non-major clinically relevant bleeding. However, fatal bleeding was less frequent in the rivaroxaban group.7
A small study looked further into the pharmacokinetics (PK) and pharmacodynamics (PD) in patients on hemodialysis without residual kidney function. This study looked to assess potential accumulation, levels of anti-Xa activity, and the timing of the dose in relation to dialysis treatments. The study found that rivaroxaban 10mg resulted in similar exposure to that of a healthy patient taking rivaroxaban 20mg and that rivaroxaban was not eliminated via dialysis.9 This study was set up as a phase I or phase II trial and studies of similar size and design have been completed since, showing that dialysis does not affect the PK and PD properties of rivaroxaban.10 These results are encouraging but larger, randomized studies still need to be performed to more conclusively study the safety and efficacy of rivaroxaban in CKD and ESRD.
Apixaban currently is FDA approved for use in hemodialysis patients despite limited safety data.3 Initially, apixaban was not recommended in patients with a CrCl less than 25 ml/min as the safety and efficacy of apixaban was not studied in this population. A sub-group analysis of the ARISTOTLE trial focused on the impact renal function had on outcomes and it was noted that apixaban significantly decreased stroke and systemic embolism as well as major bleeds regardless of renal function.11 These trends have led to further studies looking at apixaban use in comparison to warfarin in patients with renal function that would be classified as more severe than mild or moderate impairment.
A large retrospective cohort study that compared over 600 patients with advanced CKD receiving apixaban or warfarin was recently published. All of the patients included in outcome measurements had stage 4 or stage 5 CKD and patients including those concurrently on hemodialysis. The primary outcome analyzed major bleeding at 3 months after enrollment. At 3 months there was no difference in the number of patients with a major bleed in the apixaban and warfarin groups (8.3% vs. 9.9%; p= 0.48). The secondary outcome of major bleeds at 3-6 months showed a continued trend towards improvement with apixaban, but did not achieve statistical significance (apixaban 1.4% vs warfarin 4%; p= 0.07). Apixaban did show an improvement in major bleeding after 6-12 months (apixaban 1.5% vs. warfarin 8.4%; p<0.001) No differences in stroke or thromboembolism was seen between groups. Based on this study, one could conclude that apixaban may be an acceptable alternative to warfarin long-term in patients with late stage kidney disease.12 It must be considered that retrospective cohort studies are not capable of providing conclusive results, therefore randomized trials should be evaluated before using this data to revise current recommended standard of care.
Currently, large trials are in the recruiting phase looking at anticoagulation strategies in patients with AF and CKD. The RENAL-AF trial (NCT02942407) is measuring time to first major bleeding/non-major clinically relevant bleeding event in a comparison of apixaban versus warfarin in patients on hemodialysis with ESRD as well as AF.13 The XARENO trial (NCT02663076) is looking at patients with both AF and CKD who are treated with VKA or rivaroxaban as their anticoagulation agent. Primary outcomes will look at bleeding and thrombotic events, all-cause mortality, change in eGFR, major cardiovascular events, and net-clinical benefit.14 Results for these trials will likely not become available until later in 2019 but will hopefully bring some clarity to managing AF patient who have concomitant kidney dysfunction.
In summary, current guidelines still do not offer much support for the use of DOACs in patients with both AF and severe renal dysfunction. Strong and conclusive evidence supporting the use of DOACs in this patient population is still lacking, but there is encouraging research becoming increasingly available to help guide clinicians in making decisions regarding anticoagulation in this patient population. The evidence is beginning to suggest a benefit in the use of rivaroxaban or apixaban in patients with more advanced kidney disease and as more information becomes available we may see the treatment guideline governing bodies implement changes in current practice to how we manage anticoagulation in AF patients with CKD or ESRD.
The Role of Extended Thromboprophylaxis in Acutely Ill Medical PatientsAuthor: Yasmine Zeid, PharmD
BackgroundVenous thromboembolism (VTE) encompasses two interrelated conditions that are part of the same spectrum: deep vein thrombosis (DVT) and pulmonary embolism (PE).1 A DVT is a venous blood clot that typically forms in the veins of the lower extremities. A PE occurs when part of a DVT breaks off and travels to the lungs, where partial or complete occlusion of blood flow can be fatal.2 VTE affects about 900,000 patients in the United States every year.3 The risk of VTE remains even after diagnosis and treatment, with one-third of patients diagnosed with a VTE having a recurrence within 10 years. It is estimated that over 50% of hospitalized medical patients are at risk for VTE, with VTE being the second most common medical complication that can occur during a patient’s hospital stay. The total annual cost per patient for secondary diagnosis of DVT is $7,594, and the total annual cost per patient for secondary diagnosis of PE is $13,018.3-6 Early recognition of patients who are at an increased risk of developing VTE is imperative to reduce the medical and economic burden of this complication.
Assessing RiskVirchow’s Triad is a theory that describes three broad factors that are thought to increase the likelihood of VTE formation: alterations in blood flow, hypercoagulability, and vascular endothelial injury.7 Alterations in blood flow can also be referred to as venous stasis, or the slowing or stopping of blood flow.8 One of the most common contributors to venous stasis is immobilization following long-haul traveling or hospitalization. Polycythemia, a disease state that results in hyperviscosity of the blood, can also lead to slowing of blood flow. Hypercoagulability encompasses both hereditary and acquired risk factors. Factor V Leiden disease leads to a hypercoagulable state due a variant in factor V that cannot bind to protein C. Acquired risk factors include pregnancy, oral contraceptive use, obesity, and cancer. Vascular endothelial injury result from physiologic shear stress and disease states such as hypertension.9-10
There are risk assessment tools available to objectively aid in determining a patient’s risk of developing a VTE. The most commonly used one is the Padua Prediction Score Risk Assessment Tool.11 The Padua Prediction Score is comprised of 11 risk factors, both anatomic and hereditary, with each risk factor assigned a point value based on its relative contribution to risk of VTE formation. A total score of <4 means the patient has a low risk of VTE, while a score ≥4 indicates a high risk of VTE.2 Appendix A includes a complete Padua Prediction Score Risk Assessment Tool.
The 2012 American College of Chest Physicians (ACCP) guidelines address VTE prevention in hospitalized medical patients.2 Recommendations for thromboprophylaxis are based upon the calculated risk of VTE using the Padua Prediction Score Risk Assessment Tool while also taking into account a patient’s risk of bleeding. The guidelines recommend against thromboprophylaxis for patients with a low risk of VTE, chemical thromboprophylaxis for patients with a high risk of VTE and low bleeding risk, and mechanical thromboprophylaxis for patients with a high risk of VTE and a high risk of bleeding. Patient-specific factors must be taken into account when caring for high-risk patients so that the risks and benefits of treatment can be adequately weighed.
Chemical ThromboprophylaxisThere are three medications with FDA approval for the chemical prophylaxis of VTE.2 All three medications have shown to be superior to both placebo and mechanical devices used for thromboprophylaxis. Unfractionated heparin (UFH) is administered subcutaneously at a dose of 5000 units three times a day. Low molecular weight heparins (LMWH) include agents such as enoxaparin, which are also administered subcutaneously. Enoxaparin’s traditional dosing is 40 mg once daily, with dose adjustments required for patients with a creatinine clearance less than 30 mL/min, as well as in obese patients. Fondaparinux, a synthetic factor Va inhibitor, is traditionally dosed subcutaneously at 2.5 mg once daily. Dose adjustments are required in patients with renal dysfunction defined as creatinine clearance less than 30 mL/min; use is contraindicated in patients weighing less than 50 kg.
Extended-Duration ThromboprophylaxisThe 2012 ACCP guidelines recommend that VTE prophylaxis be continued throughout a patient’s acute hospital stay for the duration of patient immobilization. The guidelines go further to recommend against extending the duration of treatment beyond this time.2 The question arises as to whether or not the risk of developing a VTE is eliminated at hospital discharge, as patients may have risk factors that persist for weeks or even months after hospital discharge. The concept of extended-duration thromboprophylaxis refers to thromboprophylaxis that continues beyond its initial course.
Evidence to support extended-duration thromboprophylaxis is strongest in hospitalized surgical patients, specifically in patients who have undergone total hip arthroplasty and total knee arthroplasty.12 The 2012 ACCP guidelines recommend a minimum duration of 10-14 days of thromboprophylaxis, with a recommendation for up to 35 days of thromboprophylaxis from the day of surgery.2 Appendix B includes a table with commonly prescribed agents for extended-duration thromboprophylaxis in surgical patients.
The risk of VTE extending beyond hospitalization has been demonstrated in several studies. The MEDENOX study, a randomized-controlled trial that granted enoxaparin its FDA indication for standard-duration thromboprophylaxis, demonstrated that 8% of total VTEs occurred between days 15 and 110.13 In an observational study in 2011, data from over 15,000 patients in the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) study was analyzed to determine the incidence of VTE for 3 months after admission. The risk of VTE post-discharge was 45%.5 Moreover, an observational study published in 2012 examining the risk of VTE following hospitalization found that 56.6% of all VTE events occurred after discharge.14
EnoxaparinTo date, there are four large randomized controlled trials that have evaluated short-term versus extended-duration thromboprophylaxis in the acutely ill medical population. A table summarizing these four trials is included in Appendix C. The EXCLAIM trial, published in 2010, evaluated extended-duration thromboprophylaxis versus standard-duration with enoxaparin. All enrolled patients initially received open-label subcutaneous enoxaparin (40 mg once daily) for 10±4 days. Upon successfully completing open-label prophylaxis, patients were randomized in a 1:1 ratio to receive either subcutaneous enoxaparin (40 mg once daily) or placebo for an additional 28±4 days. The primary efficacy outcome was a composite of VTE events during the double-blind treatment period, and the primary safety outcome was major hemorrhagic complications. The EXCLAIM trial found that extended-duration enoxaparin did reduce the frequency of VTE events while also increasing the incidence of major bleeding. A subgroup analysis for two endpoints of the study, VTE at day 28 and major bleeding events, was completed looking specifically at three factors: age, sex, and immobility levels. In female patients age >75 years with level 1 immobility (defined as total bed rest without bathroom privileges), the risk of VTE at day 28 was significantly lower in the extended-duration thromboprophylaxis group.15
ApixabanThe ADOPT trial, published in 2011, evaluated extended-duration thromboprophylaxis with apixaban following standard-duration prophylaxis with enoxaparin. Patients were randomly assigned in a 1:1 ratio to receive apixaban, administered orally at a dose of 2.5 mg twice daily, or enoxaparin, administered subcutaneously at a dose of 40 mg once daily, during their stay in the hospital, for a minimum of 6 days. After 6 days, the decision to discontinue the parenteral study drug was made at the discretion of the investigators, and patients continued treatment up to 30 days with either apixaban 2.5 mg twice daily or an oral placebo. Notably, the dose of apixaban that was utilized in the ADOPT study was 2.5 mg twice daily, which is FDA-approved dose for extended-duration thromboprophylaxis in patients undergoing total hip and total knee arthroplasty. The primary efficacy outcome was a composite of VTE events during the 30-day treatment period, and the primary safety outcome was major bleeding. Extended-duration apixaban was not found to be superior to standard-duration thromboprophylaxis with enoxaparin, and a significant increase in major bleeding events was observed.16
RivaroxabanThe MAGELLAN study, published in 2013, evaluated extended-duration thromboprophylaxis with rivaroxaban versus standard-duration prophylaxis with enoxaparin. Patients were assigned in a 1:1 ratio to one of the following therapies: rivaroxaban 10 mg once daily orally for 35±4 days plus subcutaneous placebo for 10±4 days; or, enoxaparin 40 mg once daily subcutaneously for 10±4 days plus an oral placebo for 35±4 days. Similarly to the dose of apixaban in the ADOPT study, this 10 mg once daily dose of rivaroxaban was based upon the FDA-approved dose of the medication for extended-duration prophylaxis in total hip and total knee arthroplasty patients. The primary efficacy outcome was a composite of VTE events, with a non-inferiority analysis up to day 10 (compared standard-duration prophylaxis with rivaroxaban to standard-duration enoxaparin) and a superiority analysis up to day 35 (compared extended-duration rivaroxaban to standard-duration enoxaparin). The primary efficacy outcome was a composite of major bleeding or clinically relevant nonmajor bleeding events. Rivaroxaban was found to be noninferior to enoxaparin for the standard duration of therapy; additionally, extended-duration rivaroxaban was superior to standard enoxaparin prophylaxis. A significantly higher risk of major bleeding and clinically relevant nonmajor bleeding was observed in the rivaroxaban group versus the enoxaparin group.17
BetrixabanThe APEX trial, published in 2016, is the most recent study examining extended-duration thromboprophylaxis in the acutely ill medical population. It evaluated extended-duration thromboprophylaxis with the newest FDA-approved factor Xa inhibitor, betrixaban, versus standard-duration prophylaxis with enoxaparin. Patients were divided into three patient cohorts: cohort 1 included patients with elevated baseline D-dimer level greater than 2x upper limit of normal; cohort 2 included patients in cohort 1 plus patients ≥75 years of age; and cohort 3 included the overall study population. Patients were then randomized in a 1:1 ratio to receive either enoxaparin 40 mg once daily subcutaneously for 10±4 days plus placebo once daily for 35 to 42 days; or, subcutaneous placebo for 10±4 days plus oral betrixaban. Betrixaban was administered as a 160 mg loading dose followed by 80 mg once daily for 35-42 days. The primary efficacy outcome was a composite of VTE events, and the primary safety outcome was the occurrence of major bleeding. Extended-duration prophylaxis with betrixaban reduced overall VTE events compared to standard-duration enoxaparin in cohort 1, but this finding was not found to be statistically significant. While cohorts 2 and 3 did demonstrate a statistically significant reduction in VTE events, because the first cohort failed to show statistical significance, all subsequent analyses were considered to be exploratory. The efficacy results of the APEX trial were later analyzed using a modified intent-to-treat analysis (mITT) for patients who took at least 1 dose of study drug and had a follow-up assessment of VTE. Major bleeding was not significantly increased in any of the patient cohorts; however, major or clinically relevant nonmajor bleeding was significantly increased in all three patient cohorts.18-19
Betrixaban was granted FDA-approval in June 2017, and it is the first and only anticoagulant with approval for both hospital and extended thromboprophylaxis of VTE in acutely ill medical patients. The recommended dosing is 160 mg on day 1 of therapy, following by 80 mg daily for 35-42 additional days. In patients with a creatinine clearance of 15-30 mL/min and/or receiving concurrent treatment with P-glycoprotein inhibitors, the dose is reduced to 80 mg on day 1, followed by 40 mg daily for 35-42 additional days. Betrixaban must be taken at the same time every day with food to avoid high concentrations.19 The average wholesale price (AWP) for 35 days of therapy with betrixaban is about $650, compared to about $260 dollars for standard-duration enoxaparin.20
Based on the evidence available at this time, as well as current guideline recommendations, extended-duration thromboprophylaxis in the acutely ill medical population should not be routinely practiced until the potential risks and benefits have been evaluated on an individual patient-case basis. Although betrixaban is now approved for this indication, its efficacy has not yet been well established. Even though its use did not demonstrate an increase in major bleeding in the APEX trial, an increase in major or clinically relevant nonmajor bleeding was still observed. Extended-duration thromboprophylaxis may be beneficial in a niche patient population (female, age ≥75, immobilized, elevated D-dimer), and more studies are needed to better characterize this population.
1. Turpie AG, Chin BS, Lip GY. Venous thromboembolism: pathophysiology, clinical features, and prevention. BMJ 325 2002;7369:887–90.
2. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e195S.
3. Fernandez MM, Hogue S, Preblick R, Kwong WJ. Review of the cost of venous thromboembolism. Clinicoecon Outcomes Res. 2015;7:451–62.
4. Spyropoulos AC, Lin J. Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations. J Manag Care Pharm. 2007; 13: 475-486.
5. Spyropoulos AC, Anderson FA Jr, Fitzgerald G, et al. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 2011; 140:706.
6. Hull RD, Hirsh J, Sackett DL, Stoddart GL. Cost-effectiveness of primary and secondary prevention of fatal pulmonary embolism in high-risk surgical patients. Can Med Assoc J 1982; 127:990.
7. Dickson, B.C. (2004a) Venous thrombosis: on the history of Virchow’s triad. University of Toronto Medical Journal; 81, 166–171.
8. Goldhaber SZ. Risk factors for venous thromboembolism. J Am Coll Cardiol 2010; 56:1.
9. Anderson FA, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107: 19-116
10. Martinelli I, Cattaneo M, Taioli E, et al. Genetic risk factors for superficial vein thrombosis. Thromb Haemost 1999; 82:1215.
11. Barbar S, Noventa F, Rossetto V, et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost 2010; 8:2450.
12. Falck-Ytter Y, Francis CW, Johanson NA et al (2012) Prevention of VTE in orthopedic surgery patients: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141(2 Suppl):e278S–e325S.
13. Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N (1999) A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patient. N Engl J Med 341:793–800.
14. Amin AN, Varker H, Princic N, Lin J, Thompson S, Johnston S. Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients. J Hosp Med. 2012;7(3):231-8.
15. Hull RD, et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18.
16. Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med; 365: 2167-77.
17. Cohen AT, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013. 368(6): 513-523.
18. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med 2016; 375:534.
19. Bevyxxa™(betrixaban) [package insert]. San Francisco, CA: Portola Pharmaceuticals, Inc.; June 2017.
20. Micromedex Solutions. Ann Arbor (MI): Truven Health Analytics; publication year [5 January 2018]. Available from: www.micromedexsolutions.com
21. Lovenox® (enoxaparin) [package insert]. Bridgewater, NJ. Sanofi-Aventis; October 2017.
22. Xarleto® (rivaroxaban) [package insert]. Titusville, NJ. Janssen Pharmaceuticals, Inc. October 2017.
23. Eliquis® (apixaban) [package insert]. Princeton, NJ. Bristol-Myers Squibb. November 2017.
24. Pradaxa® (dabigatran) [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc. July 2017.
Additional supporting tables are below and as a PDF file.