Current Recommendations for the Use of Antiplatelet Therapy in Secondary Prevention of Non-Cardioembolic Ischemic Stroke
Author: Sarah Tortora, PharmD, PGY1 Pharmacy Practice ResidentPreceptor: Jackie Harris, PharmD, BCPS, PGY1 Pharmacy Practice Residency Director, Christian Hospital Northeast – St Louis, MO
Program Number: 2018-11-04Approval Dates: December 1, 2018 - June 1, 2019Approved Contact Hours: One (1) CE(s) per LIVE session.
IntroductionCardiovascular disease (CVD) is a major source of morbidity and the leading cause of mortality in the United States. The American Heart Association (AHA) has found that 11.5% of the adult population (27.6 million) has a diagnosis of cardiovascular disease (including coronary heart disease (CHD), hypertension, heart failure, and stroke)1. Stroke can be particularly devastating, and is the fourth most common cause of death in the United States. There are approximately 795,000 new or recurrent cases of stroke each year in the United States, and as of 2015, there were 6.6 million American stroke survivors2. Having a history of stroke is, in itself, a risk factor for having another one; one meta-analysis showed that there was a recurrence risk of 3.1% at 30 days, 11.1% at one year, 26.4% at five years, and 39.2% at 10 years3. In fact, nearly 25% of strokes annually in the United States are not first-time events, and these recurrent events are more likely to result in death than first-time strokes4,5.
The financial cost of stroke is staggering as well: an estimated $40.1 billion was spent on direct and indirect costs associated with stroke in 20131. Over 40% of that cost was due to loss of productivity and mortality. The AHA expects that, by 2035, 45.1% of American adults will have CVD in some capacity, and costs may exceed $1.1 trillion annually. Clearly, CVD is an extremely common aspect of American life, and one that will continue to have huge human and financial costs going forward. Primary prevention is and will be extremely important, but as the incidence of CVD, and thus, ischemic stroke increases, efficacious and efficient secondary prevention will be key to controlling excess morbidity and mortality. As the number of patients living with a history of stroke increases, pharmacists should be prepared to play a role in taking care of this vulnerable patient population.
The most common manifestation of CVD is CHD, with stroke not far behind; together, these plus peripheral vascular disease constitute atherosclerotic cardiovascular disease (ASCVD)1. ASCVD is characterized by a narrowing of the blood vessels, limiting blood flow to tissues downstream and putting tissues at risk of ischemic damage. In ischemic stroke, this narrowing can either be due to atherosclerosis or thromboembolism, and the damage can be especially catastrophic and potentially fatal, depending on where in the brain this ischemia occurs. While there are a number of proven strategies to mitigate the risks of having a devastating event associated with ASCVD, arguably the mainstay is antiplatelet therapy. For many years, this simply meant aspirin. But as new drugs have come to the market in the last 20 years and new data has come out, there are many more options for treating patients with a history ASCVD, including stroke. Recommendations about which agents to use and for how long vary based on the clinical scenario, time since the event, and patient characteristics. This article will review those agents, summarize current guideline recommendations, and address gray areas and current data where guidelines have not with respect to the use of antiplatelet therapy in non-cardioembolic ischemic stroke.
Risk FactorsAs with many disease states, risk factors for non-cardioembolic ischemic stroke can be modifiable or non-modifiable in nature. Well-documented non-modifiable risk factors include increased age, race, sex, low birth weight (less than 5.5 pounds), and genetic factors6. As patients age, their risk of stroke doubles with each decade they are older than 55, on average2. African Americans, Asian-Pacific Islanders, Native Americans, and Latinos experience worse outcomes for a number of metrics than whites in the United States. Among these, incidence and mortality rates are higher, age at the time of first-ever stroke tends to be lower, and as incidence of ischemic stroke has been shown to be decreasing overall and for whites in the United States since the 1990s, a similar decrease has not been noted in African Americans or Latinos2. Women represent a disproportionately high share of annual strokes in the United States, and have a one in five lifetime risk, compared to men’s one in six. However, men are more likely than women to have a stroke at a younger age2. The exact effect genetics has on one’s stroke risk is not yet fully understood, but one meta-analysis found that a “positive family history” of stroke increases one’s risk by about 30%7. In addition, having a parent with a history of stroke younger than age 65 is associated with a three-fold increase in stroke risk in their children.
There are a number of modifiable risk factors that have been shown to increase one’s risk of stroke. They include cigarette smoking, hypertension, diabetes, carotid stenosis, dyslipidemia, poor diet, obesity, physical inactivity, and other cardiovascular diseases, such as coronary artery disease, heart failure, and peripheral artery disease6. Many of these risk factors are addressed in various guidelines related to treating stroke and have high quality evidence for modifying them in order to reduce the risk of an ischemic event. For example, for those with a history of stroke (not in the first 72 hours after an acute event) should have antihypertensive therapy initiated when their blood pressure is >140/90 mmHg, with a goal of <130/80 mmHg according to the 2017 AHA/ACC guidelines8. Great care should be taken in treating patients with a history of stroke and these concomitant risk factors, as this population is already at a higher risk of having a recurrent stroke than those who haven’t had such an event.
Current Guidelines and LiteratureThere are several different guidelines that make recommendations for the use of antiplatelet therapy in the setting of secondary prevention of stroke. While their overall recommendations are quite similar, they do vary slightly. Relevant guidelines are summarized in Appendix 1. Landmark studies referenced will be summarized in Appendix 2.
As previously stated, prevention of recurrent strokes is of the utmost importance. Central to this treatment plan is the use of antiplatelet therapy. Anticoagulation in the form of vitamin K antagonists or the newer direct acting anticoagulants has been shown to be beneficial for the treatment of cardioembolic ischemic events, especially those as a result of atrial fibrillation. The majority of strokes, however, are due to progressive atherosclerosis and are better treated by antiplatelet agents9,10.
In 2018, the American Heart Association and American Stroke Association released a guideline for the early management of patients with acute ischemic stroke11. This new guideline make new and revised recommendations for the use of antiplatelet therapy in the early secondary prevention period, in which patients are particularly vulnerable to recurrence. Firstly, aspirin should be initiated within 24-48 hours of the onset of stroke symptoms. They do not make a specific dosing recommendation, and an optimal aspirin dose has yet to be determined, but numerous studies have shown that doses between 50-325 mg daily are appropriate, and higher doses within this range offer no benefit over lower doses12-16. This is similar to the corresponding recommendation made by the 2012 American College of Chest Physicians Guideline on Antithrombotic and Thrombolytic Therapy in Ischemic Stroke; they recommend 160-326 mg of aspirin daily, and then 75-100 mg daily starting one week after acute stroke treatment17.
The International Stroke Trial (IST) and Chinese Acute Stroke Trial (CAST) demonstrated the benefits of aspirin vs. placebo; 9 fewer deaths, 7 more good functional outcomes, and just 4 more occurrences of nonfatal major bleeding occurred per 1000 patients18. Another 2009 meta-analysis showed this benefit is even more pronounced when follow-up time was extended to two years19. Aspirin is considered the mainstay of secondary prevention of non-cardioembolic ischemic stroke as it is the most well studied, is relatively safe and effective, and is extremely cheap.
Until just two decades ago, this would have been the end of the discussion about antiplatelet therapy. However, a number of potential replacements or additions to aspirin have been introduced, with the workhorse being clopidogrel. Clopidogrel inhibits platelet activation by irreversibly blocking the P2Y12 site within the adenosine diphosphate receptor on the platelet surface, thus inhibiting platelet aggregation20. The 2012 ACCP guidelines make a strong recommendation for the use of clopidogrel 75 mg daily long-term, and actually less strongly recommends clopidogrel over aspirin (Grade 2B)17. This is largely the result of the CAPRIE trial (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events), which showed that in patients with a history of stroke, myocardial infarction, or peripheral vascular disease, clopidogrel significantly reduced the composite of ischemic stroke, MI, or cardiovascular death (5.32% vs. 5.83%, 95% CI 0.84-0.97; p = 0.043)21. Although insignificant, clopidogrel also resulted in 10 fewer nonfatal recurrent strokes per 1,000 patients when treated for two years, with little or no effect on mortality or major bleeding. Clopidogrel is also a good option for patients with an allergy to aspirin or another indication for antiplatelet therapy (e.g. history of MI, percutaneous coronary intervention, etc.).
The PRoFESS trial (Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke) sought to compare clopidogrel to another agent approved for secondary prevention of ischemic stroke, extended-release dipyridamole plus aspirin22. In summary, there was no difference between the two drugs with regards to recurrent stroke, major bleeding, or overall mortality. However, headache was much more common with dipyridamole/aspirin than clopidogrel (30% vs. 10%); this along with the more inconvenient twice daily dosing than clopidogrel’s once daily are major reasons for why clopidogrel is used more often in practice.
At this point, a number of clinical questions still exist. Firstly, the use of dual antiplatelet therapy is common in other acute cardiovascular events; what role does it play in the secondary prevention of ischemic stroke? For a long time, it appeared that this was not a useful strategy in any stroke patients. The Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke (MATCH) trial in 2004 showed no benefit in using clopidogrel plus aspirin over aspirin alone for reducing mortality, recurrent stroke, or MI, and did carry with it a significant increase in major bleeding23. The MATCH trial has been criticized by some, however, because a majority of its patients had lacunar infarcts, rather than atherothrombotic ischemia, which tend to benefit less from antiplatelet therapy.
In 2013, the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial compared the early use of aspirin/clopidogrel vs. aspirin24. The combination was continued for the first 21 days, and then the aspirin component was discontinued. At 90 days, there was a significantly reduced rate of recurrent strokes in the combination group (8.2% vs. 11.7%, number needed to treat = 29) and no difference in major bleeding. CHANCE differs significantly from MATCH because patients were enrolled within 24 hours of acute stroke intervention, whereas MATCH allowed enrollment for the first six months after an acute event. In addition, CHANCE only enrolled Chinese patients, limiting its generalizability to other patient populations; Chinese patients tend to have a higher incidence of stroke and are known to have more polymorphisms that affect clopidogrel metabolism. However, the Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke (POINT) trial published in 2018 utilized similar methods and had similar outcomes, and enrolled patients in North America, Europe, Australia, and New Zealand25. Further study is needed to zone in on the most effective combination, duration, and patient population in which to utilize dual antiplatelet therapy. As a result of these trials, the 2018 AHA/ASA guideline recommended dual antiplatelet therapy with aspirin and clopidogrel for the first 21 days after acute treatment (Grade IIa)11.
Unfortunately, recurrent stroke is all too common in the United States. This begs the question, how do we treat a patient who experiences a recurrent ischemic stroke despite adequate preventative antiplatelet therapy? Among those on preventative aspirin who fall into this population, a 2017 meta-analysis showed data supporting addition of or switching to a different antiplatelet agent was associated with reduced rates of recurrent stroke26. Data is less robust when the initial therapy in question is an agent other than aspirin. At this time, there isn’t enough information to make a high quality recommendation for any strategy, and will likely be the subject of more study in the future. As always, patient-specific factors need to be considered in order to make the most safe and efficacious decision possible.
Tools for CliniciansToday, it seems as if there’s a mobile application for everything, and that holds true for decision-making tools for antiplatelet therapy. For primary prevention of stroke, the Aspirin Guide, created by researchers at Brigham and Women’s Hospital and Harvard Medical School helps clinicians decide which patients would experience ASCVD benefits, including the prevention of ischemic stroke, from low-dose aspirin. Another widely used primary prevention app is the ASCVD Risk Estimator Calculator, created by the American College of Cardiology. The algorithm used in this app collects several patient characteristics and gives a current 10-year ASCVD risk, lifetime risk (for those under 60), and gives advice for statin, antihypertensive, and aspirin therapy. The ACC also supports the Dual Antiplatelet Therapy (DAPT) Risk Calculator, which gives an approximate risk of major bleeding in patients on DAPT, and what that risk would be if they discontinued therapy. The app was created for patients with an FDA indication for DAPT (e.g. MI, PCI with stents, etc.), but as data for DAPT in secondary prevention of stroke becomes more robust and the number of patients utilizing this strategy increases, it may be a useful tool for clinicians taking care of this patient population as well. All of these apps are free and available in the app store.
ConclusionStroke is a huge source of morbidity and mortality in the United States, and as the population ages, current trends suggest incidence and related costs will rise significantly. Therefore, it’s important to ensure that these patients are being appropriately treated in order to prevent a recurrent event, and antiplatelet therapy is an important feature of that. The concept of the use of dual antiplatelet therapy in stroke patients is a great example of how new data is outpacing guideline recommendations, and the importance for clinicians to remain up to date on this data in order to adequately treat patients. This will likely be the topic of much study in the future, and may result in groundbreaking changes in how to prevent current stroke from current standard of practice.
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Authors: Abigail Cordia, student pharmacist1; Amber Laurent, student pharmacist1; Yvonne Burnett, PharmD1 ,1 St. Louis College of Pharmacy
For many years, development of novel antimicrobials seemed to be at a standstill. This, combined with increasing rates antimicrobial resistance, left a very real threat that there may come a time when the antimicrobials in our arsenal will no longer be effective against deadly pathogens. Luckily, in the past year there have been quite a few new antimicrobials brought to market to combat multidrug resistant (MDR) pathogens. This article will focus on a few such agents. Below is a brief overview of Baxdela (delafloxacin) and Vabomere (meropenem/vaborbactam). While it is exciting to learn of these advances, it is important to understand where each of these fit in practice so that we may use them appropriately. As vital members of the healthcare team, pharmacists play crucial roles as antimicrobial stewards helping to keep antimicrobial use in check.
Baxdela is a fluoroquinolone antibiotic approved by the Food and Drug Administration (FDA) in June 2017 for the treatment of acute bacterial skin and skin structure infections (ABSSSI), and has broad activity against atypicals, gram positive and negative organisms, including anaerobes.1 Susceptible pathogens are similar to others in the class including Pseudomonas aeruginosa, Escherichia coli, Klebsiella spp., and Streptococcus spp., with the addition of Staphylococcus aureus, including methicillin-resistant (MRSA) strains, and Enterococcus faecalis. While there is broad gram negative coverage, Enterobacteriaceae and pseudomonal resistance to ciprofloxacin and levofloxacin already exists and is shared by delafloxacin. This antibiotic is available both orally (PO) and intravenously (IV), dosed at 450mg PO twice daily or 200mg IV twice daily. Doses should be renally adjusted for patients with CrCl <30 mL/min.1
While the expanded spectrum of activity for MRSA is exciting, delafloxacin carries the same boxed warning as other fluoroquinolones, including tendinitis, tendon rupture, peripheral neuropathy, central nervous system effects, hypoglycemia, and exacerbation of myasthenia gravis. In studies, delafloxacin was generally well tolerated with the most common adverse effects reported as nausea (8%) and diarrhea (8%), headache (3%), transaminase elevations (3%), and vomiting (2%). 1 Uniquely, delafloxacin has not been associated with QT prolongation, as compared with other members of this class.3
Two large phase 3 trials were conducted comparing delafloxacin, either 300mg IV q12 or 300mg IV q12 for 3 days followed by 450mg PO q12, to vancomycin 15 mg/kg plus aztreonam for 5-14 days for the treatment of ABSSSI.4,5 The primary endpoint for both trials was clinical response at 48-72 hours, defined as > 20% reduction in lesion size and no evidence of treatment failure (<20% reduction of erythema, additional antibiotic therapy, unplanned surgical intervention, or death within 72h after initiation). Results from both trials concluded that delafloxacin was non-inferior to vancomycin plus aztreonam. Additionally, the studies found a comparable response rate between the two groups for MRSA and gram-negative pathogens. It should be noted, that these studies included mostly white patients and had few burn and surgical wounds, infections due to gram-negative, or patients with diabetes.3 Interestingly, an additional study found increased cure rates in obese patients with delafloxacin compared to vancomycin, suggesting that it may have a place in therapy for obese patients.3
Delafloxacin appears to be an effective broad spectrum treatment and results of the published trials support the use for treatment of ABSSSI caused by S. aureus (both methicillin susceptible (MSSA) and MRSA) and Streptococcus spp. Further study focusing on MDR gram negative pathogens is warranted to support treatment of these organisms. Additionally, caution should be exercised when considering fluoroquinolone antibiotics due to the myriad of adverse events associated with their use. With many other oral options available to treat ABSSSI due to gram-positive organisms, this drug may be useful when treating polymicrobial infections when additional gram negative and anaerobic coverage is warranted, but is unlikely to be a first line anti-MRSA drug. Additional studies will prove useful to better define delafloxacin’s place in clinical practice.
Vabomere, a combination of a carbapenem, meropenem, and a non beta-lactam beta-lactamase inhibitor, vaborbactam, was approved by the FDA in August 2017 and is the first carbapenem/beta-lactamase inhibitor combination to be marketed in the United States. It is currently indicated for use in adult patients with a complicated urinary tract infections (cUTI), including pyelonephritis, caused by designated susceptible bacteria. This drug retains the broad spectrum activity of meropenem, including activity against MSSA, Streptococcus spp, Enterobacteriaceae, P. aeruginosa, and Bacteroides fragilis. The addition of vaborbactam, a potent inhibitor of class A serine carbapenemases, restores meropenem’s activity against extended spectrum beta-lactamase (ESBL) producing organisms, including carbapenemase resistant Enterobacteriaceae (CRE). It should be noted, however, that vaborbactam does not improve the activity of meropenem against Acinetobacter baumannii, P. aeruginosa, Stenotrophomonas maltophilia, or organisms that produce metallo-beta lactamases. Meropenem/vaborbactam is administered as 4g IV (2g of meropenem, 2g vaborbactam) every 8 hours infused over 3 hours and must be renally adjusted for patients with CrCl < 50 mL/min. Common side effects include headache, phlebitis/infusion site reactions, and diarrhea.6
In the phase 3 TANGO 1 study, meropenem/vaborbactam was compared to piperacillin-tazobactam for treatment of cUTI in 550 patients.8 Each medication was given for at least 5 days, for a median of 8 days. After 5 days, patients could be switched to an oral option to complete 10 days. Approximately 85% of patients grew one of the following Enterobacteriaceae species upon presentation: E. coli, K. pneumoniae, E. faecalis, Proteus mirabilis, and Enterobacter cloacae species complex. Meropenem/vaborbactam was found to be non-inferior to piperacillin-tazobactam for the primary composite endpoint of clinical cure or improvement and microbial eradication. There were no significant differences in adverse events observed between the two drugs. Meropenem-vaborbactam is administered as an extended infusion, while piperacillin-tazobactam was not in this study, which may account for slightly higher success rates, this was not found to be statistically significant.8 The TANGO 2 trial evaluated meropenem/vaborbactam compared to best available therapy in patients with cUTI, acute pyelonephritis, hospital-acquired or ventilator-associated bacterial pneumonia, bacteremia, or complicated intra-abdominal infection, due to known or suspected CRE. Best available therapy included combination or monotherapy carbapenems, aminoglycosides, polymixin B, colistin, tigecycline, or ceftazidime-avibactam. While numbers were small in this study, only 72 patients, meropenem/vaborbactam demonstrated a higher rate of clinical cure versus best available therapy. 9 Additionally, meropenem/vaborbactam has demonstrated in vitro activity against 99% of CRE isolates.10
Based on the available data, meropenem-vaborbactam is a promising antibiotic for CRE cUTIs. Further study is warranted to show meropenem/vaborbactam’s activity in the setting of additional severe drug-resistant gram-negative infections. Due to the lack of antibiotics with activity against CREs and the concern for the spread of emerging resistance, meropenem/vaborbactam should be reserved for only resistant infections to which it tests susceptible. It is also important to note that if an isolate of P. aeruginosa tests resistant to meropenem, the addition of vaborbactam will not provide additional coverage.
Delafloxacin and meropenem/vaborbactam are just a few of the new antibiotics that have been brought to market recently. Antimicrobial resistance may be on the rise, but there is rejuvenated interest in development of new agents as well as conserving the use of current antimicrobials. In the latter half of 2018, just prior to the publishing of this article, there were three additional antibiotics approved by the FDA: plazomicin (Zemdri), eravacycline (Xerava), and omadacycline (Nuzyra). Understanding each of their places in therapy is necessary to preserve their effectiveness and prevent the development of resistance. For now, these antimicrobials should be reserved for special cases, each for their own reason. Delafloxacin may prove useful for complicated polymicrobial infections with MRSA for which oral therapy is preferred, but does come with the risk of serious adverse effects. Meropenem/vaborbactam has potent activity against CREs, some of the most formidable pathogens, but should only be reserved for such cases and when susceptibility can be verified. For serious infections, patients are often treated with prolonged courses of therapy. Long term adverse effects, associated with such use for each of these agents, are unknown. By knowing when and how to use new antimicrobials, all pharmacists can play a central role in antimicrobial stewardship.
Pharmacogenetic Testing to Predict Warfarin Response
Author: Kristine Reckenberg, PharmD, PGY1 Pharmacy Practice ResidentPreceptor: Justinne Guyton, PharmD, BCACP, PGY1 Pharmacy Practice Residency Director, St. Louis County Department of Public Health/St. Louis College of Pharmacy
Program Number: 2018-11-05Approval Dates: December 1, 2018 - June 1, 2019Approved Contact Hours: One (1) CE(s) per LIVE session.
Pharmacogenetics is a subtype of pharmacogenomics in which polymorphisms in genes that encode drug metabolizing enzymes, transporters, and/or targets can impact drug effects, leading to variability among individuals in response to a medication.1 Warfarin, a vitamin K antagonist (VKA), is an oral anticoagulant commonly used for prevention of stroke in atrial fibrillation and prevention and treatment of venous thromboembolism.1 It is also an agent that displays pharmacogenetic variations between individuals that impact both pharmacokinetics and pharmacodynamics.2 Established pharmacogenetic variables are caused by variations in the cytochrome P450 system and the warfarin targets.1 These variables have the potential for a large impact as warfarin is an agent with a narrow therapeutic index that is associated with serious adverse events, notably bleeding. These differences are most significant during the dose finding stage of warfarin initiation. Based on these factors, warfarin can be initiated via a pharmacogenetic dosing algorithm, dosed clinically (dosing based off of clinical factors – age, medications, comorbidities, bleed risk, and social history), or using a standard dose approach.3
Two guidelines provide recommendations regarding the use of warfarin pharmacogenetic testing prior to warfarin initiation. The Clinical Pharmacogenetics Implementation Consortium Guidelines (CPIC) has been updated with the results of newly published trials whereas the American College of Chest Physicians Guidelines (ACCP) have not.3-4 This continuing education article will focus on the factors that impact warfarin pharmacogenetics, current guideline recommendations, and recently published data regarding warfarin pharmacogenetics.
There are two predominant genes, that have been studied extensively, that contribute to the interpatient variability in warfarin dose requirements. These include cytochrome P450 2C9 (CYP450 2C9) and vitamin K epoxide reductase complex 1 (VKORC1).5 CYP450 4F2 also plays a role in variability, however, it has demonstrated a smaller part in dose requirements during warfarin initiation.5
CYP450 2C9 is associated with multiple different polymorphisms, however, the nonsynonymous single nucleotide polymorphisms (SNPs) that influence warfarin dose requirements the most are the *2 and *3 alleles.5-6 These SNPs lead to a reduction in the enzymatic activity of S-warfarin.5-6 The outcome is a decrease in warfarin requirements due to the slowed metabolism, as the S-enantiomer of warfarin has a greater anticoagulant effect as compared to the R-enantiomer. CYP450 2C9*2 is associated with only 70% activity as compared to the wild type allele, whereas CYP450 2C9*3 is associated with only 20% activity.6 These alleles are present most frequently in Europeans, and rarely in African Americans and Asians.5
VKORC1 is an enzyme that is responsible for the regeneration of reduced vitamin K, and is the target of warfarin therapy.5-6 The SNPs that influence this enzyme include 1173 C>T and 1639 G>A.6 These alleles result in decreased translation of mRNA into proteins; ultimately leading to a lower level of expression of the VKORC1 enzyme.5 This decrease in VKORC1 is associated with lower warfarin dose requirements accounting for 25 + 8% of the variance in warfarin dose requirements.5-6 VKORC1 1639 A/A has been found to decrease initial warfarin dose requirements by approximately 40%.14 Those patients that have the wild-type haplotype (GG) have a higher rate of metabolism as compared to those that are homozygous for the variant allele (AA).6 Those that are heterozygous for the variant allele have an intermediate rate of metabolism.6 The A allele is present most frequently in patients of Asian ethnicity, followed by Europeans, and rarely in African Americans.5
CYP450 4F2 is one of the CYP450 enzymes responsible for metabolism of vitamin K.5 Those patients with the CYP450 4F2 V433M SNP have decreased metabolism of vitamin K, resulting in higher warfarin dose requirements.5 Despite this finding, CYP450 4F2 V433M SNP only contributes to approximately one percent of variability in warfarin dose requirements.5 This polymorphism is present in Europeans and Asians, but rarely in African Americans.5
Table 1 located in the appendix provides ranges of expected warfarin total daily doses based on CYP450 2C9 and VKORC1 polymorphisms, according to the manufacturer.
Current Guideline Recommendations
There are two main sources that provide recommendations regarding warfarin pharmacogenetic testing for initiation of warfarin therapy. These include guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the American College of Chest Physicians (ACCP).3-4
The CPIC Guidelines, prepared by an international consortium of volunteers, released an update in 2017 following release of results of the Genetics-Informatics Trial (GIFT).3 The CPIC recommends that in patients of non-African ancestry, warfarin dosing should be calculated using a published pharmacogenetic algorithm including genotype information for VKORC1 1639 C>A, CYP450 2C9*2 and *3.3 If this genetic information is not available, warfarin should be initiated based on clinical factors; this has a strong recommendation rating.3 In patients of African ancestry it is important to know the additional genotypes of CYP2C9*5, *6, *8, and *11.3 If available, the warfarin dose should be calculated using a validated pharmacogenetic algorithm including the variables of VKORC1 1639 C>A, CYP2C9*2 and *3.3 If the patient carries CYP2C9*5, *6, *8, or *11 alleles, the dose should be decreased by 15-30%; with a moderate recommendation rating by the CPIC.3 If this genetic information is unavailable, warfarin should be dosed clinically.3
The ACCP Guidelines published in 2012 recommend against the routine use of pharmacogenetic testing for guiding doses of vitamin K antagonists with a grade of 1B.4 This is due to the limited availability of four small randomized controlled trials, availability of a single systematic review concluding lack of evidence to support using pharmacogenetic testing to guide therapy, and multiple cost effectiveness analyses indicating lack of cost-effectiveness at the time of guideline update.4
Summary of Evidence
Before pharmacogenetic dosing of warfarin can be considered as a potential for adoption in routine clinical practice, there must be sufficient evidence provided by large randomized controlled trials. To date most randomized controlled trials have had small sample sizes with the most recent study being the largest to date. Here the three major landmark clinical trials and one systematic review exploring pharmacogenetic-guided warfarin dosing versus clinically-guided warfarin dosing will be reviewed.
The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial by Verhoef and colleagues was published first in 2013.8 This study combined data from two single-blind, randomized trials for the initiation of VKAs, acenocoumarol or phenprocoumon, in the treatment of 548 patients with atrial fibrillation or venous thromboembolism. VKAs were initiated with either a genotype-guided algorithm or clinically-guided algorithm that included clinical variables and genotyping for CYP2C9 and VKORC1, or a dosing algorithm that included only clinical variables for the first 5-7 days. After the first 5-7 days, the patients were treated based on international normalized ration (INR) and local clinical practice with intended follow-up for 12 weeks.8 The primary outcome, percent of time in therapeutic INR, was observed in 61.6% of patients in the genotype-guided group and 60.2% in the clinically-guided group (p = 0.52) during the first 12 weeks.8 However, the percentage of time in therapeutic range after the first four weeks of treatment was 52.8% in the genotype-guided group versus 47.5% in the clinically-guided group (p = 0.02). There were no differences in bleeding event rates or thromboembolic events.8
The Clarification of Optimal Anticoagulation Through Genetics (COAG) trial by Kimmel and colleagues was published in 2013.9 This was a multicenter, double blind trial comparing a warfarin dosing algorithm including genotype-guided therapy versus clinically-guided therapy during the first 5 days of warfarin therapy in 1015 patients.9 The patients received follow-up through the first 4 weeks of therapy.9 The primary outcome (percent of time in therapeutic INR from day 4 or 5 through day 28 of therapy) was observed in 45.2% in the genotype-guided group and 45.4% in the clinically guided group, with an adjusted mean difference of -0.2 (95% CI -3.4 to 3.1, p = 0.91).9 Statistically significant findings were reported with subgroups; black patients had a lower mean percentage of time in the therapeutic range in the genotype-guided group as compared to the clinically-guided group.9 There were no significant differences with regard to INR > 4, major bleeding, or thromboembolism.9
The most recent warfarin pharmacogenetic study is the Genetic Informatics Trial (GIFT) published by Gage and colleagues in 2017.10 This was a multicenter randomized clinical trial in patients initiating warfarin at the time of elective hip or knee arthroplasty. A total of 1597 patients were randomized to receive genotype-guided dosing of warfarin during the first 11 days or clinically-guided dosing of warfarin with follow-up for 90 days.10 The primary outcome (a composite of major bleeding within 30 days, INR of 4 or greater within 30 days, death within 30 days, and symptomatic or asymptomatic venous thromboembolism within 60 days of arthroplasty) was observed in 10.8% of patients in the genotype-guided group versus 14.7% in the clinically-guided group with an absolute difference of 3.9% (95% CI 0.7-7.2%, p = 0.02).10
Lastly, a meta-analysis was published in 2014 by Stergiopoulos and colleagues, which included nine randomized controlled trials and 2812 patients, and compared genotype-guided initial dosing of warfarin and its analogues to clinical dosing protocols.11 In this study, the standardized difference in means of the percent of time that the INR was therapeutic was 0.14 (95% CI -0.10-0.39, p = 0.25).11 There was not a significant difference found for risk ratio for an INR greater than 4, major bleeding, or thromboembolic events.11
With regards to pharmacoeconomic studies, varying results have been presented. Three studies found pharmacogenetic-guided warfarin dosing to be cost effective, whereas four studies were inconclusive, and five studies found pharmacogenetic-guided warfarin dosing to not be cost effective.12 Furthermore, coverage of pharmacogenetic testing for warfarin initiation varies based on insurance company. The Centers for Medicare and Medicaid Services (CMS) released an update regarding their organization’s coverage of this testing. As of January 25th, 2018, CMS does not believe that current evidence supports pharmacogenetic testing for CYP2C9 or VKORC1 for warfarin initiation due to limited studies indicating a benefit in health outcomes.12 Testing will not be covered under the Social Security Act, but may be covered under the Coverage with Evidence Development (CED) section of the Social Security Act if specific requirements are meant.12 According to CMS, these include patients who are “candidates for anticoagulation with warfarin who: have not been previously tested for CYP2C9 or VKORC1 alleles; and have received fewer than 5 days of warfarin in the anticoagulation regimen for which the testing is ordered; and are enrolled in a prospective, randomized, controlled clinical study when that study meets the standards specified in the decision memorandum.”12
Pharmacogenomic studies have indicated that warfarin pharmacogenetics can play a role in warfarin dose requirements through polymorphisms in CYP450 2C9 and VKORC1. A number of randomized controlled trials, each with their own limitations have presented variable results with regards to the benefit of pharmacogenetic versus clinically guided dosing of warfarin. In addition, cost-effectiveness studies have also produced opposing results. Therefore, clinicians should be aware of the impact pharmacogenetic testing results can have on warfarin dose adjustments and use this information, should it be available. Pharmacists should be aware of advances in pharmacogenetic dose adjustments of medications to serve as a resource for both other healthcare providers and patients.
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.